65 100 6561 http://exhibits.library.stonybrook.edu/mfp/files/original/965ac56cb625a1364d394f00e7f4693a.pdf 366544eacb662052e3aad6ee3546ad7d PDF Text Text November 20, 197h E. N. Terry, M. D. Medical Director Pharme Research (Canada) Ltd. 250 Hymns Boulevard Points Claire, P.Q., Canada Dear Stitch, I was pleased to review the data for the compound Si 93. The volume consisted of three parts: pharmacology and toxicology, dated 19 August 1970; clinical pilot studies dated November 2, 1972; and psychometric studies dated June 17. l97h. :m— wmw-ww The pharmacologic evidence indicates that Si 93 is atropine— like with tachycardia, mydrinsis, and dry mouth as predominant symytons. It is readily absorbed and at high doses inhibits gastric secretion. The anticholinergic actibity was also manifest in EEG studies-in rabbits and cats where 81 93 exhibited atropine-like patterns. The anticholinergic activity suggested its use as a spasmolytic. In the clinical studies, the dose range is defined. At there were no effects. At ho mg. anticholinergic and sedation occurred. At 60 mg, the subjects complained of fatigue and drowsi5 mg, . < ness in addition to the anticholinergic effects. In a crossover controlled study of 25 ng and 50 mg Si 93, the differences between the two doses were small with greater changes in pulse rate for the 25 mg dose. «luv-v nun-m nu-~4-uexlrw-mu—wxrﬂ g m... .m—v v“ mwn.mrv'ﬂil‘ﬂrr”" ,‘I'VIVFIE —'vr‘4 —v test data reportﬂ’interesting findings. Eight volunteers were seen in a double-blind crossoveg;gtndy of SI 93 Ild25 mg and 50 mg, oxasepen 20 mgI'IE’E'EOnparison substance, and placebo. The 50 mg dose of Si 93 elicited greater sedation than 20 mg oxasepan. but also an inner "stimulation". irritability, unpleasantness. feelings of warmth, and some clouding of sensorium. The 25 mg dose of Si 93 vss found to be pleasant and equivalent to The psychometric oxssepan. �,valnlrm...“ VW'K‘:"F ., ) ; ___.- er. , . y'vsc. .Y.. _new-m.,.. a._ “wees—w'cv a .>.. W2...”, .Inﬁu-VHW .“m-v. V V mm “4’".'—' v — - ~ V-- ~ '3 1- . sn-Mr-w rv-mww » 4-,“ w -m n. — » e. LF—IGY‘ ,, wan-VB;w-:’atv4‘lr:'t¢:gr:aw{v-a . ‘ / 4 E. N. Terry, 14.1). -2- November 20, 197k These observations strongly suggest that 81 93 has central at activity the doses studied; that the activity is pleasant and 'tranuillisina' at low doses, but unpleasant at high; that there a relatively narrow therapeutic range, for the 50 mg dose elicits is 'some of the central deliriant effects of the anticholinergics. There are interesting questions about the compound: Are the central effects similar to oxasepam (and other benzodiacepines). or like imipramine (ditran, and other thymoleptics)? some ‘Does 86 93 have a at lower doses, diphasic effect—~sedative and pleasant deliriant at higher doses? and stimulant and These questions can be answered by our present methods or electrophysiologic assay, for a classification study will define the Atype of central activity in man and yield evidence of its therapeutic range; and a dose-ranging study will give data for the stability or the nature of the central effects. ' However, the questions that must be answered by management before these studies are undertaken seem to me to be: Is there a need for a novel thymoleptic; and it there is, can 81 93 quality for further study since it may have a narrow therapeutic range? If the answer is affirmative and further studies are desired, to examine this compound. For a dose—finding study, single doses of 5.10.20, he and 60 mg should be examined. FOr a classi~ fication study, two doses and placebo could be examined in 10-12 sub-~ Jects over a post-drug four hour period with measurement of EEG, alert. ness, heart rate, blood pressure, mood ratings, symptom ratings, and critical flicker fusion (CFF). and the observations compared with our historical standard? diasepam and imipramine. we would be pleased my thanks {hr the opportunity to review these data in It seems to be an interesting centrally active originals.{ My compound. their German . best regards. Sincerely yours, Fink, M. D. Professor of Psychiatry Max Merd Again. “ah- .7 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zimmerman, Kimblerly Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-027-8-574 Date A point or period of time associated with an event in the lifecycle of the resource 1974 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/a32cce8e806d7ae0928192323a16c0e5.pdf f324152ae611e703387db26d0fafbe14 PDF Text Text , a»... .7 ,,,,,,,..._,. , M _ m!, , ,‘ a...“ Mums». H unvr “qr”... 7,. , , .w V'wanrv-cﬁuh'wm‘ . , ,q . r ,., ,‘____m,_,,,.__ - -.—... mtwlm-W-wmx-” . .. ., ,v,-.v in . mu». s."“'i".rm"’~"“ ~ November 4, 1970 Mr. Richard Zirinsky Chairman, Board of Governors Gracie Square Hospital 420 East 76th Street New York, New York 19021 Dear Mr. Zirinsky: It is with gratitude that my and I complete our studies at Gracie Square Hospital, associates and relinquish the laboratory which you so kindly made available. The Opportunity to study the treatment programs at the hospital was most valuable, allowing us to compare the clinical, memory and EEG changes in three forms of ECT. Reports of these studies have been presented and at meetings of national scientific societies (Eastern EEG Association, December 1969; Psychiatric Research Miami Beach, 1969; Society, Eastern Psychiatric Research Society, April 1970). We have completed four reports (see enclosed preprints) defining various aspects of the convulsive therapy process; two are in press. Additional reports are in progress and willalready be forwarded local to you when completed. We believe that the work done at Gracie Square Hospital has greatly enhanced our knowledge of the convulsive therapy process, and improved the stature of scientific research this field. The governmental support we obtained for thisin project underscores the national and public health importance of investigations of this valuable psychiatric treatment. You will also be pleased to know, that because of our interest and the special nature of these we have recently been asked studies, by the National Institute of Mental Health an inter~ national meeting of the scientists studying tothesponsor treatment of depression, to assess these optimistic ECT results. �Mr. Zirinsky —2- November 4, 1970 The next phase of the study requires more extensive laboratory examinations, a larger papulation of long-stay patients, and a timeconsuming treatment method (multiple monitored ECT). For these reasons we will transfer the project and equipment to Metropolitan Hospital during the next two weeks, vacating our office at Gracie Square Hospital by November 10. wish to express our deepest gratitude for the hospitality, and active coOperation that you and your staff have extended to us during the past two and a half years. Drs. Abrams, Dornbush, Feldstein, Volavka and our co~workers join me in expressing our appreciation. Without the support and tolerance of the attending, clinical and administrative staff, this project would have been impossible; with it, we have once again demonstrated that scientific research can be successfully carried out in a private institution We cordiality, with private patients and.with important results for clinical psychiatry. Warmest personal regards. Sincerely yours, Fink, M.D. Professor of Psychiatry Max MW:kt cc: David Shapiro . A nrmm � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zirinsky, Richard Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-024-9-506 Date A point or period of time associated with an event in the lifecycle of the resource 1970 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/2dfaddba8ed2b7f7af4fd7f5bb57a19d.pdf 0cf40cff6731a7b878957eec0d91afb1 PDF Text Text Date: March 11, 1997 T0: Dr. Athanasios P. Zis FAX # 604.822.7922 Total Pages (including this sheet) -5- Dear Athanasios, Sorry for the delay in answering your FAX but I have been on holiday. A search of the ECT Database ﬁnds only a few studies of parkinson’s disease and ECT. I attach the citations from the ﬁle. I know of no studies in progress on PD and ECT. A few years ago I was told that Dr. Melvin Yahr at the Mount Sinai Hospital in New York was managing such a study but I have yet to hear or read an abstract. Richard Abrams had such a study in progress in Chicago but the intake must have been slow because he retired and I have heard nothing more of it. Ray Faber at the VA in San Antonio, Texas told me of his program in ECT in PD and that he was doing maintenance treatment. Ray was the one who explained our cases of delirium and advised me to reduce the l-dopa doses. His review with Tn'mble is a good He would be the one to call for possible experience. I know of no PET studies published or in progress. Sounds like you have a good problem in hand. Go row Max From: Max Fink, M.D. FAX: TEL: 516 862-8604 516 862-6651 P.O. Box 457 St. James, New York 11780 Alternate FAX: 516 444-7534 Alternate TEL: 516 444-2990 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zis, Athanasios P. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-033-8-165 Date A point or period of time associated with an event in the lifecycle of the resource 1996 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/d2d0afe3a94ed1ab34e31fe6bc2128fa.pdf 3922ed9dc3aaab42d5311009ee7f7055 PDF Text Text April 21, Dr. and 2010 has 196% ﬁts. Engine Ziskind 9311311111! Boulevard Macks, California 90057 Daar Dr. Ziskind: Thank you may mach fm‘ your kind invitation to join home on saturday, May 2nd. Ym'm mat kind to have oxtarﬂed this inviﬁptim and I look forwan‘i to joining you in yum yen after the Biological Psydriatry meeting. Sincerely yours , ﬂax Pink, Director M. D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Ziskind, Eugene Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-018-3-336 Date A point or period of time associated with an event in the lifecycle of the resource 1964 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/2863773909e2a6464b12b30416e9fc82.pdf 194310dc7f38ae7dea0d0a05cca56cf6 PDF Text Text November 6, 196u Eugene Ziakind, MD. Gamaya Hospital 1891 Effie Street Inn Angela, 26, esiifomia mm: 12mm to talk to yum" brother. t Inmmdinws,1mdtumsthemsulmofw v'It was «a mainland bathed: Hillsm and in St. Louis inthe ‘dcvolopmantofamsnatohmmr. mile itispossibla fwamtcrtobedsvelopsdbyhavingatalnntsdyamg letting him Bungle with you, I an immense: that the main strum of Punt-1m Psydiiatric mum is located in the Mum‘szmr For this mum, mm and am. Wammdtwiningpmswartothat ImmsadﬁwopinimﬁutifGathmtomdur- Hillside Hospital, it mid mquim tha es~ tablishmntofawrystmngliaitmwiﬁmadsmt ofpsydmiatryataloualmdiualsdmlmdﬁmmlw gmtimwithﬁnul'aimfurﬁIeappoinmufa piutmd an: Wt smﬂbrinmtigmwhomyheintemstedinundertaking such a position, if it unwind thu professor- shipntthemdiualsd‘ml. Mtwiningmdunmdatims dwivefxmﬂxispomtofViw ’ Wyouformeuppunumtyofnaeﬁngymbmﬂnr mdexpwssingmopinimabmtapmblmwiﬂxwhicnl hmamxgglndformmyyem ﬁnIindiuatudtohim,I mudbeplmadtohelpyminanvwwﬂmtIum Siamly‘ yours, use Pink, ma. Inf/Is * ' � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Ziskind, Eugene Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-018-7-743 Date A point or period of time associated with an event in the lifecycle of the resource 1964 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/ddd8cc1cce7645629c8534f26a97f121.pdf 302483fad21f1367836c4d37f554eff7 PDF Text Text NW 12, 196“ Hr. Louis Ziskind Mmctor WWHospital Gateways has Angela, 26, California mar Hr. . Md: Wywvewmdlforymmletterofbimnber taveaelectedmchoioeofminmmyofthepam9mmdyo‘mnotesafomromfemnea. milelwouldmt W,Ibelieveywcaptumdﬂmsemeofmymmnen— datiomvuywell. In the event that these notes may be available team atmhoapital, Immbmnsaedﬂntaomof intended. I WWRBWMIMEQWVIM mtnkingthe liberty, transform ofoditing these notes mdmnmunningthmtoyouwithﬁmmuastﬁutaﬂxer mpiesinyourhandsmybediamdandmeseusedas replacement. V maofarasywmplmngtowritetothe maple at Hillside Hospital, writingalettertom. oopyforym. Imtaldngme libertyof mmm andanenclosinga Sincerely yours. Max Firm, M.D. Director . Inf/ls a mlmms � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Ziskind, Louis Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-018-7-766 Date A point or period of time associated with an event in the lifecycle of the resource 1964 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/938e3b91bbe7eb2bec25e4b1e4c047ba.pdf 559ae9611656156b7316a74d59558cdf PDF Text Text 73I~639 April 25. 1973 Steven Zornntzer, Ph.D., Dcpnrtmnnt of Heurosniuncon, Uhivuruity of Florida, Guineaville. Florida 32601. Don: Stava. The Therc are two quastians rqsnrding memory function and eluctrical nativity. In a seixuro naeessary for tbs alteration in unwary function! Tb-vhat extent doe: thn electrode locatian noaify the errant: on memory, regardleoa of whather the entrant is seizureuindncing or subthronhold! In our wart vith patients we hava rnpactedly fauna that the applicatian or electrical current through alestrodea whiah ﬁrm eithar an can side er bitemporal, do not change the behgv&or of thn subject. unlenl a actauro (convulsion) oeaurs. With nubthronhold Iﬁimnlation, tummovunenx does not occur. In my enrly work in did check an manory changes and axing vary gross anasuroa VB dié not tinﬂ changes in manor: function with tubthrtshold aﬁimnlation. In those dart we wtro dalightud bnasuan v. did balilva that improvamnnt and memory worked with changas ”hat hand in bsnd. ﬁbre recenxly, as unilateral oloetrodg glaaannnt. and datuilad unwary tasks fbcusnod on varbal and nonuvutbtl. visual ar auditory it parameters. vm did not npeeifionlly lack for the effects of the Iﬁbthrashold stimulation. With seizures induned through unilateral aleetradoa, we and other: haw: fauna that manory ahnngon an occur. Th: tyve and dagrco or unwary change in diroctly ralated to tbs looa$1on of tha clactrodal. Thus, bitempornl electrode placuunnt elicit: grattar engages in vurbul and auditory manory tasks than any uniluter&l electrode Electrodaa ova: tbs non~aam1nant hemisphere placumant. unutlly cliait lesser degreus of unwary interference, and thus: are tbcuaacd on non~vurba1. visual tasks. I! unilateral e1n¢trodus are pinced ova: thc dominant hemisphere. thc chanson in.munory tanks are sraaﬁar and more manltunt on verbal. auditory typo tasks. Lately, one or my cavarkcrn has ”Ar w ' for yuur additiannl figure uhieh I think gublishar has not yut reeated to our submission. Thank yau in better. ‘ - :¢.’Y"u r.— Iwmw z—meIr—f : WW?“ «3sz W'Wﬂr ‘ �Steven Zorneteer, ?h.D. Ayrll 25, 1973 ~2— series of experiments with the electrodes hlfrontelly done a placed and showed that the memory changes are even less than the unilateral nonwdominant. Unfortunately he did not do the specific tests to separate verbal tram non~verhel aspects. Thus, ve would have to answer our questions that in man tasks are interfered with.when aeituree (eonwuleione) are p-oduced and the type and degree of’memory task inter~ memory is ferenee aamehew related to electrode location. first question. whether a seizure is necessary for tunetion, does not find en answer in human literature to my knewledge. I knew the eentroverey is real in the week that Jim and other. hsve been doing. In yeur work, I would be particularly sensitive to some measures of eurrent intensity and duretiea. eleetrode location, but also evidence for selsure (and its duration) end/or convulsion. From your letter it’d: not clear to me whether yen can eleerly parcel out the contribution of eubthreshold and eupre~ threshold electric currents. an My alteration of memory With regard to your lent question, the evidence is quite eleer that if electric currents are intredueed over one side of the scalp. theme may or may not cross eontrelaterally (es reflected by the development of canvulelons or electric seizure activity) and this transfer depends directly on the emeunt or entrant delivered. The aeeampenylng ante to ell the participants in the eenrerenee will bring you my to date as to the statue of ear volume. my best personal regards. Blneerely yours, Mex Fink, M.D. Executive Director MF/id ﬁne. ‘ � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zornetzer, Steven Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-026-5-349 Date A point or period of time associated with an event in the lifecycle of the resource 1972 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/1cee063d1279f56c44e7a3b1f848b4cb.pdf 48674304a7f6d8b4d0c0070aa8bc542c PDF Text Text T383~5650T March 6th, 19?3 Steven Eomtur, PhJ). , Department or Rmmimu, University of Florida. Gaineaulle. Florida 32601. Stem. Dear have submitted your pcper to the publisher, Ind both he and I mum '3th Figure 10 (a photoyuph of a brain 311cc) will probably em out poorly. Is it possible to have that. mlwtogrnphcd to providc tn 1m. with gram contract! We Many thanks. Simuroly yours. Mu Pink, 3.3. Protuaor of Psychiatry Mir/1.1 ' ‘ gamma: ~. 4‘ � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zornetzer, Steven Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-026-5-350 Date A point or period of time associated with an event in the lifecycle of the resource 1972 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/d5d1e7183186cec93a2fc6e8d64e9ed3.pdf 949756a0f3cb3afb2f1e38fe629cb6cb PDF Text Text 731~5030T January zhth, 1973 Stevnn F. Zornetaer, Ph.D., Assistant Professar, Dept. of Hauroseience, university of Florida College of Mhdicine. Gainesville, Florida 32601. Dear Stav%;, After some delay v. are submitting all the reports of the ECT meeting to v.3. Winston & Sane, Inc. fbr publication. As we can meet their deadlinan, they have pramisad kc deliver the final yublication by Septembar 1973. . I thank you for your contributicn and an dnlighted to hear that ycu are continuing to study seizures. Sincerely yqurs, an: Fink. MF/id M.D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zornetzer, Steven Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-026-5-351 Date A point or period of time associated with an event in the lifecycle of the resource 1972 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/afa50ae2d909cfbcb251307dd59c5a3e.pdf 4ea37b7a62a35615dec0b2d3de94508c PDF Text Text ‘— »-» u 'v -u~m - vwvw—"w‘mv- 't-v'ww-l'.‘ nut—Wu" arranwww"wvﬂm u-u-w-n.w.-.,.—“7".wvrzw7w my,— ‘V-"‘n-rw'v—w-r ”whinrwn ‘. .. .,‘W.mﬁw. September 21, 1965 Professor John Zubek Professot of Psychology University of Manitoba Manitoba, Canada Dear Professor Zubak: I had the plaasurc of hearing Dr. Mike Samdcrs present of the EEG finding in your perceptual isolation study program at the mount matings in Salzburg and Vienna. His mamtation was stimdating for it omfimad many of the m swaticns years ago regarding the physiological basis for the persistence: of behavioral charges in individuals subjected to the perceptual isolation promdure made scum I inquired of Ir. Samders whether these findings had been published, he indicated that mob of the material is no» being prepared. I will be grateful for any pmprints When which you may have available regarding the electmgruphio chmgcs and bahaviorul changes counting in your study program associates in trace laboratories is now interested on a study comparing the alcctrographic dmnges in perceptual isolation in psychotic subjects and comparing the persistence of these patterns to dosages of various One of my in awaiting mtidwlimrgic drugs. 'mank you ‘ for your oo-opcmtion. Sincerely yours , Max Fimc, PM). Professor of Psychiatry MF:kp . -VWW .. “v." ”"4 w. V...V.,,.....,.,.._‘-w ”mm—mvm--. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubek, John Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-6-511 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/ce3addcc49ca1b09c5b1e743c1e2bfb0.pdf 5e175ceca9ce33d3f028973778bc8e21 PDF Text Text September 6, 1953 Mrs. L. mm:Tencmers 1mm and Annuity Association of Purim 730 Third Avenue New Yer]: 17, N. Y. Dear Hrs. Zubem Prior to delivering this TIM am mar mntmcts No. Andaman-5 for Dr. Itil, I read the contract. I am unable as domibod in the booklet ”Planning and Ratimmnt Prom" on page 81-82. For this participant, the possibility of and ”a. P—nu'nM wfimmmusomumudpmitmmymaofﬂnmty ' We hmﬁalshnoheismluwﬁmmmmﬂtyinﬁrlangw. Intheavent ﬂuthcelcctstomaininthalhited States, the TIM policy will mime. In the event that he clactstomtmtoﬁncpmwamtbeusmthuthiammity can be: mpumhmd within the stipulations on 32. Germany. page I wound appreciate: a rider to both of these policies. this effect to he issued . Simmly yours, Max Fink, Mmmr H. D.‘ for � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zuber, L. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-017-7-424 Date A point or period of time associated with an event in the lifecycle of the resource 1963 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/2c09091a517aae163b6ee9d06e06b6e1.pdf 0e5aa80327542e1835a3bf3d670fa1d7 PDF Text Text 7333-617 V 5’ W11 9th. 3 Dr. E J. Zubin, new York State 722 mm 1681:}: 5 7' 3w York, NJ. Dear 21$ : 5; : 3‘ 1973 Institute, thtmria at. , Joe, I concur with Charlie' a suggestions that you are the lagical person for this enquiry. I would be grateful if you would review it and either: approve on behalf of the APPA, if you deem it advisable; or return it to me with alternate aévice. Sincerely your-a. a» m Fink. Rd). Professor of Psychiatry was he. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, J. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-026-5-352 Date A point or period of time associated with an event in the lifecycle of the resource 1972 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/698309d829ad2bd236b14a5244dd7562.pdf d9ee51da8dcd733da9f95c90fe1aeab3 PDF Text Text '"w‘nm-wn- ,—-- ~- m um ‘ ﬁw'n‘vww‘vmn—vwwmwwu‘ a. rm-vu—wW—u—z-mw-a. wu,- -.‘ M<V 'I'-r*"'~"w‘~c:;-v- q-wr .,—.V ”mum" m‘Vv?‘ v' _... Ndmmﬂxu~20, 196a ' k- Dr.meqnxmﬁnn vammkIbmtﬂhﬂncﬁ’ﬁmmhbﬂny 722 West 168th Stmt waYbﬁ<Ciqh,Nuinﬂc Dumwkn: ﬂumkymuxmnymuwxﬁnrywm‘dIUngumstmswenyammximm Dr.Ixnnhiﬁumnand,whovdll‘dsrtwiuaym:anvb¢umdmrmmndng, lhmmﬂnrsnh. Hainpmwdcmuuiyinuuusmm:bammbhmscf nmumhmztmnlmmmmmuthasdﬁaqmmmﬁnanmyums. Mmmﬁkd val” \dé Gmdﬁdnlwnlhnn'ﬁuy « , enumnatnhann‘kmamwﬂ'amﬂ”.H‘ »=ofstmwraatmsdu3; GE‘sddaqwmmﬁn. In1ngUBt1ﬁnvmuﬂmsIthawasugymumltmn:waaﬂgu:dan rﬂw:mmn hubnmniaafnxzuxmunmmtEEGamdzeuﬂiaathm shmﬂsa. Hbtuwulnomn:hmmmmuuitMNzﬂatmapnﬂﬂunofcmn~ tbnnmapmdhnmwmamuwwmm. ﬁxuﬂugyan~bﬂnnmn:amiemmuiaun ﬂxswﬂxemmuimmmal qmnnmﬁmw‘u>dkwmﬂﬁamdamzofaMbﬁnumw'uasddaqmnwdn, Ivnnhibephummiifnuzomﬂdgpt131mmt3mnam1a1liuw mmwrmuwnn:ofymm~suwfinuM£suMJBIﬁﬁstypaofemmudu maﬁalphmhﬂpgn Dxﬂscmmnnhnmnmtis:haﬂmadmmhnmmu:aftmmﬂngkml amxnaﬂnuim‘ﬂusduamﬂﬂaniazofymmdwtkm. Hoisvnll mmwuﬁﬂmdvdrhsmurvunyeaﬁbrshxﬂes:xxdhmumvan£umis. Thuﬁ:ymavmnrmwd1fbrgmurtmdp. numwhdng. Gaxiludcin5mmr Eﬁnannhrymns, Pink, uhndmm Max mﬂﬁs M.D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-018-7-780 Date A point or period of time associated with an event in the lifecycle of the resource 1964 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/7d438c1f5b7e6013be0f32f7ec08803d.pdf 4c4140ce75d9617c26d74c1bde7de2b4 PDF Text Text June 15, 1965 Dr. Joseph Zubin Bimtr'ic laboratory State Psychiatric Institute New York New York, 722 West 168th Street New York , Dear Joe: talking to Jma‘thm Cola about another problem earlier In this this week md he mantimed your project on diaguosis. Grinker Dr. from that the mmings mail I moaivad mtifioatim I taking am enclosed "vapor: has been accepted for publication. this believe that because I tha liberty of sending you a copy make in providing will support my effect that your study grcmp cm 5.11. objective classification anthem for the mentally I wan My best regards. Sincemly yours, ﬂax Pink, 1-1.1). Professor of Psychiatry W: kp melosm � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-4-356 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/3b4bebaca3fa403a00fafc4042cb1a4f.pdf 866ffce74fdb61b106d4d95eae563361 PDF Text Text June 15, 1965 We W Dr. Joseph Zubin New York 722 West New York, State Psydziatric Institute 168th Stmet New York Dear Jon: ,3» RT I was talking week and he to Jmathm Cole about mother problem earlier. mum your project on diagnosis. In this naming mail I received notificatim from I». Grim that the enclosed report has been accepted for publicatim. I an taking unlibar-tyaf an; ywaoopybamlbeliem matthis willmpportmyﬂ‘thatyom‘auﬂymcmmwpmiding on mathods for the mum in. objective aims this ' My best regards. Sincerely yours, Pink, H.D. m Profesaor of Psychiatry 3k? enclosure � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-5-418 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/f831b1b04dd98679be8115184da0f687.pdf 907526a60c4226e98f124f215bd0563e PDF Text Text Home!“ 28, 1985 Dr. Joseph Zubin Biomatrio Laboratory New State Psydaiatrio Instimta York Mt 188th Street New York, New York 722 ‘ Daar Joe: I mjoyed your comm-Ito at the mount conference vary ouch, especially the vignett of hand. are my muting a study of simultamous tactile stimulation an! the averaged evoked response in our psychiatric animate regarding the pooulatim. I was impressed with simltanaous auditory studies which you and Dr. Sutton ware now Importing. I would be grateful for copies of any of your reprints and specifioally any pmprints that may be available at the want time. We m Hy best regards. 31ml); Max Pm, yours, I‘M). Professor of Psychiatry Hfﬂcp � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-7-630 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/3ec89f3890bbecc25c6a1f7fd3749d0b.pdf 7a246d4c4b8781ef4b6a1b751036c811 PDF Text Text July 18. 1968 Dr. Joseph Zubin 722 West l68th Street New York, New York l0032 Dear Joe, Thank you for the copy of the APPA program. My nomination for the Hoch Award is Martin Roth of Newcastle. For at least two decades he has been a leading figure in attempting clarification of psychopathology. He has written on a broad spectrum of subjects and in this regard is quite similar to Paul Hoch. Sincerely yours. Fink, Secretary Max MF:kp M.D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-022-3-259 Date A point or period of time associated with an event in the lifecycle of the resource 1968 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/3769806be659521310ceec18c1389f46.pdf eb5295d1c870ceb69c9726ee7dd4ddcd PDF Text Text May 27, 1969 Dr. Joseph Zubin 722 West 168th Street New York, New York 10032 Dear Joe, ' be m Idohothmkmtomrthismquestmdlmﬂd it dimctly or advise mum if you wand eitherSincerely yours , PM PM, Semataxy MOD. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-023-3-273 Date A point or period of time associated with an event in the lifecycle of the resource 1969 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/4f83c5a5177b2b22adf2a49b5be23503.pdf b495401f5ccdf3692ba8f4553e35a0d9 PDF Text Text Catcher 23, 1969 \ Dear Joe, Thank you change tha for the APPA program. It looks good. 0n the cover pug» for the printad program, please non~uambers to threa dollars. registration tea for For the Dutch Trltt Catktail party, is: it necessary 7 to indicate that 'canapen, courtaay of the associatiau' deletc it. Thaddeaignation inconsistent with the other I would far on: lacturer as Prof. Dr. is Aftar all, there are a few 1t is worn democratic 3nd less titles. Professors on the program, and obelaant to designate Br. Hippiua in the Elkea, Eisenberg, Katy, etc. same way an Graonblatt, Finally, the summary I sent'you was too long. I sent a second. and even this may be too long. Please use the second or edit it further. My hast regards. Sincerely years, Max Joraph Zubin. ?h.D. Biometrics Research 722 What 168 New York City Street Fink, M.D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-023-5-452 Date A point or period of time associated with an event in the lifecycle of the resource 1969 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/a73513f4ad1f90ae7a4188bcdb3c39f4.pdf 18d5b838b0e2fa51e6d30b39b8b27a7e PDF Text Text April 7, 1970 Dr. Joseph Zubin 722 West 168th Street York, New York 10032 New Dear Joe, Enclosed for the My 1970 is a typescript, proceedings of the "CNS APPA Effects of Convulsive Therapy", on “Disorders of Mood”. thanks for your invitation and the opportunity to take part in this interesting symposium. Sincerely yours, Fink, M.D. Professor of Psychiatry Max Mszp enc . � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-024-4-210 Date A point or period of time associated with an event in the lifecycle of the resource 1970 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/7c2fe1b4746afcba8bb435f563a10d82.pdf 026f14597c78624f9047b1d5e40dacfb PDF Text Text February 25, 1971 Dr. Joseph Zubin 722 West 168th Street New York, New York 10032 Dear Joe, enclosed letter from Dan Blain should be answered, and I can think of one—one better qualified than you. Would you answer this request? and The A1 Many thanks. Sincerely yours, Max Mrzkt cc: A. H. Freedman C. Shogass Fink, M.D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-025-2-094 Date A point or period of time associated with an event in the lifecycle of the resource 1971 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/06c06121134f44164945c360ecb0fe9a.pdf e8e420d43d9a0c743435a2a9ae14fead PDF Text Text w. .VVv—vr- - . a .w' ,- _,_ awr< n .-..,..__-..-.-—w..—..-~v._... .— , ~...v.....r.....-,_.,— Hwy“. , rm. . . Y N..- .. , w r. "m...“w .u. Vuﬂq..w. .,, V, o. 73S3—779SB 16 Rovambcr 1973 Barrett Booville, M.D. Division of Nourophnrnacolozy Food and Drug Administration 5600 Fisher's Lana Rookvillo. Maryland 20852 no: Door Dr. Haltroxono IRE Scoville: I on writing 13 response to a tolcphouo call from Do. Alon of tho Rational Instituto 0! Mental anlth. who indi— cated thnt chore night b. noun disuatisfaction with our IHD submission for tho uvaluation of nalcroxnno. Dr. Ramsey raised a samba: of questions. and in the lbocnco 0! clear inquirioa from your offica but anticipating that than. quootions are sermons, on at. submitting the following addendo to our sdb« miosioa of Sopteubor 1‘, 1973. Romany 1. Eviﬂcnco of not of opiates for a minimum period of on. your and at loos: two prior attempts at discontinuation of drug non will b: proraquinitaa to adoinatoo to tho program. Incronanto will follow the latest information available. which at prunout ouggonto the ottoty of 20 a; incromnnts to 100 us 9:: day. other nnrooaic antagonist will be used as a control. 3. No 4. A copy of the cousin: form now in nos 1: attaohed. “7,- �v...,.A u“«r< w..- w-u-vru ,- 'I",' -—.-u-~-n<‘..m. ”1-,... _, nv- ...... u—m‘ luv—“n... -1... B¢rruet Scavillo, H.D. 5. 6. ~2- “w“...w—rr'rnmq.‘ ,7 n- . , , ‘ . 16 Hovulbar 1973 This project was approvhd by two institu~ cional caviar enunittcas. that of the V33 Rorthport, datad June 11. 1973, and the 003138 of 5.U.R.Y. at stony Brook. urinalysis are cerucnnd in all patient. on an irregular basis. averaging twica a nick during tho first two months of «valuation and trcscnuat and weakly 7. ,,,_ .-~- we thereafter. are aware of no svidcnce rcquirina a op¢~ cial aphthalnolasical attainaaion eithar be~ fora, during, or littr drug trial. Should thin ha mandated by the FDA, wt tequnst the Justitiaation for such unndatc bu suba¢ttod, for eumpllanca with thin suggestion is Orv pcnsive and difﬁicult. Sincerely yours. Mu Fink, Hob: rrofosaor of Psychiatry HF/cin Encl. . � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-027-4-307 Date A point or period of time associated with an event in the lifecycle of the resource 1973 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/d54add39b6fc219d3a5f3f1fd016b4e1.pdf 2978436e3c74f55c7993b87c0563cef7 PDF Text Text 74AP-056AP 1 Fobruary 1974 Samuel B. Guzé. H.D. Dapartnant of Psychiatry Washington University school of Modioino St. Louis. Missouri 63110 Door Sam: I writing to thank you for your holp 1n the Nominating I have rccatvad a roger: from Frits, and I think tho suggestions at: orcollcut. am Committaa. “rm-aw»? ,.Vr-""~"v>-‘ . I kocp heating disturbing hour from 8:. Louis. We wore visited today by one of tho young fnychiatristo from Malcolm 3110., who tussestod that com: of the cans restriction: on re~ search visited on the HIP at. apparoutly being establishad ac Bliss. Fran thin distance of 1100 miles, can would wonder if a concertod effort by IU, M0. and SLU would not be called for, not only to help HIP ourvivc but to provide a dam for the "knownothing" mantality of middle Hisaouri. my thanks for your help, sincarcly yours. Max Fink, M.D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-027-5-387 Date A point or period of time associated with an event in the lifecycle of the resource 1974 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/9408dd76c14acc0b610911e3d60e89f8.pdf af128ab89957d1fd6c63fa41ccc627ee PDF Text Text Joseph Zubin, Ph.D. Chief of Psychiatric Research (Btamotrics) annrtnont of Mental Hygiene New York State Puychiatric Institute 722 What 168th new York, H. Y. Dear Street 10032 Joe. I think thn volume, "Contemporary Sexual Bohsviar" should be issued in paper-back. It is a well~collectcd not of onuayn, not supersednd by recent rasoarch. The topic is of perennial intoreot. I asked the advice of our resident anxologiat, Dr. Richard Green, and h. thought the valume of sufficient merit to be reissued. should (Incidentally, he is not a v. propose him?) mambcr of tho APPA - Congrntulations! Sincerely yours, Max Pink, M. D. -Pro£ossor of Psychiatry NF/mr � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zubin, Joseph Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-028-2-114 Date A point or period of time associated with an event in the lifecycle of the resource 1975 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/81ee668736a5881d1196baed2a9625f9.pdf 260299be3d2c7814c2d564f21bec71e7 PDF Text Text 73sB~6h3~A Dr. Stanley Zunker. Chairman, Researoh Committoc. VJ“ Heapital. Dust Doctor ﬂanker. At the time I submitted our request for the use of lwomethaﬁyl at the VAR, I acted that we were intorectod in participating in the collaborative study program. In dincuasing our participation with Dr. Sanual Kain in Whahington, be indicated that it wuuld be necestary fbr the rasnarch cummittoe at the institution to speciriaully apprave the eneloaad protocol. I am submitting this protocol as nu amendment to cur note ta ran. :nd ask that this be reviewed. In reading this protocol there are no significant differences from the ywogram that we had planned to estdbllth. (You should know that I participatcd in the devulapnsnt of this program, and have bean asked to be on the Steering Committee for the avalunﬁion). Thank yum far your aocperation. sincerely yours. M3: rink, 3.3. Professor of Payehiatry MF/ij Rue. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zucker, Stanley Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-026-5-353 Date A point or period of time associated with an event in the lifecycle of the resource 1972 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/6d2d49745021e9aad81e3a633b9bf401.pdf d0a2a4d2b119a067dafc7283034ab39c PDF Text Text '3" -~ ""ra-V— —-'w'~'-‘ 738B:079 ~ very“: ‘W‘Wr :‘ m April 2, 1973 ‘ 'v',v~’~' <~m~nw-mvw_waw-rwu. \3w1"v‘ww'nr"rr.)w fry-v r“ v-.- v v Stephen Keaton, M.D. Greeellnde Hospital Valhelle. Rev York 10595 Dear Dr. Keaton, Thank you for your kind invitation to participate in the weekly grand rounds of the Department at Grasslands. I regret that I will be unable to take part during the next few months, as I already have an impossible schedule. I have moved my laboratories from the city to Stony Brook and the transition will not be complete until the early summer. Should you wish, I would be pleased to the fall. participate in r~mw~wrwwmw~a~wrw~wm Sincerely yours, W wry-nvanwan-pmmwmwwarer-wwmmww ‘w'nm' n w "1' urr’vwww‘“ w n: “mm-v r-v 'ww-e: mum .mp- Fink, M.D. Professor of Psychiatry Mex � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zucker, Stanley Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-027-1-128 Date A point or period of time associated with an event in the lifecycle of the resource 1973 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/26a6015d56196838c90b488bfee97ad9.pdf 977a5065aab45a99122ef994e9bf05d8 PDF Text Text May 23, 1966 Dr. Willim 2mg Howital humRom Wimm Carolina uni-mm, ‘Dear Dr. 2mg: Itmaphnmtalkingtoyminhtlmticcuy. Iwuld Mmmewmmmamofyowmmmlmvim haw axis mvimd at tho radical Schoel. so that I I mt am moms copies of the pmtatim in Atlmtic City anmllasthe when pmpmbym'. Stupimmdnyself. The prom an included and I mum be pleased 1:0 discuss this with you be av at your plmm. I dimmed wiﬁu taful few any Dr. Siupim the l‘arkavim Model and I would of yeur reprints and proprints whim may he: lcsoﬂmtmmlommahwtmapplioatima. I was also 91:1de to review the effects of various meleepmdwmﬂnbeplmdmmampyofymmpmsentaﬁm inAtlmtic Citywmnasthewliermetoﬁﬂchyoumfamd. We My best mm . Sixmmly yams, HEX Fink, Mum HOD. of Psychiatry � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zung, William Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-020-5-295 Date A point or period of time associated with an event in the lifecycle of the resource 1966 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/d0ef5451631d1c2de8669dc4fbe28203.pdf 625a7ee538bbfd641c809cc05ea1ef68 PDF Text Text March 28, 1968 Dr. Hilliam Zung Veterans Administration Hospital Durham, North Dear Carolina 27705 Bill, pleased to have you visit us in New York and I have Just spoken to Dr. Itil who told me of some of the excitement at the meeting in Denver. I was set us thinking about many enjoyed your visit very much. You different problems, and we writing to ask you for two pieces of information. interested in the predictors for convulsive therapy and any suggestions you may wish to make regarding the use of the depression scale, with the established beta weights. Dr. Abrams will continue his study and this would be a useful I am I am addition. I have read the abstract of some of and when these are available. especially effects, I would be pleased to receive a My your reports in Denver those relating to drug preprint. best regards. Sincerely yours. Fink, H.D. Professor of Psychiatry Max MF:kp � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zung, William Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-022-1-005 Date A point or period of time associated with an event in the lifecycle of the resource 1967 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/f34532521868101f6c8ca5d9f20fbbf6.pdf 196adad9b9c4d447261b1a653a0dbbb3 PDF Text Text March Dr. William M. K. 7, l968 Zung Assistant Professor of Psychiatry Veterans Administrttion Hospital Fulton Street and Erwin Road Durham, North Carolina 27705 Bill, Dear I look forward If you come-in the evening (516 466-5444). home and to seeing you here I would like you to come First Avenue), at 10:00 on Wednesday, March before, please call me any. He will to Metropolitan Hospital (97th lSth floor, Mental Health Clinic. make up visit the laboratories the rest of the agenda as we Sincerely yours, Fink, M.D. Professor of Psychiatry Max Mszp my am, In the afternoon I would like you to at l?2nd Street. go a at l3. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zung, William Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-022-1-051 Date A point or period of time associated with an event in the lifecycle of the resource 1968 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/c3d3f803307940d86eb143fec0854d0c.pdf b298f3aea0592eb4c9f6233f6c927efc PDF Text Text February 7, l968 Dr. William lung Assistant Professor of Psychiatry Duke University Medical Center Durham, North Carolina 27706 Dear Dr. Zung: Both Professor Freedman and I were delighted when we vitae. I would like very much to have reviewed your curriculum you for visit York at week trip New three a our expense. Unfortunately. I am leaving this Saturday. I plan to return March 2. is a presentation from these laboratories at a local on March l4 and Dr. Freedman suggested that this might There society visit as it will give you an opportunity to know something of our recent work. But this is only a suggestion. May I ask you to call my secretary at (2l2) 369~7900 Ext 245 and arrange a date which is also convenient for Dr. Freedman, alternately to March l4, during the first week in March, except be an appropriate day to March 7. It has taken me a bit more than a year to get the clinical and laboratory facilities operational. But we now have patients on two wards at Metropolitan Hospital and from the clinic available for study. There are two fully equipped EEG laboratories and our computer installation of an IBM l800. Most important to me, is the fact that Dr. Donald M. Shapiro was appointed director of the Biomedical Infonnation Processing Division of the Medical College. He is co-director of the l800 unit and his larger facility (360 MOD 30) is available for any larger data processing. This collaboration between a computer unit. the EEG laboratories and the clinic have been very exciting during the past few months. join I look forward us soon. to your visit and hone that we can have you Sincerely yours. Fink, H.D. Professor of Psychiatry Max Mszp � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zung, William Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-022-1-077 Date A point or period of time associated with an event in the lifecycle of the resource 1968 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/32601edc0a2a1dfc7cea969acc2da57b.pdf 44ef8670931031a70c490f29e4867feb PDF Text Text 8, 1968 May Dr. William Zung Veterans Administration Hospital Durham, North Carolina 27705 Dear Bill: I trust the enclosed check will defray your expenses for your recent visit. We enjoyed having you very much and look forward to having you visit at your convenience this summer. I will be Chairing the Sunday afternoon session of the Society of Biological Psychiatry and at Dr. Koella'e suggestion will call on you early in the afternoon. My best regards. Sincerely yours, Max Fink, H.D. Professor of Psychiatry MF:kp enc . � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zung, William Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-022-2-179 Date A point or period of time associated with an event in the lifecycle of the resource 1968 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/29c61c7f40d9f488519f4b9a93ec9733.pdf 73231f4e6fa4cb9699ced57a0dcb842f PDF Text Text v , w "v.7 ---..._,..‘ v." n,‘ my...” w- .1, o. y. «N. 1-14 ‘v ma w. ~ -,n-~mn-.v»v-.,».m-.r.—---pr~x ItﬂvV-VW‘I“ “wow—,me-v—rnﬁmw,w rq'r‘vv—N'Wrn-m~. "new m..— .w '1‘. >vr..*r1€-a~-u:.rw’ “mama-”9- November William Zung, .— . 2a, 1976 M.D. Duke University Medical Center Durham, North Carolina Dear Bill, programs is quite extensive, being the 13 than more years effort. It is not possible to duplicate and the documentation without an extensive effort which Our product of the files library of justified by your letter. If there is a specific problem or program which may be of know what the question is and the capacity of your me help, let machine, its configuration and characteristics, I will be glad to send you what is needed.if we have it. does not seem Good luck. Sincerely yours, Fink, H.D. Professor of PSychiatry Max <;‘:"r —r\.‘v r.-w»~‘~»..~-—-~— - V». .— ,,_,._ . -—.—.4~ � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zung, William Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-028-4-178 Date A point or period of time associated with an event in the lifecycle of the resource 1976 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/8362e2a765870ebd89faa71930109147.pdf feccc3d31dd0f5be4e9e67a411e50d48 PDF Text Text June 17, 196‘ Mr. Robert C. Zwahlcn Hodical Liaiaoo Statf Clinical turnstigation Department Smith Klioa & Franck Laboratories 1500 Spring Garden Street Philadelphia. Pennsylvania Dear Bob: Thank you for your recent calla and helpful suggaationa regard'ing our study of amoharbital. I hara arrangad with camber: of my staff to carry out an initial survey as to whethor or not oral a-obarbital will affect tho electroencephalogram in our laboratory, using our mathoda of EEG analysis. In the event that this initial survey is satisfactory, I bcliovo we will be abla to unoartaka tho study daaoribad in our earlier letter of my 90 I am also plaaaod to tell you that the Board of Directors of tho ?ayohiatric Rasaarch Foundation of Missouri, 5 corporate body supporting the rcacarth and training programs in psychiatry at this inatitutc. has nada it possible for oar invaotigators to accapt grant support providaé that such awards are coda for tho general corporata purpoaoa of the Foundation. Thea: pur— poaaa ara to aupport the raoaarch and training programs in psychiatry of tho Diviaion of Mintal Diseases of Miaaouri. It would be appropriate, therafora. for you to consider our original raqoaat for support. providad it ia possible for your letter of transmittal to the Payohiatric Research Foundation opacity cithar that it be in support of tho general corporate purpoaaa or in aupport of the roacarch and training activitiea of the Eonndation. Thank you vary much for your cooperation. Sincerely yours, Me: Pink. Director KF/Jh 14. D. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-018-4-462 Date A point or period of time associated with an event in the lifecycle of the resource 1964 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/e481cc2b43ed52d81788dc6258aa69b8.pdf c5c6a4aeb6580792647fdae21f03d56d PDF Text Text July 6, Mr. Robert C. 1966 anhlen Medical Liaison Staff Clinical Investigation anartmont Smith Elias and french Laboratories 1500 Spring Garden Strut: Philadelphia, Pennsylvania 19101 Dear Bob: have received the capsule: and will undertake the preliminary stady within the next 20v weeks. A copy of the protocol is enclosed for your information and for your cowncnts. We I would 11k. it to refer in baing processed. you to my lettor of June 17. and Sincaraly yours, us: Fink. Ditcctor iii/1b Ban. M. D. trust thnt � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-018-5-504 Date A point or period of time associated with an event in the lifecycle of the resource 1964 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/729fb896628e8d09f2da693eb39d32b0.pdf 6dd07155aa7fdfe215c7650a293d4039 PDF Text Text July 28, 1964 Mr. Robert c. Zwuhlon Modical Liaison Staff Clinical Invcctigotion Dcpcrtmont Smith Klico and French Ldborctorica 1500 Spring Gardon Scract Philadolphia, Pcnnsylvanic 19101 Dec: Bob: is a copy of tho opcrational protocol which will be initiated as soon as no roccivc adequate aupplicn to carry Enclosed out the projoct. Under “Procedure" . thc drug dosage has been changad to: Amo- Amobarbitcl. 100 mg.; Amobaxbital. 300 mg.. 'batbitcl. W‘cuataincd rélaaac: and placdbo; and will be made up in acts 50 ngi so that each subjcct Thank you will hava four trials in rcndom soquonco. for your cooperation. Sincerely yours, Pink, Director Max MF/jb Eco. M. D. ' � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-018-5-555 Date A point or period of time associated with an event in the lifecycle of the resource 1964 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/d3c803df9eb2c78da199ed42918914cb.pdf f11a6edfac4f221c3c73f9d155e72f18 PDF Text Text February 15. 1965 Mr. Robert G. awshlen Smith. Kline 5 French Laboratories 1500 Spring Garden Street Philodelphis, Pennsylvanie 19101 Dost Bob: It was s plessure having you visit us on Thursday. The second series of analyses are new in ptngress. end I trust that will have the study completed within the next foot weeks. I I vould be gtsteful if your laboratories can help us with e specific problem. Eerly last year. the study group under or. Itil's direction ensuined the EEG and clinical effects of the comp bioetion of ohlorproneaine and bitten. They were impressed with the clinical effect and e number of triels were undertaken with other enti~cholinergio drugs. ineofsr as bitten is an experimental egont. Similar results were eohieved with stropine. However, the dosage of etropine necessary to induce clinical effects was in the tense of 10 to 20 age/day. To accomplish this doesge by the psrentersl route toquired large amounts of fluid to be injected. Insofar so we would like to administer this doolge dsily for e nnnber of weeks, we ere desirous of obtaining concentrated atropine in injectshle {one ‘ For this application, we would like to have atropine sulphate in e ooncentretion of three to five na/cc. This should be made available in either ampules or vials end we would need a quantity equsl to 5.000 units (1,000 unite st 5 malco) for the initial study. grateful if the phernsoologiets st SKI could sdvise to whether such e coneentrstion can be produced either at your laboratories. or by e commercial concern whom we any content dixeotly. If this concentration is not practical. can you advise us so to e I no es would be concentration which could be developed? Thenk you very much for your help. sincerely yours, m Pink, 3.1). Hfzjn Professor of Psychiatry � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-1-086 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/4b83eb699b0dd395fa47cba489924b79.pdf 6bf660bd722c770b4ad58434764914fc PDF Text Text April 5, Mr. Robert C. Mien Medical Liaison Staff Clinical Inmtigatim With Kline and hunch 1500 Spring Garden 1965 Wt Was Stunt Philadelphia, Pemwylvania 19101 DaarBob: Wmadomwpics 13. dinmimsotApril ofﬁmabstmctofny . mummimthathillplmtobeatﬁwSKF memo, Tussday naming. If the swim in laboratorics ﬁmmbehrge.thmitwmndbehelpfuliflhadadcvioe whid'zlaeuldpmjeat some ofmydrmingsmddata sheets. Ifthemwillbasmn,1tisjmtasaasytopassﬁmsa ﬂammable. . ' Iwillbringwithmafew2x2811dosmd,whihthese are not essential to the pmsantatim, they my portrayal if a 311d: is availabh. 12ij make a better Imsmymwillmtbemem,butldoh0peﬂwtﬁds mport justifies your faith in us. Sirmnmiy yours, Hm: Pink, M. D. meeasw of Paydxiatry Wz‘kp � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-2-167 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/02db681b3d663909594a374c9813d771.pdf 947f5f59ee68114ee0f9d95247ca5cbd PDF Text Text May 10 , 1985 Hr. Robert C. Zwahlan Medical Liaison Staff Clinical Depu'tmnt Inmtigatim 6 Smith Kline: andx laboratories 1500 Spring Garden ‘Stmet ﬁxiladelphia, Permaylvmia 19101 DearBob: Imgmt homofmypamtamdmyclosefdmdsandIdedicatcdmy Itwaaapleaamspeakingtoywinﬂewi’ork. thltlmmablstojoinywinymmsuite. MYorkistlw cvmingstomywifemdtom. Mlmmnmd,1fomdallofﬂaeinfmtimmtyou mponmichlmnmmhtingtotmthisdaminmammt. Alemthepapermmmbubitalsmdyisnmbeingmtyped dewillshortlymdyouadmftforyourstudy. Wynn forymrhelp. hadnmt. I spent yesterdaymadingitandhwe modifieda ‘Sinoemly yours. PM, K. D. meessor of Paydﬁatry Max � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-3-255 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/099ad630216a99cb9544c38f18764066.pdf 07e488aa1a74dd3852dda5563bf28609 PDF Text Text May 26, 1965 Mr. Robert C. Zwahlen Median]. Liaison Staff minim]. Investigation Department Smith. Kline e Pharaoh Laboratories Street Mindelphia. Pmylvania 1500 Spring Garden Damn 1910]. Bob: is our seemd progress report on the Salim. trouble of mtyping the draft, I arranged to it emailed. me data requested by Dr. Prue appem as can II and 111- If he or the labommrias would Enclased Klimaanduatwy. Omelfmmdwaelfpingtothe have to have saw of the raw data, the oands and send them to you. we can man to dmplicam this report represents a mthodologioal trial for us, m. Shapiro and I am intemated in having this presented, and mule! like to submit it for publication to one of the journals. Since Whgiml Ithasbeenagmat pleasmtowozkwithyou,md1 tape that this report is as stimlating m wur staff as . has been for m.- Sinoamly Max W353: Emlosms Fink, it yam, MOD. Professor of Psychiatry � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-3-304 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/7e185dbdec408603fa783ef344c26c83.pdf defe8e63bf436d5d6ddf59bff6cb34c7 PDF Text Text June 7, 1965 Mr. Robert C. Zwahlen ‘ Medical Liaison Staff Clinical Invostigatim Departmnt Smith Klim 8 From): stomtordss 1500 Spring Garden Stmt Philadelphia, Pennsylvmia 19101 Dear Bob: It is a pleasure to send you the additional copies you requsst of the report cu our project. They are being sent under separate mover. Witnl - we have not made any formal for publication as yet. have waited your oomnt md. would be grateful for trust you or yam associates may have omooming this any suggestions report. It is a difficult me to prudent sinos we feel that the study is methodologically a good one, but that the oonolusims am incomplete since additimal studios ought to be mdsrtaksn. I would be vary interested in the of your statistician. In the meanwhile, I have sent copies to Dam Clyde who is our statistical omsultmt, and Neil End: md Carl Pfsiffor. Both Carl and Neil am editorstoofDrs . journals that'may consider such a publicatim and I have them the mmusoript with a question as to whether they would besent interested mad what mommadatims they would have for mvisim, since I believe warrants I mts ”.w. ,~ . a u. a.-. m n—nrnc—A 4 .—v w "um. this-domnt is much too long for any standard journal. I will let mat their momdations are. I had sent one copy to Dr. Jonathan Cole because this study was the first mport of our computer- mthods of analysis. His associate Dc. Efren has written to us with a great of enthusiasm and asking whether we would not extend thisdeal additional to and you know Was additional dosage determinations. ’ Sincerely yours, bmwmw‘wwm.mj ﬂax Pink, M. D. Professor of Psychiatry Hfzkp � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-4-335 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/383351f147ad5cb8987a70fc75ec9baa.pdf 7a3ee24ad7177eec03de180443a570ed PDF Text Text Juno 2!», 1965 thlcn Liaium Staff Meal (minimal Mr. Robert C. Inwatigatim Department ﬁlth Kline 8 Much laboratories 1500 krin Garden Strut 19191 Winchlphla, Pamsylvmia 80!): Dual." My associates and I have mad tha careful cements made by Hikeﬁumdhiaeo—womm. Aamplamed, wwuldlikoto take thn next step in this study. amtmling those variables which a: banana mm problem in the first study. Arc than additional suggestions for this pins. of our program? To amtinm the study we envisage, will again wplios. Since I only law 31:: sets of the dmg available, any Mtiml pcmpsyoumuldlikemmdthammﬂalbutmad that maid be If you wish to do diffemtly. agreeable no, to us. In aging this stray, hmvar, we would lit: to add an additional audition. ﬁt an madam to «mom the diffemoes batman would yau Whitman and contra “haunts. For this commu- supplying us with labahd "mm-s." 30 not: of 10 m or! am, daxtmmkmtm, Ifthis is feasibls, Imuldalaolikcyoutomdm 200 Naipaul” thtIoouldmkaupaaixthaamla containing an experimtal nimlant which is of interest to us. Would you ﬂy but call as early next week to discuss these qmticms? regards. Simemly yours. ﬂax Fink, PM). Professor cf Psyehiatry PEEK}: an: Dr. ch Dr 11:11 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-4-378 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/ae99ac52e3de4c03a5ca5fff315cdac3.pdf adb4f27117f2c2d500707676163e1689 PDF Text Text June 2», 1965 Mr. Robert C. Milan Medical Liaison Staff Clinical Investigation Departmnt Smith Kline E French laboratories 1500 Spring Garden Street Hailadelphia, Pemsylvania 19101 Dear kl): associates and I have and the painstaking ccuments made his cam-workers. This study should be repeated. To do so has became a matter of high priority for us and we have already issued a cell for volmteers. We may even repeat the study in some of the sane subjects. My by Mike Free and However, we will try to control those variables which we believe were the problems in the first study. so will require some additional supplies. Since I have eight sets of the drug available, perhaps you would like to send us the em material but coded differently, and if you To do wishtodoso, thatwouldbeagmeabletous. In doing this study, however, we would like to add an additional We are anxious to determine the differences between barbiturates and central stimlmt‘s. We are interested in knowing techniques will discriminate. For this reason, I vmder if EEG would consider supplying us with 20 sets of a SKY-5 you if which includes 10 m of chxtmazphetandne. cmditim. If this is feasible, I muld also like you to send me 200 blank capsules so that I could nuke up a sixth sample containing an experimtal stimlant which is of interest to us. ' Would you Hy call me early next week to discuss these questions? best regards; Sincerely yours, Max Mfzkp cc: Fink, M.D. Professor of Psychiatry Dr. Spencer M. Free, Jr. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-4-379 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/66935152d643e26ebdc24bd21d4ed66a.pdf c5ab87c49112bb1cccc6dca0d94ec989 PDF Text Text July 12, 1955 Mr. Robert C. Zwahlen Madical Liaison Staff Clinical Investigation Departunnt 8 anch Laboratories 1500'W1ng Garden Street wadelphia, Pennsylvania 19101 Smith Kline Dear Bob: I sorry that the timing for our visit seems so inopportum. After- speaking to youmut August 10, I have discussed this with Dr. Itil and find that he will not be available at that time. While I would not object too strongly to leaving the bead) to come to Philadelphia, I really wonder if this would be helpful to us? am I will nuke whatever and you your associates . armgemnts are most suitable for In the maritime, I think it was better to cancel the hotel reservations and for me to return the check for $17u.09 (SK? A 87632), which is enclosed. Sincerely yours , Fink, M.D. Professor of Psychiatry Max 111’sz enclosum � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-5-412 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/a35fc2d3b585294dc025d22fd04cceb4.pdf e9b35ef6e35ceb597cfd47d49ac28a63 PDF Text Text ~k'.‘<-'-'", :«a w- -,;,~;.-v.wu.a—_ A n-r Jr. ’w-ars'm‘lr’rt'i' w-x-wwrm-w “erv'F-l'vwsrsrm mm- 23, ms ﬁr. ﬂour: Clinics), (2. thim Imam Dspsrmt mammal, Pansyimh 18161 Door Bob: zmmmwmmxmmm mmmvmtwm-Wmmm-mmm study. mmmmummrmzmmjmmm ism MWMMtWMMidmﬁM. mmmnmwmmmmmmmm mum. mutisprsﬁminstymw,whmt¢ wmwmmmwmmmmmtmum s- . fwthhmitmytmmsMwshbsfqu-mmr mismatmtsemdmihsabio.atﬁnttim,m_ jmifysmufthmimmmngwihKIum.mm ussd www.cw. mmmmmmsmmnmmt,muxmn ‘ r ”ﬁ‘ mm thmmtiiwsinitmstudyismhm. Simuly ms. hm fink. PM). Profuse:- af as: m. Spam» H. has. Jr. hymktry � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-6-519 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/d0a52ccc9425f7a79350844b1d71c248.pdf b62facedc868b7c76096e4b78172890c PDF Text Text Nomber 11, Mr. Robert C. 2018111011 W Medical Liaison Staff with Kline Laboratories mm Street Clinical Investigation, and em Philadelphia, Parmeylvmic 1500 Spring 1965 19101 DcarBob: During the past five weeks we have continued to carpet-1mm with the behavioral controls masonry in the second SK? study, which we discussed coma mom ago. We analyzed the data. collected during the comer. under diffamnt behavioral control conditions and mu trials with diffcmnt butlhmte- and work, the second study Mot-mine dosages. After been accepted by my associates. pmtocol was developed and has I m sanding you a few copies of this draft for yam contents. m w. are equipped to mdertakc this study now, and indood pmlindnmy runs with a few of our volmtuers have beam some within the past week. of I mm this protocol mots with yourbeapproval and that undertake pmpmd to your associates. If acceptable, on will down aubjocts and plan the analyses at that point. With that in land, m can than decide whether additional cases in blocks of four would be necessary and would be propmd to continue the study until sixteen or twenty subjects were consecutive trials in a muted. My best regards. Sinocmly yours, ﬂax Fink, Md). Professor of Paydaiatr'y qua one. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-7-588 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/d1ff20a641d1b2b192c223e8023808d8.pdf da7accfa96a3930bf86350c5e577c77a PDF Text Text November 17 , 3365 thlen Staff Mr. Robert C. Madioal Liaison Clinical Investigation Bazaar-tum: 3mm Kline 8 Fraud: Lnbomﬁoxdcs 1500 Spring 9mm St. Mindalphia, Pennsylvania 19101 Dear Bob: The local magnum including rm and mam Would News laborit, MManofamedpmdumdbym‘. or 962%. I m intemted in this mama, know: as RESP? and lemming of SK? the Amhtimhip of your laboratories to various I would be grateful if you could tell me if mums,this is handling mom-ad for study in the United States? Panda If mt, do you know who If you an, is this patinnt populatim? Many is? Wind available for study in our marks. smearely yours , ﬂax Pink, 14.». Professor'of Psymiatry � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-019-7-614 Date A point or period of time associated with an event in the lifecycle of the resource 1965 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/6e01212d8bc5acd0339a72c368ac3c86.pdf 031e02d80cf3cf3eaa8dbeb914b88ded PDF Text Text Hay Rabat-t C. I’m. 2, 1966 Mien M1031 Liaise!) Staff Clinical Investigatim Departmnt Smith, Kline and Prune}! Labozutcxies 1500 Spring Garden Smut miladelphia, Pemwylvania 19101 DearBob: Islwuldliketobringymwtodatemﬂmsxfstudy doses of ambarbital dummtias of different www.mdaumlleoﬁmpmse hasheminpmmsstormﬁmﬁvemnﬁm. Asofthia MWW. dam,twsubjwcsmmwmlm,mdﬂmmmmadditimal of clean six response subject-"a who are in process. muse subjects mquire butinaofaras unrequited four, mm, itwilltakefowmlcstobemleta,anditismyexpectation Mlve additional mtanﬂndatawillbeoollectodbytmmofﬂay. Data analyses will begin prowtly and it is cur expactatim mtmwillbeablemcouplmtheamlysea dam-ingthesmmr, harming any WOW statistical or analytic problem. 9.9wa, Iwillbemvingtotmﬁew‘fokadical Despite this transfer, It is College early in June. my intentimtoompletethissxfsmdymdmdoso, mydata analyses that am not couplemd here will be mlated in Maw York. I will wally mp1: thethisresponsibility for write—Mp and the natavial. the pmsentation of WaddmsainNmYozkwillbe: Dapartmnt of Psydﬁauy York Bhdieal College 5th Avanm md 106th Street New New York, New York 10029 I will also be spending part of my time at the Mempolitan Heapital. Ifyouwishtomachmdm‘ingthenextfewnmﬂw, muismdmysem'tarywilltellyouwmm Ian. phasecallSt. Hy umber at Metropolitan Ibepital 18: 945300. Ext. 720 (708). At the Wivemity, the number is 876-6500, Ext. 1455. (That is the Quimm's number, and his secretary will mmlly know Wt Mmlmnm‘willbeabletotmamsage formmtilIhave my am seminary.) ‘ �Mr. Zwahlm City. (emtinuad) Thank you You mat for the invitation to visit you in Atlantic know that I have anjoyad mm mlatimship ﬂuttmdatawillwmtyowfaith inourmrk.deI'npe Idolodcfomardtoemtinuingtoworkwim vars/mien, specifically with Dan What. You may be interested me of my responsibilities is to establish an Early Clinical mug Evaluation Unit with both in—~patient and cut—patient facilities. I nape that I can amplish them SK? and to hm that mtlhavetriedmacaauplishm,andlookfomardto My best regards. Very Fink, M.D.' Professor of Psychiatry Max Mfzjm sinmmly yours , � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-020-5-274 Date A point or period of time associated with an event in the lifecycle of the resource 1966 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/a1dec79a123219588c97246eeba3077a.pdf 0b9ca5ca6609ac1a372beb36ad8bd234 PDF Text Text actobur 12, 1966 Ex. Rebert C. anhleh Medical Liaison staff Clinical Investigation Department Smith. Kline and Prendh Laboratory 1500 spring Garden Street . Philadelphia, Pennsylvania 19101 Dear Bob. I would like to bring you up-to~dnte in our barbiturate ~ 830 study. The data collection ended in June and during the past few nonths, sanples at every 12 minutes were selected in relation to the reaction tine experience. These samples were dhsdked‘ for nrtefact end the data of‘the various subjects was put on a disk. _ The , first analyses were to determine Whether there were any significant differences in any of the EEG variables in the four groups prior to drug administration at any of the treatment periods. 'The datn'denonstrnted that the groups were equivalent for each of the EEG variables for eedh of the tour drug conditions. with the exception that three of thirty~seven indices dhowed considerable variability during the first study in these subjects. That is. some of the subjects ethibited lesser amounts of alpha activity and more beta activity in their tirlt recording than in the subsequent three recordings. Thin observation is not unique since many observers have reported that patients any be very anxious during the first session and perhaps this single record should have been thrown out. However. since ditterent treatments were used in the first drug period on a random basis. we do not think thet‘ will significantly bias the overall 5:1. "hi. dhenge �'Kr-(‘F‘ Hr. Zudhlcn ~2- Octdbcr 12. 1966 Tart: £6: dirtnroncun ascrthiblo to drug ottacts ondh tint period are naw in progresl and I hnva bacn natured by my 8:. Louis Isaociatas that tho at data thould h. avatlahlo within eh: next tun wicks. as I have this I w111.cwll.you.and will arrangc for up to go over them together. Thank you once again for your interelt. Sincerely yours. As soon Max Pink. H.D. Professor of Paychiatry � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-020-7-437 Date A point or period of time associated with an event in the lifecycle of the resource 1966 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/21c63a85e4830a61d385426f96d2a64e.pdf e1649af6457c8b1a3bdc8d558463e9e6 PDF Text Text F i g October 31 , 1966 i 3 § E g Mr. Robert C. Zwahlen Mical g t. g i , i E if Liaison Staff Clinical Investigation Department Smith mine and Premh Laboratories 1500 Spring Garden Street Philadelphia, Pennsylvania 19101 E Dear Bob, 7 l I .. first analyses of the EEG changes. at twelve minute intervals , using variables demonstrates significant differences amng the oonpomds at various times. We are now ready to plot these variables and to select those that appear to be the most discrimimtive. The 17 . I am W heartenedeby this finding, because it means that we in the data, probably have significant discrim'nation although at this point I cannot tell you which from which. The plotting should be done within the week and the necessary analyses will be undertaken on November 11, when I go to St. Louis. My best regards. _ Sincerely yours, Pink, M.D. Professor of Psychiatry Me): mka � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-020-7-471 Date A point or period of time associated with an event in the lifecycle of the resource 1966 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/78a47845cee07edce4a71995ab6b6597.pdf e58c8f54ad834e3f70c9e112260ae355 PDF Text Text January 30, 1967 Mr. Robert C. Zwahlen Medical Liaison Staff Clinical Investigation Department Smith Kline and French laboratories 1500 Spring Garden Street Philadelphia, Pennsylvania 19101 - _ Dear Bob, I should like to bring you up-to-date on the amobarbital Since last writing to you, we have run a trial on an additioml set of analyses and found that the programs required significant modification for our purposes. This was undertaken, andhascnlybeenconpleteddtmmgtl'xepastmek. WhenDon Shapiro was in New York on Wednesday, we reviewed the project andwereabletoagreeonthenextste . Wehavetakenthis masourprincipal that we will have nostudyforthenmctfewweeksandItmst additional analytic difficulties. As soon as the analyses are done, I shall devote full time to ccmpleting the study. report. Incidentally, I have been able to establish a unit for the study of new drugs in the out-patient department at Metropolitan Hospital and I am pleased with the way the initial drug studies amnowgoing. Donhasbeenkindermghtoaendussaneplacebo for Thorazine and this will make possible an enhanced teaching program. May My I take this opportunity to‘thank you for your patience. best regards. Sincerely yours , Max Fixﬂc, M.D. . Professor of Psychiau'y MFﬁq; cc: Mr. Donald Cheetham, Jr. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Correspondence to: Zwahlen, Robert C. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-05-00-021-2-025 Date A point or period of time associated with an event in the lifecycle of the resource 1966 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Correspondence -- Correspondence Relation A related resource The Max Fink Collection Description An account of the resource Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Correspondence http://exhibits.library.stonybrook.edu/mfp/files/original/491a406bfc36b0865ea98089beb94eec.pdf 8b176841a98af4f8f1d1cc5a94eac7a1 PDF Text Text MAX FINK, M.D. 11 Buttonfield Lane South Hadley, MA 01075 Cell: 631.637.1730 fink.max@gmail.com maxfink55@gmail.com PRESENT APPOINTMENT Professor of Psychiatry and Neurology, Stony Brook University 1972-1997 Professor Emeritus 1997CERTIFICATIONS Diplomate, National Board of Medical Examiners 1946 Diplomate, American Board of Psychiatry and Neurology Certified in Neurology Certified in Psychiatry 1952 1954 William Alanson White Institute of Psychoanalysis Certificate in Psychoanalysis for Physicians License, Practice of Medicine and Surgery New York Missouri 1953 1946 1962 EDUCATION University College, University Heights Campus New York University, B.A. cum laude, Honors in Biology 1939-1942 New York University College of Medicine, M.D. 1942-1945 William Alan White Institute for Psychoanalysis Certificate in psychoanalysis for physicians 1948-1953 Morrisania City Hospital, Rotating Internship July 1945-April 1946 Montefiore Hospital, Residency in Neuropsychiatry July 1948-June 1949 Bellevue Psychiatric Hospital, Residencies in Neurology and Psychiatry July 1949-December 1951 Hillside Hospital, Resident in Psychiatry January 1952-December 1952 Mount Sinai and Hillside Hospitals, Fellow in Neuropsychiatry; National Foundation for Infantile Paralysis (also January 1951-December 1951) January 1953-December 1953 �ACADEMIC and RESEARCH AWARDS C. Charles Burlingame Award, Lecture, Institute for Living, CT 2019 Thomas William Salmon Award and Medal, New York Academy of Medicine 2011 Honorary Member, Associazione Italiana per la Terapia Elettroconvulsivante (AITEC) 2006 Honorary Member, European Forum for Electroconvulsive Therapy (EFFECT) 2006 Honorary Fellow, International Pharmaco-EEG Society (IPEG) 2000 Fellow, Association for Convulsive Therapy 2000 Arrigo Prize for Lifetime Achievement in Neurophysiology, University of Pavia 1998 Lifetime Achievement Award, Society of Biological Psychiatry 1996 Lifetime Achievement Award, Psychiatric Times and CME, Inc. 1995 Gold Medal Award of the Society of Biological Psychiatry 1988 Laszlo Meduna Prize of the Hungarian National Institute for Nervous and Mental Diseases 1986 Taylor Manor Hospital Psychiatric Award 1983 Anna Moniker Foundation Prize for Contributions to the Study of Endogenous Depression 1979 Samuel W. Hamilton Award, American Psychopathological Association 1974 Alpha Omega Alpha, New York University 1973 A.E. Bennett Psychiatric Research Award, Society of Biological Psychiatry 1958 Electroshock Research Association Award 1956 Elected Phi Beta Kappa and Alpha Pi Christopher Coates Biology Prize Phi Lambda Upsilon Chemistry Prize, New York University 1939-1942 2 �TEACHING AWARDS “Teacher of the Year,” Department of Psychiatry Stony Brook University 1992, 1993, 1996 MEMBERSHIPS Distinguished Life Fellow American Psychiatric Association (APA) Secretary, Chairman, section on Brain Function and Behavior Member, Task Force on Electroconvulsive Therapy Nassau Neuropsychiatric Society Suffolk County District Branch 1957, 1958, 1962 1975-1978, 1988-1990 1954-1962 (President, 1959) 1973- Fellow New York Academy of Medicine American College of Neuropsychopharmacology (ACNP) Association for Convulsive Therapy International -Pharmaco-EEG (IPEG) Vice President Councillor Honorary Fellow 1981-1984 1986-1990 2000 Senior Member Society of Biological Psychiatry 1960 Member American Psychopathological Association Secretary Vice President President-Elect President 1968-1971 1971-1972 1972-1973 1973-1974 Association for Convulsive Therapy Chairman, Task Force on Ambulatory ECT 1995 Collegium Internationale Neuro-Psychopharmacologicum (CINP) 1960 Deutsche EEG Gesellschaft 1962 International Brain Research Organization (IBRO) 1964 International Society for Psychoneuroendocrinology 1964 Instituto de Psiquatria y Psicologia de Montevideo 1964 World Federation of Societies of Biological Psychiatry Chairman, Task Force on ECT 2002-2005 3 �EDITORIAL APPOINTMENTS Founding Editor, Convulsive Therapy, 1984-1994 Editorial Board, 1995Contributing Editor Comprehensive Psychiatry (1972-2000) Currents Developments in Psychopharmacology Directions in Psychopharmacology Journal of Clinical Psychiatry (1980-1999) Neuropsychiatry, Neuropsychology & Behavioral Neurology (1988-2003) Neuropsychology (Associate Editor, Pharmaco-EEG, 1983-1997) Pharmacopsychiatry Psychiatric Journal, University of Ottawa (1980-1992) Clinical Pharmacology & Therapeutics (1977-1981) Psychopharmacologia (1975-1978) Sleep &Wakefulness (1978-1981) PRIOR APPOINTMENTS Academic Assistant in Neurology, New York University 1952-1954 Research Professor of Psychiatry, Washington University 1962-1966 Professor of Psychiatry, University of Missouri 1963-1966 Visiting Professor University of Istanbul National Institute of Neurology of Mexico University of California at Irvine Organon Special Visiting Lectureship, Netherlands 1968, 1969 1969 1976 1988 Honorary Member, Societe Royale de Medecine Mentale de Belgique 1969 Professor of Psychiatry, Albert Einstein College of Medicine 1998-2005 4 �Hospital Staff Neurologist, Long Island Jewish Hospital Associate Attending Neurologist, North Shore Hospital 1954-1959 1954-1962 Supervising Psychiatrist; Director of Research Director, Department of Experimental Psychiatry Hillside Hospital, Glen Oaks, NY 1954-1962 Director, Missouri Institute of Psychiatry, St. Louis, MO 1962-1966 Director, Division of Biological Psychiatry, NY Medical College 1966-1973 Attending Psychiatrist Metropolitan Medical Center Flower & Fifth Avenue Hospitals Bird S. Coler Hospital University Hospital, Stony Brook University 1965-1973 1966-1973 1966-1973 1980-1997 Consulting Psychiatrist Grasslands Hospital Central Islip Psychiatric Center V.A. Hospital, Northport, NY 1971-1973 1974-1979 1972-1981 Director, Division of Clinical Sciences Long Island Research Institute 1976-1983 Attending Psychiatrist, Department of Psychiatry Long Island Jewish Hillside Hospital 1981-2005 CONSULTANT Committee on Clinical Drug Evaluation Psychopharmacology Service Center, NIMH 1962-1965 Division of Mental Diseases of the State of Missouri 1962-1966 VA-NIMH-SAODAP Collaborative Studies in Opiate Dependence 1972-1974 Bureau of Drugs, Food & Drug Administration 1970-1973 American Psychiatric Association Task Force on ECT 1975-1978 V.A. Merit Review Board on Behavioral Sciences 1977-1980 German BGA Commission of Pharmaco-EEG 1980-1981 NIMH Committee on Collaborative ECT Project 1980-1982 5 �National Academy of Sciences, National Research Council Committee on Toxicology: Committee on Anticholinergic Drugs Panel 1981-1982 U.S. Army Workshop on the Feasibility of Using Incapacitating Agents Against Terrorists 1986 American Psychiatric Association Task Force on Electroconvulsive Therapy 1988-1990 MILITARY SERVICE Captain, U.S. Army Medical Corps. School of Military Neuropsychiatry, Fort Sam Houston Chief, NP Clinical Service, Fort Knox Station Hospital 1946-1947 PRIVATE PRACTICE Ship Surgeon Grace Line American Export Line 1947-1948 1948 Neurology and Psychiatry 275 Middle Neck Road, Great Neck, NY 1954-1958 6 �PUBLICATIONS 1950 1. Subdural hematoma developing during hospitalization. Amer. J. Psychiat.,107: 381-383 (with M. Green). 2a. Patterns in perception of simultaneous tests of face and hand. Trans. Amer. Neurol. Ass., 75: 250 (with M.B. Bender and M. Green). (abstract). 1951 2b. …ibid., Arch. Neurol. Psychiat. (Chic.), 66: 355-362. 1952 3. The face-hand test as a diagnostic sign of organic mental syndrome. Neurology (Minneap.), 2: 46-58 (with M.B. Bender and M. Green). 4. Tactile perceptual tests in the differential diagnosis of psychiatric disorders. J. Hillside Hosp., 1: 21-31 (with M.B. Bender). 5. A clinical evaluation of carotid angiography. Contin Neurol. (Basel), 12: 181-195 (with J.M. Stein). 6a. Exosomesthesia, or displacement of cutaneous sensation into extra-personal space. Trans. Amer. Neurol. Ass., 77: 260-262 (with M.F. Shapiro and M.B. Bender). (abstract). 6b. …ibid., Arch. Neurol. Psychiat. (Chic.), 68: 481-490. 7a. Order of dominance in cutaneous perception. Trans. Amer. Neurol. Ass., 77: 238-240 (with M.B. Bender and M. Green). (abstract). 7b. Patterns of perceptual organization with simultaneous stimuli. Arch. Neurol. Psychiat. (Chic.), 72: 233255 (with M.B. Bender and M. Green), 1954. 1953 8. Perception of simultaneous tactile stimuli in normal children. Neurology (Minneap.), 3: 27-34 (with M. B. Bender). 9. Perception of simultaneous tactile stimuli by mentally defective subjects. J. Nerv. Ment. Dis., 117: 43-49 (with M.B. Bender and M. Green). 10. Spinal fluid findings following cerebral angiography. Neurology (Minneap.), 3: 137 (with J.M. Stein). 11. A statistical study of a psychoanalytic hypothesis: absence of a parent as a specific factor determining choice of neurosis. J. Hillside Hosp., 2: 67-71 (with S. Tarachow). 7 �12. Effects of intravenous barbiturate on perception. Trans. Amer. Neurol. Ass., 78: 244-245 (with M.B. Bender, P. Bergman, and M. Nathanson). (abstract). 13. Homosexuality with panic and paranoid states case report. J. Hillside Hosp., 2: 164-190. 1954 14. Standardization of the face-hand test. Neurology (Minneap.), 4: 211-217 (with M. Green). 1955 15. The “Amytal test” in patients with mental illness. J. Hillside Hosp., 4: 3-13 (with R.L. Kahn and E.A. Weinstein). 16. Delusional reduplication of parts of body after insulin coma therapy. J. Hillside Hosp., 4: 134-147 (with R.L. Kahn and D. Graubert). 1956 17. Relation of Amobarbital test to clinical improvement in electroshock. Arch. Neurol. Psychiat. (Chic.), 76: 23-29 (with R.L. Kahn and E.A. Weinstein). 18. Evaluation of high dose reserpine therapy for the relief of anxiety. J. Hillside Hosp., 5: 67-77 (with M. Wachspress, A.G. Blumberg, and J.S.A. Miller). 19. Relation of Changes in Memory and Learning to Improvement in Electroshock. Confin. Neurol. (Basel), 16: 88-96 (with H. Korin and S. Kwalwasser). 20. Denial of blindness following cerebral angiography. J. Hillside Hosp., 5: 238-245. 21a. Quantitative studies of slow wave activity following electroshock. Electroenceph. Clin. Neurophysiol., 8: 158 with R.L. Kahn). (abstract). 21b. Relation of EEG delta activity to behavioral response in electroshock: quantitative serial studies. Arch. Neurol. Psychiat. (Chic.), 78: 516-525, 1957 (with R.L. Kahn). 1957 22a. EEG and clinical response to Megimide. Electroenceph. Clin. Neurophysiol., 9: 180 (with M. Green). (abstract). 22b. Clinical and electroencephalographic effects of Megimide in patients without cerebral disease. Neurology (Minneap), 8: 682-685 (with M. Green). 23. A unified theory of the action of physiodynamic therapies. J. Hillside Hosp., 6: 197-206. 24. Perception of embedded figures after induced altered brain function. American Psychologist, 12: 361 (with R.L. Kahn). 25. Social factors in selection of therapy in a voluntary mental hospital. J. Hillside Hosp., 6: 216-228 (with R.L. Kahn and M. Pollack). 8 �26. Role of stimulus intensity in perception of simultaneous cutaneous electrical stimuli. J. Hillside Hosp., 6: 241-250 (with H. Korin). Added 2/25/17 Soviet Medical Advances: Importance of making literature available to American scientists. New York Times Letters, 15 Nov 1957, pg 26. 1958 27. Changes in language during electroshock therapy. In P.H. Hoch and J. Zubin (eds.), Psychopathology of Communication. Grune and Stratton, New York, 1958: 126-139 (with R.L. Kahn). 28. Lateral gaze nystagmus as an index of the sedation threshold. Electroenceph. Clin. Neurophysiol., 10: 162-163. 29a. Effects of Diethazine on EEG and significance for theory of convulsive therapy. Electroenceph. Clin. Neurophysiol. 10: 207-208. (abstract). 29b. Effect of anticholinergic agent, Diethazine, on EEG and behavior: significance for theory of convulsive therapy. Arch. Neurol. Psychiat. (Chic.), 80: 380-387. 29c. ..ibid., In J.H. Masserman (ed.), Biological Psychiatry. Grune and Stratton, New York, 1959, 1: 184-194. 30. Experimental studies of the electroshock process. Dis. Nerv. Syst., 19: 113-118 (with R.L. Kahn and M. Green). 31. Comparative study of Chlorpromazine and insulin coma in the therapy of psychosis. J. Amer. Med. Ass., 166: 1846-1850 (with R. Shaw, G. Gross, and F.S. Coleman). 32. Electroencephalographic correlates of the electroshock process. Dis. Nerv.Syst., 19: 227 (with M. Green). (abstract). 33a. Experimental studies of convulsive and drug therapies in psychiatry: theoretical implications. Arch. Neurol. Psychiat. (Chic.), 80: 733-734 (with R.L. Kahn and M.A. Green). (abstract). 33b. Alteration of brain function in therapy. In N.S. Kline (ed.), Psychopharmacology Frontiers. Little, Brown & Co., Boston, 1959: 325-332. 34a. Effect of anticholinergic compounds on post-convulsive electroencephalogram and behavior. Electroenceph. Clin. Neurophysiol.,10: 776. (abstract). 34b. Effect of anticholinergic compounds on post-convulsive electroencephalogram and behavior of psychiatric patients. Electroenceph. Clin. Neurophysiol., 1960, 12: 359-369. 1959 35. Effects of diffuse altered brain function on perception. In Proc. XV Int. Congr. Psychol. North Holland, Amsterdam: 238-239 (with R.L. Kahn and H. Korin). (abstract). 36. Psychological factors affecting individual differences in behavioral response to convulsive therapy. J. Nerv. Ment. Dis., 128: 243-248 (with R.L. Kahn and M. Pollack). 9 �37a. Significance of EEG pattern changes in psychopharmacology. Electroenceph. Clin. Neurophysiol., 11: 398. (abstract) . 37b. EEG and behavioral effects of psychopharmacologic agents. In P. B. Bradley, P. Deniker, and C. Radouco-Thomas (eds.), Neuro-Psychopharmacology. Elsevier, Amsterdam, 1959, 1: 441-446. 38a. Electroencephalographic and behavioral effects of Tofranil. Canad. Psychiat. Assoc. J., 4 Suppl.: 166171. 38b. …ibid., Electroenceph. Clin. Neurophysiol., 1960, 12: 243-244. (abstract). 39. Relation of tests of altered brain function to behavioral change following induced convulsions. In L. van Bogaert and J. Radermecker (eds.), First International Congress of Neurological Sciences. Pergamon Press, London, 1959, 3: 613-619 (with R.L. Kahn and H. Korin). 40. The Role of set in the perception of simultaneous tactile stimuli. Amer. J. Psychol., 72: 384-392 (with H. Korin). 41. Personality factors in behavioral responses to electroshock therapy. J. Neuropsychiat., 1: 45-49 (with R.L. Kahn). 42. Sociopsychologic aspects of psychiatric treatment in a voluntary mental hospital: duration of hospitalization, discharge ratings and diagnosis. Arch. Gen. Psychiat., 1: 565-574 (with R.L. Kahn and M. Pollack). 1960 43. Efficacy of divided and single dose schedules in insulin coma therapy. Amer. J. Psychiat., 116: 839-840 (with A.G. Blumberg and P. Laderman). 44. Changes in verbal transactions with induced altered brain function. J. Nerv. Ment. Dis., 130: 235-239 (with J. Jaffe and R.L. Kahn). 45. Drug induced changes in interview patterns: linguistic and neurophysiologic indices. In G.J. Sarwer-Foner (ed.), The Dynamics of Psychiatric Drug Therapy. C.C. Thomas, Springfield, IL, 1960: 29-44 (with J. Jaffe and R.L. Kahn). 46. Social attitude California F Scale and convulsive therapy. J. Nerv. Ment. Dis., 130: 187-192 (with R.L. Kahn and M. Pollack). 47. Figure-ground discrimination after induced altered brain function. Arch. Neurol. (Chic.), 2: 547-551 (with R.L. Kahn and M. Pollack). 48. Prognostic value of Rorschach criteria in clinical response to convulsive therapy. J. Neuropsychiat., 1: 242-245 (with R.L. Kahn). 1961 49. Modification of psychotherapeutic transactions by altered brain function. Amer. J. Psychother., 15: 46-55 (with J. Jaffe, H. Esecover, R.L. Kahn). 10 �50. Neuropsychologic response patterns of some psychotropic drugs. In E. Rothlin (ed.), Neuropsychopharmacology. Elsevier, Amsterdam, 1961, 2: 381-384 (with M. Pollack, E. Karp, G. Krauthamer, and D.F. Klein). 51. …ibid., Problems of antagonists to psychotropic drugs, 30-32. 52. Inhalant-induced convulsions. Arch. Gen. Psychiat., 4: 259-266 (with R.L. Kahn, E. Karp, M. Pollack, M.A. Green, B. Alan, H.J. Lefkowits). 53. Behavioral patterns in convulsive therapy. Arch. Gen. Psychiat., 5: 30-36 (with R.L. Kahn). 54. Sociopsychological characteristics of patients who refuse convulsive therapy. J. Nerv. Ment. Dis., 132: l53-l57 (with M. Pollack). 55. EEG techniques in study of psychotropic drugs. Acta of the Internationat. Meeting on the Techniques for the Study of Psychotropic Drugs, Bologna, 1960. Societa Tipografica Modenese, Modena, 1961: 3pp. 56. Withdrawal symptoms following discontinuation of Imipramine therapy. Amer. J. Psychiat., 118: 549-550 (with J.C. Kramer and D.F. Klein). 57. Experimental psychiatric research at Hillside: review and prospect. J. Hillside Hosp., 10: 159-169. 58. Prediction of individual patient response to convulsive therapy. VA Cooperative Chemotherapy Studies in Psychiatry, 6: 317-324. 59. Social aspects of psychiatric treatment in three hospitals: methodological problems. VA Cooperative Studies in Psychiatry, 6: 202-206 (with M. Pollack, N. Siegel, and R.L. Kahn). 59b. Sociopsychological aspects of psychiatric treatment in three voluntary hospitals. A.M.A. Arch. Gen. Psychiat., 14: 20-25 (with R.L. Kahn and N. Siegel). 60. Quantitative electroencephalography and human psychopharmacology: I. Frequency spectra and drug action. Med. Exp. (Basel), 5: 364-369. 1962 61. The critical flicker frequency and EEG alpha: a reliability study. Electroenceph. Clin. Neurophysiol., 14: 60-63 (with E. Karp and M. Pollack). 62. The mode of action of convulsive therapy: the neurophysiologic-adaptive view. J. Neuropsychiat., 3: 231-233. 63. Disordered perception of simultaneous stimulation of face and hand: a review and theory. In J. Wortis (ed.), Biological Psychiatry. Plenum Press, Inc., New York, 1962, 4: 362-369 (with M. Pollack). 64. Tachistoscopic perception after induced altered brain function: influence of mental set. J. Nerv. Ment. Dis., 134: 422-430 (with M. Pollack, R.L. Kahn, and E. Karp). 65. Motivation for psychotherapy. Comprehens. 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Friedhoff (eds.), Psychopathology and Psychopharmacology, Baltimore, Johns Hopkins Press, 1973, pp. 108-111. 210. Effects of cannabis on human EEG and heart rate: evidence of tolerance development on chronic use. In T.A. Ban, et al. (eds.), Psychopharmacology, Sexual Disorders, and Drug Abuse. Prague, Avicenum, pp. 703-704. 211. Questions in Cyclazocine therapy of opiate dependence. In S. Fisher and A. M. Freedman (eds.), Opiate Addiction: Origins and Treatment. Washington, DC, V. H. Winston and Sons, pp. 203-210. 22 �1974 212. Psychobiology of Convulsive Therapy. Washington, DC, V.H. Winston and Sons (with S. Kety, J. McGaugh, and T. Williams (eds.), 312 pp. 213. …ibid., Induced seizures and human behavior, pp. 1-18. 214. …ibid., Clinical progress in convulsive therapy, pp. 271-278. 215. EEG applications in psychopharmacology. In M. Gordon (ed.), Psychopharmacological Agents Vol. III). Academic Press, New York, pp. 159-174. 216. 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Stefanis, A. Liakos, J. Boulougouris, A.M. Freedman). 241a. Quantitative EEG studies of marijuana, delta-nine-Tetrahydrocannabinol, and hashish in man. In M.C. Braude and S. Szara (eds.): The Pharmacology of Marijuana. New York, Raven Press, 383-391 (with J. Volavka, C.P. Panayioutopolis, and C. Stefanis). 241b. …ibid., Electroenceph. Clin. Neurophysiol. 42: 430, 1977. (abstract). 24 �242. Controlled clinical and quantitative EEG Studies of Triflubazam (ORF-8063) in patients with anxiety. Curr. Therap. Res. 19: 307-315 (with T. Itil, S. Akpinar, N. Polvan, M. Huque, and K. Sungerbey). 243. Antipsychiatrists and ECT. (letter). Brit. Med. J. 1: 280, Jan 31, 1976. 244. Concentration of 5-Hydroxyindoleacetic Acid, Homovanillic Acid, and Tryptophan in the cerebrospinal fluid of depressed patients before and after ECT. Biol. Psychiat. 11: 85-90 (with R. Abrams, W.B. Essman, M.A. Taylor). 245. Book review: LSD: A Total Study, S. Sankar. Westbury, New York, PJD Publications, 1975. Amer. J. Psychiat 133: 593-594. 246. Book review: Safeguarding Psychiatric Privacy, E.M. Laska and R. Blank (eds.), New York, John Wiley & Sons, 1975, Amer. J. Psychiat. 133: 726-727. 247. Pharmacokinetic analysis of quantitative EEG data. In Rationality of Drug Development. Amsterdam, Excerpta Medica #383, 177-180 (with P. Irwin and M. Gastpar). 248. Relation of EEG to blood levels of psychoactive drugs. In L. Gottschalk and S. Merlis (eds.): Pharmacokinetics, Blood Levels, and Clinical Response. New York, Spectrum Publications, 243-250 (with P. Irwin). 249. Blood levels and EEG effects of Diazepam and Bromazepam. Clin. Pharm. Therap. 20: 184-191 (with P. Irwin, R. Weinfeld, M. Schwartz, A. Conney). 250a. EEG and Blood Level Correlations for Psychoactive Drugs. In M. Matejcek and G.K. Schenk (eds.): Quantitative Analyses of EEG. Konstanz, Switzerland, AEG Telefunken, 119-126 (with P. Irwin). 250b. Electroencephalographic measures for pharmacodynamic analysis of psychoactive drugs in Man. In P. Deniker, C. Radouco-Thomas, and A. Villeneuve (eds.): Neuropsychopharmacology. Oxford, England, Pergamon Press, 1203-1207, 1978. 251. An empirical comparison of three EEG digital conversion techniques. In M. Matejcek and G.K. Schenk (eds.): Quantitative Analysis of EEG. Konstanz, Switzerland, AEG Telefunken, 379-394 (with P. Irwin). 252. Chronic Cannabis Use. Edited by R.L. Dornbush, A.M. Freedman and M. Fink, Annals N.Y. Academy of Sciences, 282: 430 pp. 253. Effects of acute and chronic inhalation of hashish, marijuana, and THC-delta-9 on brain electrical activity in man: evidence for tissue tolerance. In R. Dornbush, A. Freedman and M. Fink (eds.): Chronic Cannabis Use. Annals N.Y. Academy of Sciences 282: 387-398. 254. Summary. Chronic cannabis use. Annals N. Y. Academy of Sciences 282: 427-430. 255a. EEG and task performance after ACTH 4-10 in man. Neuropsychobiology 2: 293-290 (with W. Sannita, P. Irwin). 255b. EEG and behavioral effects of ACTH 4-10 in normal volunteers. Electroenceph. Clin. Neurophysiol. 50: 2-3, 1980 (with W. Sannita, P. Irwin). (abstract). 25 �1977 256. CNS sequellae of EST: risks of therapy and their prophylaxis. In C. Shagass, S. Gershon and A. Friedhoff (eds.): Psychopathology and Brain Dysfunction. New York, Raven Press, 223-239. 257. EST: a special case in pharmacotherapy. In W.E. Fann, I. Karacen, A.D. Pokorny and R.C. Williams (eds.): Phenomenology and Treatment of Depression. New York, Spectrum Publications, 285-294. 258. The treatment of narcotic poisoning. In H.F. Conn (ed.): Current Therapy, 1977. Philadelphia, W.B. Saunders, 894-895 (with A. Zaks). 259. Hypothalamic peptides and brain function. In E. Usdin, D. Hamburg, and J. Barchas (eds.) Neuroregulators and Psychiatric Disorders. New York, Oxford Press, 296-298. 260. Hashish: A Study of Long-Term Use. C. Stefanis, R. Dornbush, and M. Fink (eds.). New York, Raven Press, 181 pp. 261. …ibid., Medical studies in long-term hashish users. II. 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Deniker, C. Radouco-Thomas, and A. Villeneuve (eds.): Neuropsychopharmacology. Oxford England, Pergamon Press, 215-217. 269. Psychoactive drugs and the waking EEG. In M.A. Lipton, A. DiMascio, and K.F. Killam (eds.): Psychopharmacology: A Generation of Progress. New York, Raven Press, 691-698. 270. EEG response strategies in psychiatric diagnosis. In Spitzer, R. and D.F. Klein (eds.): Critical Issues in Psychiatric Diagnosis. New York, Raven Press, 253-263. 271. EEG study of Mianserin (GB-94) in depressed patients. Brit. J. Clin. Pharmacol. 5 Supplement (1): 43S49S (with P. Irwin). 26 �272. Sieben jahre klinische erfahrung mit opiat-antagonisten bei Opiatabhangigkeit. In W.F. Biniek (ed.): Drogenabhangigkeit. Darmstadt, Wissenschaftliche Buchgesellschaft, 422-431. 273. Efficacy and safety of induced seizures (EST) in man. Comprehens. Psychiat. 19: 1-18. 274. ECT in metropolitan New York hospitals: A survey of practice 1975-1976. Amer. J. Psychiat. 135: 479482 (with G.M. Asnis, S. Saferstein). 275. Is EST a useful therapy of schizophrenia? In J.P. Brady and H.K.H. Brodie (eds.): Controversy in Psychiatry. Philadelphia, W.B. Saunders Co., 183-193. 276. Electroshock therapy: myths and realities. Hosp. Pract. 13: 77-82. 277. EEG and psychopharmacology. In Cobb, W.A. and van Duijn, H. (eds.): Contemporary Clinical Neurophysiology Suppl. 34, Electroenceph. Clin. Neurophysiol. 45: 41-56. 278. Book review: Neuropeptide Influences in the Brain and Behavior. Adv. Biochem. Pharmacol. 17: L.H. Miller, C.A. Sandman and A.J. Kastin (eds.), New York, Raven Press, 298 pp, 1977. Quart. Rev. Biol. 53: 195. 279. Book review: Psychopharmacology. A Biochemical and Behavioral Approach. L.S. Seiden and L.A. Dykstra (eds.), New York, Van Nostrand Co., 451 pp., 1977. Quart. Rev. Biol. 53: 196. 280. Book review: Psychotherapeutic Drugs. Part 1: Principles. Part 2: Applications. E. Usdin and I.S. Forrest (eds.), New York, Marcel Dekker, 698+699 pp., 1976. Quart. Rev. Biol. 53: 210-211. 281. Book review: Hemi-Inattention and Hemisphere Specialization. E.A. Weinstein and R.P. Friedland (eds.), New York, Raven Press, 156 pp., 1977. Quart. Rev. Biol. 53: 211. 1979 282a. Convulsive Therapy: Theory and Practice. New York, Raven Press, 308 pp. 282b. Convulsive Therapy: Theory and Practice. Published in Japanese translation, Tokyo, Seiwa Shoten, 394 pp., 1980. 283. Mania and electroseizure therapy (EST). In Shopsin, B. (ed.): Manic Illness. New York, Raven Press, 219-228. 284. A history of convulsive therapy. Psych. Jrl. Univ. Ottawa Fac. Med. 4: 105 - 110. 285. Efficacy of ECT. Lancet 2: 1303 -1304. (letter). 286. EST and other somatic therapies of schizophrenia. In L. Bellak (ed.): Disorders of the Schizophrenic Syndrome. Basic Books, New York, 353-363. 287. CNS effects of the antihistamines, Diphenhydramine and Terfenadine RMI-9918. Pharmakopsych. Neuro-Psychopharmakologie 12: 35, 44 (with P. Irwin). 288a. Phenytoin: EEG effects and plasma levels in volunteers. Therap. Drug Monitoring 1: 93-104 (with P. Irwin, W. Sannita, Y. Papakostas, M.A. Green). 27 �288b. EEG study of phenytoin in normal volunteers at non-toxic doses. Electroenceph. Clin. Neurophysiol. 49: 83 (abstract). 289a. EEG profile studies of clozapine in volunteers and psychiatric patients. Pharmakopsych. Neuro-Psychopharmakologie 12: 184-190 (with P. Irwin and P. Weinhold). 289b. EEG effects of clozapine: Association or dissociation of EEG and behavior? NeuroPsychopharmacology. Oxford, Pergamon, 363-369. (abstract). 290. Anxiety, anxiolytics and the human EEG. In w. Fann, I. Karacen, A. Pokorny, and R.L. Williams, (eds.): Phenomenology and Treatment of Anxiety. New York, Spectrum Publications, 237-250. 291. Neurobiology Group Report, Dahlem Conference. In K.S. Fu and T. Pavlidis (eds.): Biomedical Pattern Recognition and Image Processing. Life Sciences Research Report 15. Verlag Chemie, Basel, 364-394 (with D.B. Cooper, M. Abeles, G. Bodenstein, et al.). 292. Normal prolactin responses in tardive dyskinesia. Psychopharmacology 66: 247-250 (with G.M. Asnis, E.J. Sachar, G. Langer, F.S. Halpern). 293. Book review: Contemporary Research in Behavioral Pharmacology. D.E. Blackman and D.J. Sanger (eds.), New York, Plenum Press, 506 pp., 1978. Quart. Rev. Biol. 54:118-119. 294. Book review: The Endorphins. Adv. Biochem. Pharmacol. 18. E. Costa and M. Trabucchi (eds.), New York, Raven Press, 379 pp., 1978. Quart. Rev. Biol. 54: 119. 295. Book review: Rational Anti-epileptic Drugs Therapy. P.J.M. Guelen and E. van der Kleijn. Amsterdam, Elsevier/North Holland. Trends in Neurosciences 2: 492-494. 296. Book review: Psychotropic Drugs: A Guide for the Practitioner. H.M. van Praag, New York, Brunner/Maxel, 1978. Comprehens. Psychiat. 20 :494-495. 1980 297a. A neuroendocrine theory of convulsive therapy. Point of view. Trends in Neurosciences 3: 25-27. 297b. …ibid. Nervenheilkunde 1: 26-29, 1982. 297c. Convulsive therapy and depression: A neurohumoral and neuroendocrine theory. In Saletu, B. (ed.): Neuro-Psychopharmacology. Oxford, Pergamon, 41-44. (abstract). 297d. A theory of convulsive therapy in endogenous depression: Significance of hypothalamic functions. Psychiatry Research 2: 49-61 (with J.O. Ottosson), 298. Convulsive therapy and endogenous depression. Pharmakopsychiat. 13: 49-54. 299. Neuroendocrinology and ECT: A review of recent developments. Comprehens. Psychiat. 21: 450-459. 300. ECT, mood and hormones. In D. de Wied and P. A. van Keup (eds.): Hormones and the Brain. MTP Press, Lancaster, England, 253-262. 301. Convulsive and drug therapies of depression. Ann. Rev. Med. 32: 405-412. 28 �302a. Neuroendocrine measures in psychiatric patients: Course and outcome with ECT. Psychiatry Research 4: 55-64 (with Y. Papakostas, J. Lee, P. Irwin, L. Johnson). 302b. Dexamethasone suppression test and outcome with ECT. In C. Perris, G. Struwe, and B. Jansson (eds.): Biological Psychiatry 1981. 1075-1078, 1981. 303. Random thoughts about ECT. (editorial). Am. J. Psychiat. 138: 484-485. 1981 304. Toward a rational theory of behavior. Career Directions 7: 2-12. 305. An objective classification of psychoactive drugs. Prog. Neuro-Psychopharm. 4: 495-502. 306. EEG and behavioral profile of flutroline (CP-36,584), a novel antipsychotic drug. Psychopharmacology 72: 67-71 (with Peter Irwin). 307. EEG and behavioral effects of pirenzepine in normal volunteers. Scand. Jrl. Gastroenterol. 15 Supplement 66: 39-46 (with Peter Irwin). 308. Classification of psychotropic drugs: Quantitative EEG analysis in man. In van Praag, H.M., Lader, M.H., Rafaelson, O.J. and Sachar, E.J. (eds.): Handbook of Biological Psychiatry. Volume VI. Marcel Dekker, New York, 309-326. 309. The significance of quantitative pharmaco-electroencephalography in establishing dose-time relations and its impact on clinical pharmacology: Critical review and perspectives. Psychopharm. Bull. 17:94. (abstract). 310a. Lateral cerebral differences in psychotropic drug effects. Psychopharm. Bull.17:98. (abstract). (with Peter Irwin). 310b. Do psychoactive drugs affect the EEG from the cerebral hemispheres differently? In C. Perris, D. Kemali and L. Vacca (eds.): Electroneurophysiology and Psychopathology. S. Karger, Basel, Adv. Biol. Psychiat 6: 121-125 (with P. Irwin). 311a. Critical flicker-fusion frequency, EEG, and psychoactive drugs. Psychopharm. Bull. 17: 103. (abstract). (with P. Irwin). 311b. EEG, CFF and behavior. Pharmakopsychiatria 15: 36-38, 1982 (with P. Irwin). 312. A single measure of EEG spectral differences with heuristic value in assessing drug effect. Electroenceph. Clin. Neurophysiol. 51: 32P (abstract). (with P. Irwin). 313. CNS effects of clonidine in normal volunteers. Psychopharm. Bulletin. 17: 16-17 (with P. Irwin). 314. Pharmaco-EEG and bioequivalence: A practical methodology for psychoactive drugs. Psychopharm. Bulletin 17: 120-121. 315. Pharmacoelectroencephalographic study of brotizolam, a novel hypnotic. Clin. Pharm. Therap. 30: 336342 (with P. Irwin). 29 �316. EEG and behavioral effects of aspirin in asymptomatic volunteers. In C. Perris, G. Struwe, and B. Jansson (eds.): Biological Psychiatry 1981, Elsevier, Amsterdam, 227-229 (with P. Irwin) 317. Clinical trials with des-Tyr-gamma-Endorphin GK-78. In C. Perris, G. Struwe, and B. Jansson (eds.): Biological Psychiatry 1981, Elsevier, Amsterdam, 398-401 (with Y. Papakostas, J. Lee, T. Meehan, L. Johnson). 318. Book review: The Psychosurgery Debate. E. S. Valenstein (ed.). W.H. Freeman & Co., San Francisco, 1980. Amer. J. Psychiat. 138: 408-409. 319a. Book review: Divergent Views in Psychiatry. M. Dongier and E. D. Wittkower (eds.). Harper & Row, Hagerstown, MD, 1981. Am. J. Psychiat. 138: 1641. 319b. Divergent views of divergent views: Dr. Fink replies. (letter). Am. J. Psychiat. 139: 1219-1220, 1982. 320. Book review: Neural Peptides and Neuronal Communication. E. Costa and M. Trabucchi (eds.). Raven Press, New York, 1980. Quart. Rev. Biol. 56: 98. 321. Book review: Differential Psychopharmacology of Anxiolytics and Sedatives. J. R. Boissier (ed.). S. Karger, Basel, 1979. J. Nerv. Ment. Dis. 169: 469-470. 322. Book review: The Psychodynamic Approach to Drug Therapy. M. Ostow (ed.). Van Nostrand, Reinhold, New York, 1980. Science Books and Films 16: 209. 323. Book review: Law and Ethics in the Practice of Psychiatry. C.K. Hofling (ed.). Brunner/Mazel, 1981. Science Books and Films 17: 64-65. 1982 324. Mianserin. In H. Lehmann (ed.): Non-MAOI and Non-Tricyclic Antidepressants. S. Karger, Basel. Mod. Probl. Pharmacopsychiat. 18: 70-101 (with R. Pinder). 325. Quantitative pharmaco-EEG to establish dose-time relations in clinical pharmacology. In W.M. Herrmann (ed.): Electroencephalography in Drug Research. Gustav Fischer, Stuttgart, 17-22. 326a. Guidelines for pharmaco-EEG studies in man. Pharmacopsychiat. 15:107-108 (with G. Stille, W.M. Herrmann, D. Bente, T.M. Itil, W.P. Koella, S. Kubicki, H. Kunkel, J. Kugler, M. Matejcek. and Petsche, H.). 326b. …ibid., Empfehlungen für pharmakoelektroenzephalographische Untersuchungen am Menschen. EEGEMG 13: 1-2. 327. Anticholinergic drugs and the EEG. In Committee on Toxicology, National Academy of Sciences. Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents: I: Anticholinesterases and Anticholinergics. National Academy Press, Washington, DC, June 1-8. 328. Neurophysiologic methods to establish antidepressant activity. Neurophysiologische Methoden zum Nachweis antidepressiver Wirkung. Arzneimittelforschung 32: 857-859. 329. CNS effects of acetylsalicylic acid Aspirin (with P. Irwin). Clin. Pharm. Therap. 32: 362-365. 30 �330a. Pharmaco-EEG study of 6-azamianserin ORG-3770: Dissociation of EEG and pharmacologic predictors of antidepressant activity (with P. Irwin). Psychopharmacology 78: 44-48. 330b. …ibid., Psychopharm. Bull. 19: 96, 1983. 331. Blood levels and quantitative EEG response to CNS-active drugs: Retrospective observations. Electroenceph. Clin. Neurophysiol. Suppl. 36: 447-452 (with P. Irwin). 332. Predictors of outcome in convulsive therapy. Psychopharm. Bull. 18: 50-57. 333. Convulsive therapy: A risk-benefit analysis. Psychopharm. Bull. 18: 110-116. 334. Placebo-controlled studies of ECT. Br. J. Psychiat. 141: 213-214. (letter). 335. Neuroendocrine aspects of convulsive therapy. In R. Abrams and W. Essman (eds.): Electroconvulsive Therapy: Biological Foundations and Clinical Applications. Spectrum Publications, New York, 187-198. 336a. Monitoring the duration of ECT seizures: ‘Cuff’ and EEG methods compared (with L. Johnson). Arch Gen. Psychiat. 39:1189-1191. 336b. EEG monitoring of ECT preferred to cuff method. Reply. Am. J. Psychiat. 140: 1649, 1983. 336c. ECT Seizure Monitoring. Arch. Gen. Psychiat.: 106-107, 1984 (with L. Johnson). (letter). 337. The enigma of convulsive therapy: An effective, safe and controversial treatment. In J.O. Cavenar and H.K.H. Brodie (eds.): Critical Problems in Psychiatry. J. B. Lippincott, Philadelphia, 203-219. 338. ECT in the elderly. In C. Eisdorfer and W.E. Fann (eds.): Treatment of Psychopathology in the Aging. Springer Publishing Co., New York, Chapter 7, 97-111. 339. ECT in anxiety: An appraisal. Am. J. Psychother. 36: 371-378. 340. The present status of electroconvulsive therapy. Directions in Psychiatry. Hatherleigh Co. Ltd., New York, 35:1-8. 341. Book reviews: ECT in Great Britain. J. Pippard and L. Ellam: Electroconvulsive Treatment in Great Britain, 1980. Gaskell, London, 162 pp., 1981; and R. L. Palmer (ed.): Electroconvulsive Therapy: An Appraisal. Oxford, New York 316 pp., 1981. Am. J. Psychiat. 139:958-959. 342. Book review: Drug Development Research. H. Lal and S. Fielding (eds.). A.R. Liss, New York. Quart. Rev. Biol. 57: 234. 1983 343. Guidelines for electroconvulsive therapy in the elderly. In T. Crook and G. D. Cohen (eds.): Physicians’ Guide to the Diagnosis and Treatment of Depression in the Elderly. Mark Powley Associates, New York, VI: 55-60. 344. Missed seizures and the bilateral-unilateral electroconvulsive therapy controversy. Am. J. Psychiat. 140: 198-199. (editorial). 345. Bias against ECT: again. Contemp. Psychol. 28: 246-247. (letter). 31 �346. Antidepressant effects of electroconvulsive therapy. Br. Med. J. 286:1744 1745. (letter). 347. Electroshock and Berkeley: II. Biol. Psychiat. 18: 610-613. (editorial). 348. ECT and depression: What have we learned? In F.J Ayd, I.J. Taylor, and B.T. Taylor (eds.): Affective Disorders Reassessed: 1983. Ayd Medical Communications, Baltimore, pp. 56-72. 349. Pharmacoelectroencephalography. Neuropsychobiol. 9: 45-46. (editorial). (with D. Bente and H. Kunkel). 350. Book review: The Unfathomed Mind: A Handbook of Unusual Mental Phenomena. W.R. Corliss. Glen Arm, MD, 754 pp., 1981. Science Books and Films 18: 242. 351. Book review: Neurobiology. G. M. Shepherd. Oxford University Press, NY, 611 pp., 1983. Science Books and Films 19: 83. 352. Book reviews: Advances in Biochemical Pharmacology. Vol. 31. Typical and Atypical Antidepressants: Molecular Mechanisms. Vol. 32: Clinical Practice. E. Costa and G. Racagni (eds.). Raven Press, N.Y. 391 pp. and 400 pp., 1982. Non-Tricyclic and Non-Monoamine Oxidase Inhibitors. H.E. Lehmann (ed.). S. Karger, Basel, 1982. Quart Rev. Biol. 58: 300-301. 1984 353. Theories of the antidepressant efficacy of convulsive therapy ECT. In R.M. Post and J.C. Ballenger (eds.): Neurobiology of Manic Depressive Illness. Williams & Wilkins, Baltimore, 721-730. 354. Theories of convulsive therapy: A neuroendocrine hypothesis. In B. Lerer, R.Weiner, and R.H. Belmaker (eds.): ECT: Basic Mechanisms. John Libbey &. Co., London, pp. 115-123. 355a. Convulsive therapy: Fifty years of controversy. Clin. Neuropharmacol. 7. Supplement 1: 8-9 (abstract). 355b. Meduna and the origins of convulsive therapy. Am. J. Psychiat. 141: 1034-1041. 356. Neuroendocrine aspects of the relief of melancholia by induced seizures ECT. In E. Usdin, M. Asberg, L. Bertilsson, and F. Sjoqvist (eds.): Frontiers in Biochemical and Pharmacological Research in Depression. Adv. Biochem. Psychopharm. 39: 345-357. 357. Pharmaco-EEG effects of antihypertensive agents. Clin. Neuropharmacol. 7 Supplement 1: 119 (abstract). 358. Familiarization session and the placebo control in EEG studies of drug effects. Neuropsychobiology. 10: 173-177 (with P. Irwin). 359. ECT: For whom is it justified? J. Clin. Psychopharmacol. 4: 303-304 (editorial). 360. The present status of unilateral ECT: Some recommendations. Jrl. Affective Dis. 7: 245-247 (editorial). (with R. Abrams). 361. Book review: L.B. Kalinowsky, H. Hippius, and H.E. Klein. Biological Treatments in Psychiatry. Grune & Stratton, New York, 424 pp., 1982. Compr. Psychiatr. 25: 126-127. 32 �362. Book reviews: Vaillant, G. E. The Natural History of Alcoholism. Harvard Univ. Press, Cambridge, MA, 359 pp., 1983; B. Tabakoff, P.B. Sutker, and C.L. Randall (eds.): Medical and Social Aspects of Alcohol Abuse. Plenum Press, New York, 403 pp., 1983; R.G. Smart, F.B. Glaser, Y. Israel, H. Kalant, R.E. Popham, and W. Schmidt (eds.): Research Advances in Alcohol and Drug Problems vol. 7, Plenum Press, New York, 472 pp., 1983. Quart. Rev. Biol. 59: 369-370. 363. Book review: P. Carlton. A Primer of Behavioral Pharmacology. W. H. Freeman & Co., 301 pp., 1983. Quart. Rev. Biol. 59: 511-512. 1985 364. Pharmaco-electroencephalography: A note on its history. Neuropsychobiology. 1984; 12: 173-178. 365. Convulsive Therapy. Convulsive Ther. 1985; 1: 1-3. (editorial). 366. Reducing memory loss in electroconvulsive therapy. Convulsive Ther. 1985; 1: 77-80. (editorial). 367. A ‘gratuitous’ conclusion on ECT. Am J Psychiatry 1985; 142: 1129. (letter). 368. Anesthesia in electroconvulsive therapy. Convulsive Ther. 1985; 1: 155-157. (editorial). 369. Convulsive therapy: Fifty years of progress. Convulsive Ther. 1985; 1: 204- 216. 370. The ethics of placebo. In L. White, B. Tursky, G.E. Schwartz (eds.): Placebo: Theory, Research and Mechanisms. Guilford Press, New York, 1985; 423-430. 371. Anesthesia in ECT. J Clin Psychopharmacol. 1985; 5: 312. (letter). 372. MAOI, anesthesia, and ECT. J Clin Psychopharmacol 1985; 5: 313. (with K. Freese). 373. National Institutes of Health Consensus Conference on ECT. Convulsive Ther. 1985; 1: 231-233. (editorial). 374. Pharmaco-EEG as a method to assess bioequivalence of CNS active substances in man. Integrative Psychiatry 1985; 3 Supplement: 12S-19S. 375. Summary. Integrative Psychiatry 1985; 3 (Supplement): 92s-93s (with L. Hollister). 376. Book review. E.A. Turner. Surgery of the Mind. Carmen Press, Birmingham UK, 238 pp., 1982. In Am J Psychiatry 1985; 142: 374-375. 377. Book review. M. Fraser. ECT: A Clinical Guide. John Wiley, New York, 134 pp., 1982. In Convulsive Ther 1985; 1: 66-67. 378. Book review. N.S. Endler. Holiday of Darkness: A Psychologist’s Personal Journey Out of Depression. Wiley-Interscience, New York, 169 pp., 1982. In Convulsive Ther. 1985; 1: 140-142. 33 �379. Book reviews: L. Kalinowsky, H. Hippius, H.E. Klein. Biological Treatments in Psychiatry. Grune & Stratton, New York, 424 pp., 1982; R. Abrams, W.B. Essman (eds.): Electroconvulsive Therapy: Biological Foundations and Clinical Applications. Spectrum Publications, New York, 270 pp., 1982. In Convulsive Ther. 1985; 1: 222-223. 380. Book review: S.E. Luria. A Slot Machine, A Broken Test Tube. Harper & Row, New York, 230 pp., 1984. In Am J Psychiatry 1985; 142: 1210-1211. 381. Book review: G.G. Nahas. Marijuana in Science and Medicine. Raven Press, New York, 312 pp., 1984. In Quart Rev Biol. 1985; 60: 551-552. 382. Book review: R.G. Smart et al. (eds.): Research Advances in Alcohol and Drug Problems. Vol 8. Plenum Press, New York, 333 pp. In Quart Rev Bioi 1985; 60: 552. 385a. Historical Article: Autobiography of L. J. Meduna. Convuls Ther. 1985; 1(1): 43-57. 1986 383. Neuroendocrine predictors of ECT outcome: DST and prolactin. Annals New York Academy Sci 1986; 462: 30-36. 384. Convulsive therapy today: A decade of increased understanding and acceptance. Psychiatry Letter 1986; 4: 7-12. 385b. Autobiography of L.J. Meduna. Ideggyogyaszati szemle 1986; 39: 225-34. (article in Hungarian). 386. Electroconvulsive therapy today. Currents 1986; 5: 5-12. (interview). 387. Convulsive therapy and epilepsy research. In M.R. Trimble and E.H. Reynolds (eds.): What is Epilepsy? The Clinical and Scientific Basis of Epilepsy. Churchill Livingstone, Edinburgh, 1986, 217-228. 388. Serial dexamethasone suppression tests in ECT. Clin Neuropharm 1986; 9: Suppl. 4: 444-446 (with K. Gujavarty K, L. Greenberg). (abstract). 389. Multi-lead EEG dynamic mapping during ECT. Clin Neuropharm 1986; 9: Suppl. 4: 536-537 (with M. Fink, L. Greenberg, K. Gujavarty). (abstract). 390. Convulsive therapy: How it evolved. Psychopharm Bull 1986; 22: 357-459. 391. A new evaluation of convulsive therapy: The Ontario report. Convulsive Ther 1986; 2: 73-76 (editorial). 392. Training in ECT. Convulsive Ther 1986; 2: 227-230. (editorial). 393. Book review: J. Winson. Brain and Psyche: The Biology of the Unconscious. New York, Doubleday, 1985, 300 pp. In Science Books and Films 1986; 21: 157. 394. Book review: D.C. Horwell (ed.): Drugs in the Central Nervous System Disorders. New York, Marcel Dekker Inc. 1985, 354 pp. In Quart Rev Biol 1986; 61: 146. 34 �1987 395. Serial dexamethasone suppression tests and clinical outcome in ECT. Convulsive Ther 1987; 3: 111-120 (with L. Greenberg, K. Gujavarty). 396. Electroconvulsive therapy and neuroleptic medication in the treatment of therapy resistant positivesymptom psychosis. Convulsive Ther 1987; 3: 185-195 (with K. Gujavarty, L. Greenberg). 397. Isoflurane anesthesia therapy: A replacement for ECT in depressive disorders? Convulsive Ther 1987; 3: 269-277 (with L.B. Greenberg, J. Gage, S. Vikun). 398. Update on ECT. Psychiatric Annals 1987; 17: 47-53 (interview). 399. Convulsive therapy in affective disorders: A decade of understanding and acceptance. In H. Meltzer (ed.): Psychopharmacology: A Third Generation of Progress. Raven Press, New York, 1987, Chap 108: 1071-1076. 400. ECT: A last resort treatment for resistant depression? In J. Zohar, R. Belmaker (eds.): Treating Resistant Depression. PMA Publishing Co, New York, Chap 9: 163-173. 401. Convulsive therapy. In G Adelman (ed.): Encyclopedia of Neuroscience. Birkhuser, Boston, 1987, 277278. 402. Neuroendocrine aspects of convulsive therapy: Review of recent developments. In C.B. Nemeroff, P.T Loosen (eds.): Handbook of Clinical Psychoneuroendocrinology. Guilford Press, New York, 1987, Chapter 11: 255-265. 403. New technology in convulsive therapy: A challenge in training. Am J Psychiatry 1987; 144: 1195-1196 (editorial). 404. Neuropsychiatry and behavioral neurology. Convulsive Ther 1987; 3: 91-92 (editorial). 405. Is ECT usage decreasing? Convulsive Ther 1987; 3: 171-173. (editorial). 406. Maintenance ECT and affective disorders. Convulsive Ther 1987; 3: 249-250 (editorial). 407. Contraindications to electroconvulsive therapy. Anesth Analg 1987; 66: 918 (letter). 408. A case of resistant schizophrenia. Br J Psychiatry 1987; 150: 562-563 (letter). 409. Book review: A.V. Valdman (ed.): Drug Dependence and Emotional Behavior: Neurophysiological and Neurochemical Approaches. Plenum Publ Co., New York, 1986. In Quart Rev Biol 1987; 62: 120-121. 410. Book review: W. Kalow, H.W. Goedde, D.P. Agarwal (eds.): Ethnic Differences in Reaction to Drugs and Xenobiotics. AR Liss, New York, 583 pp., 1986. In Quart Rev Biol 1987; 62: 124. 411. Book review: M.H. Van Woert, E. Chung (eds.): Cooperative Approaches to Research and Development of Orphan Drugs. AR Liss, New York, 204 pp., 1985. In Quart Rev Biol 1987; 62: 124-125. 35 �412. Book review: E.S. Valenstein. Great and Desperate Cures. Basic Books, New York, 338 pp., 1986. In Convulsive Ther 1987; 3: 79-81. 413. Book review: M. Brause, A.M. Zimmerman (eds.): Genetic and Perinatal Effects of Abused Substances. Academic Press, New York, 211pp., 1987. In Quart Rev Biol 1987; 62: 469. 1988 414. Prospective electroconvulsive therapy in delusional depressed patient with a frontal meningioma. Br J Psychiatry 1988; 153: 105-107 (with L.B. Greenberg, R. Mofson). 415. Convulsive therapy for affective disorders. In A. Georgeotas and R. Cancro (eds.): Depression and Mania. Elsevier, North Holland and New York, 1988; 29: 452-460. 416. Convulsive therapy: A manual of practice. Review of Psychiatry VII. 1988; 21: 482-497. APA Press, Washington DC. 417. The present status of electroconvulsive therapy: An update. F. Flach (ed.): Directions in Psychiatry 1988; 1-8. Hatherleigh Co., New York. 418. Forward. Electroconvulsive Therapy, Richard Abrams, 1st ed., Oxford University Press, New York, 1988; vii-x. 419. Forward. Electroconvulsive Therapy: The Myths and the Realities. N.S. Endler, E. Persad, Hans Huber, Toronto; 1988; ix-xi. 420. Fifty years of electro-convulsive therapy. Convulsive Ther 1988; 4: 2-4 (editorial). 421. ECT for Parkinson disease? Convulsive Ther 1988; 4: 189-191 (editorial). 422. How does ECT work? Psychopharmacol Bull 1988; 24: 385-386 (with W. Potter). 423. Neuroendocrine hypothesis of antidepressant action of ECT. Psychopharmacol Bull 1988; 24: 400-402. 424. Use of ECT in the United States. Am J Psychiatry 1988; 145: l33-134. (letter). 425. ECT instrumentation. Biol Psychiatry 1988; 24: 360-361. (letter). 426. The diagnosis and treatment of depression in the old. JAMA 1988; 260: 1405. (letter). 427. ECT: The continuing controversy. Consensus in Psychiatry 1988; 1: 1. 428. Brain imaging and pharmaco-EEG. Consensus in Psychiatry 1988; 1: 1-2. 429. Book review: Kurt Eissler: Freud as an Expert Witness. IUP Press, Madison CT, 1986. In Convulsive Ther 1988; 4: 250-251. 36 �430. Book reviews: M.A. Taylor, F.S. Sierles, R. Abrams. General Hospital Psychiatry. Free Press, New York, 1985; A. Stoudemire, B.S. Fogel (eds.): Principles of Medical Psychiatry. Grune & Stratton, Orlando FL, 1987; A.J. Frances, R.H. Hales (eds.): Review of Psychiatry VII, American Psychiatric Press, Washington DC, 1988. In Convulsive Ther 1988; 4: 175-177. 431. Book review: I. Rosenfield. The Invention of Memory: A New View of the Brain. Basic Books, New York, 1987. In Science Books & Films 1988; 24: 77-78. 432. Book reviews: B. Aperia. A Psychoendocrinological Study of Electroconvulsive Therapy in Major Depressive Disorder. Thesis. Department of Psychiatry, Karolinska Institute, St Gyran’s Hospital, Stockholm, Sweden, 1985. P. Silfverskiyld. Depression and Mania: Clinical and Neurophysiological Aspects and Effects of ECT. Thesis. Department of Psychiatry, University of Lund, Lund, Sweden, 1987. In Convulsive Ther 1988; 4: 177-179. 433. Book review: Current Approaches: ECT. J. Malkien, S. Brandon. Duphar Laboratories, UK, 1988. In Convulsive Ther 1988; 4: 335-336. 434. Book review: R.E. Hales, S.C. Yudofsky (eds.): Textbook of Neuropsychiatry. APA Press, Washington DC, 1987. In Neuropsychiatry, Neuropsychol Behav Neurology 1987; 1: 153-155. 435. Book review: P.H. Wender. The Hyperactive Child, Adolescent and Adult: Attention Deficit Disorder Through the Lifespan. Oxford University Press, New York, 162 pp., 1987. In Science Books & Films, 1988; 23: 244. 436. Videotape Review: Healthcare Information Network, Princeton NJ. Electroconvulsive Therapy: A New Age, A New Understanding. Series: Mind and Body. Distributed by MECTA Corporation, Portland OR, 1987. In Convulsive Ther 1988; 4: 180. 1989 437. Convulsive therapy: A reappraisal. In J.G. Howells (ed.): Modern perspectives in the Psychiatry of Affective Disorders. Brunner/Mazel Inc., New York, 1989; 22: 393-410. 438. Electroconvulsive therapy: The forgotten option in the treatment of therapy resistant depression. In I. Extein (ed.): Treatment of Tricyclic Resistant Depression. APA Press, Washington DC, 1989, 135-150. 439. A comparison of etomidate and methohexital anesthesia for electroconvulsive therapy. Annals Clin Psychiatry 1989; 1: 39-42 (with L.B. Greenberg, R. Boccio). 440. A neuroendocrine view of ECT. Convulsive Ther 1989; 5: 296-304 (with C.B. Nemeroff). 441. Convulsive therapy and kindling. In M. Trimble and T. Bolwig (eds.): The Clinical Relevance of Kindling. John Wiley & Sons, Chichester. 1989; 13: 195- 208. 442. Electroconvulsive therapy: A review. Organorama 1989; 26: 24-25. 443. Update on “Shock” therapy. Health & Medical Horizons. Macmillan Co., New York, 1989; 197-198 (commentary). 444. Recommendations for EEG and evoked-potential mapping. Neuropsychobiology 1989; 22: 170-176. International Pharmaco-EEG Group; (with W. Herrmann et al.). 37 �445. Reversible and irreversible dementia. Convulsive Ther 1989; 5: 123-125 (editorial). 446. ECT in Parkinson disease. The Psychiatric Times 1989; 63: 6-7. (commentary). 447. Maintenance ECT is a continuing saga. The Psychiatric Times 1989; 64: 13-14. (commentary). 448. Reversible dementia and ECT. The Psychiatric Times 1989; 65: 23-24. (commentary). 449. Primo Levi need not have died. The New York Times. January 5, 1989. A20. (letter). 450. The efficacy of electroconvulsive therapy in therapy-resistant psychotic patients. J Clin. Psychopharmacol 1989; 9: 231-232. (letter). 451. Max Hamilton. Biol Psychiatry 1989; 26: 218-219. (homage). 452. Maintenance ECT. In response. Jefferson Jrl Psychiatry 1989; 7: 71-72 (letter). 453. Videotape review: J. David. Four Lives: A Portrait of Manic Depression. Fanlight Productions, 1988. Hosp & Commun Psychiatry 1989; 40: 347-348. 454. Book review: Lader M., Lang R., Wilson G.D. Patterns of Improvement in Depressed In-Patients. Oxford University Press, Oxford UK, 1987, 118 pp. In J Nerv Ment Dis 1989; 177: 498-499. 1990 455. How does convulsive therapy work? Neuropsychopharmacology 1990; 3: 73-82. 456. Response to commentaries on “How does convulsive therapy work?” Neuropsychopharmacology 1990; 3: 97-100. 457. Electroconvulsive therapy and cyclophosphamide in combination for severe neuropsychiatric lupus with catatonia. Am J Medicine 1990; 88: 443-444 (with G.L. Fricchione, L.D. Kaufman, B.L. Gruber). 458. Rat brain concentration of fluphenazine during a course of electroconvulsive shock. Convulsive Ther 1990; 6: 273-9 (with I. Zervas, L.B. Greenberg, R.F. Suckow, T. Cooper, L. Jandorf). 459. Electroconvulsive therapy in the elderly. Psychiatric Annals 1990; 20: 99-101. (with L.B. Greenberg). (review). 460. Electroconvulsive therapy. Current Opinion in Psychiatry 1990; 3: 58-61. (review). 461. Electroconvulsive therapy of anxiety disorders. In R. Noyes, M. Roth, G.D. Burrows (eds.): Handbook of Anxiety IV: The Treatment of Anxiety. Elsevier Science Publishers BV, Amsterdam, Chap 25: 511-518, 1990. 462. A trial of ECT is essential before a diagnosis of refractory depression is made. In J.D. Amsterdam (ed.): Refractory Depression. Adv Neuropsychiatry Psychopharmacology 1990; 2: 87-92. Raven Press, New York. 463. Is catatonia a primary indication for ECT? Convulsive Ther 1990; 6: 1-4. (editorial). 38 �464. The 1990 APA task force report: A quiet revolution. Convulsive Ther 1990; 6: 75-78. (editorial). 465. ECT in modern literature. Convulsive Ther. 1990; 6: 191-193. (editorial). 466. Electrode placement: A clinician’s guide. Convulsive Ther. 1990; 6: 263-265. (editorial). 467. Clozapine and electroconvulsive therapy. Arch Gen Psychiatry 1990; 47: 290-291. (letter). 468. Continuation ECT today. Harvard Medical School Mental Health Letter. (forum). 1990; 6: 8. 469. Guidelines for the long-term use of convulsive therapy. JAMA 1990; 264: 1174. Questions and answers. 470. Book review: L.G. Kiloh, J.S. Smith, G.F. Johnson. Physical Treatments in Psychiatry. Blackwell Scientific, Melbourne, 1988. In Am J Psychiatry 1990; 147: 1239-1240. 471. …ibid., In Convulsive Ther. 1990; 6: 60-62. 472. Book review: M.R. Trimble, E.H. Reynolds (eds.): Epilepsy, Behaviour and Cognitive Function. John Wiley & Sons, Chichester UK, 1988. In Am J Psychiatry 1990; 147: 665-666. 473. Energy parameters of ECT devices need reassessment. Psychiatric Times 1990; 7: 23, 26. (commentary). 474. Catatonia and ECT. Psychiatric Times 1990; 7: 32-33. (commentary). 1991 475. Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, betaendorphin and somatostatin. Br J Psychiatry 1991; 158: 59-63 with C.B. Nemeroff, G. Bissette G, H. Akil). 476. Catatonia: A separate category for DSM-IV? Integrative Psychiatry 1991; 7: 210 (with M.A. Taylor). 477. Impact of the anti-psychiatry movement on the revival of ECT in the U.S. Psychiatric Clinics N.A. 1991; 14: 793-801. 478. Electroconvulsive therapy, 1989-1990. Current Opinion Psychiatry 1991; 4: 73-77 (with I. Zervas). 479. The revival of ECT in America. Bolletino di Psichiatria Biologica. 1991: 6: 25-29. 480. What is an adequate treatment in convulsive therapy? Acta Psychiatr Scand 1991; 84: 424-427. 481. Electroconvulsive therapy. Review of APA Task Force report. Wn Jrl Med 1991; 155, 515. (review). 482. Present use of ECT. Integrative Psychiatry 1991; 7: 69-70. (letter). 483. Pharmacotherapy and ECT. Convulsive Ther 1991; 7: 77-80. (editorial). 484. A scientific society for ECT. Convulsive Ther 1991; 7: 155-156. (editorial). 39 �485. ECT for refractory Parkinson’s Disease. Convulsive Ther 1991; 7: 222-223 (with I. Zervas). (letter). 486. A historical review of electroconvulsive therapy. Jefferson Jrl Psychiatry 1991; 9: 97-99. (letter). 487. Steroid induced catatonia. Br J Psychiatry 1991; 159: 445. (letter). 488. ECT in long-term follow up of BPD. Biol Psychiatry 1991; 30: 1172. (letter). 1992 489. Soziale und politische Aspekte der Elektrokonvulsionstherapie in den USA: Lektionen fur die deutsche Psychiatrie. Social and political aspects of ECT in the U.S.: Lessons for German psychiatry). Biologische Psychiatrie. Springer Verlag, Heidelberg, 1992, 88-90. 490. The use of ECT in geriatric patients. In G.S. Alexopoulos (ed.): Clinics Geriatric Medicine 1992; 8: 349354, W.B. Saunders: Philadelphia (with L.B. Greenberg). 491. Electroconvulsive therapy. In E.S. Paykel (ed.): Handbook of Affective Disorders. 2nd ed. ChurchillLivingstone, London, 1992; 22: 359-368. (review). 492. Induced seizures ECT and memory. In D Barcia Salorio (ed.): Trastornos de la Memoria. Editorial MCR, Madrid. 1992; 5.1: 383-396. 493. Pharmaco-Electroencephalography: A science ignored. Pharmacopsychiatry 1992; 24: 183-184. (editorial). 494. Qualification for ECT. Convulsive Ther 1992; 8: 1-4 (with R. Abrams). (editorial). 495. ECT and public mental health services. Convulsive Ther 1992; 8: 87-91. (editorial). 496. Catatonia and DSM-IV. Convulsive Ther 1992; 8: 159-162. (editorial). 497. Book review: Electroconvulsive therapy. Psychiatric Clinics N.A. 1992; 14: 693,1020. In Convulsive Ther 1992; 8:54-55. 498. Book review: ECT awaits its Lavoisier. R. Abrams. Electroconvulsive Therapy, 2nd ed. Oxford University Press, New York, 340 pp., 1992. In Convulsive Ther 1992; 8:213-216. 499. Book review: B.N. Gangadhar (ed.). Proceedings of the National Workshop on ECT. NIMHANS, Bangalore, India, 264 pp., 1992. J Krzyzowski. Leczenie Elektrowstrzasami. Z.D. Poligraficzny, Warsaw, Poland, 215 pp., 1991. In Convulsive Ther 1992; 8: 216-217. 500. Failure to use ECT in a case of catatonia. Am J Psychiatry 1992; 149: 145. (letter). 501. The treatment of catatonia: Benzodiazepines or ECT? P.J. Rosebush, A.M. Hildebrand, M.F. Mazurek (letter). Dr. Fink replies. Am J Psychiatry 1992; 149: 1279-1280. (letter). 502. ECT response in catatonia. Am J Psychiatry 1992; 149: 581-582 (with A. Francis). (letter). 40 �503. Why not ECT for catatonia? Biol Psychiatry 1992; 31: 536-537. (letter). 504. ECT and delirium in Parkinson’s Disease. Jrl Neuropsychiatry & Clin Neuroscience 1992; 4: 231 (with I. Zervas). (letter). 505. Follow-up: Letter on review of APA Task Force report by Peter Breggin. Readings: A Journal of Reviews and Commentary. American Orthopsychiatry Association). 1992; 7:22-23 (with L. Eisenberg). (letter). 506. Role of Dopamine in mood disorders. Comprehens Psychiatry 1992; 33: 417-417 (with L. Fochtmann). (letter). 507. ECT and delirium in Parkinson's Disease. Am J Psychiatry 1992; 149: 1758 (with I. Zervas). (letter). 508. Missed neuroleptic malignant syndrome. BMJ 1992; 304: 1246. (letter). 509. Catatonia: incidence and treatment in a university hospital. Convulsive Ther 1992; 8: 60-61 (with I. Zervas, J. Pataki J). (abstract). 1993 510. Blood pressure, memory, and electroconvulsive therapy. Convulsive Ther 1993; 9: 14-22 (with I. Zervas, A. Calev, L. Jandorf). 511a. Caffeine pre-treatment enhances clinical efficacy and reduces cognitive effects of ECT. Convulsive Ther 1993; 9:95-100 (with A. Calev, G. Petrides, A. Francis, L. Fochtmann). 511b. Effect of ECT with caffeine pre-treatment on efficacy for depression and memory deficits. Biol Psychiatry 1993; 33:84A (with A. Calev). 512. Who should get ECT? In C.E. Coffey (ed.): The Clinical Science of Electroconvulsive Therapy. 1993; 1: 3-16. APA Press, Washington, DC. 513. Catatonia: A treatable disorder, occasionally recognized. Directions in Psychiatry. 1993; 13(3): 1-8 (with G. Bush, A. Francis). 514. Die Geschichte der EKT in den USA in den letzten Jahrzehnten. (Recent history of electroconvulsive therapy in the U.S.) Nervenarzt. 1993; 64: 689-95. 515. Subjective symptoms in depression and during the course of electroconvulsive therapy. Neuropsychiatry, Neuropsychol Behav Neurol. 1993; 6: 187-92 (with N. Tubi, A. Calev, D. Niga1, B. Shapira, H.L. Pass, L. Jandorf, B. Lerer). 516. Post-ECT delirium. Convulsive Ther 1993; 9: 326-330. (review). 517. Reversible dementia and affective disorder: The Rip van Winkle Syndrome. Convulsive Ther 1993; 9: 209-16 (with L. Bright-Long). (case report). 518. Combining drugs and electroconvulsive therapy: Safe and/or effective? J. Clin. Psychopharmacology 1993; 13 2): 85-86. (commentary). 41 �519. Prolonged seizures. Convulsive Ther 1993; 9: 87-89. (commentary). 520. ECT in children and adolescents. Convulsive Ther 1993; 9: 15S-7. (commentary). 521a. The next challenge: The mode of action of ECT. Convulsive Ther 1993; 9: 192-7. (annotation). 521b. The mode of action of ECT. Psychopharmacol. Bull. 1994; 30: 309-12, 1994. 522. ECT and drugs: Concurrent administration. Convulsive Ther 1993; 9: 237-40. (with C.H. Kellner). (commentary) 523. Commentary on J.B. Welch: Topographic brain mapping: Applications and pitfalls. Integrative Psychiatry 1993; 9: 67-8. 524. EEG and behavior: Association or dissociation in man? Integrative Psychiatry 1993; 9: 108-123. (hypothesis). 525. Catatonia and psychotic delusional depression, distinct syndromes in DSM-IV. Am. J. Psychiatry 1993; 150: 1130-1. (letter). 526. Using MEDLINE to solve clinical problems. JAMA 1993; 270: 2053 (letter). 527. Book review: “Round up a new set of suspects...” Review of M.K. O’Connor, T.A. Rummans (eds): Updating ECT. Psychiatric Annals, 1993; 23:1-47. In Convulsive Ther 1993; 9: 141-2. 528. Book review: Psychiatry: The next phase. Review of M. Taylor: The Neuropsychiatric Guide to Modern Everyday Psychiatry. The Free Press, New York, 530 pp., 1993. In Convulsive Ther. 1993; 9: 143-5. 529a. Question the Experts: Blood levels of nortriptyline. J Clin Psychopharmacology 1993; 13: 296. 529b. Reply to “Question the Experts.” J Clin. Psychopharmacology 1993; 13: 359. 530. Book review: Psychiatry’s frog or prince? Electroconvulsive Therapy. Richard Abrams, Oxford University Press, 1992. In BJP Review of Books 6:18-19, July, 1993. 531. Book review: Electroconvulsive Therapy. Richard Abrams, Oxford University Press, 1992, 2nd ed. In Am. J. Psychiatry 1993; 150:1747-8. 532. Book review: Neuropsychological Perspectives on Emotion. F.N. Watts. Hillsdale, NJ: Lawrence Erlbaum. In Science Books & Films 1993; 29:261. 533. Book review: Motor Disorders in Psychiatry. D. Rogers, Wiley & Sons, Chichester UK, 1992. In Neuropsychiatry, Neuropsychol Behav Neurol 1993; 6: 267-8. 534a. Catatonia: A rating scale and prospective study utilizing lorazepam and ECT. Amer Col Neuropsychopharmacology Abstracts, pg 88, December 1993 (with G. Bush, A. Francis, G. Petrides, F. Dowling). 534b. What is catatonia? The Harvard Mental Health Letter 1995; 11: 8 (with G. Bush, G. Petrides). (commentary). 42 �1994 535a. Continuation ECT for relapse prevention in depression. Convulsive Ther 1994; 10: 77 (with G. Petrides, D. Dhossche). (abstract). 535b. A prospective study of continuation ECT. Biol. Psychiatry 1994; 35: 652-3 (with G. Petrides , D. Dhossche, A. Francis). (abstract). 535c. Continuation ECT: Relapse prevention in affective disorders. Convulsive Ther 1994; 10: 189-94 (with G. Petrides G., D. Dhossche, A. Francis). 536. Indications for the use of ECT. Psychopharmacol. Bull. 1994; 30: 269-80. 537a. Combining electroconvulsive therapy and drugs: A review of safety and efficacy. CNS Drugs 1994; 1: 370-376. (review). 537b. ECT and psychoactive drugs combined. ASCP Progress Notes Newsletter 1994; (52): 3. (review). 538. Optimizing ECT. L’Encephale 1994; 20: 297-302. (review). 539a. ECT in adolescents. The Harvard Mental Health Letter 1994; 10: 8. (commentary). 539b. ECT in adolescents. Psychiatric Times 1994; 12: 18-19,1995. (commentary). 540a. Catatonia in DSM-IV. Biological Psychiatry 1994; 36: 431-3. (commentary). 540b. DSM-IV and catatonia. Psychiatric Times 1994; 11: 35. (commentary). 541. Public perceptions of ECT. Jefferson Jrl. Psychiatry 1994; 12: 83-86. (letter). 542. Administrative problems limiting electroconvulsive therapy. Br. J. Psychiatry 1994; 164: 850-1. (letter). 543. Diazepam or lorazepam for prolonged seizures? Convulsive Ther 1994; 10: 236. (letter). 544. Convalescence and ECT. Convulsive Ther. 1994; 10: 301-3. (letter). 545. Book review: The Clinical Science of Electroconvulsive Therapy. C.E. Coffey (ed.), American Psychiatric Press, Washington DC, 259 pp., 1993. In The Psychiatric Times, Feb. 1994, pg. 25. 546. Book review: Drugs and Disease. J. L. Harris. Twenty-First Century Books, New York, 1993. In Science Books 1994; 30: 82. 547. Book review: Cannabis, Politically Incorrect. Marihuana, The Forbidden Medicine. L. Grinspoon, J.B. Bakalar. Yale University Press, New Haven, CT, 1993. In Am. J. Psychiatry 1994; 151: 1091. 548. The half-age stimulation strategy for bilateral ECT. Biol. Psychiatry 1994; 35: 653 (with G. Petrides). (abstract). 549. Alternative stimulation strategies for bilateral ECT. Convulsive Ther 1994; 10: 77 (with G. Petrides). 43 �(abstract). 1995 550. Convulsive therapy in delusional disorders. Psychiatric Clinics North America 1995; 18 (2): 393-406. (review). 551. ECT and non-memory cognition: A review. Br. J. Clin Psychology 1995; 34: 505-15 (with A. Calev, E.A. Gaudino, N.K. Squires, I.M. Zervas). 552. Recognizing NMS as a type of catatonia. Neuropsychiatry Neuropsychol Behav Neurol. 1995; 8: 75-6. (commentary). 553. Treat NMS as catatonia. Psychiatric Times 1995; 12 (3): 34. (commentary). 554. ECT in mania: A rediscovered use. Psychiatric Times 1995; 12 (6): 16. 555. ECT and schizophrenia. Psychiatric Times 1995; 12 (10): 30. 556. Milton Greenblatt: a remembrance. Convulsive Ther 1995; 11: 151-3 (with F. Frankel). 557. Convalescence and ECT: Comment on Letter by Dr. Brackin. Convulsive Ther 1995; 11: 220-21. (letter). 558. ECT and young minds. Lancet 1995; 345: 519. (letter). 559. NMS and catatonia: Reply to Raja and Miti. Neuropsychiatry Neuropsychol Behav Neurol 1995; 8: 2301. (letter). 560. “An ethical dilemma ....” Psychiatric Bulletin 1995; 19: 650-1 (with D.F. Klein). (letter). 561. ECT and pre-pubertal children. J Am Acad Child Adolesc Psychiatry 1995; 34: 1256-7 (with G.A. Carlson). (letter). 562. Book review: F.E. Bloom, O.J. Kupfer (eds.): Psychopharmacology: The Fourth Generation of Progress. New York, Raven Press, 1995, 2002 pp. In Neuropsychiatry, Neuropsychol. & Behav Neurol. (84): 303-4. 563. Book review: Asaad, Ghazi: Understanding mental disorders due to medical conditions or substance abuse: What every therapist should know. Brunner Maazel, NY, 1995. In Science Books & Films 31 (5): 1345. (book review). 564. Book review: J. Morrison: DSM-IV Made Easy: The Clinician’s Guide to Diagnosis. Guilford Press, NY, 1995. In Science Books & Films 31 (8): 233. 1996 565. Atrial fibrillation, anticoagulation, and electroconvulsive therapy. Convulsive Ther. 1996; 12: 91-98 (with G. Petrides). 44 �566. Ambulatory electroconvulsive therapy. Task force report of the association for convulsive therapy. Convulsive Ther. 1996; 12: 42-55 (with R. Abrams, S. Bailine, R. Jaffe). 567. Convulsive therapy for schizophrenia? Schizophrenia Bull. 1996; 221: 27-39 (with H.A. Sackeim). 568. Catatonia: I: rating scale and standardized examination (with G. Bush, G. Petrides, F. Dowling, A. Francis). Acta psychiatr. Scand 1996; 93 (2): 129-36. 569. Catatonia: II. Treatment with lorazepam and electroconvulsive therapy (with G. Bush, G. Petrides, F. Dowling, A. Francis). Acta Psychiatr. Scand 1996; 93 (2):137-43. 570. Catatonia. In T.A. Widiger, A.J. Frances, H.A. Pincus et al. (eds.): DSM-JV Sourcebook, 1996; vol 2:181-192. 571. The “half-age” stimulation strategy for ECT dosing. Convulsive Ther 1996; 12: 138-146 (with G. Petrides). 572. Toxic serotonin syndrome or neuroleptic malignant syndrome? Pharmacopsychiatry 1996; 29: 159-161. (case report). 573. A second quiet revolution: Ambulatory ECT. Convulsive Ther 1996; 12: 1-2 (with C.H. Kellner). (editorial). 574. Seizure adequacy: Does EEG hold the key? Convulsive Ther. 1996; 12: 203-206 (with C.H. Kellner). (editorial). 575. Neuroleptic malignant syndrome and catatonia: One entity or two? Biol Psychiatry 1996; 39: 1-4. (editorial). 576. Ambulatory ECT and managed care. The Psychiatric Times 1996; 13: 42. 577. Response to “Neuroleptic malignant-like syndrome due to cyclobenzaprine?” J Clin Psychopharmacol. 1996; 16: 97-9. (letter). 578. “Abnormal EEG effects of Clozapine.” J Neuropsych Clin Neuroscience 1996; 8: 114-115. (letter). 579. Algorithm accuracy. Comment on the International Psychopharmacology Algorithm Project. Psychiatric Times 1996; 13(8): 5. (letter). 580. Treating the syndrome before the complications. Am J Psychiatry 1996; 153: 1371 (with A. Francis). (letter). 581. Choosing a dosing strategy for electrical stimulation in ECT. J Clin Psychiatry 1996; 57: 487. (with G. Petrides). (letter). 582. ‘Catatonic schizophrenia’ is not ‘schizophrenia.’ Schizophrenia Res 1996; 18: 118. (abstract). 583. Book review: C. P. Freeman (ed.): The ECT Handbook. Royal College of Psychiatrists, London, 153 pp., 1995. In Convulsive Ther 1996; 12: 127-130. 45 �584. Book review: Bergsholm P.: Electroconvulsive Therapy: Issues related to narcosis, physiology, radiological anatomy, electrode placement, and endocrinology. Forde/Bergen, University of Bergen, 1995. In Convulsive Ther 1996; 12: 131-132. 1997 585. Catatonia. In M. Trimble, J. Cummings (eds.): Contemporary Behavioural Neurology. 1997; Chapter 16; pages 289-309. Butterworth/Heinemann, Oxford, UK. 586a. Prejudice against ECT: Competition with psychological philosophies as a contribution to its stigma. Convulsive Ther 1997; 13: 253-265. 586b. Response to Zigmond M. Lebensohn. Convulsive Ther 1997; 13: 268. 586c. Electroshock and psychoanalysis: schism in American psychiatry. Convulsive Ther 1997; 13: 51-52. 587. Recognition and treatment of the catatonic syndrome. Jrl Intensive Care Med. 1997; 12: 135-147 (with G. Fricchione, G. Bush G, M. Fozdar, A. Francis). (review). 588. Neuroleptic malignant syndrome: Identification and treatment. Essential Psychopharmacology. 1997; 2: 209-16. (review and commentary). 589. Energy dosing in ECT: Threshold stimulation or formula? Convulsive Ther. 1997; 13: 4-6. (debate with Richard Weiner). 590. Clinical common sense versus theoretical correctness. Reply to Harold A. Sackeim. Convulsive Ther. 1997; 13: 41-43 (with G. Petrides). 591. The decision to use ECT: For Whom? When? In A.J. Rush (ed.): Mood Disorders: Systematic Medication Management. Modern Probl. Pharmacopsychiatry. 1997; 25: 203-214. Karger, Basel, Switzerland. 592. Electroconvulsive therapy in affective disorders: Efficacy and mode of action. In A. Honig, H.M. van Praag (eds.): Depression: Neurobiological, Psychopathological and Therapeutic Advances. 1997; Chapter 23, pages 397-412. John Wiley & Sons, Ltd. Sussex, England. 593. What is the role of ECT in the treatment of mania? The Harvard Mental Health Letter 1997; 18: 8. 594. Cognitive screening instruments in neuropsychiatry: A report of the committee on research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 1997; 9:189-97 (with P.F. Malloy, J.L. Cummings, C.E. Coffey, J. Duffy, E.C. Lauterbach, M. Lovel, D. Royall, S. Salloway). 595. Lethal catatonia, neuroleptic malignant syndrome, and catatonia: A spectrum of disorders. Reply. J Clin Psychopharmacol. 1997; 17: 237. (letter). 596. The importance of a differentiated psychopathology of catatonia. Acta Psychiatr. Scand. 1997; 95: 358-9 (with G. Petrides, G. Bush, A. Francis). (letter). 597. ECT Update. Psychiatric Times. 1997; 14: 39-41. (review and lesson). 46 �598. Catatonia and NMS: Recognition and treatment. The Psychiatric Times. 1997; 14: 42-49. (review and lesson). 599. A.E. Bennett and curare. Convulsive Ther 1997; 13: 92. (commentary). 600. Book review: Squire L. A History of Neuroscience in Autobiography. Washington DC, Society for Neuroscience. vol 1, 1996. In Science Books & Films 1997; 33: 137. 601. Book review: New histories of psychiatry: Somatic and dynamic views contrasted. Shorter E. A History of Psychiatry. From the Era of the Asylum to the Age of Prozac. John Wiley & Sons, N.Y. 1997; Stone MH. Healing the Mind. A History of Psychiatry from Antiquity to the Present. W.W. Norton & Co., N.Y. 1997. In Convulsive Ther 1997; 13: 280-1. 1998 602. Electroconvulsive therapy and managed care. Am Jrl Managed Care. 1998; 4: 107-112 (with S. Bailine). 603. ECT and managed care. Journal Watch: Psychiatry. 1998; 4: 76 (73). 604. ECT in older patients: Benefits and risks. Psychiatric Times 1998; 15(2): 68-71. (lesson). 605. ECT certification. J ECT 1998; 14: 1-4 (with C.H. Kellner). (editorial). 606. ECT and clozapine in schizophrenia. J ECT 1998; 14: 223-6. (editorial). 607. ECT in mania: An ignored and effective treatment option. Jrl Bipolar Disorders 1998; 2: 19-21. (review). 608. Electroconvulsive therapy. In C.E. Coffey and R. Brumback (eds.): Textbook of Pediatric Neuropsychiatry, 1998; Chapter 54: 1389-1408. American Psychiatric Press, Washington, DC (with C.E. Coffey). 609. EEG monitoring in ECT: A guide to treatment efficacy. Psychiatric Times 1998; 15 (5): 70-2 (with R. Abrams). 610. Misguided consent for ECT. Austral NZ Jrl Psychiatry. 1998; 31: 209. (letter). 611. Theophylline and ECT. J ECT 1998; 14: 286-9 (with H.A. Sackeim). (letter). 612. Delirium following cessation of alcohol consumption. Am J Psychiatry 1998; 155: 1638. 613. Pharmaco-electroencephalography: A debate in psychopharmacology. In T. Ban, D. Healy, E. Shorter (eds.): The Rise of Psychopharmacology and the Story of the CINP, 1998; 151-6. Animula Publishing House, Budapest. 614. The case for formal certification in ECT. J ECT 1998; 14: 132. (abstract). 615. To titrate or not to titrate: A debate with a twist. J ECT 1998; 14: 133-4. (abstract). 616. Concurrent use of ECT and atypical antipsychotic medications. J ECT 1998; 14: 139-40 (with G. Petrides, A. Abaza, A. Francis). (abstract). 47 �617. Book review: Principles of Neuropsychopharmacology. R.S. Feldman, J.S. Meyer, L.F. Quenzer. Sinauer: Sunderland, MA, 1997. In Quart Rev Biol 1998; 73: 122. 618. Video Review: Brainstorm: The Hidden Epidemic of Depression. Filmakers Library, New York, 1998; 53 min. video. In Science Books & Films 1998; 34: 150. 1999 619a. ELECTROSHOCK: Restoring the Mind. Oxford University Press, New York, 157 pp. Re-issued in paperback as Electroshock: Healing Mental Illness, 2002. 619b. Eletrochoque. Restaurando a Mente. Portugese translation by Dra. Andrea Favano. Sao Paulo Brazil: Editora Roca Ltda, 2003. 620. www.electroshock.org. (website, July 1999). 621a. Electroconvulsive therapy and mental retardation. J ECT 1999; 15: 140-9 (with M. Thuppal). 621b. Electroconvulsive therapy and mental retardation. J ECT 1998; 14: 142 (with M. Thuppal). (abstract). 622. Delirious mania. Bipolar Disorders 1999; 1: 54-60. 623. ECT in delirious states. J ECT 1999; 15: 175-77. (editorial). 624. Convulsive therapy. In G. Adelman, B.H. Smith (eds.): Elsevier’s Encyclopedia of Neuroscience. Elsevier Science. B.V., New York and Amsterdam, 466-468, 1999. 625. Convulsive Therapy. In H. Freeman (ed.): A Century of Psychiatry, Mosby-Wolfe, London, 1999; I: 96-99; II: 229-32. 626. Ladislas J. Meduna. Images in psychiatry. Am J Psychiatry 1999; 156: 1807. 627. Intractable seizures, status epilepticus, and ECT. J ECT 1999; 15: 282-4 (with C. Kellner, H.A. Sackeim). (letter). 628. Pediatric ECT. Psychiatric Times 1999; 169: 63-5 (with C. Foley). 629. Neuroleptic malignant syndrome: Recognition and treatment. Psychiatric Times 1999; 16 (8): 6. (commentary). 630. Book review: J.L. Beyer, Weiner R.D., Glenn M.D.: Electroconvulsive Therapy: A Programmed Text. American Psychiatric Press, Inc., Washington DC, 1998, Am J. Psychiatry 1999; 156: 333. 48 �2000 631. Electroshock revisited. Amer Scientist 2000; 88 (2): 162-167. 632. Catatonia. In C. Andrade (ed.): Advances in Psychiatry. New Delhi, Oxford University Press. Chapter 2, pp. 26-44, 2000 (with G. Petrides). 633. A clinician-researcher and ECDEU: 1959-1980. In T. Ban, D. Healy, E. Shorter (eds.): The Triumph of Psychopharmacology and the Story of the CINP. Budapest, Animula, 2000, 82-96, 2000. 634. Can delirium relieve psychosis? Comprehens Psychiatry 2000; 41: 450-453 (with C. Malur, A. Francis). 635. ECT has proved effective in treating depression. Nature 2000; 405: 826. (letter). 636. The interaction of delirium and seizures. In P.T. Trzepacz (ed.) Seminars in Clinical Neuropsychiatry 2000; 52: 31-35. 637. Educational resources for electro-convulsive therapy. Arch Indian Psychiatry 2000; 6: 6-9. 638a. ECT in the management of delirium, NMS, and catatonia. Essential Psychopharmacology 2000; 3: 116. 638b. ECT in the management of delirium, NMS, and catatonia. Directions in Psychiatry 2000; 220: 367-376. (lesson). 639. Herman C.B. Denber. Neuropsychopharmacology 2000; 23:474-475. (obituary). 640. Undiagnosed Stupor: A treatable syndrome of catatonia? ASCP Progress Notes 2000; 10: 1,4,7. 641. Fixed high dose right unilateral ECT. (commentary). Evidence-Based Mental Health 2000; 3: 114-115. 642. Controversies in the diagnosis and treatment of manic-depressive illness. World Jrl Biological Psychiatry 2000; 1: 219. (letter). 643. NMS best treated as catatonia. Psychiatric Times 2000; 17 (11): 28-29. (commentary). 644. Book review: The Science of Happiness: Unlocking the Mysteries of Mood. Stephen Braun. NY, Wiley, 2000. In Science Books & Films, 2000:36 (5): 212. 645. A neuroendocrine view of convulsive therapy. Neuropsychopharmacology 2000; 23: S91. (abstract). 49 �2001 646. Convulsive therapy after 65 years. J Affective Dis. 2001; 63: 1-15. 647. ECT remission rates in psychotic versus non-psychotic depressed patients: A report from CORE. J ECT 2001; 17: 244-253 (with G. Petrides, M.M. Husain, R. Knapp, A.J. Rush, M. Mueller, T.A. Rummans, K.M. O’Connor, K.G. Rasmussen, H.J. Bernstein, M. Biggs, S.H. Bailine, C.H. Kellner). 648. The influence of age on the response of patients with major depression to electroconvulsive therapy. Am J Geriatr Psychiatry 2001; 9: 382-390 (with K.M. O’Connor, R. Knapp, M.M. Husain, T.A. Rummans, G. Petrides, G. Smith, M. Mueller, K. Snyder, H. Bernstein, A.J. Rush, C. Kellner). 649. ECT has much to offer our patients: It should not be ignored. World Jrl Biological Psychiatry 2001; 2: 18. 650. Electroconvulsive therapy in medication-resistant depression. In Jay Amsterdam, Mady Hornig-Rohan, and Andrew Nierenberg (eds.): Treatment resistant mood disorders. 2001; 11: 223-238. Cambridge University Press, Cambridge UK. 651. Convulsive therapy in the 21st Century. In M.G. Gelder, J.J. Lopez-Ibor and N.C. Andreasen (eds.): New Oxford Textbook of Psychiatry, Oxford University Press, London. Chap 6.2.9.1; pp. 1342-1352. 652. The many varieties of catatonia. European Arch Psychiatry Clin Neurosci 2001; 251: Suppl 1: 8-13 (with M.A. Taylor). 653. Catatonia: Syndrome or schizophrenia subtype? Recognition and treatment. J Neural Transmission 2001; 108: 637-644. 654. The broad clinical activity of ECT should not be ignored. J ECT 2001; 17: 233-235. (editorial). 655. New research improves ECT outcomes. Psychiatric Times 2001; 18: 21. (review). 656. Electrode placement and electroconvulsive therapy: A search for the chimera. Arch Gen Psychiatry. 2001; 58: 607-608. (with S. Bailine, G. Petrides). (letter). 657. Modal ECT is effective: Response to Letter by Sackeim et al. J ECT 2001; 17: 222-225. (letter). 658. Treating neuroleptic malignant syndrome as catatonia. J Clin Psychopharmacol. 2001; 21: 120-121. (letter). 659. Treating manic stupor. Indian J Psychiatry 2001; 433: 286-287. (letter). 660 Treating bipolar affective disorder. BMJ 2001; 322: 365. (letter). 661. Book review: A Century of Psychiatry. Hugh Freeman. London, Mosby-Wolfe Medical Communications. In Neuropsychiatry, Neuropsychology Behavioral Neurology 2001; 14: 77. 2002 662. The efficacy of ECT and “Treatment Resistance.” J ECT 2002; 18: 1-2. 50 �663. Move On! Commentary on R. Abrams: stimulus titration and EC T dosing. J ECT 2002; 18: 11-12. 664. Catatonia and ECT. Reconsidering Meduna’s hypothesis of a biological antagonism between dementia praecox and epilepsy. World Jrl Biol Psychiatry 2002; 3: 105-108. 665. The 21st century clinical evaluation of psychoactive drugs. In T. Ban, D. Healy, E. Shorter (eds.): From Psychopharmacology to Neuropsychopharmacology in the 1980s and the Story of CINP as told in Autobiography. Budapest: Animula Publishing, 2002; 21-26. 666. ECT: an effective, but ignored, treatment of psychosis. In B. Green (ed.): Focus on Antipsychotics. London: Librapharm/Petroc Press, 2002, 3: 10-17. 667. Equivalency of rTMS and ECT unproven. Biol Psychiatry 2002; 52: 1032-1033 (with C.H. Kellner, M. Husain, G. Petrides, T. Rummans). (letter). 668. Electrotherapeutics. J ECT 2002; 18: 114-115. 669. Catatonia and NMS. (Grand Rounds Response) Psychiatric Bull. 2002; 26: 393. (with M.A. Taylor). (letter). 670. ECT in neurological disorders. Psychiatric Times 2002; 19 (9): 28-29. 671. Catatonia in adolescents and children. Psychiatric Times 2002; 19 (9): 28-29. 672. Book review: American Psychiatric Association. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training and Privileging. 2nd ed. Psychiatric Services. 2002; 53: 1040-1041. 673. Book review: Rage Against Electroshock. Kneeland TW, Warren CAB. Pushbutton Psychiatry. Westport CT: Praeger, 2002. J ECT 2002; 18: 112-113. 674. Book review. Electricity in Medicine: Ugo Cerletti’s Contribution. Electric Bodies: Episodes in the History of Medical Electricity. Paola Bertucci, Giuliano Pancaldi (eds.). Bologna, Italy: Universita di Bologna, 2001. J ECT 2002; 18:165-166. 2003 675a. Catatonia. A Clinician’s Guide to Diagnosis and Treatment. Cambridge UK: Cambridge University Press (with M.A. Taylor). 675b. Catatonia. Guía clinica para el diagnóstico y el tratamiento. Translated into Spanish by Beatriz M. Ruiz and Miguel B. Arroyo. Barcelona: Masson, 2005. 675c. …ibid., Translated into Japanese by Kazumasa Suzuki. Tokyo: Seiwa Shoten, 2007. 676. Catatonia in psychiatric classification: A home of its own. Am J Psychiatry 2003; 160: 1233-1241 (with M.A. Taylor). 677. A Beautiful Mind and insulin coma: social constraints on psychiatric diagnosis and treatment. Harvard Review of Psychiatry 2003; 11: 284-290. 51 �678. A Gilles de la Tourette form of catatonia: Response to ECT. J ECT 2003; 19(2): 115-117. (with H. Trivedi, A. Mendelowitz). 679. ECT Update: Recognizing and treating psychotic depression. J Clin Psychiatry 2003; 64: 232-234. 680. Therapy-Resistant Depression: When to consider ECT. Algorithm seeks respect for neglected therapy. Current Psychiatry 2003; 2: 49-54. 681. Commentary on “Successful use of ECT as the sole modality of treatment in a case of motility psychosis”: The classification of catatonia. J ECT 191: 48- 49, March 2003 (with M.A. Taylor). 682. Electroshock 2003. Masterminds Indian Psychiatric Society (Jan) 2003, 3-4. 683. Letter from India: Conflicts in the use of ECT. Psychiatric Times 2003 (Mar); 20: 10. 684. Book review. A classic text updated. Abrams R: Electroconvulsive Therapy, New York: Oxford University Press. J ECT 2003; 19:123-124. ibid. Psychiatric Times 2003 (Jun); 20: 25. 685. Book review. D. Healy. The Creation of Psychopharmacology. Cambridge MA: Harvard University Press, 2002. Psychiatric Times 2003; 220: 29. 686. Book review. G. Parker, D. Straton, K. Wilhelm, P. Mitchell; M-P. Austin, K. Eyers, D. Hadzi-Pavlovic. Dealing with Depression: A Commonsense Guide to Mood Disorders. New South Wales: Crows Nest, 2002. Am J Psychiatry 2003; 160:1365-1366. 687. Book review: K. Hugdahl, R.J. Davidson. The Asymmetrical Brain. Cambridge MA: MIT Press, 2003. Science Books & Films 2003; 9: 160. 2004 688a. Ethics of Electroconvulsive Therapy. New York: Brunner-Routledge (with J.O. Ottosson). 688b. …ibid., Translated into Japanese by Mitsuru Nakamura. Tokyo: Seiwa Shoten, 2006. 689. Pharmaco-Electroencephalography: A Selective History of the Study of Brain Responses to Psychoactive Drugs. In History of CINP, vol IV. Edited by T. Ban, E. Shorter, D. Healy. pp. 661-672. 690. Speed of Response and Remission in Major Depressive Disorder with Acute ECT: A Consortium for Research in ECT (CORE) Report (with M.M. Husain, A.J. Rush, R. Knapp, G. Petrides, T. Rummans, M.M. Biggs, K.M. O’Connor, K. Rasmussen, M. Litle, W. Zhao, H.J. Bernstein, G. Smith, M. Mueller, S.M. McClintock, S.H. Bailine, C.H. Kellner). J Clin Psychiatry 2004; 65: 485-491. 691. Efficacy of ECT in catatonia. In S.Caroff, S.Mann, A. Francis, G Fricchione (eds.): Catatonia. From Psychopathology to Neurobiology. Washington DC: American Psychiatric Press. 13: 151-160 (with G. Petrides, C. Malur). 692. Induced seizures as psychiatric therapy: Ladislas Meduna’s contributions in modern neuroscience. J ECT 2004; 20: 133-136. (commentary). 693. Response to T.E. Schlaepfer: Learning from the history of neuroscience: Dogma and patient interests. J 52 �ECT 2004; 20: 138. 694. Melancholy or Malarky? In Spitzer R.L., First M.B., Gibbon M., Williams J.B.W. (eds.): Treatment companion to the DSM-IV-TR casebook. Washington DC: American Psychiatric Publishing, 2004; 112-119. 695. Response to critique: classification of catatonia. Am J Psychiatry 2004; 161: 1136 (with M.A. Taylor). (letter). 696. Response. Catatonia in psychiatric classification. Am J Psychiatry 2004; 161: 2328. 697. Non-convulsive status epilepticus and electroconvulsive therapy. J ECT 2004; 20: 131-2. (letter). 698. Treat TSS and NMS as malignant catatonia. BMJ (rapid responses) 2004; 329: 1333-1335. 699. Convulsive therapy electroshock (ECT). In G. Adelman, B.H.Smith (eds.): Encyclopedia of Neuroscience, 3rd ed. Amsterdam: Elsevier B.V., 2004. 700. Insulin coma therapy (ICT). Encyclopedia of Neuroscience. In G. Adelman, B.H. Smith (eds.): Encyclopedia of Neuroscience, 3rd edition. Amsterdam: Elsevier B.V., 2004. 701. About Meduna’s pioneer activity. Neuropsychopharmacol Hung 2004; 6: 39. (letter). 702. ECT: Serendipity or logical outcome? Psychiatric Times 2004; 211: 21-22. 703. A new appreciation of ECT. Psychiatric Times 2004; 214: 32-35. 704. ECT at 70: What have we learned? Psychiatric Times 2004; 21(8): 13-14. 705. Book review. The Mount Everest Challenge. Lisanby S.H. (ed.): Brain Stimulation in Psychiatry. Washington DC: American Psychiatric Publishing Inc. Am J Psychiatry. 2004 (161): 2149-2150. 706. Book review. Schroeder B.E.: Ecstasy. Philadelphia: Chelsea House, 2003. Science Books and Films 2004 (May-June); 127. 2005 707. Catatonia. Guia clinica para el diagnóstico y el tratamiento. (Spanish translation). Barcelona: Masson Elsevier. 708. Psychobiology of Electroshock. In J. Licinio (ed.): Biology of Depression. Weinheim, Germany: WileyVCH, 2004. Chap 7: 211-221. 709. Relief of expressed suicidal intent by ECT: A Consortium for Research in ECT Study. Am J Psychiatry 2005;162: 977-982 (with C.H. Kellner, R. Knapp, G. Petrides, M.M. Husain, T. Rummans, M. Mueller, H. Bernstein, K. Rasmussen, K. O’Connor, G. Smith, A.J. Rush, M. Biggs, S. McClintock, S.H. Bailine, C. Malur). 710. Should the dexamethasone suppression test be resurrected? Acta Psychiatrica Scandinavica 2005; 112: 53 �245-9. (commentary). 711. Is the practice of ECT ethical? World Jrl Biological Psychiatry 2005; 6 (Supplement 2): 38-43. 712. The “treatment resistant” label in bipolar disorder is a misnomer. Psychiatric Annals 2005; 35: 965-8. (review). 713. Predicting the response to ECT. J ECT 2005; 21(3): 137-8. (editorial). (with V. McCall). 714. William Karliner: practitioner, experimentalist, and teacher. Obituary. J ECT 2005; 21: 201-2. 715. Suicide risk reduced. Psychiatric Times 2005; 222: 94-95. 716. The bean-counters view of ECT. Psychiatric Times 22; 10: 54. 717. Continuation ECT Today: What we know and what we need to know. Psychiatric Times 2005; 2214: 7677. 718. Use of pharmacologic coma for adult status epilepticus. Epilepsy & Behavior. 2005; 6: 292 (letter). (with D. Anschel). 719. Cheap shot at ECT. Lancet 2005; 365: 937 (with C. Kellner, V. McCall). (letter). 720. Book review. Kelleher, C.A.: Brain Trust. New York: Paraview Pocket Books, 2004. Science Books and Films 2005; 41:105. 721. Book reviews. Scull A. Madhouse: A Tragic Tale of Megalomania and Modern Medicine. New Haven: Yale University Press, 2005; J. El-Hai. The Lobotomist: A Maverick Medical Genius and his Tragic Quest to Rid the World of Mental Illness. New York: Wiley, 2005. J ECT 2005; 21: 191-3. 722. Book review. A. Scull: Madhouse: A Tragic Tale of Megalomania and Modern Medicine. New Haven: Yale University Press, 2005. Science Books and Films 2005; 41: 251. 2006 723. Melancholia: The Diagnosis, Pathophysiology, and Treatment of Depressive Disorders. Cambridge UK: Cambridge University Press, 2006 (with M.A. Taylor). 724. Catatonia in autistic spectrum disorders: A medical treatment algorithm. In D. Dhosshe, L. Wing, M. Ohta, K-J Neumarker (eds.): Catatonia in Autism Spectrum Disorders. Amsterdam: Elsevier/Academic Press. Int Rev Neurobiology 2006; 72:233-244 (with M.A. Taylor, N. Ghaziuddin). 725. Patterns of Psychotropic Medication Use Among Severely Depressed Patients Referred for Electroconvulsive Therapy: Data from the Consortium for Research on ECT. J ECT 2006; 22: 116-123 (with K.G. Rasmussen, M. Mueller, C.H. Kellner, R.G. Knapp, G. Petrides, T.A. Rummans, M.M. Husain, K. O’Connor, J.L. Black, S. Sampson). 54 �726. Continuation ECT versus pharmacotherapy for relapse prevention in major depression: a multi-site study from CORE. Archives General Psychiatry. 2006; 63: 1337-44 (with C.H. Kellner, R.G. Knapp, G. Petrides, T.A. Rummans, M.M. Husain, K. Rasmussen, M. Mueller, H.J. Bernstein, K. O’Connor, G. Smith, M. Biggs, S.H. Bailine, C. Malur, E. Yim E, S. Sampson, M Fink). 727. The case against evidence-based principles in psychiatry. Medical Hypotheses 2006; 67: 401-410. (with R.L. Levine). 728. Catatonia: Subtype or syndrome in DSM? Am J Psychiatry 2006; 163 (11): 1875-6, (with M.A. Taylor). (commentary). 729. Challenges to British ECT clinical practice. J ECT 2006; 22: 30-32. (commentary). 730. ECT in therapy-resistant mania: Does it have a place? Bipolar Disorders 2006; 8: 307-9. (commentary). 731. The DST riddle. Psychiatric Times 2006; 23 (2): 25-26. 732. Should the diagnosis of melancholia be revived? Psychiatric Times 2006; 23 (6): 78-80. 733. The Camelford hysteria: A lesson for ECT? Psychiatric Times 2006; 23 (11): 69-72. 734. Interseizure EEG slowing after ECT is not NCSE. Pharmacopsychiatry 2006; 39: 119. (letter). 735. Neuroleptic malignant syndrome is malignant catatonia, warranting treatments efficacious for catatonia. Prog NeuroPsychopharmacol Biol Psychiatry 2006; 30:1182-1183. (with M.A. Taylor). (letter). 736. Book review: G.S. Ungvari. Catatonia: An anthology of classical contributions. Hong Kong: Scientific Communications Int. Ltd. 2006. J ECT 2006; 22: 277-8. 737. AV Review: Healthy Brains. Chip Taylor Communications. Science Books & Films 2006; 42: 138. (review). 2007 738. Resurrecting melancholia. Acta psychiatrica scandinavica 2007; Supplement 433: 14-20 (with M.A. Taylor). 739. Melancholia: Restoration in psychiatric classification recommended. Acta Psychiatr Scand. 2007; 115: 89-92 (with T.G. Bolwig, G. Parker, E. Shorter). (conference summary). 740. DSM melancholic features are unreliable predictors of ECT response: A CORE publication. J ECT. 2007; 23: 139-146 (with A.J. Rush, R. Knapp, K. Rasmussen, M. Mueller, T. Rummans, K. O’Connor, M. Husain, M. Biggs, S. Bailine, C.H. Kellner, and CORE group.) 55 �741. Antidepressant Treatment Failure Does Not Predict Lower Remission Rates with ECT for Major Depressive Disorder. A Report from the Consortium for Research in ECT. J Clin Psychiatry 2007; 68: 17011706 (with K.G. Rasmussen, M. Mueller, R.G. Knapp, M.M. Husain, T.A. Rummans, S.M. Sampson, M.K. O’Connor, G. Petrides, C.H. Kellner). 742. Electroconvulsive therapy: Evidence and challenges. JAMA 2007; 298: 330-332 (with M.A. Taylor). 743. Complaints of the loss of personal memories after electroconvulsive therapy: Evidence of a somatoform disorder? Psychosomatics 2007; 48: 290-293. 744. Data management and design issues in an unmasked randomized trial of electroconvulsive therapy for relapse prevention of severe depression. J ECT 2007; 23: 244-250 (with K.G. Rasmussen, R.G. Knapp, M.M. Biggs, G.E. Smith, T.A. Rummans, G. Petrides, M.M. Husain, M.K. O’Connor, C.H. Kellner). 745. Belling the cat: ECT practice standards in the United States. J ECT 2007; 23: 3-5 (with C.H. Kellner). (commentary). 746. What we learn about continuation treatments from the collaborative ECT studies. J ECT 2007; 23: 215218 (commentary). 747. Ambulatory electroconvulsive therapy. J ECT 2007; 23: 130. (history). 748. Antidepressant medications and other treatments of depressive disorders: A CINP Task Force report based on a review of evidence. International Journal of Neuropsychopharmacology 2007; 10: S1-S207. (with N. Sartorius, T.C. Baghai, D.S. Baldwin, B. Barrett, D. Brand, W. Fleischhacker, G. Goodwin, H. Grunze, M. Knapp, B.E. Leonard, J. Lieberman, Y. Nakane, R.M. Pinder, A.F. Schatzberg, J. Svestka, P. Baumann, K. Ghalib, J.C. Markowitz, F. Padberg, T. Furukawa, K.N. Fountoulakis, P. Jensen, S. Kanba, A. RiecherRossler). 749. Improving electroconvulsive therapy practice. Psychiatric Times 2007; 24 (4): 10-11. 750. Electroshock works. Why? Psychiatric Times 2007; 24 (6): 59-60. 751. Major studies on ECT for depression: What have we learned? Psychiatric Times 2007; 24 (12): 26-28. 752. Catatonia or no catatonia: Still beyond lorazepam/amobarbital. Letter and Reply. Am J Psychiatry 2007; 164: 525 (with M.A. Taylor). 753. The renaissance of ECT. Forward for Electroconvulsietherapie: Aanbevelingen voor de praktijk. P. Sienaert, J. De Fruyt, M. Dierick (eds.). Ghent: Academic Press, 2007: xv-xviii. 754. …ibid., Book review: Dukakis K, Tye L. SHOCK: The Healing Power of Electroconvulsive Therapy. New York: Penguin Group, 2006. J ECT 2007; 23: 131-133. Commentary: Ambulatory electroconvulsive therapy (p.130). 2008 755. Restoring melancholia in the classification of mood disorders. Jrl Affective Disorders 2008; 105: 1-14 (with M.A. Taylor). 756. The medical evidence-based model to identify psychiatric syndromes: Return to a classical paradigm. Acta Psychiatr Scand 2008; 87: 81-84 (with M.A. Taylor). 56 �757. Karoly Schaffer and his school: The birth of biological psychiatry in Hungary, 1890-1940. Eur Psychiatry 2008; 23(6):449-456. (with B. Baran, I. Bitter, G. Gazdag, E. Shorter). 758. Change in seizure threshold during ECT: A CORE study. J ECT 2008; 24: 114-116 (with G. Petrides, C.H. Kellner, M. Mueller, R. Knapp, M.M. Husain, K. Rasmussen, T.A. Rummans, K. O’Connor). 759. Outcome of ECT by race in the CORE multi-site study. J ECT 2008; 24: 117-121 (with M. Williams, T. Rummans, S. Sampson, R. Knapp, M. Mueller, M. Husain, K. Rasmussen, K. O’Connor, G. Smith, G. Petrides, C.H. Kellner). 760a. The efficacy of acute ECT in atypical depression. J Clin Psychiatry 2008; 69: 406-411 (with M.M. Husain, S.M. McClintock, A.J. Rush, R.G. Knapp, T.A. Rummans, K. Rasmussen, C. Claassen, G. Petrides, M.M. Biggs, M. Mueller, S. Sampson, S.H. Bailine, C.H. Kellner). 760b. ECT not proven for atypical depression. Response to Letter C.M. Swartz. J Clin Psychiatry 2008; 69: 1662-3. (with M.M. Husain, S.M. McClintock, A.J. Rush, R.G. Knapp, T.A. Rummans, K. Rasmussen, C. Claassen, G. Petrides, M.M. Biggs, M. Mueller, S. Sampson, S.H. Bailine, C.H. Kellner, S.H. Lisanby). 761. Conceptual issues in DSM-V development (commentary). Am J Psychiatry 2008; 165: 799. (with M.A. Taylor). 762. Continuation treatments for melancholic depression. Commentary to M. Webber: electroconvulsive therapy, BMJ 2008; 337: 2998 (rapid response). 763. Catatonia in autism is treatable. Psychiatric Times 2008; 25: 17, 20. 764. Why evidence-based medicine cannot be applied to psychiatry. Psychiatric Times 2008; 25: 10-12. 2009 765. Electroconvulsive Therapy: A Guide for Professionals & Their Patients. New York: Oxford University Press, 2009. 766. Serendipity and science: A double anniversary of a treatment and a journal. J ECT 2009; 25: 1-2. 767. Laszlo Meduna’s pilot studies with camphor induction of seizures: The first 11 patients. J ECT 2009; 25: 3-11 (with G. Gazdag, I. Bitter, G.S. Ungvari, B. Baran). 768. Electrotherapy of melancholia: The pioneering contributions of Benjamin Franklin and Giovanni Aldini. J ECT 2009; 25:15-18 (with T. Bolwig). 769. Induced therapy in man. In Encyclopedia of Neuroscience. 2009: 5: 117-123. Edited by Larry Squire, Floyd Bloom, Fred Gage, Nick Spitzer. Oxford: Academic Press. 770. Electroconvulsive Therapy. In New Oxford Textbook of Psychiatry. Edited by M.G. Gelder, J.J. LopezIbor, and N.C. Andreasen. New York: Oxford University Press, 2009, vol II;6.2.10.1: 1251-1259. 771. Catatonia: A syndrome appears, disappears, and is rediscovered. Can J Psychiatry 2009; 54: 23-31. 772. Catatonia: Forgotten but not gone. Arch Gen Psychiatry 2009; 66: 1173-77 (with M.A. Taylor). 57 �773. Catatonia in 100 words. Br J Psychiatry 2009; 194: 325 (with M.A. Taylor). 774. Melancholia in 100 words. Br J Psychiatry 2009; 194: 463 (with M.A. Taylor). 775. The electroshock riddle: effective but rejected. Br J Psychiatry 2009; 195: 390. 776. Biological markers for melancholic depression are effective. Comment on the WFSBP Task Force Report. World Journal of Biological Psychiatry 2009 (103):252-3 (with M.A. Taylor). 777. Seizure threshold in a large sample: Implications for stimulus dosing strategies in bitemporal ECT. A report from CORE (with G. Petrides, R.J. Braga, M. Mueller, R. Knapp, T. Rummans, M. Husain, K. Rasmuussen, S. Bailine, C. Malur, K. O’Connor, C.H. Kellner). J ECT 2009; 25: 232-237. 778. Electroconvulsive therapy in the treatment of intractable status epilepticus. Epilepsy & Behavior 2009; 16:189-90. (letter). (with C.H. Kellner). http://dx.doi.org/10.1016/j.yebeh.2009.06.022 779. DSM-V: Applying the medical model. Psychiatric Times. 2009, June 9: 26 (6): http://www.psychiatrictimes.com/display/article/10168/1420772. 2010 780. Endocrine Psychiatry: Solving the Riddle of Melancholia (with E. Shorter). Oxford University Press. 781. Remembering: the forgotten neuroscience of pharmaco-EEG. Acta Psychiatr Scand 2010; 121: 161-73. 782. Catatonia is not schizophrenia: Kraepelin’s error and the need to recognize catatonia as an independent syndrome in medical nomenclature. Schizophrenia Bulletin 2009; doi: 10.1093/schbul/sbp059; 2010; 36: 31420. (with E. Shorter, M.A. Taylor). 783. The failure of the schizophrenia concept and the argument for its replacement by hebephrenia: applying the medical model for disease recognition (with M.A. Taylor, E. Shorter, N.A. Vaidya). Acta Psychiatr Scand 2010; 122: 173-183. 784. Phenomenology is not enough. J. McCarthy letter (response). Acta Psychiatr Scand. 2011; 123: 82-83. (with M.A. Taylor, E. Shorter, N.A. Vaidya). 785. The intimate relationship between catatonia and convulsive therapy. J ECT 2010; 26: 243-245. (commentary). 786. Catatonia in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. A. Francis , F. Appiani, A. Bertelsen, T.G. Bolwig, P. Braunig, S.N. Caroff, B.T. Carroll, A.E. Cavanna, D. Cohen, Cottencin O, M.J. Cuesta, J. Daniels, D. Dhossche, G.L. Fricchione, G. Gazdag, N. Ghaziuddin, D. Healy, D.F. Klein, S. Krüger, J.W.Y. Lee, S.C. Mann, M. Mazurek, W.V. McCall, W.W. McDaniel, G. Northoff, V. Peralta, Petrides G, P. Rosebush, T.A. Rummans, E. Shorter, K. Suzuki, P. Thomas, G. Vaiva, L. Wachtel). J ECT 2010; 26: 246-248. (letter). 787. Whither melancholia? The case for its classification as a distinct mood disorder (with G. Parker, E. Shorter, M.A. Taylor, H. Akiskal, G. Berrios, T. Bolwig, W.A. Brown, B. Carroll, D. Healy, D.F. Klein, A. Koukopolous, R. Michels, J. Paris, R.T. Rubin, R. Spitzer, C. Swartz). Am J Psychiatry 2010; 167: 745-47. (letter). 58 �788. Laszlo Meduna’s immigration to the United States in 1939: Correspondence with Victor Gonda (G. Gazdag, M. Fink, G. Ungvari, E. Shorter). J ECT 2010; 26: 79-81. 789. The human side of Laszlo Meduna. J ECT 26: 77-78. (commentary). 790. ECT is equally effective in unipolar and bipolar depression (with S. Bailine, R. Knapp, G. Petrides, M. Husain, K. Rasmussen, S. Sampson, M. Mueller, S. McClintock, K.G. Tobias, C.H. Kellner). Acta Psychiatr Scand 2010; 121: 431-436. 791. Bifrontal, bitemporal, and right unilateral electrode placement in ECT: A randomized trial (with C.H. Kellner, R. Knapp, M. Husain, K. Rasmussen, S. Sampson, M. Cullum, S. McClintock, K. Tobias, C. Martino, M. Mueller, S. Bailine, G. Petrides). Br. J. Psychiatry 2010; 196: 226-234. 792. A randomized controlled trial comparing the memory effects of continuation ECT versus continuation pharmacotherapy: Results from the CORE study (with G.E. Smith, K.G. Rasmussen, M. Cullum, M.D. Felmlee, G. Petrides, T.A. Rummans, M. Husain, M. Mueller, H. Bernstein, R. Knapp, M.K. O’Connor, S. Sampson, S.H. Bailine, C.H. Kellner). J Clin Psychiatry 2010; 71: 185-193. 793. The end of the asylum era in Central-Eastern Europe. History of Psychiatry 2010; 21: 501-504. (with G. Gazdag, B. Baran, Z. Rihmer). 794. ECT (Electroconvulsive Therapy) as first line treatment for psychotic depression. Letter reply to B.S. Meyers, A.J. Flynt, A.J. Rothschild et al.: The Study of Pharmacotherapy of Psychotic Depression STOP-PD. Arch Gen Psychiatry 2009; 66:838-47. (with C.H. Kellner, K. Tobias, G. Petrides). Arch Gen Psychiatry, 9 Feb 2010. (letter). 795. F.D. Zepf et al.: A 16-year-old boy with severe gamma-butyrolactone (GBL) withdrawal delirium. Pharmacopsychiatry 2010; 43: 157-8. (letter). 796. The perplexing history of electroconvulsive therapy in three books. Psychiatric Times 2010; (Oct) 27: 31 (with C.H. Kellner). (book review). 797. Book Review. Hysteria: The Biography. Andrew Scull. New York: Oxford University Press, 2009. SB&F April 2010. 798. Obituary: Sidney Merlis, 1925-2010. Neuropsychopharmacology 2010:35: 2648. 2011 799. Catatonia from its Creation to DSM5: Considerations for ICD. Indian Jrl Psychiatry. 2011; 53: 214-217. 800. Melancholia is a distinct identifiable mood disorder that warrants a separate category in DSM5. In: C.R. Soldatos and D.G. Dikeos (Ed): Psychiatry and the Neurosciences: International Perspectives. Bologna Italy: Editografica, 2011: 5-13. 801. ECT resurrected: Its successes and promises after 75 years. Can J Psychiatry 2011; 56:3-4 (Commentary). 802. Presidential Perspective: Defining clinical diagnoses by the medical model. In: Cottler L (Ed): Mental Health in Public Health: The Next 100 Years, NY: Oxford University Press, 2011: 278-281. 59 �803. Anti-NMDA receptor encephalitis vs. pediatric catatonia. [Comment on Case Report "Anti NMDA receptor encephalitis" Am J Psychiatry 2011;168: 245-51]. Am J Psychiatry 2011; 168: 749. [Dhossche D, Fink M, Shorter E, Wachtel LE] (Letter) 804. Transcranial magnetic stimulation is not a replacement for electroconvulsive therapy in depressive mood disorders. J ECT 2011; 27: 3-4. (Commentary) 805. Stimulus dosing in electroconvulsive therapy. J ECT 2011; 27:268. [Petrides G, Braga RJ, Fink M, Mueller M, Knapp RG, Husain M, Rummans T, Bailine SH, O'Connor K, Malur C, Kellner CH.]. (Letter) 806. ECT for melancholia. New York City Voices 2011; 18: 16. (Letter) 807. A response to Not “Au Revoir” but "Merci Beaucoup. J ECT 2011; 27:339. [Bailine S, Petrides G, Kellner C, Fink M, Bolwig T, Freeman C, Greenberg R, Kramer B, Fox H, Francis A, O'Connor K, Ray L, Satin A, Guerra F, Hermann C, Kayne E, Sevi S, Braga R.] (Letter) 808a. Obituary: Alfred M. Freedman. Psychiatric Times, June 2011, pg 24. 808b. Obituary: Alfred M. Freedman. Neuropsychopharmacology 2011, 36:2784. 809. Book Review: Nash Boutros, Silvana Galderisi, Oliver Pogarell, Silvana Riggio: Standard Electroencephalography in Clinical Psychiatry: A practical handbook. Chichester UK: Wiley-Blackwell, 2011. Acta psychiatr scand 2011; 124: 239-40. 810. Book Review. Will I Ever Be the Same Again? Transforming the Face of ECT (Shock Therapy). J ECT 2011; 27:262-3 [Kellner CH, Fink M.] 811. Book Review. Hobson, J.Allan. Dream Life: An Experimental Memoir. Science Books & Films 2011; 47(4):186. 2012 812. Hidden in plain sight: Catatonia in pediatrics. Acta psychiatr scand. 2012: 125:11-12. [Commentary] 813. Oral History of Neuropsychopharmacology: The First Fifty Years: Neurophyiology. Thomas Ban and Max Fink, Editors. Brentwood TN: ACNP. Volume 2: 319 pp. 814. Book Review: Bor, Daniel The Ravenous Brain: How the New Science of Consciousness Explains our Insatiable Search for Meaning. Science Books & Films 2012; 48(9): 243-4. 815. The responsible role for ECT in suicide prevention and treatment. In: A. Shrivastava, M. Kimball, D. Lester (Editors): Suicide from a Global Perspective: Risk Assessment and Management. Chap 14: pg 119126. 2013 816. Rediscovering Catatonia: The Biography of a Treatable Syndrome. Acta psychiatr Scand. 2013; 127: Supplement 441;1-50. [Fink M.] 817. Clinical practice to change with divorce of catatonia and schizophrenia. J Clin Pychopharmacology 2013; 33(3): 287-88. [Fink M.] 60 �818. Electroconvulsive therapy (ECT) for children, adolescents and adults with developmental disability and severe mental illness: A call for action. Am J Psychiatry 2013 [Wachtel L. Dhossche D. Fink M, Jaffe R, Kellner CH, Weeks H, Shorter E.] (Editorial). 819. Are depression's causes biological? The New York Times, September 16, 2013; pg A22. Letter. [with Edward Shorter]. 820. Introduction. Electroconvulsive Therapy: A Guide for Professionals and their Patients. Korean Edition; translated by Sangsoo Lee. Seoul S. Korea: Hana Medical Publishing Co., 233 pp. [Fink M.] 821. The Diagnostic and Statistical Manual of Mental Disorders, Fifth edition, divorces catatonia from schizophrenia. J Clin Psychopharmacology. 2013; 33(3):1-2. 2014 822. The mechanism of action of ECT. In: N. Ghaziuddin and G. Walter (Eds.): Electroconvulsive Therapy in Children and Adolescents 2014. New York: Oxford University Press. Chap 2, pp 18-28. [Fink M.] 823. The role of ECT in suicide prevention. J ECT:30: 5-9. [Fink M, Kellner CH, McCall V.] 824. What was learned: Studies by the Consortium for Research in ECT (CORE) 1997-2011. Acta Psychiatrica Scand. 129: 417-426. [Fink M.] 825. Thirty years of publication and continuing. [Editorial] J ECT 30: 1-2 [McCall WV, Kellner CH, Fink M.] 826. Celebrating 80 years of inducing brain seizures as psychiatric treatment. JECT 2014; 30:90. [Fink M.] 827. Revive flurothyl inhalation treatment in psychiatry? Psychiatric Times March 19, 2014 [Fink M, Shorter E] 828. The seizure, not electricity, is essential in convulsive therapy: The flurothyl experience. J ECT 2014; 30:91-93. [Fink M.] 829. The chemical induction of seizures in psychiatric therapy: Were flurothyl (Indoklon) and pentylenetetrazol (Metrazol) abandoned prematurely? J Clinical Psychopharmacology. 2014; 34(5):602-7. [Cooper K, Fink M.] 830. Convulsive and non-convulsive treatments in psychiatry. In: S. Bloch, S. Green, J Holmes (Eds.): Psychiatry: Past, Present and Prospect. New York: Oxford University Press, 2014. 831. Obituary. Turan M. Itil. Neuropsychopharmacology 2014; 39:3133-3134 2015 832. Electroconvulsive therapy versus pharmacotherapy for bipolar depression. Am J Psychiatry 2015; 172(3) 295-6. [Kellner CH, Fink M.] 833. Reply. [Comment on Wachtel L: Recognition of neuroleptic malignant syndrome and delirious mania as malignant catatoniain an autistic man with prompt relief with ECT.] Acta Psychiatr Scand. 132:320 61 �834. Seeing the King’s frenzy as catatonia. Acta psychiatr scand 132(6): 500-501. 835. Book Review. Le Bihan, Denis. Looking Inside the Brain: The Power of Neuroimaging. Princeton U Press. AAAS Science Books & Films. 2016 836. Catatonia is a systemic medical disorder. Acta psychiatr scand. 2016; 133(1): 250-1. [Fink M, Fricchione G, Rummans T, Shorter E.] 837. Bearing Witness: Personal and poetic descriptions of seizure therapy. J ECT 2016; 32(1): 13-16. [Fink M.] 838. Optimizing ECT technique in treating catatonia. J ECT 2016; 32(3):149-150. [Fink M, Kellner CH, McCall V.] 839. Barbara Fish: In Memoriam. Neuropsychopharmacology 2016; 41(13): 3118. 840. Hyperthermia for Major Depressive Disorder? JAMA Psychiatry. 2016 Oct 1; 73(10): 1096. 2016.1627. [Fink M, Shorter E.] 2017 841. Katatonie: Často Sevyskytující Klinický Syndrom Rozpoznatelný a Léčitelný. Catatonia: A Common Systemic Clinical Syndrome, Recognizable and Treatable. Čes a slov Psychiat 2017; 113(2): 84–93. 842. Does persisting fear sustain catatonia? Acta Psychiatr Scand 2017; Nov; 136(5):441-444. [Fink M, Shorter E.] 843. To define melancholia, follow the path of catatonia. Bipolar Dis 2017;19(5);401- 2. 844. Electroconvulsive therapy for self-injurious behavior in autism spectrum disorders: Recognizing catatonia is key. Current Opinion. 2017 Dec 18 [Epub ahead of print]. [Wachtel LW, Shorter E, Fink M] 845. Book Review. Electroshock as Means for Social Control. Sadowsky, J. Electroconvulsive Therapy in America: The Anatomy of a Medical Controversy. JECT 2017; 33:144-5. 846. ECT for catatonia and melancholia: No need for ambivalence. Psychiatric Times 2017; Sep: 16-17F. (Kellner CH, Fink M). 2018 847. ECT for Self Injurious Behavior in Autism: A New Indication. Psychiatric Times. 56 (2): 6-9. [Wachtel LE, Kellner CH, Fink M.] 848. Book Review: Electroconvulsive Therapy: Revival in German speaking Countries. JECT 34:70-71. 849. The Madness of Fear: A History of Catatonia. NY: Oxford University Press. [E. Shorter, M. Fink] 850. Electroconvulsive therapy for self-injurious behavior in autism spectrum disorders: Recognizing catatonia is key. Current Opinion. 2018; 31(2):116-122 [Wachtel LW, Shorter E, Fink M] 62 �851. Induced seizure therapy (ECT): Effective and safe, but stigmatized. Scientific American Psychiatry. DOI 10.2310/7800.13068 08/17 852. A useful example of pharmaco-electroencephalogram science. J Clin Psychopharmacology 38(6): 552554. (Invited Commentary). 2019 853. Electroshock Therapy and Catatonia: A Productive Synergism. JECT 2019; 35(4):219-221. 854. Catatonia: A Recognizable and Treatable Systemic Syndrome. In: Oxford Textbook of Neuropsychiatry, Chap 36; 437-445. NY: Oxford University Press, 2019 855. Book review: Semple, David. Pragmatic Guidance for EEG Interpretation. 2nd edition. Amazon Digital Services LLC, JECT 35(4):e60-61.2020 2020 856. Expanding the catatonia tent: Recognizing electroconvulsive therapy responsive syndromes. JECT: 2020 Oct 27. doi: 10.1097/YCT.0000000000000729 857. A protocol for a prospective descriptive prevalence study of catatonia in an acute mental health unit in urban South Africa. BMJ Open. Zingela, Z, Cronje J, Fink M, Van Wyk, S. BMJ Open 2020;10:e040176. doi: 10.1136/bmjopen-2020-040176 2021 858. Random Controlled Trial of Sham ECT Therapy: A Historical Note. JECT 2021 Mar 4. doi: 10.1097/YCT.0000000000000759. Online ahead of print. PMID: 33661180 . 63 �64 �Internet, Web-Based Articles 1998 W.01 Is catatonia a subtype of schizophrenia? http://www.mhsource.com/whatsnew/mfin-cataton.html W.02 EEG monitoring in ECT: A guide to treatment efficacy. http://www.mhsource.com/pt/p980570.html with Richard Abrams 1999 W.03 Pediatric ECT: An update. http://www.mhsource.com/pt/p990963.html with Carmel Foley W.04 Electroshock. An effective treatment for mental illness. http://www.electroshock.org W.05a The use of ECT in bipolar disorder (Consumer) http://www.mhsource.com/bipolar/ect2.html W.05b The use of ECT in bipolar disorder (Professional) http://www.mhsource.com/bipolar/ect1.html 2000 W.06 Pediatric ECT . A Review, June 2000. http://www.electroshock.org/archives/adolescent_ECT_review.htm W.07 NMS is best treated as catatonia. http://www.electroshock.org/archives/NMS-catatonia_review.htm W.08 ECT 2000. http://www.longislandpsych.org/arch/ECT/ECTframe.html W.09 ECT 2000. http://www. mdvista.com/library/journal/psychiatry/electroconvulsive_therapy_2000.htm 2001 W.10 ECT is effective in bipolar disorder. http://www.BMJ.com/cgi/content/full/321/7272/1302 W.11 Treating bipolar affective disorder. http://www.bmj.com/cgi/content/full/322/7282/365/a> W.12 Neuroleptic malignant syndrome and malignant catatonia: Effective treatment, http://www. mdvista.com/ 2002 W.13 Insulin coma therapy. 65 �http://www.pbs.org/wgbh/amex/nash/filmmore/ps_ict.html 2005 W.14 The social sources of psychopharmacology. http://media.snow.utoronto.ca:8080/ramgen/extra4/BE2005/BE2005-April29-5.rm 2009 W.15 ECT in treating status epilepticus. http://dx.doi.org/10.1016/j.yebeh.2009.06.022 2011 W.16 The race to Patent bio-Tests for Schizophrenia and Depression. http://www.psychiatrictimes.com/schizophrenia/content/article/10168/1994367 Updated April 15, 2019 66 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Biographical Files Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Curriculum Vitae of Max Fink Subject The topic of the resource <a title="Autobiography" href="http://id.loc.gov/authorities/subjects/sh85010050" target="_blank" rel="noreferrer noopener">Autobiography</a>, <a title="Psychiatry" href="http://id.loc.gov/authorities/subjects/sh85108381" target="_blank" rel="noreferrer noopener">Psychiatry</a>, <a title="Neurosciences" href="http://id.loc.gov/authorities/subjects/sh91006099" target="_blank" rel="noreferrer noopener">Neurosciences</a>, <a title="Neurology" href="http://id.loc.gov/authorities/subjects/sh85091139" target="_blank" rel="noreferrer noopener">Neurology</a> Description An account of the resource The Curriculum Vitae or CV of Max Fink, updated in 2021. Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank" rel="noreferrer noopener">Fink, Max, 1923-</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Date A point or period of time associated with an event in the lifecycle of the resource 2021-03-25 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank" rel="noreferrer noopener">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Relation A related resource The Max Fink Collection Format The file format, physical medium, or dimensions of the resource application/pdf Language A language of the resource en-US Type The nature or genre of the resource text Identifier An unambiguous reference to the resource within a given context mfp-cv-20210325 Biographical http://exhibits.library.stonybrook.edu/mfp/files/original/f36132b2b1eb8c86e51e7a9456e9e17d.pdf aca2be98c9971c66ad807e1d64ee1b8a PDF Text Text Reprinted from JOURNAL OF THE HILLSIDE HOSPITAL Volume IV July, 1955 Number 3 ��DELUSIONAL REDUPLICATION OF PARTS OF THE BODY AFTER INSULIN COMA THERAPY1 ROBERT L. Ph.D.,2 N. GRAUBERT, M.D.,3 and MAX FINK, M.D.4 KAI-IN, DAVID In recent years studies of behavioral changes occurring in altered states of brain function have gone beyond the description and interpretation of isolated phenomena. Emphasis has been placed on such factors as the particular environmental situation in which the behavior occurs, the total constellation or syndrome of associated behavioral changes, and the inﬂuence of the premorbid personality. Using these additional methods of study it has been demonstrated that many types of behavior found in brain disease are not defects, such as impairment of perception or memory, but represent forms of adaptation to the stress of illness (16). It has also been shown that various phenomena are not bizarre curiosities or unrelated fragments of neurological dysfunction, but form part of an orderly and meaningful pattern of an altered interaction with the environment. This report of a single case is presented because of the unusual opportunity it provides to study some of these behavioral changes. First, the patient was in a psychiatric hospital, under observation and in psychotherapy for four months, which made it possible to have an accurate and comprehensive picture of his behavior prior to brain damage. Secondly, the neurological symptoms were of rapid 1From the Research Service, Hillside Hospital, Glen Oaks, New York. This investigation was supported in part by grant M-927 from the National Institute of Mental Health of the National Institutes of Health, Public Health Service and by a fellowship of the Dazian Foundation for Medical Research (Dr. Kahn). This paper was read, in part, at a meeting of the New York Society for Clinical Psychiatry at Hillside Hospital, on March 10, 1955. 2Research Assistant, Hillside Hospital, Glen Oaks, New York. 3Resident Psychiatrist, Hillside Hospital, Glen Oaks, New York. iDirector of the Research Service, Hillside Hospital, Glen Oaks, New York. 134 �REDUPLICATION OF BODY PARTS IN I.C.T. 135 onset and actually developed in the presence of the examiners. Finally, it was possible to observe the patient intensively for a prolonged period afterwards, so that the subsequent changes in behavior could be adquately studied. It is the purpose of this report to evaluate (1) the signiﬁcance of the alterations in behavior, particularly the delusion of having extra parts of the body, and (2) the implication of the subsequent change in behavior for the understanding of the mechanism of somatic therapies. CASE HISTORY Present Illness The patient, a 34-year-old man, became acutely ill the night of September 25, 1954. Standing with clenched ﬁsts, gritting his teeth and without saying a word, he kept his wife in a corner of their bedroom for hours. The patient's family summoned a psychiatrist who referred him for immediate hospitalization. He received 15 electroshock treatments in a three~week period with some improvement. On transfer to Hillside Hospital, however, the patient was lethargic and failed to answer many questions. He said that he had come to the hospital for such reasons as “stomach disease,” “to talk over something with my wife,” and “to prepare myself for an examination." He felt he was being watched; that he was inﬂuenced by voices coming through the heating system; was being poisoned from a distance; and that there were changes in his body. He said he knew the exact minute when his wife was being unfaithful to him and expressed feelings that the world was coming to an end. There were frequent auditory hallucinations of being called unpleasant and derogatory names. Past History and Premorbid Personality This was the patient’s ﬁrst recorded psychotic episode. He is the youngest of ﬁve siblings, being the only boy. His father and mother were continually busy running a candy stand, and the patient was cared for primarily by his sisters. As a child he was dependent, demanding, and sought to be the center of attention. He developed a ﬂair for comedy and playing the clown to the extent that he was expected to have a career as a comedian, and on one occasion won second prize in an amateur show. At 12 years of age he became interested in playing drums. This became his sole preoccupation, for he devoted every spare moment to them. The patient suffered episodes of rheumatic fever at 10 years of age and again at 20 and, �136 KAHN—GRAUBERT—FINK at these times, was pampered by his family. During his late adolescence he was withdrawn, spending much of his time at his parents’ candy stand. He became overly concerned with his appearance and masculinity, brushed his hair for lengthy periods, exercised to acquire a good build, worried about his chest expansion and, according to his family, stared at his reﬂection in a mirror “kind of waiting for hair to grow on his chest." He spent much time exercising his left arm because he wanted it to be as strong as his right. He was concerned about a tooth that had not developed fully on the right side of his mouth. To prevent people from noticing this he developed the habit of talking and laughing out of the left side of his mouth, giving the appearance of facial asymmetry. He never enjoyed or settled down to any work. Besides his efforts as a comedian and drummer, he worked in a pocketbook factory, in a ladies apparel concern, and wrote songs and short stories. He was discharged from one position because he clowned all day long amusing his co-workers. He became a beautician after a friend interested him in it. He wanted to quit this too, but remained at the insistence of his fiancee. He was not ambitious for money, but very much wanted to ﬁnd a place for himself, needing reassurance about his sense of belonging. Although he comes from a secretive family where each member keeps things to himself, the patient was de— scribed as warm and friendly and drawn to the cause of people he considered the underdog or discriminated against. He was sentimental, being quite upset when having to visit someone in a hospital. He was overly sensitive and easily hurt, though not argumentative. The family reported a change in his behavior during the past six years. He had become more secretive about his friends and activities. He went with his ﬁancée for more than a year before anyone in the family knew about it. He developed many somatic complaints so that frequent visits were made to his physician, without his family’s awareness. Similarly, he told no one that he was in psychiatric treatment, and maintained his secret even though he found it necessary to steal money from his mother’s store to for pay this. He also kept secret his difﬁculty in hearing for many months. During the war he was drafted into service, became worried about having to go overseas, and sought and received a medical discharge because of rheumatic heart disease. Since 1948 he has been in intermittent psychiatric treatment. This was begun at the persuasion of a friend who was in therapy. The psychiatrist stated that the main effect of the therapy was to get him to look for some �REDUPLICATION OF BODY PARTS IN I.C.T. 137 kind of work, although he conﬁrms the patient’s inability to hold one job for any length of time. During this period two of his sisters have been under extensive psychiatric treatment for severe phobic reactions. He has been married for 21/2 years, never having dated much previously. His mother believes this the result of his being “pretty much of a home boy” and his fears about his rheumatic heart. His sister, on the other hand, reports that the mother made him feel guilty about leaving her alone in the store. She said he felt the responsibility of helping his mother ever since his father’s illness and death, and that he expressed feelings of guilt in leaving her to get married. The patient met his wife in 1951 at a party, and was married in 1953. During the ﬁrst two years of their marriage, the patient’s wife had two miscarriages. The second one in particular affected the patient. Soon thereafter he complained that there was something wrong with him, that he was not enough of a man, and that there must be a sickness in his body causing his wife to have abortions. He became increasingly depressed, withdrawn and fearful. Later, he became convinced his wife was unfaithful to him and that his wife and brother-in-law were conspiring against him. Course in Hillside Hospital During his hospitalization he became more withdrawn, and careless in his appearance and in the care of his room. He had little contact with other patients, and was preoccupied with his delusional thoughts and hallucinations. Physical examination revealed a presystolic and systolic murmur at the apex and a systolic murmur at the base without accentuation of the pulmonary sounds, or signs of enlargement of the heart. His blood serology was negative. There were no neurological ﬁndings except for right facial asymmetry and bilaterally diminished hearing. An electroencephalogram shortly after admission showed well-modulated, occasional random 5-7 cps activity, with 90% alpha. It was interpreted as showing minimal abnormality, consistent with drowsiness or a history of recent electroshock therapy. An amytal test for brain disease (13) was done on November 24, 1954. There was no change in orientation or awareness of illness, but he became more communicative and showed less overt tension during the procedure. Insulin coma treatment was instituted on December 8, 1954, and he had his ﬁrst coma on December 30. During the course of 18 coma treatments there was no signiﬁcant change in �138 - KAHN—GRAUBERT—FINK behavior until the morning of January 27, 1955. On that day he had his 19th treatment, was given 370 units of insulin, and went into coma for an hour and 50 minutes, comparable to his previous reactions. Following gavage he did not respond in the usual time, and he was given glucose intravenously. He awakened promptly, and was responsive, but a marked right hemiplegia was noted. He lay in bed with his head and eyes deviated to the left. There was no evidence of aphasia when tested for naming objects. He had a right facial paresis and a right homonymous hemianopia on confrontation. Reﬂexes were diminished on the right with a positive Babinski, and there was a right hemisensory syndrome with extinction on simultaneous stimulation tests. He raised his left arm on command but failed to respond when told to move his right arm. When his right arm was raised by the examiner and he was asked to identify it, he looked at it for some moments and said it was a “stranger” and “an intruder.” He reported smilingly that there was an extra arm on the right. He was unable to move his right leg on command, and he asked if it were his own. saying that he had seen him sometime in the past. The patient consistently showed this phenomenon of the reduplicated arm for the next hour. He referred to it as an “extra arm,” “a third arm,” and “a bootleg arm,” or personiﬁed it as a “stranger,” "this intruder” and “that fellow.” When his right arm was shown to him, he denied knowing whose arm it was, asking one of the attendants, “Did you slip me this arm—did you pick this old at an up auction in the neighborhood?” Another time when asked to whom it belonged, he said “I’m willing to pay a reward for it, and you’re asking me point blank.” He said he was sure that the arm was not his because “it doesn’t extend from my body” and “the dirt under the ﬁngernail is not recognizable.” The patient denied any disability of his own right arm, but said he’d never seen the extra arm work. He said, “My arm I can move with a brain impulse; this one I have to move manually since it isn’t mine.” During the course of questions about weakness in his right arm he said, “If that extra arm belongs to me, then I’m sicker than I thought I was.” The patient did not react to painful stimulation applied to his �REDUPLICATION OF BODY PARTS IN I.C.T. 139 right arm or leg. Even with his eyes open and his attention directed to the point of stimulation, he denied perceiving any stimulation on the right arm, saying “You’re not fooling me—you’re not touching me—you’re touching this third arm, that intruder.” He correctly identiﬁed stimuli applied to the right shoulder, but from the elbow down the touch was displaced to the extra arm. The patient lay with his head and eyes deviated to the left throughout the examination. He had difﬁculty perceiving any stimulus in the right side of space, a phenomenon which has been termed “spatial inattention." When given phrases to read he ignored the right side, reading only the material on the extreme left. Thus, “GOOD HUMOR ICE CREAM” was read as “GL.” When his right arm lay at his side he had trouble ﬁnding it. Once, when he was asked to show it to the examiner, he looked over his left side only and said, “I think I’ve been robbed—where is it?” A lumbar puncture was done and a clear, colorless ﬂuid obtained. The ﬂuid was under increased pressure even though the patient was relaxed. The pressure was recorded as 300 mm., the total protein was 32 mg. per cent, and there were two white cells per cubic mm. During the ensuing hours the patient continued to be euphoric and loquacious. He recited long-forgotten lessons and parts of neurological texts whose source was unknown to him. For instance, he gave a complete description of the course of the facial nerve, and described the muscles of the face, calling them by their correct Latin names. He laughed frequently, and recited cryptic remarks as “in the instrument—insulin—instrument—insulin—instrument ward.” Disturbances in memory or recall were not elicited. The delusional “extra arm” disappeared. An electroencephalogram obtained that afternoon was ﬂat in all leads on the left side and showed random 5-7 cps activity, chieﬂy on the right side. Both alpha and beta were prominent on the right side only. The record was interpreted as showing diffuse dysfunction with left-sided accentuation. In the afternoon the patient was subdued. The weakness of the leg and arm showed some resolution. His relationship to his therapist was completely changed compared to his previous behavior. There was a complete absence of anger, negativism, withdrawal and depression. He clung to his doctor, shook hands, held him back and did not want to be separated from him. He was pleasantly preoccupied with the morning’s episode and joked about it. He was eager to communicate, and even his hearing seemed to have improved. The next morning the patient was depressed, restless, bewildered, �140 KAHN—GRAUBERT—FIN K slow in answering questions and failed to respond when asked about his illness. He spoke in a low voice, at times inaudible. He was disoriented for time of day and was aware of “numbness” in his right arm. He spontaneously asked, “What happened to me—why am I taking all this depletion?" Minimal weakness of the right arm and leg were noted. There was astereognosis in the right hand, but tactile stimuli were correctly localized, and there was no evidence of hemianopia or inattention. When asked about the extra arm the patient was vague and evasive, but did say, “Evidently somebody else was with me and it was their arm I picked up." That afternoon the patient was given 0.5 gm. amytal sodium. Besides its use as a test for organic brain dysfunction, the drug was given in an attempt to elicit the delusion again (14). At this time there was neither a change in orientation nor a recurrence of the reduplication. There was, however, a marked change in mood and language. The patient became very euphoric and talkative. His speech was characterized by ornate, circumstantial, pedantic, histrionic, and cryptic features, with much use of clichés. For example, asked about the extra arm, he said, “I think it will come looking for me when and if the occasion is propitious, as it were.” When asked why he was here, he said, “On the recommendation of the right honorable Dr. Fink, most distinguished doctor on the eastern seaboard Atlantic area whose fame has spread far and wide." Several times he blurted out the cryptic remark—“transference of aggression." When asked what he meant, he said, “If you can’t kick your mother-in-law in the head, you try your father-in-law.” When asked about his arm the patient was evasive, circumstantial and jocular. For example, asked how the extra arm was different from his own arm, he said, “How was it different? For one reason, in the sensitivity of feel. I raised up my left arm and that was all right. When I went to raise up what I thought was right my arm that was all right. But when I went to raise this third arm I did not feel any sensitivity when raising it, lifting it, touching it or otherwise in no manner could I relate it to my corpus—.” When asked about weakness in his right arm, he said, “It feels little less a dynamic in its volition, and I’m tempted to believe in its delivery, as it were.” While the delusion was not present at this time, the patient insisted that there had been an extra arm the day before, saying, “I was lying in bed and it came to my aware the presence of another arm in my bed.” When he was told that the extra arm was really his own right arm, he said, “Well, I’ll tell you. I never argue with �REDUPLICATION OF BODY PARTS IN I.C.T. 141 facts. You see if you’re surmising that it was, and I were to agree, it would be only for professional courtesy’s sake.” Or at another time, when the possibility of the extra arm was being questioned by the examiner, the patient said, “I don’t think it was mine. It might have been mine, you see, but then I would have to have a comprehensive knowledge of the numerous preponderous volumes of ancient history in associated situations. And then I might be even able to volunteer that extra leg which you spoke of before—and beyond. I might even—be able to extend some photographs of the uterus which I own. If I could have the extra arm, the additional leg, and as I said, other things.” For the next two days he continued to be depressed, spoke slowly in a low voice, and showed no spontaneity. He complained of feeling “depleted.” There was no difficulty getting him into a conversation and he would elaborate in a circumstantial way about the pain in his head and the numbness in his hand. He refused to get into conversation about his extra arm, saying, “You're making fun of me." Neurological examination was completely negative. An electroencephalogram on February 2, 1955 showed a resolution of the asymmetry and abnormality of the previous record. It was similar to that obtained on admission. The patient was given amytal again on February 2 and 9. On both occasions he showed a similar response to that obtained on January 28, with euphoria and changes in language. His attitude, however, toward the extra arm and to the weakness of his right arm was altered. He now said that the extra arm might have been a hallucination due to the drugs he was receiving. He also admitted having had weakness of his right arm, saying, “To the best of my recollection there was a general weakness which might have had a speciﬁc attenuating dilemma in the appearance of an arm which might have been, to some degree, in a state of difﬁculty.” On March 2, he was given amytal again. This time his reaction was more like that seen on admission, although he became slightly euphoric and loquacious toward the end. In the weeks following the eventful insulin coma, there was a change in his clinical behavior. He appeared more sure of himself, and was co-operative and friendly. He started to press for his discharge. He said that there were things to be done which he, and not somebody else, should do, but would not specify these things. His wife visited him and told him she had decided to divorce him and would not accept him back in his home. The patient took this announcement without overt emotion. He was unable to give any reason for his wife’s plans, and stated that he forgot to ask her why. �142 KAHN—GRAUBERT—FINK He still wanted to be sent home as soon as possible because, he said, he was ready to take up some kind of business. He felt that he had failed up to now because of reasons unclear to him, but that if he were careful, it would not happen to him again. This behavior was markedly different from that shown admison sion. In contrast to hisprevious aggressive, uncommunicative and withdrawn behavior, he was co-operative, ingratiating, overanxious to please, and made attempts at socializing with other patients. His of a psychiatrist. DISCUSSION The delusion of reduplication of parts of the body has rarely been reported. The earliest reports are by Bechterev (1) in 1926 and Ehrenwald (3) in 1930. In 1935, Schenderov and Gamaleja (9) described six cases and suggested that more might be found if the phenomenon were better known. In these early studies the phenomenon was regarded as a neurologic curiosity and was explained on the basis of sensory disturbances. In the work of Critchley (2), who reported a similar case in 1952, it was considered as a manifestation of disturbance in “body image" due to a parietal lobe lesion of the nondominant hemisphere. In 1954, four cases were reported by Weinstein et al. (14) demonstrating that the phenomenon could not be explained on the basis of sensory impairment, and was not dependent on a focal parietal lesion. They interpreted the delusion as a symbolic phenomenon rather than a sensory or perceptual disturbance, and showed that it occurred only in a setting of diffuse cerebral dysfunction. indiThey cated that parts of the body were redupli‘cated which were defective in some way, regardless of whether or not there was any neurological involvement. It was pointed out that the delusional reduplication of body parts is but one manifestation of reduplicative phenomena. Thus reduplication for time, place and person has also been reported (11). In reduplication for time the patient confabulates that a present experience has also been experienced at a time in the past. For example, a patient identiﬁes members of the staff as old friends or relatives. Reduplication for place is the confabulation that two or more places with the same name and similar attributes exist, when actually. there is only one. Thus, a patient may say there are two �REDUPLICATION OF BODY PARTS IN I.C.T. 143 hospitals with the same name and same staff, but locate one closer to his home and describes it as a hospital which treats convalescent or minor cases only. In reduplication for person the patient confabulates the existence of two persons when there is actually only one. One woman, for instance, said she had two sons, one named “Bill,” and the other “Willie," when actually she had one son named William. It was shown by Weinstein et a1. (14) that reduplication was usually expressed in more than one modality. All patients with delusional reduplication of body parts showed, in addition, reduplication for time, place and/or person. In the present case the patient also expressed temporal reduplication, describing one of the examiners as someone he had known prior to his hospitalization. The symbolic importance of the various phenomena of reduplication is evident in their motivational character. In the perception of a doctor as an old friend or a relative the patient is reassuring himself that he has less to fear than he would from a total stranger. In reduplication for place the patient who locates the extra hospital near his home or describes it as treating only convalescent or minor cases is minimizing his illness. The patient who confabulated having two sons, while denying her own illness, complained that poor “Willie" was in an accident and was afraid that something terrible had happened to him, thus displacing her concern from herself to the extra person. The delusion of reduplication of parts of the body also is a mechanism facilitating denial of illness. While the patient states that there is nothing wrong with his own body, it is the reduplicated arm or leg which is said to be weak or impaired. In the present instance the patient, who in his premorbid behavior was excessively worried about bodily ailments, was unconcerned about his severe disability. Instead, by denying having any trouble with his arm and saying it was the ”extra” arm that didn’t work, he was able to maintain his euphoria and jocularity. While reduplication is shown mainly as a symbolic adaptation to the problem of illness, it may also be a symbolic expression of other wishes, needs and feelings. For example, a patient with intractable pain had been noisy and demanding and had aroused the antagonism of members of the staff. Following a course of electroshock therapy her complaints of pain were gone and her relations with the staff were considerably improved. Along with other changes in orientation, she confabulated that there were two Mount �144 KAHN—GRAUBERT—FIN K Sinai Hospitals, the old one where people were mean to her, and the new one where everybody was so nice (12). The delusional reduplication of parts of the body appears to be related to certain aspects of the premorbid personality. In the present case, and in those reported by Weinstein et al. (14), all the patients demonstrated a special concern with the symbolic importance of physical characteristics. Our patient was concerned with his build, the strength of the muscles of his left arm and the presence of hair on his chest. He was also sensitive about a tooth which had not come out fully and attempted to conceal it. In the earlier study (14) a patient who had developed the delusion of multiple heads following a craniotomy, had been preoccupied with his baldness and had engaged in numerous extramarital affairs to prove that he was capable of attracting women. A patient, who confabulated having three eyes, was very sensitive about a prosthetic eye and would face people directly forward so that divergence Of his eye would not be noticed. He was also preoccupied with his build and physical appearance, engaged intensively in Yogi and Judo, and was concerned with his ability to satisfy his wife sexually. In recent writings on “spatial inattention” (16, 17) it has been indicated that this, too, represents a form of symbolic adaptation. In this case the patient consistently avoided looking to the right side, was unable to ﬁnd the “extra” arm when it lay at his side, and only read the extreme left part of phrases shown to him. This behavior facilitated the denial of weakness of his right arm as well as helped maintain his delusion of the extra extremity. His personality also showed features that have been described as characteristic of persons with “spatial inattention” (17). He was very secretive, especially in recent years, and seemed overly concerned with the symbolic signiﬁcance of violence, as shown by his discomfort on visiting hospitals, his fear of going overseas and by an apparent confabulation that he had once been a secret witness to a murder. The marked ludic behavior shown by the patient during the period of his delusion and during the later amytal tests is also related to his premorbid personality. He was described as having been a good mimic with a ﬂair for clowning. Ludic behavior has also been regarded as a form of adaptive behavior (15) in which the patient acts out a feeling of well-being, implicitly denying his illness. It is of theoretical interest that the delusional reduplication and “spatial inattention” occurred with right-sided symptoms. Disorders of the “body image” and spatial awareness have been regarded as characteristic of nondominant lesions. In this case, with apparent �REDUPLICATION OF BODY PARTS IN I.C.T. 145 dominant hemisphere involvement but without aphasia, it was possible to study these behavioral changes as clearly as with nondom— inant lesions. One must conclude that in the usual case of a dominant lesion, pathology which is sufficiently extensive for these changes to occur, will also result in an aphasic disorder which masks the phenomena. The neurologic lesion which was the basis for the reported of diffuse behavior in alteration dysfunction a and was phenomena the cerebrum with accentuation of the left hemisphere. Such disturbances in neurologic function are not uncommon in insulin coma therapy, and are the result of persistent cellular dysfunction despite restoration of the glucose level of the blood. While one may ascribe etiological importance in the production of this patient’s hemiplegia to the history of rheumatic fever and the cardiac murmurs, this is not warranted considering the absence of other rheumatic phenomena either before or subsequent to the event. It is more meaningful to regard this incident as one manifestation of the central nervous system damage incurred by prolonged hypoglycemia. Such manifestations include all aspects of nervous system functions including seizures, transient hemiplegia and aphasia, confusional syndrome and Korsakoff psychoses, prolonged coma and death (6). Recent studies of the electroencephalographic changes during prolonged coma (18) and minor neurologic signs following insulin coma treatment (19) amplify the variety of neurologic sequelae of this treatment. The importance of cerebral damage in the mechanism of somatic therapies has recently been re-emphasized by Weinstein and Kahn (12, 16). They suggest that improvement following somatic therapies is characterized by manifestations of denial in a milieu of altered brain function. A study in this laboratory (5) has supported this hypothesis concerning electroshock therapy; Improved patients showed signiﬁcantly earlier and more persistent alterations in brain function as measured by the amytal test (13) and by serial electroencephalographic studies (4), and more changes in language and behavior indicative of denial, than did patients who failed to improve. Recent case reports of the effects of prolonged insulin coma by Revitch (8), Kwalwasser and Caplan (7), Shagass and Rowsell (10), and Yeager et a1. (18) point to the behavioral improvement and discerebral when of damage superschizophrenic symptoms appearance venes. In this patient, too, there was an immediate, marked and cerebral with concomitant behavior damage. in change persistent �KAHN—GRAUBERT—FINK 146 It was possible here to demonstrate not only explicit verbal denial of illness, but other aspects of denial as reduplication, spatial inat- tention and changes in mood and language. Thus, the observations in his case are consistent with the hypothesis of Weinstein and Kahn. Further studies of the role of premorbid personality in denial, and on the mechanism of somatic therapies are now in progress. SUMMARY AND CONCLUSION A case history is presented of a 34-year-old man with a fourmonth history of acute mental illness who was placed on insulin coma therapy. After his 19th coma he developed a right hemiplegia, hemianopia, hemisensory syndrome and “spatial inattention,” and became ludic, euphoric and loquacious.'At this time he showed delusional reduplication of body parts, expressing the conviction that while there was nothing the matter with his right arm, there was an “extra" arm in his bed which did not belong to him and which did not work. 2. The signiﬁcance of reduplication is discussed in terms of a symbolic adaptation to illness. This phenomenon, as well as his other changes in behavior such as “spatial inattention" and ludic behavior, is considered to be related to his premorbid personality. 3. The presence of these phenomena in a case with right-sided symptoms is considered with reference to anatomical localization. These ﬁndings contradict the traditional view that “body image" disorders and “spatial inattention” depend on a nondominant hemisphere lesion. 4. The subsequent changes in the patient’s behavior, in which he showed complete recovery from his illness, is discussed in terms of its implications for the mechanism of action of insulin coma therapy. The results are considered to support the theoretical view that improvement in the somatic therapies is characterized by manifestations of denial in a milieu of altered brain function. 1. REFERENCES Bechterev, V. M.: Obozr. Psikh., 1926, cited by Schenderov and Gamaleja. Critchley, M.: A Phantom Supernumerary Limb after a Cervical Root Lesion, Arq. Neuro-Psiquit., 10:269-275. 1952. (3) Ehrenwald, H.: Altered Perception of the Body Image with Consequent Psychosis in Left Hemiplegia. Mschr. f. Psychiat. u. Neurol., 75:89-97, 1930. (4) Fink, M. and Kahn, R. L.: Relation of Electroencephalographic Changes and Improvement in Electroshock Therapy. In preparation. (1) (2) �REDUPLICATION OF BODY PARTS IN I.C.T. 147 Kahn, R. L., Fink, M., and Weinstein, E. A.: Relation Between Altered Brain Function and Denial in Electroshock Therapy. In preparation. (6) Kalinowsky, L. B. and Hoch, P.: Shack Treatment, Psychasurgery and Other Somatic Treatment in Psychiatry (2nd ed.). New York: Grune 8c Stratton, (5) 1952. and Caplan, M.: A Case of Prolonged Insulin Coma: Treatment. This Journal, 1:145-155, 1952. Revitch, E.: Observations on Organic Brain Damage and Clinical Improvement Following Protracted Insulin Coma. Psychiat. Quart., 28:72-92, 1954. Schenderov, L. I. and Gamaleja, K. N.: Peculiar Disturbance of Body Scheme in Hemiplegics (Pseudomelia). J. Nevrol. Psihhiat. i Psikhogig., 4:361-372, (7) Kwalwasser, S. (8) (9) 1935. and Rowsell, P. W.: Serial Electroencephalographic and Clinical Studies in a Case of Prolonged Insulin Coma. A.M.A. Arch. Neural. (‘5' Psychiat., 72:705-711. 1954. (11) Weinstein, E. A., Kahn, R. L., and Sugarman, L. A.: Phenomenon of Reduplication. A.M.A. Arch. Neural. & Psychiat., 67:808-814, 1952. (12) Weinstein, E. A., Linn, L., and Kahn, R. L.: Psychosis During Electroshock Therapy: Its Relation to the Theory of Shock Therapy. Am. J. Psychiat., (10) Shagass, C. (13) (14) (15) (16) 109:22-26, 1952. Weinstein, E. A., Kahn, R. L., Sugarman, L. A., and Linn, L.: Diagnostic Use of Amobarbital Sodium (“Amytal Sodium") in Brain Disease. Am. J. Psychiat., 109:889-894, 1953. Weinstein, E. A., Kahn, R. L., Malitz, S., and Rozanski, ].: Delusional Reduplication of Parts of the Body. Brain, 77:45-60, 1954. Weinstein, E. A., Kahn, R. L., and Sugarman, L. A.: Ludic Behavior in Patients with Brain Disease. This journal, 3298-106, 1954. Weinstein, E. A. and Kahn, R. L.: Denial of Illness. Springﬁeld, 111.: Charles C. Thomas, 1955. (17) Weinstein, E. A., Kahn, R. L., and Slote, W.: Withdrawal, Inattention and Pain Asymbolia. A.M.A. Arch. Neural. (9 Psychiat., in press. (18) Yeager, C. L., Simon, A., Margolis, L. H., and Burch, N. R.: Electroencephalographic Studies in Posthypoglycemic Coma. J. Nerv. & Ment. Dis., 118:435-441, 1953. (19) Ziegler, D. K.: Minor Neurologic Signs and Symptoms Following Insulin Coma Therapy. J. Nero. (3' Ment. Dis., 120:75-78, 1954. �6&3»; a; M '4 ’ u ��an m w ‘~ w m at m w m was. M M , ' , .. ”MW; mm a; m. . M3mg, W M §F mm man—5.... ��mmmmmwwmmmiw- mummmuummmnmmmmm~' hag-6“} m IZLv*"' ,-Mv.-..‘w+,w A .w ~ ��' ~19- a We "a u ' of W M w W m M a -::.,.; m m mm mm M m u m . ��WW*WWMWW“WWMMWW ‘ WMWNWWWQﬂiwwm‘ a m. m m mm m mm w - Wmmwgmmwwmamwmw . *meummmim «WM W W M Wm w w m «mm W (X); . mammary In wmmmmmmwmwmm �,, m w W» m W mm m m ��m mM m - , �Vt,“ ~ m as. a. m » ~ ~ ‘ - � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Delusional reduplication of parts of body after insulin coma therapy. Journal of the Hillside Hospital, 4: 134-147, 1955. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-001-16-020 Date A point or period of time associated with an event in the lifecycle of the resource 1955 Creator An entity primarily responsible for making the resource Kahn, Robert L.; Graubert, David N.; <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [Preprint] and reprint. Reprint from JOURNAL OF THE HILLSIDE HOSPITAL Volume IV July, 1955 Number 3. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/f7c87e4b8450f1ed2913d4dcd19d8101.pdf 28b2641c12bb8afccfb2c988034e1cc8 PDF Text Text Reprinted from the ISRAEL STRAUSS COMMEMORATIVE VOLUME Journal of the Hillside Hospital Volume V, Numbers 3 - 4 October, 1956 �DENIAL OF BLINDNESS FOLLOWING CEREBRAL ANGIOGRAPHY MAX FINK, M.D.1 In the ﬁfty-eight years since the original report of Anton (1), there has been controversy in the literature as to whether denial of blindness is the result of a speciﬁc focal cerebral lesion or of a generalized disturbance of brain function without speciﬁc localizing signiﬁcance.2 In reviewing the cases of denial of blindness, the majority of reports describe the patients as “confabulating,” “disoriented,” or “showing a Korsakoff psychosis.” Such descriptions lend support to the concept that denial occurs in a milieu of altered cerebral function. Studies of denial of hemiplegia, usually described under the term “anosognosia,” bring out identical arguments as to the signiﬁcance of the phenomenon for localized dysfunction. Indeed, in many reports of denial of blindness, note is made of simultaneous denial of hemiplegia or of other defects. The literature of denial of illness, as well as clinical and experimental evidence to support their concepts, has been recently summarized by Weinstein and Kahn (23). They conclude that various forms of denial are a unitary phenomenon without cerebral localizing value, and that denial is an adaptation to a defect in the milieu of diffusely altered cerebral function. In this regard, most of the defects denied are of rapid onset, are not limited to one defect, are accompanied by confabulation, amnesia, changes in mood and absence of anxiety. The degree of altered cerebral function which provides the milieu for such adaptation is usually severe. Thus, their reports, as well as those of other authors cited (see footnote 2), Director, Research Service, Hillside Hospital, Glen Oaks, N. Y. 2The reviews of Critchley (6) and Weinstein and Kahn (23) present the two aspects of this problem. For speciﬁc reports ascribing the phenomena to focal cerebral disease see Barkman (2), Gerstmann (10), von Hagen and Ives (21, 22), Ives and Nielsen (l2), and Paul (16). Reports ascribing the phenomena to diffuse cerebral disturbances include Lunn (13), Redlich and Bonvicini (l7), Redlich and Dorsey (18), and Sandifer (19). 238 1 �DENIAL OF BLINDNESS 239 describe the phenomena of explicit denial of blindness and of hemiplegia as occurring in patients with brain tumors, subarachnoid hemorrhages and vascular disease. The following case history is presented as exemplifying various aspects of the syndrome of denial. The data support the thesis that the phenomenon is an adaptive response to a defect under the conditions of altered cerebral function, rather than the result of focal cerebral pathology. A patient, under observation for enlargement of the sella turcica presumably the result of pituitary adenomatous growth, was subjected to cerebral Iodopyracet (Diodrast) angiography. Before the procedure he was alert and oriented, but immediately following the second series of injections of Iodopyracet, he developed left hemiplegia, which gradually resolved. In the ensuing hours, blindness developed and was denied by the patient. The syndrome persisted for 48 hours, and then resolved. When the patient was seen in a follow-up visit eight months later there was an amnesia for the period of denial. Case Report:3 E. S., a 58-year-old right-handed male, was admitted for diagnostic study to the Monteﬁore Hospital with a sixmonths history of headaches and blurring of vision. Four months previously he had an episode of ptosis of the right lid associated with dilatation of the right pupil, which had persisted for a few weeks. Headaches became increasingly severe, and X—ray examination of the skull prior to admission demonstrated an enlarged sella turc1ca. He related his own history; appeared neither acutely nor chroni— cally ill; was alert, well oriented, and cooperative, with good memory and calculating ability. He was jovial, made friends readily, and was well liked. He denied previous severe illnesses, or persistent somatic complaints. He was fastidious about his personal belongings and was reluctant to intrude. The general examination was normal except for palpable enlargement of the right lobe of the thyroid gland. Neurological examination was normal except for the cranial nerve examination. His pupils were dilated, the right larger than the left. The reaction to light was sluggish on the right, and the pupils reacted well to near vision. The fundi showed well-outlined papillae with clear margins, deﬁnite temporal pallor, and normal vascularization. Visual acuity was 15/20 on the right, and 15/40 on the left. Visual ﬁelds to 1/2000 white test object demonstrated a relative bitemporal hemianopsia without macular sparing. The lumbar puncture and routine blood and urine studies were normal. Skull X-ray revealed enlargement of the sella turcica; atrophy of the anterior and posterior clinoids; and calciﬁcations along 3 Patient studied through the courtesy of Dr. Nathan Savitsky at the Monte- ﬁore Hospital. �240 MAX FINK the lateral border of the sella. Pneumoencephalography demonstrated encroachment of the cisterna chiasmatis and pontis by a mass originating from the sella. An electroencephalogram showed a slight degree of electrical abnormality on the left side, mainly inferior and posterior. Alpha frequencies and amplitude were symmetric. For further clariﬁcation of the pathologic process, carotid angiography was recommended. Under local anesthesia, the right common carotid artery was exposed, and forty cc. of 35% Iodopyracet (Diodrast) was administered. Since the serial angiograms thus made were unsatisfactory, another injection of 15 cc. Iodopyracet was made. Immediately following this injection, the patient developed a complete left hemiparesis, including the face. He was restless, confused and irritable. He appeared drowsy; failed to obey commands and was irrelevant in speech. Vasodilators were administered, and the hemiparesis showed some improvement. That evening he was restless, directing his gaze most often to the right. When spoken to from his left side, he would turn his head to the right or backward, before ﬁnally localizing the voice correctly. He answered questions relevantly. Visual acuity was reduced to light perception, and pupillary reactions were present, though sluggish. He was unable to localize the position of a light nor identify ﬁngers or objects; yet he denied his inability to see, confabulating seemingly appropriate responses. He was oriented for place but only approximately for time and date. Despite a large neck bandage, he denied the recent cutdown. A lumbar puncture was performed. The initial pressure was 140 mm. CSF, ﬁnal pressure of 60mm. after the removal of 8 cc. of clear, colorless ﬂuid which had no cells and a protein content of 43 mg%. Twelve hours later, now oriented in space and time on gross questioning, he was still unable correctly to localize light or perceive objects. There was a residual left hemiparesis. He denied both his weakness and his blindness. When walking about the room he stumbled over objects and bumped into the wall and the bed. He correctly identiﬁed the various examiners by their voices, and named a coin, key, pencil and comb by touch. There was no sensory loss on single stimulation; gait was hesitant; and the reﬂexes were increased on the left with bilateral Babinski responses and absent abdominal reﬂexes. Thirty-six hours later the hemiparesis had cleared except for a residual left Babinski response. He perceived light and localized it well in‘space, but image formation for reading or ﬁne identiﬁcation was impaired. Despite the partial nature of his vision, he still failed to recognize his impairment, confabulating many responses. An electroencephalogram at this time showed a change from the original record. There was bilateral asymmetry with high per cent time delta activity and a slowed, poorly organized alpha rhythm, mostly on the right. Forty-six hours later his vision had returned so that he was able �DENIAL OF BLINDNESS 241 to read. He was oriented, alert, affable and friendly. He maintained that he had been able to read and to see throughout the previous two days. He had an amnesia for the surgery, the hemiparesis and the blindness. During the ensuing weeks, visual acuity returned to normal; with visual ﬁelds manifesting minimal bitemporal hemianopic defect. An electroencephalogram one week later showed posterior voltages to be less depressed; per cent time delta activity had decreased; and there was desynchronization of the record on delta the of accentuation focal abnormality There was opening. eye in the right frontal leads. Three weeks later the electroencephalo— inwith abnormalities of the resolution increased showed gram creased and bilaterally equal per cent time alpha; decreased per cent time delta and resolution of the electrical asymmetry of the hemispheres. On examination eight months after this episode and after a course of radiation therapy for pituitary adenoma, this patient was alert, oriented and cooperative; with only occasional complaints of headache. The neurological examination was completely negative with normal visual acuity and a slight (10°) bitemporal hemianopic defect with 1/1000 white test objects. He denied any experience of blindness or weakness but did recall the neck dissection that preceded the angiography. When told of the experience, he jokingly denied the weakness and the blindness by saying that I was mistaking him for another patient. Discussion: Two aspects of this case report warrant ampliﬁcation: the signiﬁcance of the denial phenomenon and the cause of complications following cerebral angiography. The various aspects of denial of illness described by Weinstein and Kahn are well exempliﬁed here. The acute onset of hemiplegia and blindness was followed by a period of restlessness, disorientation, and altered consciousness. Within a few hours, these gross symptoms were replaced by a calm, disinterested, smiling attitude in which the multiple defects of left-sided weakness and blindness were denied. He confabulated, was disoriented for time and date, and later was amnestic for this period. An electroencephalogram demonstrated bilateral diffuse slow wave activity of high voltage. Furthermore, despite the visual loss, the phenomenon of spatial inattention4 was observed. This complex of symptoms and signs is generally noted in diffuse cerebral disorders. While much effort has gone into localizing these defects, it is difficult to conceive a single focal lesion affecting the visual tracts bilaterally, the right hemisphere in an Various terms have been applied to the unawareness of one half of the body and the body space, such as imperception for one half of body (Schilder, 20), hemi-depersonalization (Ehrenwald, 7) and autosomatagnosia (Gerstmann, 10). See also Critchley (6, pp. 237-241), and Brain (4). 4 �242 MAX FINK area productive of hemiplegia and the frontal areas assumed to be productive of apathy, denial, and loss of anxiety. While the possibility of a focal lesion as the basis for this syndrome cannot be ruled out, it is more tenable to conclude that diffuse cerebral dys~ function was present. This conclusion is supported by the electroencephalogram, and also by experimental evidence noted below, demonstrating the effect of intra-arterial Iodopyracet as inducing severe vasospasm followed by generalized cerebral edema and increased permeability of the blood-brain barrier. The signiﬁcance of the phenomenon of denial is to be seen in its defensive nature. While undergoing a test procedure, the patient suddenly suffers a catastrophic disability. His initial response of severe anxiety, manifested by restlessness, startle reaction, and irritability, is soon replaced by explicit denial. This primitive, “psychotic” defense is normally present only in childhood. But under the special conditions of cerebral dysfunction, with disturbances in spatial and temporal orientation and perception, denial of reality becomes tenable. It is maintained so long as the disability and the milieu of cerebral dysfunction persist. In this patient, as soon as visual perception was sufficient for reading, confabulation and explicit denial were no longer actively maintained for ongoing events. In the special situation of interviews with the staff during the period of visual and motor loss, the patient manifested no concern and confabulated responses readily. When visual acuity returned and his hemiparesis cleared, he maintained the same is imthis it In attitude. unconcerned regard affable, friendly, of denial in factor the explicit characterological to note portant illness. To the extent that the information is now available, this patient manifested a considerable number of the features described by Weinstein and Kahn (24). Special note should be made of the phenomenon of spatial inattention. The patient’s original visual complaint of blurred vision was accompanied by a minimal bitemporal hemianopia, apparent only on testing with 1/2000 white test objects. During the period of visual loss he was unable to locate a light and confabulated responses. One week later the bitemporal hemianopia was present to 3/2000 white test object, but in addition there was an irregular left homonymous upper temporal ﬁeld defect to 5/2000 white. Evidence of a left homonymous ﬁeld defect persisted in examinations for three weeks, after which only residual bitemporal defects were persistently reported. Left spatial inattention was prominent in the ﬁrst 48 hours of this syndrome only, at the time when visual im- �DENIAL OF BLINDNESS 243 pairment was maximal, and when hemiparesis was present. When the hemiparesis receded, visual function returned, and orientation was intact, then spatial inattention disappeared. Thus, spatial inattention was an aspect of the total disturbance in function, possibly motivated by the left-sided defects, and was probably not dependent on a speciﬁc visual ﬁeld defect. The syndrome of blindness and its denial following cerebral angiography is unique. Focal lesions producing transient hemiplegia, hemisensory defects, seizures, aphasia, and various cranial nerve syndromes have been described. In a series of 117 percutaneous carotid angiograms, Fink and Stein (9) noted an 8 per cent morbidity of such transient phenomena. Other series variously report such complications from 3 to 15 per cent of the cases.5 These ﬁgures do not include the few patients in whom the complications as hemiplegia, aphasia or exaggeration of their basic disease are permanent; or who succumb. In these studies of the complications of angiography, emphasis is placed on the relation of the concentration of the contrast medium, the rate and quantity of contrast substance injected and the time within which the injections are repeated. In experimental studies Olsson (14), Broman and Olsson (5) and Bloor et al. (3) demonstrated summation of toxic effects when the contrast substance was rapidly injected into animal arteries; and noted increased vascular permeability, cerebral edema and petechial hemorrhages not limited to the side of the injection. While it is possible that the complications of angiography are the result of thrombus formation at the needle site and focal embolization, it is more likely that diffuse toxic cerebral vascular changes are induced as seen experimentally. The diffuse character of the defects and the transient nature of the phenomena in this patient are readily understood in this context. Summary and Conclusions: In the course of carotid angiography in a patient with evidence of a pituitary adenoma, an acute transient episode of blindness and hemiplegia developed. Following a short period of restlessness and confusion, the patient became calm, denied his blindness and weakness, confabulated responses to questions, was disoriented, and manifested spatial inattention. The diffuse nature of the cerebral dysfunction underlying this syndrome is emphasized by noting the distribution of the presumed lesions, the bilateral, diffuse slowing of the electroencephalogram, 5For reviews of the complications of cerebral angiography, see Engeset Fink and Stein (9), Green and Arana (ll), (8), Perese et a1. (15) and Wickbom (25). �244 MAX FINK and the diffuse nature of the toxic sequellae of intra-carotid Iodopyracet (Diodrast). The defensive-adaptive signiﬁcance of the syndrome of denial of blindness and hemiplegia is discussed, with emphasis on the development of this attitude under the special conditions of altered frames of temporal and spatial reference provided by altered cerebral function. REFERENCES (1) Anton, G.: Uber Herderkrankungen des Gehirnes welche von Patienten selbst nicht wahrgenommen werden. Wien. Klin. Wchnschr., 11:227-229, 1898. (2) Barkman, A.: De l’anosognosie dans l’hemiplegie cerebrale. Acta Med. Scand., 62:235-254, 1925. (3) Bloor, B. M.: Wrenn, F. R.; Margolis, 6.: Experimental Evaluation of Certain Contrast Media Used for Cerebral Angiography. ]. Neurosurg., 8:585—594, 1951. Brain, W.: Perception and Imperception. ]. Ment. Sci, 1022221-232, 1956. Broman, T. and Olsson, 0.: Tolerance of Cerebral Blood Vessels to a Contrast Medium of the Diodrast Group. Acta Radiol., 30:326-342. 1948. (6) Critchley, M.: The Parietal Labes. London: E. Arnold 8: Co., 1953 (see Chap. VIII, pp. 225-255; IX, pp. 258-263). (7) Ehrenwald, H.: Verandertes Erleben des Korperbildes mit konsekutiver Wahnbildung bei linksseitiger Hemiplegie. Mtschr. Psychiat. (2» Neural, (4) (5) 75:89-97, 1930. (8) Engeset, A.: Cerebral Angiography with Perabrodil. Acta Radial, Suppl, 56, 1944. (9) Fink, M. and Stein, J. M.: A Clinical Evaluation of Carotid Angiography. Conﬁm'a Neural, 12:181-195, 1952. (10) Gerstmann, J.: Problem of Imperception of Disease and of Impaired Body Territories with Organic Lesions. Arch. Neural. (5' Psychiat, 48:890-913. 1942. J. R. and Arana, R.: Cerebral Angiography: A Clinical Evaluation Based on 107 Cases. Am. ]. Raentgenol., 59:617-650, 1948. Ives, E. R. and Nielsen, J. M.: Disturbances of Body Scheme. Bull. L. A. Neural. Soc., 22120-125, 1937. Lunn, V.: Uber mangelnde Wahrnehmung der eigenen Blindheit. Acta (11) Green, (12) (13) Psychiat. é} Neural, 16:191-242. 1941. (14) Olsson, 0.: Cerebral Angiography: Tolerance for Contrast Media of Diodrast Type. J. Neural, Neurosurg. é, Psychiat., 12:312-316, 1949. (15) Perese, D. M.: Kite, W. C.; Bedell, A. J.; Campbell, 12.: Complications Following Cerebral Angiography. A.M.A. Arch. Neurol. é} Psychiat., 712105-115, 1954. (16) Potzl, 0.: Uber Storungen der Selbstwahrnehmung bei linksseitiger Hemi- plegie. Ztschr. ges. Neural. (9 Psychiat., 93:117-168, 1924. (17) Redlich, E. and Bonvicini, G.: Uber das Fehlen der Wahrnehmung der eigenen Blindheit bei Hirnkrankheiten. Jahrb. f. Psychiat., 29:14.23, 1908. (18) Redlich, F. C. and Dorsey, J. F.: Denial of Blindness by Patients with Cerebral Disease. Arch. Neural. {‘7 Psychiat., 53:407-417, 1945. (19) Sandifer, P. H.: Anosognosia and Disorders of Body Scheme. Brain, 69:122137, 1946. (20) Schilder, P.: Localization of the Body Image. Assoc. Res. New. Dis., 13:466-484. 1932. {9'- Ment. �DENIAL OF BLINDNESS 245 (21) von Hagen, K. and Ives, E. R.: Anosognosia, Imperception of Hemiplegia. Bull. L. A. Neural. Soc., 2:95-103, 1937. (22) von Hagen, K. and Ives, E. R.: Two Autopsied Cases of Anosognosia. Bull. L. A. Neural. Soc., 4:41-44, 1939. (23) Weinstein, E. A. and Kahn, R. L.: Denial of Illness. Springﬁeld, 111.: Charles C. Thomas, 1955. (24) Weinstein, E. A. and Kahn, R. L.: Personality Factors in Denial of Illness. A.M.A. Arch. Neurol. (5» Psychiat., 69:355-367, 1953. (25) Wickbom, I.: Angiography of the Carotid Artery. Acta Radiol., Suppl., 72,1948. �" Mamma: . mm. W W W6 63mm WWW mm,ljh9.* 3 Iran tau _.; a» V 1 3, Baum Sam», mill-ids Hospital, 61m Oaks, law mm ”imam, Rinaldo Hospital. W 1% 2’ A Luz/$4M“ [/m Mace rm éwm M429 Jaw / W1T �W a: Blindness removing Gombml 112310ng mm In an titty-.0131“; years since the apart or mm (1398); at than has Mon cmtroveuy 1n the litommm as to whether hunches; in tho result at a. specific fecal cembral lesion or at I. gua- «mum m1 disturbame or brain: Motion without specific localizing Moving the use: at initial or manna, tho majority of reports describo tho wasn‘t: an ’emfabulating,‘ “Manta maximums» (1). In ad,“ or ”shaving o lonakat‘f paychem.‘ Such satanptim lend support to tho meapt that denial com in a milieu of: almond heroism mum. studios of denial. of heniplagu, usually described under the term ”moon cantata", bring out Martina}. as to the significance at tho 1:: many topaz-ts of denial phenmm for lowland dysfunohim. W» of blinmhs, note ma, is undo of aimultmeun denial at haiplema or of other defects. Th: literature. at donul at 113m”, as imam evidence by to support 3013th and Kuhn ao 611111.081 and expert- ”may amazed They concludo that various farm of dam than (1955) a ten cmcaptn, has tea: m a mitary Monomer: without tantra}. Realising value, and that mm is an adaptstian to a Meet in tha milieu a: dummy alt-sud eembml function. In thin regard, mat of the defeat. mm are at 0:1.th (1953) and Museum and m (1955) prom the taro aspects of m: prom“. For mastic raparta “exiting the to fetal «am-um; disease as. Bum (1925). 9mm (19M), Hagan me 1m (1937. 1,939). I»: sue 3181301: (1937) and Pots}. (1921:). (1) the minus or y Reports aseribing tho phenomena to Mano mm disturbances mamas m (19M), Retinal: and mm (1911), Ramon and money (1916) and 8mm" (191:6). - ��*5and m “was mt m m m: hummus, than @13me the will mmm. K0 unnamed mr 915398“ earnestly iamutied them» 1m Wnbythoirwim, mamas. am, by, mailman}: by tmxch. Thus was no amou- W a: single: swam; gait. m mutant; mam mm»; mm inward an Babinski mama”: and album. thawing}. the ma um: mama reflexes. Minna” W mm 51ml Mt light napalm. W mater tho had cleaned mph for a nu it well in am... but. 1mg: {amnion tar reading or ﬁne identiﬁcation m mpaired. new“ the Be pameiveé and 106mm WWWW my reams.still mm: nature or his vision, he to An name him impairment, 319W ﬂagmatthiamathamngofmﬁuoﬂm remand. Wm may with high par mm; was @91th activity bilateral poem armined alpha rhythm mm an that» right. and a» slaved, Wan-six hours later his vision had returned «a that be we able to read. Ha an: omenmd, alert, affable and friendly. E maintained mthehadhemabhtomadmwmthmughoutmmmmu mail; far the surgery, the: hemipamm and tho Minn“. Baring the ensumg nah, visual wuw'm’mmd ta normal} with man. tieléa Wetting minim}. bimmpom Wop“ detect. in He had an: W caphnlow we we): later came! posterior manages to he lean dam-us:ed; per mt time delta activity had gamed; md than was Wehrmmm or the mom-d m syn .;,- Thor. m mm accantmmm at the claim 3.1930th in the right imam 1m. nurse weeks later the incmaad mwluum o: the swam-111m: with olectmemeqahahgm ma �am; dacmmd pa:- wt was clans. am! maeluum a: the chemical awn-y or the mmﬁmughtnmm mum apiaode Matter-a 3mm of radiation therapy £0: pituitary Wm, this patient was alert, orient-u ed and Wmum “weal: Wilma]. complaints of headache. m mmlom m mlately negatim with. normal visual acuity and a 311mm” amoral ammo. arm. with 1/1000 mu is» mama and 1311315911113 aqua). per cent the may. mm 9mm. Ra _ denied any experience a! 13mm“: or weakness but can an moi: dimatim that mama the Mummy. W did ran— m mm of my mm» and, tho blindness w mumums, he saw m we I m Blanking him tar mother mutant. the ��.3. «swung mmwmmmmnamm, m effact or mtmmm Wmt as inducing mam mam followed «Magma. ' by generalized 131006431913 W. «row-1 em Wand pamabili‘by at the and muwmuoxmmnmotmmnmummm ' mnwmm. miter: a. ontastmphia disability. Wily new of mm mm His Muted by mam-mu, aw maﬁa, 13w, ma ”placed by mum. is pm, initial a test Whil- m. chum. min punitive, normally prawn. mly in the and gamut irritability, in "Wm” Mme 3mm the special amdiﬁmn of oembml. dysfuncﬁm. with MammGea in spatial and Wm]. estimation and panoptim, denial of minty bums tenable. It is mintamd so long as the disability and m mum at eembnl gym; china mint. But In this patient, an saw as visual pompmm m M!» fur reading, «Mahatma .ami explicit denial are no 1mm 3mm maintained for main wants; In the main). Inuktitut at interview with thy staff charm; the period or visual and mum- loan, the 14mm. pat—Lark Wound m mum and Mahmud vim acuity mtumd and hi: W readily. Mm alumni, he maintainad the same «farm, memeamd amimm In this regard it u mportant to note that chamtemlegim factor in upliait at 111mas. it: w extant mm. the momma: i.- naw available, this patient 11033119111931: mm, m1 Wasted a Widemble new of the reams download by and Kuhn (1953). special note should be made the patina“: original visual WW of the phenomena of spatial inattemﬁm. Wt of ma Man was mama �.9... by a W humeral manom, apparent any out team with 1/2900 white teat. obgews. During the pexied or visual loss be was unable to Meats a Mt and cmfubulated mums. later tho um. obﬁaet, but in adﬁﬁm One week ' mu m pmmt m kW mmimmmlmhmmnmpertmpom madafoettOSﬂOw to 3/2009 mm“ of a lots; mm. A 1101:! mm persim in m ‘um for thm mm,- after which unity residual mammal. detect; mm persistently reporwd. Loft spatial inatmuon m prominent. in mam my, nun mmumw paiment m maximal, and m Mme!” m pram“. Hum tho mummmhahoam «this pares“ receded, visual function rammed, and orientation was intact, than spatial inattontim amppcmd. 21m:, spatial imthntion m an 3» Wm, 1:08“ny motivated by the aspect at the tow. Emit-aim Mac“, and w“ pro-mar Mt; 25¢th an a mafia visual field Moat. mm The grapm 1: 1:an of hunting“ am! its denial £91m osmium). anginmm. hum producing transient heuiplegia, new... «hum, «Ma, and various cranial nor" man-ms mm. mow Menu, have hm deans-Aha. In a. W’ of 317 pemtanwua carotid angiagrm. m and Stein (1952) now an What nation variaualy row-s as! much mama; at mm. transient Whammy: tram 3i W 15% of the such cases (3% when figure: do net inaluda the few patients in was: thin ammonium as Mplegu, aphasia or Manama: at their bum (3) Fur (191%), W: a! the «@11qu at «alum angiagraphy, sea mm. m and 3m {1953), emu and Anna (19w), (19514) and Him (191$). Fem-as a a. �diam m parliament; Imam a: Mommy, or m mm. In than studio: at tbs mm in phone! an the mutton of! the mun- cm mum: at 132m coma-alt man, we rat. and quantity or mtmst sub-n same wasted and the um vim which tho. indoctim an mpoam Wan]. studies 018m (19%, Em and 01m (19%) and Bloc: (1951} mum of Ma ﬁst-mt. M the cantmt suntan“ in mm m mpddly instead in?» animal arteries; and noted Mama mam:pemammy, mmbral «dam aids of the macaw. 331111; ram“ an mm tom Wéum, it uh: and patéchial hemorrhages mt. 9:? it is 3303311311: that the maidens likely m durum We «mm. mm. um Mums am} the Walnut mm of; m phenomm in m indumd uxparimntauyg Th» wade-ram in this context of 0‘ W chamber at tho @2113, 11y I Wu: .famtim at. m: needle site and 5.. mar. {ﬂanges mm to the patient an mad-n �WWW in I. mum: with Mama: 0: In the warm anarchic! a 19:1me mu transient walled. blmmMs m5Waving ashore patina at waﬂamw of an plagia developed. mum, thapamntbocm ma, mmtm. Wu and own mmbmmmwomu. can» tabulated responses to questions. ‘ and m 6180an and manifested spatial mm» nature, at the annual mum underlying thin «yaw arm in mum by mung an distribuum of the pramd mam. ‘ 5 [the mmm5 wmmwmmmmemmmw» fuss nature at that m defend“ We aoqmllae at inn-«mud (mm). 1W:mm of aiminam o: the uyndrm of blindness and Mylegia is ﬂawed, with emu-t m m a! ma atﬁtudo mm the mam. mum' of alum at bupawl and spatial aroma provided by altered comm Manna. a; adapts.” Wt m �um:- ﬁarchrkmnmgm do: Eskimo: Velma Anton, a. (1893), nelbst niaht 2 .. 9,. .1. A. {1925): DI WW £2“; mm. m. w.- Hahnmgg" 3;: 9 * van limaegmsio clans Patienm 227-239. Planning“ combmlm .5331; 34. 23545!» mow, 3.14., “rum, LR. and litmus, G. (1951); Maximal Mum 03m Gmtmt Media Used tar cerebral lagiograpiv. 5. Human“. of E! 5354“? ‘ . am; (1955), Parcaptian and Wampum. g. m. w. m: Brain, w. W32. Rm; '2. and Men, '0. (19143), 2019mm at 60:10me Blood Vessels to Cmtrast Mun at Grimm 24. m1. (1.953), Pp. the Madmt Groups m Page“; 225—2553 11, 133:. “NE W Landau: n. 258—263.) 3: o. 326cm. Amid a no. (no chap. (1930),?omnaarm 3mm m mmmum nit maekutiwr ma, mm. wmnm 3. mm 393%. no: linkaaei’aigar Hemiplegio. 89497. , set, i A. (19111:); Gorabml $123me a. Rink, 2;. and sum, m. W 60mm. J. n an. Magnum with kmbmdil. $5.“; (1952), A clinical Evaluation or Carotid mummy. m: Immptinn of (19132), Problem remnants Gram, '12,. 15,: with Organic brim. 5%. and Arena, R. (191:8), Bum! an 107 Gaul. &- g.- of 91mm and at ﬂ! w. W. i Mum 890.913. Eambm angiagraphy: Eoenm-1. Impaired Bow 52: 617-650. 611mm �7'93 Ham: :0 and IND, Edi. (193?). m‘ a. m m. a.» (1939), W3. O - Womeptiom a! a: 95403. Tim Autapsied Cases Wash. of Anoaognosia, ibid. 5: hum. mam, MI. (193?), 359$ 3.} W5... Ives, 3.22. and Disturbance of Bow schem« %‘ .13. 5 W. Vina». 1mm mm. am 191m. g gm. m. 613m; one (19w). comma. momma relax-am for 6mm mm a: 5. W“ mm“ 3: W. Puma, Bacall, Ad. (191a). Luna, . Hahmehmng der Eigam Echo)? ya: ‘ Type. Kenmsum.. nu, 16.0., 33.11., 10m. Paul, 6‘ (19%); Kamiplagia. Bedlam, E. and w. W. du 13mm. g... m. Pm... ("19%). 123-137. Egg. :9. 6. (1938). Helm mm. bed. 31 (1932). 53 W and mum of the Qt hMﬁh. Thoma. , ' i'ehlen do: 5,. Wahmalmmng W. as: g3: 1-9133. Blindness by Patients with 53} M’Hal'iu of Body 3m. ﬁg Q: (.1953), W Body Image. 5. M“ b m. gm. Springfield. ma Pemmlity Factors in mm o: Mama. W& a Egghiuh Q3 355”367a new, 32. (19M); ingiomplv of mo emua Artery. W hwmt Eu I. Enid ‘36:}. l‘ 1;: _ charm 6. 7 m. a mutant. m. a: m. W. Magnesia Warden 5%. Manama, 3m and ham, 3.1.. {1955), , cmmum 213 117MB; and Barﬂy, mu. (191:5). Gembral 131mm. 3mm», (1951;), Haber Stet-tinge}: der selbumhmahmng bai unkemitigaw aim Blinéiwit ﬁendifer, 0mm; B. cambm Angina-am. 5.2%.» 9.9;. Renewing Web, me. and 312616.. g5 W � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Denial of blindness following cerebral angiography. J Hillside Hosp. 1956:5:238-245. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-001-20-024 Date A point or period of time associated with an event in the lifecycle of the resource 1956 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [Preprint] and reprint. Reprint from the ISRAEL STRAUSS COMMEMORATIVE VOLUME Journal of the Hillside Hospital Volume V, Numbers 3-4 October,1956 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/d22bf8e1eaccf5f9a01c426789665f0e.pdf 7c6234b95a1768fbfe1c37f8a9076215 PDF Text Text Reprinted from THE DYNAMICS OF PSYCHIATRIC DRUG THERAPY Edited by G. J. Sarwer-Foner, M.D. CHARLES C THOMAS ° PUBLISHER 0 Springﬁeld ' Illinois ' U.S.A. W DRUG INDUCED CHANGES IN INTERVIEW PATTERNS: LINGUISTIC AND NEUROPHYSIOLOGIC INDICES By MAX FINK, M.D., JOSEPH JAFFE, M.D., and ROBERT L. KAHN, PHD. In studies of the effects of newer psychopharmacologic agents on behavior, we are inclined to emphasize their effects on the patient. The newer compounds do, indeed, have specific physiologic effects, and we propose to review some of the induced neurophysiologic changes. But psychopharmacologic agents affect more than the patient alone—and it is the interactive effects that are the focus of this conference. I am reminded in this regard of the story told at a similar conference by Dr. David Rioch about a psychopharmacologic his that the On of earlier days an amphetamine. era, agent patients took amphetamine, Dr. Rioch reported, they seemed much better. However, on the day when he took the medication, the patients also were considerably improved! How can such changes in human interaction be measured? Of the many aspects of behavior that are altered by the new agents—and it is clear that all aspects of behavior, as perception, ideation, motor activity, mood and judgment are altered—verbal behavior has numerous attributes that make it suitable for the evaluation of changes in interpersonal relations. Verbal behavior is easily recorded, is readily quantified as it is already in units (words, phrases and sentences) and can be recorded and measured without the introduction of artificial sets, equipment, tests or instructions. Furthermore, speech is the core of psychotherreflect in of and measurement language changes may patterns apy changes in the ongoing relationship. For these reasons, we have Aided by Grants M-927 and MY-2092, National Institute of Mental Health, US. P.H.S., and Grant 56-151 of the Foundations’ Fund for Research in Psychiatry. 29 �The Dynamics of Psychiatric Drug Therapy 30 undertaken studies of language patterns—of the patient and of the therapist—as influenced by the newer psychopharmacologic agents. The groundwork for this report was laid in a study by R. L. Kahn of the language changes following convulsive therapy (1) . Under the conditions of the alteration in brain function induced by repeated convulsions, changes in syntactical aspects of language were observed which were related to the degree of cerebral dysfunction and to clinical ratings of improvement. Prior to treatment patients expressed their problems and their aspirations in the present tense and first person, without denial, evasion or cliche’s. During treatment, however, they increasingly utilized the past or future tense and the third person mode with qualification, evasion, denial, displacement, cliches and cryptic responses. Such language patterns on the part of the patient resulted in an alteration in the language patterns of the thera— pists. They, too, found interpretive statements in the present tense less communicative, and increasing use of the future tense, displacement, and minimization of symptoms as aspects of a reassuring attitude became prominent (2, 3). Syntactic analyses are essentially grammatic content analyses, and are dependent upon interpretations by the observer of the subject’s communication. More recently, the dyadic TTR, another measure of language change, has been applied to this problem by J. Jaffe (4, 5). The two person group, or dyad, comprising the interview is treated as a unitary system. The language measure involves the pooling of the verbal behavior of both participants—the patient and the therapist in psychotherapy. In these studies, the tape recorded interview is transcribed in temporal sequence without regard to the speaker of the words, and then divided into consecutive 25 word units of intereaction. TTR, or type-token-ratio, is an established psychological index of language diversity. The ratio reflects the number of different words (the types) to the total number of words (the tokens) in the sample. The TTR is calculated for each 25 word unit and the pattern of consecutive scores is studied. In patients undergoing convulsive therapy, there was a �The Dynamics of Psychiatric Drug Therapy 3] consistent decrease in the mean TTR and an increase in variability (standard deviation) about the mean. These changes reflect greater stereotypy and repetitiveness in the interaction. In a control group of subjects, without induced brain dysfunction, there was neither a change in mean TTR nor in the degree of variability, although there was a tendency for the variability to decrease (6). When these two language measures—one a grammatic content analysis and the second, a formal diversification score—were compared, a decrease in the mean and an increase in variability of the TTR patterns were observed in the subjects who evinced two or more syntactic language changes. Conversely, in those with less than two syntactic language changes, no significant difference in the mean or standard deviation of TTR was observed. These observations indicate that with increased syntactical language changes, there is also a decrease in language diversity with greater stereotypy and repetitiveness. Furthermore, when analyses of each language measure were made with the degree of induced neurophysiologic change, as reflected in the degree of delta activity in the electroencephalogram, significant differences were shown only by the subjects with high degrees of delta activity. In the earlier studies of convulsive therapy, a neurophysiologic-adaptive hypothesis of the mode of action of this form of therapy was expressed (7). In this hypothesis, the therapeutic process is ascribed to a persistent alteration in cerebral function, which provides the milieu for a change in interaction of the subject with his environment. Recently, this hypothesis has been applied to the newer tranquilizing agents (8) and validating studies are now in progress. The studies of verbal behavior are one part of the investigation. We would like to describe our present experimental techniques, report the data from the neurophysiologic and language studies for a number of compounds, and discuss the significance of language measures as indices of change in the ongoing interpersonal behavior of therapist and patient. �The Dynamics of Psychiatric Drug Therapy 32 METHODS At present, all observations are made in the EEG laboratory. Following a routine EEG recording, an unstructured psychiatric interview, with short periods of structured inquiry, is taperecorded. With EEG running, an intravenous injection is then given at a slow rate. When specific EEG or clinical changes are induced, EEG recording is stopped and the interview repeated. Periods of EEG recording and verbal interaction recording are alternated for the duration of the period of observation. The EEG is measured for changes in synchronization, shifts in dominant frequencies, and per cent time of slow wave (9) , alpha or beta frequencies. The tape recordings are transcribed and measured for the diversification of consecutive 25 word samples of dyadic speech (4, 5) and syntactical changes (1). The dyadic analyses have been described. In the syntactic analyses, the response to three standard questions is evaluated as to changes in grammar and content: “What is your main troubleP”; “Why did you come to this place?”; and “What do you wish for more than anything else?” Changes in syntactical use of person, alteration in tense, evasion (as answering a question with a question or “I don’t disof the the subjunctive, use as by know”), qualification, placement or verbal denial of symptoms, increased use of stereotyped expressions or clichés, cryptic responses or withdrawal and silence were scored as changes in the communication pattern. Consecutive patients referred for drug or convulsive therapies in a voluntary psychiatric hospital were seen prior to, and at various intervals during, treatment. To date, the following agents have been studied by these methods: amobarbital, benactyzine, chlorpromazine, diethazine, iproniazid, lysergic-acid diethylamide and Win-2299 (2-diethy1aminoethy1 cyclopentyl—Z-thienyl— glycolate) . �The Dynamics of Psychiatric Drug Therapy 33 OBSERVATIONS l. Electroencephalogram In a previous study (8), it was observed that agents that increase EEG synchronization or induce a shift in EEG frequencies to the slow range generally induce behavioral changes of sedation and tranquilization. Agents that desynchronize the record, however, or induce irregular fast activity, are associated with hallucinatory, excitatory or illusory activity. Of the first group of agents, we have tested amobarbital and chlorpromazine. Amobarbital regularly induces high voltage, well synchronized, fast activity, at 20-24 cps. The regularity of the appearance of this increased synchronized fast activity has become the basis for the “sedation threshold” (10). Chlorpromazine has a variety of effects, depending upon the pre-injection record. In subjects with well defined alpha activity, both alpha voltages and the percent time alpha activity increase (1 l) With poorly modulated, low voltage, fast records, the per cent time alpha increases. In patients with low degrees of slow wave activity, voltages of slow wave activity increase, and the per cent time of both delta and alpha increase. Diethazine, benactyzine, LSD, and Win-2299 are examples of the second group of compounds. In tests of diethazine (12), in subjects with well modulated high per cent time alpha records, there is a decrease in voltage and per cent time of alpha activity and irregular low voltage fast activity appears. In records with high voltage slow wave activity, decrease in voltage and per cent time of slow wave activity is prominent and is associated with irregular fast activity. Similar patterns have been observed for benactyzine, Win-2299 and LSD. . 2. Language Analyses Changes in language occur with these induced changes in brain function (Table I). With chlorpromazine and amobarbital (Class I) there is a decrease in the mean TTR and an increase in variability (standard deviations) of consecutive scores. These changes are similar to the changes noted earlier for elec— tro convulsive therapy (6) . In contrast, diethazine, benactyzine, �34 The Dynamics of Psychiatric Drug Therapy LSD and Win-2299 (Class II) induce an increase in mean and a decrease in variability. TTR TABLE I TTR Class I Class II CHANGE WITH DRUG ADMINISTRATION (N223) (N227) Difference Class Mean Standard Deviation —0.78 +0.44 +1.42* —l.00“ 220‘ 1.44“ I “ Class II Diethazine Benactyzine Amobarbital (l3) Chlorpromazine (10) LSD-25 Win-2299 p > .02 (9) (5) (3) (10) We have not, as yet, applied syntactic methods of analysis to these recordings. Syntactic analyses were done, however, in the earlier studies of the effects of amobarbital and diethazine in patients with varying amounts of slow wave activity after convulsive therapy. Amobarbital amplified, and diethazine reversed, the syntactic patterns produced by convulsive therapy. With amobarbital, denial, displacement, minimization, and use of third person and future and past tense increased significantly (1), while after diethazine, there was a significant decrease (l2) . DISCUSSION We have observed consistent relationships between the neurophysiologic effects of various drugs and changes in two measures of verbal interaction. We have not underscored, although we have consistently observed, that both the behavioral changes and the clinical ratings of improvement are dependent upon the induction of persistent neurophysiologic changes. We have sug— gested, therefore, that the language changes constitute an important segment of the cues upon which the evaluations of “improvement” are based (1) . These language measures provide an operational basis for studies of changes in interpersonal relations without resort to hypothetic energic or topographic constructs. �The Dynamics of Psychiatric Drug Therapy 35 Also important for our discussion is the demonstration that different patterns of verbal behavior may be related to the different neurophysiologic effects of various therapies. Language analyses provide another means of investigating and measuring neurophysiologic effects. Weinstein and Kahn’s (13) demonstrations that language patterns of orientation, confabulation and denial in structured interviews were valuable indices of brain disease, heralded such applications. The demonstration here of consistent changes in dyadic TTR scores suggests that unstructured verbal interviews may also be used successfully in neurophysiologic analyses. The measures described here are crude, and the data preliminary. The consistent nature of the findings as we have investigated each new agent has been striking. Other language measures have been suggested, including changes in rate of speech, tense, and relative amount of verbalization by each participant. Further analyses with other psychopharmacologic agents, and other measures of language analyses are in progress. How can we relate these observations to the problems of this conference? First, generalizations about the psychologic or psychodynamic effects of psychopharmacologic agents are probably untenable unless the varied neurophysiologic and language behavioral effects are encompassed in the hypothesis. While introspective analyses provide some measure of drug effects, more objective data are needed, and these may be provided by language analyses. For example, the successful use of chlorpromazine in the management of hallucinatory and excited states has been well-documented. In such states, high diversification of language, reflective of diffuse associative processes is prominent. This diversity clinically manifest in tangential, incoherent and neologistic speech, with rapidly shifting frames of reference (5) . With chlorpromazine therapy (and the induced alteration in brain function) there is a decrease in the diversification of the verbal interaction, with a decrease in the use of present tense and first person speech. These language patterns may provide the basis for the change in interaction between therapist and patient. Conversely, in apathetic, redundant, blocked or withdrawn pais �36 The Dynamics of Psychiatric Drug Therapy tients, the administration of LSD (14) or mescaline (15) have been suggested. These agents induce an increase in associative is reflecdiversification a increased which of language processes tion. These agents also increase the use of first person and of facilitate thus and tense speech survey may patterns, present the paﬁents premnn:atdtudes and feehngs “ﬁnch the therapbt is interested in exploring. In summary, we have indicated that concurrent neurophysiologic (EEG) and language behavior (syntactic and dyadic diversification) measures are techniques for the operational analyses of the effects of psychopharmacologic agents, in the two-person system of doctor and patient. Further exploration of language measures are suggested as a rational basis for the understanding of the psychologic effects of these new therapies. REFERENCES Kahn, R. L., and Fink, M.: Changes in Language During Electroshock Therapy, in Psychopathology of Communication, Hoch, P. and Zubin, J. eds. New York, Grune 8c Stratton, 1958, pp. 126—139. 2. Esecover, H., Jaffe, J., and Kahn, R. L.: Psychotherapeutic techniques with electroshock patients. J. Hillside Hosp, 7: 17-25, 1958. 3. Jaffe, J., Esecover, H., Kahn, R. L., and Fink, M.: Modification of psychotherapeutic and supervisory relationships by altered brain function. 1. In preparation. 4. Jaffe, J. An Objective Study of communication in psychiatric inter— views. ]. Hillside Hosp, 6:207-215, 1957. 5. Jaffe, J. Language of the Dyad. Psychiatry, 21:249-258, 1958. 6. Jaffe, J., Kahn, R. L., and Fink. M.: Communication patterns with altered brain function. Read at Eastern Psychologic Assoc, April 1958. 7. Kahn, R. L., Fink, M., and Weinstein, E. A.: Relation between altered brain function and denial in electroshock therapy. A.M.A. Arch. Neurol. dy' Psychiat., 76:23-29, 1956. 8. Fink, M.: A unified theory of the action of physiodynamic therapies. ]. Hillside Hosp, 6:197—206, 1957. 9. Fink, M., and Kahn, R. L.: Relation of EEG delta activity to behavioral 63' Arch. A.M.A. Neurol. electroshock. in Psychiat., 78:516response 525, 1957. 10. Shagass, C.: The sedation threshold. A method for estimating tension in psychiatric patients. EEG Clin. Neurophysiol, 6:221-233, 1954. ��at 3:2» W mu mm. W WWW “a“ M I. 3., and mm mm mm and It 3.1%., April 12, mum, 11.: 8.1:»: at. 1958. mF?“ '1'? , immummdw mama» was: Wm, mmmumwuwam mu: m). 3,: ... 9 w_ gs 191.206. 1991. �Drug Indueod Ghana-l in Imam“ know: man ma Hwophylielogie XII Indiana ’m 11.9., Jawb- JII‘. xi)... ma Rabat In Kuhn PILD. mmm quoal' ﬁnd for Rani-eh in Fayehutry. PM the Ewart-mt a! Puemtry, Wain 3mm, Elan om, Jul. , 3.1. Aided by ﬁrm“ “2? and name, trident]. Inﬂux“ of Kmtal Ktllth, 6.83.8.3” and Grant 56451 the: a! new at. tho ‘Goatamno an Payahodynuie, hyahomnlytm ma Meleaie Aspect: at tho Hmloptie Drum 11: Myehintry, neutral, April 11.13, 1953. III: 980-53 (3.“) �Drug .Indueod Ghana” Linguistic and in Imam“ Patter-nu Imhyuolagic indie» nmr pumphammlo‘sie wants an mun: saw «that: an the paumt. In studies at the extant: at who bmﬂw, m m incline! to am amend: d9, induce}, has maniac play-1910310 £190“, and we propel. a! the induced mmmiologm changes. But paehophumlmo to ruins: want: aﬂoat more than the patiant «lam - and it in the murmur. «but: m m the term a: thin wafermca. I a 2mm in this regard a: the ﬁery told at. a similar ”afﬁrm: by Dr. David Mach that : wahwphmloxia «out at m. mun an, that Wotan-m. an the day: m1; his: patient: took Mainline, Dr. Bloch mud Inch button ﬁmr, an the day than 93 tack 1:11: "Gianna, the mum“ Ilia ware Worth}: Mme“ 3w m we}: MI}! in hm interwtim b: WM? 9: the um ”poet: at mum:- thut we wiper-Bod, thaw dim-0d by the aw lama u peraeptim, mama, mbljl banner hat "ﬂatten at in ﬁlm that all upset. at hauler, ~ mm- nativity, um ma m m: the: ”trim" that ask. 12. .. and M. .1th aw was mm. 3.11%.!»me relations. Verbal bmmr is “silly roam-M, in rudﬂy quantitiod u it it LII-way in ma (warm, phrmn chanson 1n ma lawman) and can bc rammed and momma artificial um, mimt, test: or mmmm. Whom“, the mm at pvchoﬂmrnpy and any ”that dthmt the mmemm change: in tha‘ Wt much is a! change: in manna. patum mom; ralﬁiamm. Fur thou roman, ms... of 1W0 patterns .. at than putt-at. and or the n Mum by the am:- pvthmalogin agents. the mum}: for than mart m laid in t study by 3.1» Xahn undertaken 1W0 of amass following convulsive therapy (1). under than n has therapist a: the awaiting: at ��tar «ch 25 ward "unit and the pottorn at aomcutivo were: is studied. m In patients “adorning «mulling thorapy, thoro o eanoiotont docrouo in tho noon and on maroon in Mobility (otondord deviation) m man who» chanson afloat gmtor otorootwy and ropotitivonou in the intonatien. 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In tho earlier otudioo of Batman.“ thoropy, o neuropwnoloﬂcnodoptin hypathooio of tho ”do a: oetian or this for: a: thoropy m unwound (7) . In this Martha“, the timer-youth prawn ‘1: ”embed ta 0. poroiotont I dogma antral :mmn, whieh prev-moo the million for a Mo in interactian at tho “that with his omitaxmt. Roemtly, this: impathooio altorotinn hoo boon 1n own“! to the am:- tranquilning agents (8) and "random studio!» �.11... in warm. 'fhga ark-adieu a: verbal bender arc am part at tha inwatixntion. in Wild 11k: to duaribe m parent experimental techniquu, an new rope-rt um «um a: wands, rm the: ammhyuelme and unsung. and studios far a num- dim ‘tha simian”. at human W6. n main: ‘0! chm. in the swing tannin-wan]. baud” at mama.“ am! patimt. prount, all abnrnﬁom m m. in thi m Watery. taunting a maﬁa. m. manna, an pmhiﬁric interview, with Ibex-t para-.06: at mama inquiry, is tapwnmrdcd. With m running, an or intmmm Mention is then given at a. (law fats. 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In _ ﬁﬁntrm, diathisim, bmacmmc,’ L813 ind Win-vim (Glut II) induce am 11mm in man an uni a. dderauﬁ in variability. m hm “warnings. m, u yot, 81138431318 appliﬁd 'mmtia mi. mm to than 91' malarua 'mc dang, 11mm, in the earlier Me: at the aﬂoat: a! LMbarhital and diothalim in paﬁionts with vagina amt! of slow inn nativity an» eonmlaiw thﬁrayy mom-81m amplified, and I manic pattern: prﬁduﬁﬁd by mullahs max-aw. With anabarbital, dﬁnial, dimlaﬁmnt, W131“, and m of third person mm mm" and m' mu incrﬁuod madam (1.), while after dicthuine, diethuino than m round, ‘a the Wimt donut.“ (12). i �Hun w .1. 61m x ﬁlm as: (ll-27,) (at-23) . : , «Mk 43.78 . . Meme; standard amnion mai’ $1.00“ , $.25 * p chat 1.35315“ ~ V > .§. now-mm (13) chlammuino (10) I 231mm. (9) swmm (‘5) 1.313% (3} Him-«2299 (10') .02 �We hi." abut-70d Mutant minimum: batman ﬂu mbysialogia extents of variant We Mg. mt nudmaorod, have sham» in and althaugh the botanical engage: and the awn ,the m mum: at verbal intormtinn. we have consistently ohumd, that bath Med new: at inprnvmnt are depmdmt mam at persistent nunreplvtiologia changes. Wt ham: mt muted, a: the in. languag- ahmgu Giannini. tn Wax-tam can npan tibial; in: «ﬁlament at "impremmt' m hand (1). Elam language gravid. an aperitiml hail tar “We: of chug“ in int-warm}. ”litmus uithant rmrt ta momma margin or West-whit: “attracts. A1,» Want tar our anemic»: 1-! than ammunition tint differ-uni tharot‘aro, am. We. yum: of 10er heavier w b: related to the elitist-ant nonraplv‘aialogie aﬂoat: at minus thumping. Language may”: pmvidc miner mm mating and mm; nwwama mucus. (13) immanent (mm in “mint-ad imam-vim herald“ man mutations» M: m soar“ Wu and anon-um in 21» m wanna wminmt nature a! the finding: bun “rifting. Other 1W0 other new” n2 (imam-Man bars 01‘ ”mum. changes in urinal intarvim m :1» ha that neat-«physiologic “an, M, participant. Furthcr wetnmin and mu... The Indy-u. W! gamma hm no nude, in rite of a: oricntatian, ”uranium and valuable inéicu at brain dine», that language 133%ch and a w ham: Wamt relative wt «to. p imntignhd nah m ngont and have been » Muted including at wrbaliutian by _ has aka/mg” nah malaria with ethor pummelegic manta, and of lawn: analyses we in pram". �*3 a... hmwmmmwmmﬂmunt’mh mmwtmmmwwwwmmmwu WWWmMWuL-umm WMWWﬂmmWM .mmmm mmwnmmmmmmu Mmmmummmmehm WWW term-,mmmamm mmmmacmmmmmrmm'mmmmm' mm nmmwummam.mcuw «mmmunmmum mamwum; ‘mxmh m Wm. «a 2mm W, mutmctmmts}. mammw¢wm m mamumummmmuxmumammm «mwummuaamml'Mmdymm-u mwmmmmwmmmmm maummmmwm w,uwm. NWuammmmmumM) w‘nmmw3-MNMW' mmmamu _' Mumamwwammu‘ Mum mmmmmmaﬂmwm3 ‘ Mmmmm,mww:mmmam thwawmrwmmwunm MW hm,muwmmmmmm(m) MW¢W(WmmﬂMMWm �tum” for tho apex-gum]. may”: at the «feat: at mcmhac agents, in tho Mm mm a: “Mr a and patient. Further mention Imus: mm“ m :33ng u mum but: far the underﬂmdinc of the whim «that: 0: than an tharnpiu. at �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Drug induced changes in interview patterns: linguistic and neurophysiologic indices. In G.J. Sarwer-Foner (ed.), The Dynamics of Psychiatric Drug Therapy. C.C. Thomas, Springfield, IL, 1960: 29-44. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-45-011 Date A point or period of time associated with an event in the lifecycle of the resource 1960 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Jaffe, Joseph; Kahn, Robert L. Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint, [preprint] and outline. Reprint from THE DYNAMICS OF PSYCHIATRIC DRUG THERAPY Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/4e44a5022aa24b8167f7810c1ba666eb.pdf 6c8bb654be03cc6faa66ea6f3e6b84ab PDF Text Text ��mm“mh«f.~«»-MM ��Patients with High Delta Activitv during Second, Third Weeks of ﬁeatmnt. Clinical Katina EEG Delta Both High High One None [ﬁramwr - high Moderatelz Imgroved Unimproved Much ImEroved (18) 12 (67%) h (22%) 2 (11%) (16) h (25%) 8 (50%) h (25%) ('20) 6 (30%) 7 (35%) 7 7mm] - (35¢ ��Clinical Ratings Cogpared to EEG and Amobarbital Test Results much Improved High Delta and Positive Amobarbital (29) Either High Delta or Amobarbital (26) Positive Neither High Delta nor Positive Amobarbital (36) [arm - x7414] Moderately Improved Uhimproved 25 3 1 10 ll 5 5 10 21 �and Ruth. Mt: M (29) man: or mum Mu ('16) mm may am: at num- Etc: man Mm mg: (36) �mm. (29) min: mm: W mu a:- mum - Mus m! “WW“! (3% �EEG Delta - Amobarbital Test Delta Activity; Records Middle Low High EEG Amobarbital Test Positive Negative [ﬁﬂ'ﬁ/ - Ifxg' (15) (346) 29 8 8 10 16 20 �(cast rbi Positive (’35) , (M) negative ,.. ! i ,‘ [I \ . I A ’ H' -,‘ I x ‘\\| x\.‘. \ x K i r ‘ 1 (j. ‘\ ; 1 I z E 10 16 20 ��A.m..‘+l__-.A_MA;.“__ A... < �; a M ��uhL—JCICHXU m I Prepared by “MS WEEK IN CHICAGG {DE—JD C) {SINH “ﬁg“ “UL—:X‘Cl A W «LE .00 N ��MURRAY 11an 8-2077 S. F. KURZER VICE-PRESIDENT IN CHARGE OF SALES GRUNE 8: STRATTON MEDICAL PUBLISHERS 381 FOURTH AVENUE NEW YORK 16. N. Y. ��M Merri/ébﬂ M HOTEL WILLIAM HENNING RUBIN PRESIDENT FAMOUS FOR THE "5"" OZMMMC ' — CHICAGO JOHN B. GRANDE GENERAL MANAGER WHERE FAMOUS PEOPLE EAT ��ESRA No. 37 1957 Program -1- ELECTROSHOCK RESEARCH ASSOCIATION SCIENTIFIC SESSION- Thirteenth Annual Meeting Sunday, May 12, 1957 Hotel Morrison Chicago, Illinois Chairman: Ernest B. Parsons, M.D., Pres. Cotillion Room A.MJﬁ: 9:00 Registration \v 9:30 A.M.' 1. 9:45 10:00 2. 3. rNeurophysiology Studies of EEG change with EST with or without Atropine in Man and Rat. Tetsuo Fukuda, M.D., John A. Stern, Ph.D., George A. Ulett, Ph.D., M.D. Discussion opened by: Bernard L. Pacella, M.D. . A.M. A.M. . 15A X/ MIL u 10: Mm" “2?? 30 W1? A. M. Psychological Aspects Personality Factors affecting Clinical Responses to Electroshock Therapy. Robert L. Kahn, Ph.D., Max Fink, M. D. An Evaluation of the Peculiar Selective Quality of Pos Electrotherapy Amnesia. Aloysius S. Church, M.D., 5}t Psychopathology of Electroshock Therapy. W“ ,,. 10:h5 A.M. Bernard L. Pacella, Discussion of 2, 3, 5. 11:15 A.M. Technigues Current Patterns in Cerebral Electro-Therapy. 6. 11:30 A.M. l1:45 A.M. M.D. & 4 opened by: Leo Alexander, M.D. Gerhard Hirschfeld, M.D. Further Studies on the Analeptic Action of Peripheral Electrical Stimulation in Hypoglycemic Coma. Charles H. Jones, M.D. Discussion of 5 and 6 opened by: William L. Holt, M.D. R. Embassy Room P 12:30 to 2: 30 PM 105/” Annual Luncheon and Business Meeting. �' -1- EJJ .. » .u ..., 111'. .j,. . . 4 . ,.‘... ,, - . v 7. ‘ 6‘ r: . . -. - ....£x~ ~ . .“- . .." ' ‘ . -. ‘ ;-‘ . ' . ,.. ... ' -. : I , .-. ..‘ d.I ’ "x - s 1' .- ., L «i=2» '_ " . . f‘: .1)- 1'! 1 ~ I \ WOV'.J“%£M{1A .. ‘ t 4. '- .' . :- .- .- \‘J.'\ .r. . ‘ :' ..:.'.-.3 .~... .. .. ”-0.“.-. : . ' . n}. I . . -,-.L z .‘ ' . 1‘ ' . ‘ ‘ . 5“ma...— ’ ‘I ‘ - -- ‘ ' " ' . . �ESRA No. 37 Cotillion 1957 Program -2- Room 7. 2:30 P.M. 8. 2:45 P.M. 9. 3:00 P.M. 3:30 P.M. 3:#5 P.M. 10. 4:00 P.M. ll #:15 P.M. #:30 P.M. Clinical Aspects Clinical Applicationscﬁ'Nonconvulsive Electro-Cerebral Stimulation. John D. Moriarty, M.D. Indications for Electroconvulsive Treatment in Office Psychiatric Practice. Paul H. Wilcox, M.D. Discussion of 7 and 8 opened by: David J. Impastato, M.D. The Use of Electra-Cerebral Stimulation in Mentally Defective Patients. Harold H. Berman,M.D., Milton ’ Jacobs, M.D., and Joseph Spielman, M.D. Discussion opened by: Charles Buckman, M.D. Drugs and ECT A Comparative Evaluation of the Safety of the Use of Chlorpromazine and Reserpine in Conjunction with Electroshock Therapy: A Review of the Literature and a Clinical Report. David J. Impastato, M.D., Seymour Berg, M.D., Anthony R. Gabriel, M.D. Electroconvulsive Therapy Combined with Chlorpromazine and Reserpine. Frank J. Ayd, Jr., M.D. Discussion of 10 and 11 opened by: Herman C. B. Denber,M.D. ��___.._——.————~—————-————-—————— _m, —-———~———_.———..——————-————-——-——— �mm“. Wm -_ w— _———~——————————_— ! —-——-————-—————__—____.__.._.— p.4— ““—.— __.._._____.. ————————————___——-——____—._— _____ ‘ . __ __ ~ ___.___ .____ ._..._ _ ...___.__._. .— ��w v«w 1. w VW. . ,_ . . wv ﬂ . 9 «x; M“ a? s. ks \ x\ W”. x ‘ \ tn .\n. as .9: ��l L. . x, 93‘1“” nerT/‘wr'y . ‘ V. t i Mm,» ,‘(Z R �rwﬂ‘mrﬂ~“w~&uwwé_é< Wn:~'5~‘~".m . l _ __-. A—e ,...r‘_;..,1... , �PUBLISHED BY INFORMATION SERVICE VOL. 9, NO. 10 OFFICE OF THE MEDICAL DIRECTOR Available to non-members at 35.00 per year. JUNE-AUGUST 1957 (SUMMER EDITION) Dr. Alan Gregg Dies APA Honorary Fellow Dr. Alan Gregg died at his home in Big Sur, California on June 19 at the age of 67. He served as Vice-President, Division of Medical Sciences, Rockefeller Foundation for two decades and in this position of national leadership made psychiatry one of his major interests. Few men have had so profound an effect on the advancement of medical sciences as he. He will be sorely missed by physicians the world over and by psychiatrists most particularly. NINTH MENTAL HOSPITAL INSTITUTE For the ninth year over 400 staff people from all types of mental hospital installations in Canada and the U. S. will come together at the Hotel Cleveland, Cleveland, Ohio, Sept. 30 Oct. 3 to consider common problems and directions of progress. Major topics at this year’s Institute will deal with the problems of the open hospital, revision of commitment laws, management principles, role of private hospitals, mental deficiency as a psychiatric problem and many others. Prof. James L. Hayes, Department of Business Administration, St. Bonaventure University, will deliver the Academic Lecture. The enrollment fee is $50. See program and registration form in Mail Pouch. - All who plan to present papers at the 1958 Annual Meeting in San Francisco please note Form for submitting proposals to the Program Committee in the Mail Pouch this month. NOTICES 1. THE ANNUAL APA DESK APPOINTMENT BOOK FOR 1958 WILL BE OFF THE PRESS THIS SUMMER. USE ORDER BLANK IN THE MAIL POUCH. DEMAND EXCEEDED SUPPLY LAST YEAR. SUGGEST ORDERING PROMPTLY. ($3.00 PER COPY). 2. WE HAVE A FEW HUNDRED COPIES LEFT OF THE BOOK OF SUMMARIES OF SCIENTIFIC PAPERS OF 1957 ANNUAL MEETING, BUT THEY ARE GOING FAST. ($1.00 PER COPY). THE AMERICAN — GRADUATE TRAINING IN PSYCHIATRIC HOSPITAL ADMINISTRATION Two outstanding courses in psychiatric hospital administration are now available and merit the attention of all psychiatrists concerned with advancing professional standards in this area. One is at Columbia University and the other at the Menninger School in Topeka. The Columbia University Course This course, which leads to a Master of Science Degree, is under the auspices of the School of Public Health and Administrative Medicine and the Department of Psychiatry of the Faculty of Medicine. It encompasses basic courses in administration, specialty courses in the Department of Psychiatry, and supervised field work. Recognizing that mental hospitals are hard put to let a staff doctor leave for prolonged periods, Columbia has made every effort to tailor the course to meet candidates’ needs. It extends over 20 months, but ei ht of these are in academic residence broken into four quarters of 2 months each. The preferred plan is for the candidate to spend four months in academic residence, followed by 12 months in a supervised administrative residency or in a position already occupied by the candidate during which time he may carry out a special project. This is followed by a final four months in residence. For candidates who already occupy key administrative posts and who cannot be away for more than one quarter at a time, special arrangements can be made. As for costs, each candidate’s need is likewise evaluated individually. The total tuition for the 8 months of academic residence is $900.00 and Public Health Service stipends are available which will pay this plus ordinary living costs. Frequently, state funds in the state where the candidate works, are available to pay travel costs. There are some openings for the year starting in Sept. Write for details to: Exec. Officer, School of Public Health, Columbia University, 600 W. 168 St., M PSYCHIATRIC . ASSOCIATION Office of Medical Director, I785 Mass. Ave., N.W., Washington 6, D.C. Canada Office, 2I6 W. St. Clair Ave., Toronto 5, Ontario Office of Executive Assistant, I270 Avenue of the Americas, New York 20, N. Y. PLEASE ADDRESS ALL NEWSLETTER COMMUNICATIONS TO OFFICE OF MEDICAL DIRECTOR �The Menninger School of Psychiatric Hospital Administration This School offers a one-year integrated course, leading to a Certificate, which draws on the resources of the Menninger Foundation, Winter V.A. Hosp., and Topeka State Hosp., supplemented by other Kansas state hosps. and schools, an industrial concern, a general hospital, two universities, and several state government agencies. The curriculum consists of didactic instruction in basic administration while clinical experience is provided by systematic rotation in the departments of participating institutions accompanied by seminars with department heads and special projects. With regard to costs, applicants may apply with state sponsorship. The sponsoring state may pay the stipend with the understanding that the applicant will remain in the employ of the state after he completes training. A limited number of stipends at $625 a month are available to unsponsored applicants. The next course starts in September. For full information write to the School, Menninger Foundation, Topeka, necessary. (work on the new home is expected to start this month. Hope is to have it finished by January 1). . Approved setting up separate fund for receiving miscellaneous gifts (such as royalties from publication of lecture series of North Shore Hospital) with proceeds to . be used to add to APA library. . . . Authorized and appointed Committee to work with planning group for the Jamestown Festival this fall which will celebrate Williamsburg State Hospital, the oldest in US. Drs. Zigmond Lebensohn, David Wilson, David Young, and R. Finley Gayle, Jr. are on the Com. with Robert L. Robinson of this office as advisor. . . . Approved contribution of $50 to the National Society for Medical Research. . . . Continued APA membership in the World Congress of Psy- chiatry. . . . Designated Francis J. Braceland as official delegate to the General Assembly of the International Society for the Organization of World Congresses of Psychiatry. . . . Approved in principle proposed constitutional amendment prepared by the District Branch Assembly regarding election to membership in APA through the Branches; and also another proposed amendment incorporating present practices regarding creation and operation of District Branches. . . . Approved recommendation Kansas. of Medical Director to consolidate all central office APA Position services for mental hospitals and to explore ways to Our Association has always insisted that Supts. and finance increased services in this area. . . . Suggested Med. Dirs. of institutions for the mentally ill should be appointments of APA representatives as follows: Dr. Frank J. Curran to World Federation of Mental Health psychiatrists. In doing so, however, it rec0gnizes the need for special training in administration for those who meeting in Copenhagen; Herman C. B. Denber to Congres de Medecins Alienistes et Neurologistes de France et wish to qualify for these positions. des Pays de Langue Francaise at Lyon, France; Rudolph The courses described above have been established with the encouragement and support of the Committee on C. Novick to Advisory Com. of National Congress of Certification of Mental Hospital Administrators. Only a Parents and Teachers. (These appointments were made handful of psychiatrists have completed them thus far. by President Solomon). . . . Recommended to Council The courses are expensive for the sponsoring agencies to reappointment of Dr. Henry Brosin to the American Board of Psychiatry and Neurology. . . . Directed that problem offer and experienced persons have put great effort into of improving dental care in mental hospitals be explored at curriculum development. Commissioners, superintendents, and others in admin- next Mental Hospital Institute. . . . Received announceistrative positions, as well as those who aspire to these ment of retirement of Dr. Frederick L. McDaniel as CIB positions, would do well to give serious thought to sign- inspector and expressed appreciation for his services over five years. . . . Changed dates for fall Council meeting to ing up for these courses. Available financial support should be an encouraging factor. November 23-24 (Sat.-Sun.) in Boston, Massachusetts. . . . Selected Saturday, October 26, as date for next meeting of NIMH GETS $4 MILLION INCREASE: The US ConngS}. has voted $39,217,000 for the Nat. Inst. of M. H. under/h" Robert Felix’ direction. This is $4 million more than/ last year—remarkable in view of general economy dri e. Testimony of Dr. Braceland for the APA and Mike Go of National Committee Against Mental Illness played i portant part in explaining need for additional monies in these areas to the Senate and House Committees. Senator Lister Hill and Representative John F ogarty, always strong supporters of mental health, spearheaded the effort to get the appropriations through Congress. EXECUTIVE COMMITTEE ACTIONS them \ O A pilot training and research program stressing the interrelations of biological and physical sciences as key to better understanding of the nervous system and human behavior has been set up at Albert Einstein Coll. of Medicine, Yeshiva Univ., (Eastchester Rd. and Morris Park Ave., N.Y.C. 61) with a $1,700,000 grant from the Nat. Inst. of M.H. There is provision for 36 pre- and st-doctoral fellowships. The grant covers a six-year d. Write to Labe Scheinberg, M.D., Dept of Mediher details. ° FALL COMMITTEE MEETINGS: Woodner Hotel, WashThe Exec. Com. met at the APA Central Offices June ington, D. C. The following Committees will meet all 29. (Unusual and pleasant feature was that most of the day on Friday and Saturday, Oct. 25-26: Standing Coms. APA staff members attended to become better acquainted on Technical and Community Aspects and Professional with the Com. members and general affairs of the AssoStandards. Also Standing Coms. on Budget, Ethics, ciation.) Among other things, the Com.: With regard to Program and Nominations. Ad Hoc Coms. will meet only financing remodeling of new home, delayed taking out any on request of the Chairmen and with clearance of the mortgage unless and until expenditures appear to make it Coordinating Com. Chairman to whom they are assigned. . �~\ The Council this year will not meet to receive Committee reports until November 23-24, but the Executive Com. will meet with the other Coms. on Sat., Oct. 26. Canadian Mental Hospital Institute Plans for the first Canadian Institute are shaping up nicely. It will be held at the King Edward-Sheraton Hotel in Toronto, Jan. 20-24, under joint auspices of APA and the Canadian Psychiatric Assn. This Institute will be patterned after the U.S. meetings. Major theme will be “The Mental Hospital and the Changing Community," Dr. Mary Jackson is Chm. of the Program Com. with Drs. C. Buck, W. Boothroyd, J. Griffin, J. Hagan, A. Miller, D. Lewis, and Drs. C. Roberts and J.Gilbert of the M.H. Section, Dept. Nat. Health and Welfare as advisors. Since it will have a clinical orientation, this first Canadian Institute is planned for psychiatrists in senior posts in all types of Canadian mental hospitals and for the administrators of Federal and Provincial mental hospital systems. More details in the fall. New Printing of Glossary With the first printing of 30,000 copies of A Psychi- ASSEMBLY OF D,B, NOTES . . . .Met May 13-14 during Annual Meeting. . . . Installed following officers for 1957-58: David C. Wilson, Speaker; Walter H. Obenauf, Deputy Speaker; John R. Saunders, Recorder; Policy Com., (Area I) Albert M. Biele, Frank P. Pignataro (Alt.); (II) Lester E. Shapiro, Ulysses SchutZer (Alt.); (III) J.G.N. Cushing, Edward H. Williams (Alt.); (IV) James L. Sagebiel, G. Wilse Robinson (Alt.); (V) Alfred Auerback, Edward G. Billings (Alt.). . . . Volunteered to assist Med. Dir. in obtaining accurate information to publish obituary notices in Newsletter. . . . Revised Procedural Code. . . . Suggested Council action to seek extension of MEDICARE program. . . . Commended Dr. Wilson for Assembly exhibit at Annual Mtg. . . . Decided to study inspection of psychiatric facilities and depts. of psychiatry in gen. hosps., and facilities of public mental hosps. . . . Submitted two proposed Constitutional amendments for consideration by Council. . . . Will investigate planning of Divisional Meetings. . . . Scheduled next mtg. for May 12-13, 1958 at St. Francis Hotel, San Francisco. PERSONALS. . . S. Spafford Ackerly was honored by a atric Glossary exhausted, a new printing of 22,000 copies Testimonial Dinner on June 19 in recognition of his 25is now available. A limited number of copies have been year contribution to psychiatric education and community health in Louisville and Kentucky. . . . Paul V. Lemkau made up with a hard-cover library binding for libraries has returned to Johns Hopkins Univ. as Prof. of and others who would like it in more durable format. The Public Health Admin. (mental health) at School of Hyhard-cover copies have no cover design—merely the 8: Public Health following a 2-year leave of giene of title the book. They sell for $2 per copy. The paperbound edition remains at $1 per copy. Order from Mental absence. . . . Baruch Silverman was presented a Canadian Mental Health Award on Apr. 17 in recognition of “his Health Materials Center, 1790 Broadway, N.Y. 19, N.Y. outstanding contribution to the mental health of the CaDid you know that the following Isaac Ray Award nadian people,” . . . Alan D. Miller, Dir. of MH Study Lectures had been published and are available through Center of Nat'l Institute of Mental Health, was transferred to England on June 18 for advanced study and reany bookstore? The Psychiatrist and the Law, byL Overholser, 1953; Psychology of the Criminal Act and search. Stanley F. Yolles has succeeded Dr.Miller as Punishment, G. Zilboorg, 1954; The Guilty Mind: PsyDir. of the Center. . . . Major admin. appointments in N.Y. chiatry and the Law of Homicide, by judge John Biggs State on July 1 were: Arthur G. Rodgers (LF) as Dir. of Syracuse State School; Ulysses SchutZer as Dir. of Jr., 1955 (all these by Harcourt Brace 8: Co.); and The Urge to Punish, H. Weihofen, 1956 by Farrar-Straus and Binghamton 8. Hosp.; Charles Greenberg as Senior Dir. Cudahy. The latter publisher will also publish the of Rome State School; and William C. lohnston as Dir. lectures by Dr. Philip 9. Roche given at the Univ. of of Craig Colony. . . . Franz j. Kallmann received an Michigan this year. honorary medical degree as one of 6 scientists in differfields honored ent Third so Int'l Congress of Medical at The General Practitioner Education Project now operQ Arts, Turin, Italy during 1-9. June program, . . .17; from the Office Central E. ating (Charles Goshen, Projand Gantt Harold Horsley Rosen were Visiting Professors would information about psychi- for ect Director) appreciate 2 weeks this spring at Univ. of Arkansas Dept. of atric courses for GPs now in planning stage. It is sugDon D. Psychiatry. . . . Jackson appointed Asst. Clin. gested that when a course is being planned effort should Prof. of Stanford Univ. Med. School and Psychiatry at be made to have it approved for credit by the Amer. elected of Pres. Mid-Peninsula Psychiatric Soc. . . . of Acad. General Practice (through its local or state William H. Kelly has accepted position of Asst. Dir. of branches) as inducement to attendance. Dr. Goshen of Mental Health and Head of Mental Hygiene Div. Dept. will be glad to assist in publicizing such courses. for State of Michigan. 0 The Smith, Kline and French Foundation Fellowship NEW PRESIDENTS 8: SECRETARIES . . . Ark. D. 8.: Committee awarded 19 new Fellowships in May. 13 of Robert G. Carnahan & Leroy D. Lamm. . . . Cent. Calif. them will enable medical students to participate in reWilliam S. Fife & Arnold Sheuerman, Jr. . . . N_o. D.B.: search and training programs this summer. Among other Calif. P. Soc.: Thomas A. Gonda 8: Maleta Jo Boatman. Fellowships announced, one doctor will study research . . . .Kings County (N.Y.) D.B.: Morton H. Hand 8: organization at Boston Psychopathic Hosp., another will Abbott Lippman. . . . Hawaii P. Soc.: Robert A. Kimtake a Master’s degree in public health, and two lecture- mich 8; Robert S. Spencer. . . . Md. D.B.: Leo Kanner & ship programs will be established. Applications for Charles Ward. . . . No. Pacific D.B.: Herman A. Dickel consideration in October this year should be submitted 8r D.E. Alcom. . . . Quebec D.B.: Graham 8; Taylor 16. and Information forms by September application may Henry Kravitz. . . NP Soc. of Va.: Thomas F. Coates, . be obtained from the Fellowship Committee, Box 7929, & W.D. Buxton. . . . Washington P. Soc.: Seymour Jr. J. Philadelphia, Pa. Rosenberg & Marvin L. Adland. . . . Del. P. Soc.: George I �DeCherney 81 Walter Davis. . . . East Bay P. Assn.: Louis B. Boyer & Marion E. Roudebush. . . . Long Island P. Soc.: Edgar D. Congdon 8: Harry H. Gonda. . Milwaukee NP Soc.: David Cleveland 8: Edward C. Schmidt. . . . No. Pacific Soc. of N&P: D.E. Alcorn & Robert M. Rankin. of P. at the Univ. of Miss. under Floyd Moore and Oscar Hubbard. Also visited State Hosp. at Whitfield where . Wm. L. Jaquith and John Head have built up a fine program since 1949. They have a high patient turnover now and a new building for maximum security patients especially worth seeing. Also renewed acquaintance with Beverly Smith and Willard Waldron in Jackson. . . . On BRIEFS. . . . All who attend the World Congress in Sept. June 21 went to NY to speak to Bd. of Directors of will be glad to hear that Nat’l Committee Against N.A.M.H. APA members present were Hon. Fellow Mrs. Mental Illness, Inc. has (through APA) made funds availHenry Ittleson, Walter Baer, G.S. Stevenson, Jules able for simultaneous translation of papers. . . . Herman Coleman, Marion Kenworthy and Paul Lemkau. Was B. Snow, Supt. of St. Lawrence State Hosp. in NYS, pleased by much support from the floor for closer ties writes that 90% of his patients are in open wards exand strong Support for APA’s programs. . . . On June 28 cept at night. . . . Iago Galdston, Chm. of Com. on Int. joined Ewen Cameron’s Com. in Boston on future planRels., has sent over 100 copies of the Summaries of ning for the CIB in Pres. Solomon’s office. Drs. BarteAnnual Meeting Papers to colleagues abroad. . . . I have meier, Ewalt, Braceland, and Yerbury also there. . . . prepared a little pamphlet about my favorite vacation Flew back to Washington to meet with Joseph Barrett on haunt called ”Day Sailing and Cruising in Mahone Bay, planning for celebration of opening of Williamsburg N.S.” and I’ll send you a copy if you write. . . . Chas. State Hosp. (1773) in conjunction with Jamestown FestiBush and David Gaede are inspecting hosps. in Mich., val this October. . . . After the Exec. Com. mtg. Pres. having just finished up in Mo. Hope to start in NYS in Solomon and I flew to Nashville to participate in dedicaa few weeks. . . . Warren Johnson, my asst., recently tion of magnificent new admission and treatment building conferred with Cyril Ruilmann, F. Williams, and O. S. at Central State Hospital named after the Supt. O. S. Hauk in Nashville on psychology legislation in Tenn. . . Hauk. Wm. S. McCullagh, Pres. of the So. Psychiatric Smith, Kline & French Labs. have just granted $10,000 Assn. and Frank Luton also were among the speakers. to the Nat. Acad. of Relig. and Psychiatry for fellowAsst. Supt. White presided and Cyril Ruilmann introships for clergymen who want to become mental hospital duced the speakers. Gov. Clement gave the main chaplains (there are over 300,000 clergymen in the address. The Tenn. program has improved remarkably in country). . . . Sorry to hear of the death in June of Miss the past two years. . . . Forgot to mention last month that Dorothy Clark who rendered such valuable service as in course of Mental Health Week speaking tour I particiAPA Nursing Consultant from 1949-1951. . . . Write to pated in inspiring award ceremony for employees at St. Dr. Leo Alexander for details about the fifth Annual Louis State Hosp. where over 700 have served for 10-25 Institute of Psychiatric Treatment to be held in Philaof Nurses Dirs. his Kohler, Supt. Congratulated years. delphia Oct. 17-19. . . . A lady reporter at the Ann.Mtg. and Volunteers who organized the program. . . . Mike in Chicago was overheard to say, "Next to the White Gorman and I had stimulating talk with Robert Felix and House crowd this is the nicest group I’ve met.” . . . . Seymour Vestermark recently concerning NIMH programs Chas. Goshen and I attended meeting of APA Liaison in coming year which will be expanded with increased Com. with Amer. Acad. of General Practice in NYC to appropriations. . . . Also attended meeting of Wyoming discuss Gen. Practitioner Educ. Project. (R.Matthews, Valley M.H. Soc. in Scranton, Pa. where I met APA Chm., Frank Luton, Phineas Sparer, and Merritt Foster members Robert C. Murphy and Emlyn T. Davies. . . . were there for APA)....On June 6 spoke at Ann. Mtg. of Received notice this month that NIMH Advisory Council the M.H. Soc. in N.J. and on the 10th at the opening had turned down our application for renewing M. H. session of the M.H. Institute at Lansing, Mich. where Architecture Study grant; but funds are available to V. A. Stehman had brought in representatives of all Mich. continue it to end of and in meantime effort will be year hospitals. It was an outstanding meeting well attended. made to find other ways of keeping it going. . . . Expect . . . Went from Lansing to Battle Creek with E.F. Jones, to be off to Mahone Bay, Nova Scotia by end of month for Mgr. of VA Hosp. there, and showed his staff pictures of a few weeks of sailing and loitering. . . . Happy vacationforeign hospitals. . . . Did same thing for residents at ing to you all. . . . The next Newsletter will be in Sept.... Ray Waggoner’s Institute in Ann Arbor a few days later where also talked with Moses F rohlich who (as Chm. of Com. on Nomenclature) is hard at work on system for recording case data on IBM cards. . . .With Robert L. Robinson met in Toronto with Program Com. for Canadian Mental Hosp. Institute to finalize details on June 21 and was also able to visit Homewood Sanitarium at Director Medical Guelph (A.L. MacKinnon, Dir.) where the Ontario Psychiatric Soc. was meeting on the 22nd. . . . Also recently spent several days in Conn. with Chas. Bush where we consulted with the Governor on the mental health prohas Blasko that reJohn there. to Sorry report gram signed the Conn. Commissionership for another job; but P.S. Don’t forget to order of the Desk 1958 copies your his efforts to have the law changed to give the Commisand Book of Summaries the the (33) Appointment have been successsioner more administrative authority Scientific before the (81) Papers supply runs out. the 19 On Dept. visited expanding rapidly ful. . . . June ��WV-..— -»——————. ———_,—_a—.__.._—_,-__ ._________, __._ —_________.___._. _ __ .__- .__.__._. _____... —*_ ��October, 1956 vs Age EST # 1 & 2 - h Below 115 us yrs. over Changes - Reiter - £9 pts. 6 7 H L M 5 S 8 (id—ﬂ) 7 3 10 (50%) 13 5 10 (35%) 6 h 19 (65%) L yrs 50 over yrs 8: Distribution Age — H M 8 h 16 (57%) 12 3 6 (28%) 5 3 13 (61%) - EST 1 & 2 patients h9 5 3 31 - [10 yrs. 1 3 I41 - SOyI‘S. ll yrs. over - 6 5 10 2 3 Reiter vs Medcraft - .ii:;.L_ Reiter (EST # 2) H 12 (h8%) yrs. yrs M 7 30 & L 6 - 61 H 7-2 20 51 " 60 9 M h-6 Below 50 - L yrs. & EEG 25 Medcraft (EST # 3) 16 ptS. pts. LWC - h all ages 6 _Z_:_2_ L M H L M H 11 5 9 7 3 15 2 5 9 1 6 9 �Beiter vs Medcraft h Reiter (EST # 2) ‘17 Medcraft (EST # 3) CONCLUSION: 9 M pts. 8 3 Pts. 2 1 all ages and at h—é and at 7-9, xrs. from left to right. - over - 7 9 L M H 6 h 2 11 6 1 3 5 H older group only) whereas with Reiter Medcraft produces maximal change early in treatment and in changes & 6 L Both groups ( same - MS % it H records with.Medcraft increases. Therefore later changes consist only ��95 (I M hWé/Mv/ém W W/f 44’me Wm" PHI/M41; be M 52/15 ’4 gal/ﬁe): MM) 686cm; Mwwﬁﬁw ��\. \ Séwrﬁ‘sax «wk? '».,_ *Mﬁw'yr-Ea ”138:3? ‘ ��4‘ .' .ﬂu/W aw ' , . b; Izaak?“ wumad, W ’ 147? Xv 520’? ��Ti? V 1‘ s: I. 7:. V Z 1 - \_ rm . 111374;? : 7'“: _ ‘ " - . > v, ‘ y; ’ * Winn-n35 "W" ______ r - “22:! ‘ - -——~‘——‘ . ‘ ~ ' . ‘ ’ ' ‘ ‘ ( ‘ ‘ . I J ‘ 7 ‘ I v ' - ' V n I l ' ¥ ‘ ‘- ��', ’03. Alll‘llll �. ,7 — v Q ,.. r. ‘ _ T TrK. u _ ,.., . V, 9.. 1 , . ., a ‘ ,_. ‘ w, w . n 5 . . , . . i .A . :i.» ,. ...L. I, ( :4 . , ,. . < 5,: _. . . . . z .,. "“ ; .; 'n’hr ' ‘ 1 V 13—, ., awh'A_ “,1 “1.“..«2 , ‘ n .‘ r r 1 . . .a . _ _ ‘ ._ u... , a, h J _, N ‘ '5 _, ‘ v F :. , 'v h, .7 . ‘ 4‘;- _‘ , . x; x , .31.. , u . . . , .. ,2 .. _ "1 , A . ..a h .u '. A ... . i , , . N m. u . 1 , J 1-: I :. r. , , ‘ r ._ ; . . . . .ﬁ . . , rJ . :., I ‘ V, sv,._______-_._..:_:>..7;_.;_T t.« n—' n a. r r , :J: I. I; » .n .= . . II\ ' ' J any. ‘_.‘ , 2 Mr .7 . _ . .3 ‘l ,_ g» ..‘ I .a‘ . ,~ L, m .H _ J ,V , --.,-_.' r, 7 , n .T» . 1 H . — , . ”37:-.." \.L. \I Z" W“ ‘ K A [“97 '. .1:..." , .u: ._, Nu L x; ' ,- , . .. a w H _ H _ _. .,. . . .> . 7 wm _, . . . ., l , ,.. ., ,. . m "W”. 5,2 , , ' .3 1 ., . j A . g ‘ ., i. .. . ‘ V.,, Hutu” ﬂ A, 1 ��.g.W- an}, , 3 ‘ \——r —- --m I-L I I I I ' Mr n/f r? l' 2, 7 6 1 ‘. é ' / ./ o -’ I ' _» ’ //,,../ ’ ‘ , * Q 3 5* �W INDIVIDUAL PSYCHIATRIC TREATMENT INDICATIONS Paul H. Wilcox, M.D. Revised Nov. 21, 1953 Li PREDOMINANTLY NEUROTIC if and Org., B.P., F, otherwise IF start Nm, Ag, 3, 0-0, G, HqA, with Sequence Ir, Un, Of, or Par, start with Sequence I III PREDOMINANTLY SCHIZOPHRENIC if and D or Ag, otherwise I5 (Psychosomatic symptOms, anxiety or reactive depression) start start with with Sequence Sequence I PREDOMINANTLY ENDOGENOUS DEPRESSION start with Sequence Sequence Sequence I Sequence E.S.nc. II III Sequence IV E.C.T. COznc. 002 II \/, \ \ ___, 4______e 93 MANIC _, COznc. ___, E.C.T. ___, ___, low E.C.T. 1: Eu if Tr ______+ 602 \ifD ._____, II ifC 1:0 if c __, if t _____, if 'r _, ___, (III) (for termination of trance) 002m. (II) \<: (III) high E.C.T. C02 (IV) E.S.nc. (I) E.S.nc. (I) ifT if t plus 0...? terminate D if _____, E.C.T. (II) Note: Appropriate psychotherapy should accompany all phases of treatment wherever indicated. The goal of therapy is for the patient to have a mild 002 reaction (t) and be essentially symptom-free (O) for an observation period of at least two months. £21 - anxiety increasing Ag - agitation B.P. - systolic B.P. over 170 mm. Hg., systolic c - brief confusion (e.g. only 5 min.) C - prolonged confusion (e.g. more than AS min.) Cf - clinical confusion coznc. - non-coma 002 (whiffs) C02 - coma 002 D - persisting or increasing depression E.S.nc. - non—convulsive electrostimulation E.C.T. - electroconvulsive therapy Eu - euphoria F - marked fear and anxiety A H-A G Ir - Nm 0 — - severe guilt feelings - marked hate and aggressive tendencies marked irritability severe nightmares symptompfree - for 2 mos. or more obsessive-compulsive features Org. - organic changes Par. - paranoid trends O-C s - sleepless tT - mild tension - mounting tension Tr - prolonged trance state Un - unreality feelings ��52 m - �MAX F'INK. M. D. 275 MIDDLE NECK ROAD GREAT NECK. N. Y. HUNTER 7-4542 \; . :\ \ \ . w . .\\\ a h {zitgiisézirié \ ,5:11:15rfie1 v, flhhugavwx.§.1 at»; J. 3.11.. , _ if NDD‘ $5.. . J 3.25.1.5 4.51 1. $313 £511:er “V :2 1! ��a M.“ .7 �-7 r. v my .‘__r,\~. ‘_,_ an" .7 ”amt , 0, .7.— ..w . x 7 , ,...r,_ ‘_— v-4 . . ,_ w “K- mﬂ.w~..—-~_‘nr—._;_i , _ 7 _ 7V -_.-N,...~ . 1,-.. ~..~._.V..,.v .,_‘,.r_._h., V . if"? ��mw "">‘- aw ﬁn ’4_l4 I; Ant“ . ��4...»... ”Mu-L" ��Ft: £13 3"! HM (M) ��i 3 i E .1 i ��. _ a-‘v—{WWG’W’W‘tVF‘r‘Fw—ugfva , WNW—“W “WW. _ , . , . , ‘ W. . , _. ,' , ‘ A,.V,.. 3m, .zwu -..m~w~ W «RM-4mm "F v :i‘\ @ﬁ - A» \\\ 'l ‘3“ l." ..,. ‘ “ \.§;‘.§g was. wig-33;; __ ‘ ' _ ‘ A Em ' axis: .3, ��(L ALLA 4 4T ��;; i ��For creative activity, as possibly, for problem solving, the hyperh alert state must be avoided. In the alerted individual, discrimination is more focused, acute, and differences are sharply maintained. Under such conditions, old pathways are clearly maintained and the possibility of new associations is less. For creative work, pathways must be connected ected before. This can only be accomplished were not con; discrimination is diminished. reverie; by fatigue (creativity late at night); by isolation; by alcohol; etc. Perhaps in the EST situation, the cerebral state induced This ? is if that done by is similar to drowsiness (Surely the EEG - perceptual effects are similar) patient is able to use ("create") available before. and thus the new defenses which were not Also, in the tachistoscopic situation, the presentation is a hyperalerting situation - but, the reverie state (or dream) afterwards, permits of greater elaboration of the memories (greater range of imagery - greater creativity,). I/e3ﬂd �January 7, 1957 Role of Altered Cerebral Motion in Behavioral Change Following Induced convulsions m m, 14.9., Babe” In M; 31.3. m Hm Karin, 31.1). role of altered consciousness in the clinical behavior of epileptioe, patients with mental disorders, and in the diagnosis: of dis-orders of the central nervous system is unclear. Recent studies of the electroshook therapy process amonamtcd the crucial nature of persist.ent alteration in brain fxmction for the behavioral changes induced. In the course of theee studies, an appreoietion was obtained of the types of alteration in behevior induced 120' diffuse cerebral dysfunction; the role of the pmoz‘bid personality in the behavioral pattern; and the smith. 1w of various tests on indiooe of altered brain function. To define and measure the effeotc of alteration in consciousness Pmblem """"‘""'"" (manning rm diffuse control dysfunction) on clinical be. havior patter-no. The Kethod: Subjects on a voluntary paychiatric hospital referred for electro— shock therapy were studied concurrently by psychiatric, psychologic and neuroplwciologic techniol. Alteration in brain function (the demo of organic mental I; sycamo- was measured by four indicee: (a) Eleotroenoophalogm, moored for per cent time delta under nesting and activated conditions; (1:) Diaoriontetion, confabulatm-y responses one language changes following intravenous mobarbital. (c) Dininution in perceptual discrimination of simultaneous tactile threshold stimulation touts. (d) Interference with recall of 3 letter words after interpolated looming of nonsense syllables (”retroactive inhibition of recall") . mound by repeated psychiatric intent and reports of therapists and hospital personnel timing 2) Behavioral ohengec were views with subjects; and after the period of therapy. pmorbid percoaolity was eotimted by Cstructured interviews with relatives and by Rorschach tests (scored for H o reopens”). ROM“! 1) Modification of twavior is related to the dogma and persistence of alteration in hrm function, as measured by the electroencephalogram, amobarbital teats and perceptual discrimination teats. 3) The �in! 0' J c‘u pattern at the induced behavioral change, manifested by ahnnges in lmguags, mood, attitudes and symptom, is related to the preamorbid personality structure. Such behavioral patterns as euphoria, donisl, withdrawal, severe wry loss and disorientation, paranoia, WMrzitability and installed musty, have been obsemd. 3) Various indicss or altered cembrsl function have different sensitivities to modification depending upon the extent and activity (recent or old) at the dysfunction, and the personality of the subject. 2) The ’ leusiem 1) Behaviors]. nodii‘icstian in canditims inducing altered brain fanatics is ths adaptive response of tbs argmism under the conditian of an aims-stint: in the state of camcioumss. 2) has type of adaptive response is dependant upon tbs premorbid pemomiity of tbs subject and the milieu in which the behavior occurs. altered brain function mt be interpreted in tons of thsir sensitivity; their time of application in the ongoing process; and the pmrbid persmlity “the subject. This significance of them observations in tha understanding of epilepsy; the treatment. or mental illness; and in medsfinition 5f altered states of consciousness will be dissusssd. 3) Tests 01‘ Iron tbs Heumplwsiolom‘r Laboratory, Department of Fotperimental Psychiatry, Hillside Hospital, Gian Oaks, New Iork, U.8.A. �January 7, 1957 Therapy of Schizophrenia: Effect of Alteration of Brain Function on Behavior In the course of experimental studies of the mechanism of actidn of electroShock therapy in patients with psychiatric disorders, a hypothesis was elaborated regarding the mode of action of other therapies in patients with schizophrenia. 1t has been demonstrated that the essenp a electroshock is in therapy behavioral change to pre-requisite tial EEG defined by function as of brain delta, loss altered sustained degree of discriminatory ability on perceptual tests, and disorientation followThe behavioral response sodium. amobarbital of administration the ing under the conditions of an altered state of nervous system activity is an adaptive response of the subject, dependent on the premorbid person, ality . who and the environment. Similar factors have been demonstrated as operating in patients Show sustained improvement following insulin coma therapy. studies of drug therapies in schizophrenia demonstrate that the therapeutic efficacy of the newer psychopharmacologic agents demonmechanisms which brain are to the degree to related is directly strably altered. Conclusion: The mode of action of the various physiodynamic therapies (ICT, EST, Drug) is directly related to the degree of sustained alteration in brain function induced; such alteration being defined by changes in the resting and activated electroencephalogram, disorientation tests, and perceptual discrimination tests. , Ongoing ��can ﬁrsthand for the pemeption 01‘ words momma anti aubjem were unable to Mantify m wows with increasing degrees at cerebral 3-) Wmotim, We: in percoptim were highly sex-minted with other boo Moral chug”, inﬂiaaﬁve of an alumni interaction with the omirmmt. Minimum 1) Diffuse alter-nuns: in brain mum, as measured by elactrmcaphalomﬁzm 631%: mad emanation tests after mammal, results in altemtiw at pamytm pat-toms by an increase in threshold, impaired Metamucil: of stimuli, of which the ability to diacriminato a rignre from a. comply: backgromxd in a 5min h) ' ma We! ' 2) Alteration in pemepbim mpmanu sweet an m rather than a speciﬁc as? altered behavioral interaction with the envirmnt, Maialogieal defect, This factor sham be considered in peroeptnal 112.20.00.21. brain lemma as will. nudist {51% Ion-k, ”.34: m W; mar”?! �December 17, 1956 Concept of Cerebral Localization vs Mass Action Effects Certain functions ascribed to 1) CNS are "localizable", as vision, motor power, motor aphasia; While others, as memory, judgment, insight, cal- culation, figure—ground, are non-localizable. (more peripheral than central); have marked effects; and EEG damage The is generally first group are cortical permanent; small lesions is usually not pathological. lesions are generally deep or basal; recovery of function is possible; small lesions have no effect (i.e. a mass action law is applicable) and EEG effects are prominent. The non—localizable It results in a non-localizable lesion - with diffuse dysfunction. is the technic par excellence to study such mass action lesions. 2) EST 3) Psychological measure mass tests of "OMS” are positive to the degree that they action effects rather than focal - except if focal dysfunction interferes with performance as in lesions affecting vision, motor power and speech. h) Concept of Active vs Static Lesions: In studies of head injuries, lobotomy and post operative cases of six or more months duration, the studies reflect localizable (cortical) defects mainly: for the deeper activities nd are longer active. Any defects in fun- ction are expressions of specific cortical localizable damage. In contrast, studies of brain tumors, immediate post-traumatic states, post- (early) are studies of active dysfunction - a combination of the focal and the diffuse defects. The degree of dysfunction depends on the mass lobotomy, and EST effect, plus the localized defect. m away. ”cw-u W7»: 6% 2.2 .-W M- ��«M m a» mum at :1“er bum mum the dun» Mariam mum sum and chm a! me: aluminum; m vat-um a! the mmw‘mpu and tho «the submit ammmmm mammmmﬁg mumammnwmmm. Mmumafmw mun Winemwnuwm at them mm“). mm 1»th mm mu with annWtupmhupmrbm uwamwmmwwmm, the Mine of at a act-Latin Wm m by th"W”, WV. the an dwaﬁmt mm mm»: Mum Mow, m W: m that mum and. at my m Mum; torﬁumohanin WWMemlmm meettheu MWMWMWMNW¢ » �(July 2, 1965) Jan. 3, 1958 HOLE OF ACTION OF BIOCHEMICAL AGENTS The CNS is IN BEHAVIOR dependent upon a umber of enzyme systems for cholinestemseand including fmction, mtabolisn proper acetylcholine, gluoose-pkwsphetase, etc. CNS function and, thereby, affect of that agents variety behavior- is large, since processes in equilibrim may be shifted The in either direction by increasing or decreasing the available quantity of a metabolite . A. For drug action, therefore, the following are considerations in potency: (a) Does a drug affect an enzyme system in a reliable it way? to affect the system? (c) What defenses does organism process to block CNS? in action once limit drug's or (b) Can B. Secondly, get to mile (NS an agent may directly affect the metabolism CNS the dependent upon the is extent that to of a specific system, system? Is the defect thw induced simificant for the netsbolism of CNS underlying behavior? that defenses can body cell into play when system is affected to substitute other energy system? Thus, the variation in drug effects in behavior depend upon: (a) Behavior at onset; and predisposition (personality) to response; (b) Drug dosage - availability to has on an enzyme system; CNS and the effect it �(c) Dependence of organism on specific enzyme - and organismic defenses (i.e.,-~ substitution for affected system) . Whether effect was gmdual (allowing for system ((1) defenses, i.-e . , alternate mtabolic system) or acute (not allowing defense). Imividual diffemnma in response may be due, thus, to differences in: (a) Dosage, mtio S mute of Ministmtim (b) dependence on the affected system (c) adaptive ability to biochemical changes. To these clauses, EEG is a gross approximation and indicator, reflecting the homeostatic balmce in various enzym systems of the CNS. ��Personality-O.M.S. Tests of O.M.S. 2-5-57 The All our tests of changes in cerebral function tapas continuum. degree of cerebral dysfunction at the time of examination will determine which tests will The degree of “ show changes in patterns. cerebral dysfunction is dependent on numerous variables including; Rate of develogment of dysfunction Premorbid state of functioning on the tests employed Stress of the examination- needs and motivation of the subject Localization of the cause of the dysfunction (local vs. diffuse) ' factor, the premorbid state of functioning, as characterized the present evaluations of personality organization by the Rorschach One by test and by interviels, graphic fashion; can be pictured as operating in the following ‘ ��V E F E E F E ;‘ ﬁs‘;’*;)¢¢2\ _ a '“ﬁ‘ �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource EEG (notes), 1955-1957 Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-002-3-003 Date A point or period of time associated with an event in the lifecycle of the resource 1955-1957 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence: EEG notes Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/c02d31143a5f498973505a8a964ce076.pdf b8c3ce2c33d87b8f3f28b4f66c1d2afb PDF Text Text Reprinted from Neuro-Psychopharrnacology EEG AND BEHAVIORAL EFFECTS OF PSYCHOPHARMACOLOGIC AGENTS* M. FINK Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, Long Island, N. Y. (U.S.A.) Recent studies have presented data supporting a neurophysiologic—adaptive View of the convulsive therapy process“: 15. This hypothesis holds that the clinical efﬁcacy of repeated induced convulsions is dependent upon the induction of a persistent alteration in cerebral function, which provides the milieu for changes in the subject’s inter— action with the environment. In these studies the best index of neurophysiologic change has been those aspects of cerebral function reﬂected by 8 activity in the electroencephalogramS—lo. The efﬁcacy of newer psychopharmaceuticals in altering psychotic behavior patterns led to the suggestion of a similar hypothesis for the mode of action of these agents“, and to studies of the relationship and speciﬁcity of altered behavioral patterns to neurophysiologic change as reﬂected in electroencephalography. This report summarizes some of the experimental data observed in on—going tests of this hypo— thesis. ‘ SUBJECTS AND METHODS We have studied consecutive patients, suffering from depressive psychoses, agitated and excited schizophrenic states and severe psychoneurotic disorders, referred for physiodynamic therapies (convulsive, psychotropic drug, insulin coma) in a voluntary, open—ward, psychiatric hospital. Serial electroencephalograms were taken prior to, Aided, in part, by grants M-927 and MY—2092, National Institute of Mental Health, National Institutes of Health, U.S.P.H.S., and Bristol, Wyeth and Smith, Kline and French Laboratories. * References p. 446 . �M. FINK 442 during and after the course of therapy. In addition, at various stages of the treatment As done. convulsive both studies chlorand were acute experimental program promazine therapies elicit varying degrees of EEG slow wave activity, these acute observations have been made in two groups of subjects: those without slow wave activity, and those with diffuse slow wave (HSD, LSD) or burst and slow wave (BSD) activity”. Observations have been made in the EEG laboratory. Following a routine bipolar EEG recording, an unstructured psychiatric interview was tape—recorded. Under continuous EEG recording, medication was administered intravenously at a set rate until EEG or behavioral effects were observed. Following the injection the interview was repeated and recorded. Periods of EEG recording and interview recording were alternated for the duration of the drug activity. Behavioral evaluations have been based both on clinical descriptions by the participants (subject, physician and technician) and analyses of changes in language patterns12:14. Electroencephalograms were measured for shifts in dominant frequencies, and changes in voltage, modulation, and per cent time of or, {3 and 8 frequency bands. The psychopharmacologic agents were administered orally for extended periods in clinical trials, and intravenously in the acute experimental trials (Table I). Dosage for each compound varied, but in each instance sufﬁcient medication has been given to achieve clinical behavioral effects. TABLE I PSYCHOPHARMACOLOGIC AGENTS STUDIED (Oral and intravenous) Chlorpromazine Prom azine Triﬂupromazine Perphenazine * Reserpine Iproniazid ** Deanola ** Amobarbital ** Thiopental Atropine Diethazine Amphetamine Methamphetamine Meprobamate * ** LSD—2 5b ** Win—22996 ** J B—3 I 8d J B-336e ** Benactyzine Dimethylaminoethanoll". b Lysergic acid diethylamide. 0 2-Diethylaminoethyl cyclopentyl (2-thieny1) glycolatel“. d N—Ethyl—3-piperidy1 benzilatel. e N-Methy1-3—piperidyl benzilatel. a * Oral only. H Intravenous only. OBSERVATIONS (a) Electroencephalographic Four broad types of EEG patterns may be identiﬁed according to the characteristics of frequency shift and synchronization‘l: References 35. 446. �443 INVESTIGATONS IN NORMAL HUMAN SUBJECTS I) Increase in slow wave activity and in synchrony; Increase in synchrony without frequency shift; 3) Increase in fast wave activity and in synchrony; 4) Desynchronization and frequency irregularity. Examples of each are seen in Figs. 1—4. During convulsive therapy, an increase in slow wave activity and synchrony is manifests. With drug administration similar changes in frequency spectrum and in synchrony can be observed. Such changes include an augmentation of the slow wave activity8 or a marked decrease in such activity with desynchronization of frequencies? .Of the psychopharmaceuticals tested in acute experiments an increase in synchrony With or Without an increase in slow Wave activity has been observed for chlorpromazine, promazine, and triﬂupromazine. Barbiturates regularly induce an increase in fast activity With an increase in synchrony, While amphetamine and 2) W W W MW W WWW WWW |600 PER DAY 3 MONTHS IZOO MG PER DAY 2 MONTHS PRE-DRUG LAT—LF MG WWW/WWW , LPT-LO ‘ 0-0 RPT-RO JWVWWMMNMM it 2049 HH 4* 2143 HH 2l95 50M— ISEC HH Fig. I. Chlorpromazine, oral (male, age I 5). 800 - PRE-DRUG MG | ‘WWW ' PER DAY MONTH wwwwvwwwmmwm LAT'LF AFTER 350 MG LAT-LF RAT-RF RAT-RF \ LF-RF ’ LF-RF W LPT‘LO LPT-LO NWWMMWM WWWNWWWWMWWVI o-o “MIN/WWW . MAM/WM wmwm |9|5 # |962 SOle—l RPT-RO a: W W W W mm PRE-DRUG HH - SEC HH Fig. 2. Chlorpromazine, oral (female, age 34). www—ﬁu o-o M‘WVWM WWW , Ill/WWW RPT-RO 5°VV‘—_|SEC #0 2'51 HH Fig. 3. Amobarbital, intravenous (male, age 31). methamphetamine increase fast activity Without increased synchrony. Desynchronization of frequencies is prominent after diethazine, LSD-25, Win-2299, JB-3I8, JB-336, and benactyzine. Refeyences p. 446. �M. FINK 444 In subjects with post—convulsive 3 activity, acute administration of chlorpromazine, promazine, triﬂupromazine, amobarbital and pentothal increased the per W W ,W W W» PRE-bRUG LF-LO WWW _ MIN + 80 MIN wWWM-NMWNM Rf-RO LAT-LP + 40 AFTER 3.2 mg .. RAT-RF LPT-LO . I 0-0 “WW“M‘M‘WW“ RPT-RO WWWW WW WW | SEC #ZOISIHH Fig. 4. Win-2299, intravenous (female, age 41). cent time and voltage of slow wave activity. Decrease in voltage and per cent time of slow wave activity is seen with LSD-25, benactyzine, Win—2299, JB-3I8, JB-336 and diethazine5’ 6. Similar electrographic patterns are noted in chronic oral administration of these compounds. Chlorpromazine, promazine, high doses of reserpine and occasionally perphenazine elicit increased synchronization and a shift of frequencies to the 8 range. Increased synchronization without frequency shift is occasionally observed with iproniazid. Increased high voltage fast activity is observed with meprobamate and barbiturates. Oral administration of LSD-25 and benactyzine induces EEG desynchronization with an increase in fast frequencies. (6) Behavioral Initial studies of convulsive therapy noted that behavioral change was dependent upon the development of synchronous slow wave activitys. Prominent among the associated behavioral effects were sedation, tranquillization and euphoria in agitated, depressed subjects, and a decrease in somatization, paranoid ideation, hallucinations and delusions in schizophrenic and excited subjects. Increasing agitation, paranoid ideation and panic were observed in less than IO 0/0 of the subjects. Similar behavioral relationships were prominent with these psychopharmacologic agents. In acute experiments, administration of chlorpromazine, promazine and triﬂupromazine was associated with increasing sedation, drowsiness, denial and euphoria, decreasing agitation, panic, excitement and delusional and hallucinatory activity, and minimization and displacement of symptoms. Sedation, euphoria, denial and minimization were similarly associated with amobarbital. Administration of amphetamine and methamphetamine resulted in behavioral alerting, hypomania, excitement, and increased motor activity. Similar increased alerting, excitement, tension and panic were observed after benactyzine. In addition to these patterns, illusory sensations and hallucinatory, delusional and paranoid ideation were observed with diethazine, LSD-25, Win-2299, JB—3I8, and J 13-336- References {3. 446. �INVESTIGATIONS IN NORMAL HUMAN SUBJECTS 445 Equally prominent with the behavioral changes were alterations in patterns of language. Previous studies of convulsive therapy had indicated that speciﬁc syntactic language patterns (as in the use of the third person mode, past and future tense, dis— placement, minimization, denial, clichés, and cryptic remarks) increased with increasing neurophysiologic change”. These language patterns were further exaggerated by intravenous amobarbita114’15. In the present studies, chlorpromazine, triﬂupromazine and iproniazid increased these language patterns. Diethazine, LSD—25, Win-2299, and benactyzine decreased and reversed these language patterns, increasing the use of the present tense, ﬁrst person mode, and somatization7. Relation of behavioral and electrographic observations The electrographic patterns Were consistently altered concurrently with behavioral changes both in the acute and chronic administration studies. Tranquillization, euphoria, sedation and minimization of symptoms were commonly associated with increased EEG synchronization and shift of frequencies to the delta range. Agitation, tension, panic, excitement, illusions and hallucinations were associated with a desynchronization of frequencies. Similar patterns were demonstrated in subjects with prior 8 activity. Agents that tended to synchronize frequencies, as chlorpromazine and barbiturates, augmented the per cent time 8 activity and enhanced clinical patterns, while agents that desynchronized frequencies, as diethane, LSD—25 and benactyzine, minimized the clinical effects ascribed to repeated convulsions5-7. (0)} DISCUSSION These observations are consistent with the neurophysiologic—adaptive hypothesis of the mode of action of the newer psychopharmaceuticals“. This hypothesis states that the clinical efﬁcacy of psychotropic drugs is dependent upon the induction of a per— sistent alteration in cerebral function which provides the milieu for changes in the subjects’ interaction with the environment. The variety of neurophysiologic patterns induced by these agents is in contrast to the limited patterns resulting from convulsive therapy and thus provides ampliﬁcation of the original hypothesis. It is evident from these studies that the type of neurophysiologic alteration induced, as reﬂected in EEG synchrony and frequency patterns, is related to speciﬁc types of behavioral adaptation. With increasing synchrony and a shift to the 8 frequency spectrum, tranquillization, sedation and decreased agitation become prominent, while desynchronization and a shift to [3 frequencies are associated with excitement, illusions and delusional ideation. These studies are also consistent with numerous reports of the neurophysiologic effects of these compoundsm’ll’ 13:19:21, and speciﬁcally support and amplify those of WIKLER who concluded, in his studies of morphine and mescaline, that “regardless of the nature of the drug administered, shifts in the pattern of the electroencephalogram in the direction of desynchronization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness”2°. This hypothesis, and the electrographic measure of neurophysiologic change, lends itself to application in the assay of new psychotropic drugs“, the rational References p. 446. �446 M. FINK application of pharmacotherapy7, and as a basis for further experimental study of neurophysiologic—behaviora1 relationships in psychiatry. ACKNOWLEDGEMENT We are grateful for the cooperation of the following laboratories who made supplies of the various psychopharmaceuticals freely available: Ciba Pharmaceutical Prods. (reserpine), Lakeside Laboratories (JB—318, 336), Eli Lilly & Co. (amobarbital), Merck, Sharpe & Dohme (benactyzine), Riker Laboratories (deanol), Roche Laboratories (iproniazid), Sandoz Pharmaceuticals (LSD-25), Schering Corp. (perphenazine), Smith, Kline & French Laboratories (chlorpromazine, diethazine), E. R. Squibb & Sons (triﬂupromazine), Winthrop Laboratories (Win—2299), Wyeth Laboratories (promazine, meprobamate) . REFERENCES 1 L. G. ABOOD, A. M. OSTFELD AND J. BIEL, Proc. Soc. Exptl. Biol. Med., 97 (1958) 483. 2 3 4 5 6 7 K. ANDERMANN, Med. ]. Australia, 2 (1957) 1. P. B. BRADLEY AND J. ELKES, Brain, 80 (1957) 77. M. FINK, ]. Hillside Hosp, 6 (1957) 197. M. FINK, A.M.A. Arch. Neurol. Psychiat., 80 (1958) 380. M. FINK, Electroencephalog. and Clin. Neurophysiol., IO (1958) 776. M. F INK, J. JAFFE AND R. L. KAHN, Drug—induced changes in interview patterns: linguistic and neurophysiologic indices, in J. SARWER-FONER, The Dynamics of Psychiatric Drug Therapy, Springﬁeld, Ill. 8 M. FINK AND R. L. KAHN, A.M.A. Arch. Neurol. Psychiat., 78 (1957) 516. 9 M. FINK, R. L. KAHN AND M. A. GREEN, Diseases of Nervous System, 19 (1958) 113. 10 M. FINK, R. L. KAHN AND H. KORIN, Proc. Intern. Congr. Neurol. Sci, 1957, Brussels, in the press. 11 S. GARATTINI AND V. GHETTI, Psychotropic Drugs, Elsevier, Amsterdam, 1957. 12 J. JAFFE, ]. Hillside Hosp, 6 (1957) 207. 13 R. S. JORGENSEN AND M. H. WULFF, Electroencephalog. and Clin. Neurophysiol., 10 (1958) 325. 14 R. L. KAHN AND M. FINK, in P. HOCH AND J. ZUBIN, Psychopathology of Communication, Grune & Stratton, New York, 1958, p. 126. 15 R. L. KAHN, M. FINK AND E. A. WEINSTEIN, A.M.A. Arch. Neurol. Psychiat., 76 (1956) 23. 13 H. PENNES AND P. HOCH, Am. Psychiat., 113 (1957) 887. ]. 17 C. C. PFEIFFER et al., Science, 126 (1957) 610. 13 H. STRAUSS, M. OSTOW AND L. GREENSTEIN, Diagnostic Electroencephalography, Grune & Stratton, New York, 1952. 19 G. VERDEAUX AND R. MARTY, Rev. neurol., 91 (1954) 405. 20 A. WIKLER, Nervous Mental Disease, 120 (1954) 157. ]. 21 D. L. WINFIELD AND G. H. AIVAZIAN, Electroencephalog. and Clin. Neurophysiol., 10 (1958) 575. C. C. THOMAS, Printed in The Netherlands �EEG and Behavioral Effects of Psychopharmacologic Agents Max From Fink MOD. the Department of Ekperimental Psychiatry, Hillside Heapital, Glen Oaks, L010, NIY. Institute of Mental in part, by grants III-927 and MY—2092 , National Health, National Institutes of Health, U.S.P.H.S., and Bristol, Smith, Kline Aided, French and Wyeth Laboratories. Read at the Collegian Internationale Neuro-Psychophamacologicum, September 12, 1958. IV:9-3-53 Rune, and �EEG and Behavioral Effects of ggzchophgrmacologic Aggnts Recent studies have presented data supporting a neurophysiologica adaptive view of the convulsive therapy process (1, 2). This hypothesis holds that the clinical efficacy of repeated induced convulsions is dependent upon the induction of a persistent alteration in cerebral function, which provides the milieu for changes in the subject's interaction with the environment. In these studies the best index of neuroplnrsiologic change has been those aspects of cerebral function reﬂected by delta activity in the electroencephalogram (3 ,h,5). efficacy of newer psychopharmaceuticals in altering psychotic behavior patterns led to the suggestion of a similar hypothesis for the mode of action of these agents (2), and to studies of the relationship The and specificity of altered behavioral patterns to neurophysiologjc as reflected in electroencephalogram. experimental data observed in ongoing SUBJECTS AND We change This report smunarizes some of the tests of this hypothesis. MODS: patients, suffering from depressive excited schizophrenic states and severe psycho- have studied consecutive psychoses, agitated and neurotic disorders, referred for physiodynamic therapies (convulsive, psychotropic drug, insulin coma) in a voluntary, open-wand, psychiatric hospital. Serial electroencephalograms were taken prior to, during and sitar the course of therapy. In addition, at various stages of the treatment and program acute experimental studies were done. As both convulsive chlorpromazine therapies elicit varying degrees of EEG slow wave activity, �.2these acute observations have been made in without slow wave activity, and those with diffuse s1 or burst EEG w wave (HSD, LSD) activity (6). and leW'WaVB (BSD) Observations have been bipolar of subjects: those two groups in the made laboratory. Following a routine EEG recording, an unstructured psychiatric interview recorded. Under continuous EE‘3 intravenously at a set rate until was recording, medication was administered EEG or behavioral effects were observed. Following the injection the interview was repeated and recorded. EEG drug tape- Periods of recording and interview recording were alternated for the duration of activity. Behavioral evaluations have been based both on clinical descriptions by the participants (subject, physician changes in language patterns and technician) and analyses of (7,8). Electroencephalograms were measured for shifts in dominant frequencies, and changes in voltage, modulation, and per cent time of alpha, beta and delta frequency bands. The psychopharmacologic agents were administered periods in clinical trials (Table I). trials, Dosage and intravenously for each compound orally for extended in the acute experimental varied, but in each instance sufficient medication has been given to achieve clinical behavioral effects. �I TABLE PSYCHOPHARMAGOIDGIC AGENTS STUDIED (Oral and Intravenous) chlorpromazine amobarbital atropine ** promazine thiopenzal ** diethazine ** LSD-25 triflupromazine (b) " perphenazine amphetamine Win~2299 reserpine* methamphetamine JB-318 (c) (d) ** JB—336 (e) iproniazid deanol (a) meprobamate ** * benactyzine a. dimethylaminoethanol (9 ) b. lysergic acid diethylamide c. 2-d1ethylaminoethyl cyclopentyl (2-thieny1) glycolate (10) d. n~ethyl-3~p1peridy1benzilate (11) e. n-methyl—B—p1peridy1benzilate (11) * oral only ** intravenous only ** �OBSERVATIONS: (a) Electroencephalographic: patterns, observed on acute drug be identifieci according to the characteristics Four broad types of administration, of frequency may shift EEG and synchronization (2): activity in synchrony; 1) Increase in slow 2) Increase in synchrony without frequency shift; 3) Increase in wave fast wave activity and and h) Desynchronization and frequency Examples of each are seen in figures l-h. -0- ---”-“-U- u -- Fig. 1, 2, 3, ,4 in synchrony; irregularity. �-5 During convulsive therapy, an increase in slow wave synchrony is manifest. (Fig.5) ‘iith Fig. activity and drug administration similar changes 5 -------in frequency spectrum and in synchrony are observed (Figs. 6, 7). Figs. 6 7 0f the psychophnrmaceuticals tested in acute experiments in synchrony with Sr without an increase in observed for chlorpromazine, promazine regularly induced an increase and slow wave triflupromazine. in fast activity with an prominent after diethazine, increase activity has been Barbiturates increase in synchrony, while amphetamine and methamphetamine increased without increased synchrony. an fast activity Desynchronization of frequencies was LSD-25, Win-2299, JB-BlB, JB-336 and benactyzine. In subjects with post-convulsive delta activity, acute administration of chlorpromazine, promazine, triflupromazine, amobarbital and pentothal increased the per cent time and voltage of slow wave activity. Decrease in voltage and per cent time of slow wave activity was seen with LSD-25, benactysine, Win-2299, JB-318, JB~336, and diethazine (12-13). Similar electrographic patterns administration of these compounds. were noted in chronic oral Chlorpromazine, promazine, high do$s of reserpine and occasionally perphenazine elicited increased synchronization and a shift of frequencies to the delta range. Increased �.6synchronization without frequency shift was occasionally observed with iproniazid. Increased high voltage fast activity was observed with meprobamate and barbiturates. benactyzine induced EEG Oral administration of LSD-25 and desynchronization with an increase in fast frequencies. (b2 Behavioral: Initial studies of convulsive therapy noted that behavioral change was dependent upon the development of synchronous slow wave (3). Prominent among tranquillization activity the associated behavioral effects were sedation, and euphoria in agitated, depressed subjects, and a decrease in somatization, paranoid ideation, hallucinations and delusions in schizophrenic ideation and excited subjects. Increasing agitation, paranoid and panic were observed in less than Similar behavioral relationships pharmacologic agents. 10% of the subjects. were prominent with these psycho~ In acute experiments, administration of chlorpromazine, promazine and triflupromazine was associated with increasing sedation, drowsiness, denial and euphoria, decreasing agitation, panic, excitement and delusional and hallucinatory activity, and minimization and displacement of symptoms. Sedation, euphoria, denial and minimization were similarly associated with amobarbital. Administration of amphetamine and methamphetamine resulted in behavioral alerting, hypomania, excitement, and increased motor activity. Similar increased alerting, excitement, tension and panic were observed after benactyzine. In addition to these patterns, illusory sensations and hallucinatory, delusional diethazine, and paranoid ideation LSD-25, Win-2299, JB-318 and JB—336. were observed with �-7Equally prominent with the behavioral changes were alterations in patterns of language. Previous studies of convulsive therapy had indicated that specific syntactic language patterns (as in the use of the third person mode, past and future tense, displacement, minimization, denial, cliches, and cryptic remarks) increased with increasing neurophysiologic change (7). These language patterns were further exaggerated by intravenous amobarbital (l, 7). In the present studies, chlorpromazine, triflupromazine and iproniazid increased these language patterns. Diethazine, LSD-25, Win-2299, and benactyzine decreased and reversed these language patterns, increasing the use of the present tense, first person mode, and somatization (1h). (0) Relation of Behavioral The and Electrqgraphic Observations: electrographic patterns were consistently altered concurrently with behavioral changes both in the acute and chronic administration studies. Tranquillization, euphoria, sedation.and minimization of symptoms were commonly synchronization and associated with increased EEG shift of frequencies to the delta range. Agitation, tension, panic, excitement, illusions and hallucinations were associated with a desynchronization of frequencies. Similar patterns were demonstrated in subjects with prior delta activity. Agents that tended to synchronize frequencies, as chlorpromazine and barbiturates, augmented the per cent time delta activity and enhanced clinical patterns, while agents that desynchroniaed frequencies, as diethazine, LSD-2S and benactyzine, minimized the clinical effects ascribed to repeated convulsions (12, 13, 1h). �-8DISCUSSION: These observations are consistent with the neurophysiologic-adaptive hypothesis of the mode of action of the newer psychopharmaceuticals (2). is This hypothesis states that the clinical efficacy of psychotropic drugs persistent/alteration in cerebral function which provides the milieu for changes in the subjects' interaction with the dependent upon the induction of a variety of neurophysiologic patterns induced by these agents is in contrast to the limited patterns resulting from convulsive therapy and thus provide amplification of the original hypothesis. It is environment. The evident from these studies that the type of neurophysiologic alteration induced, as reflected in EEG synchrony and frequency to specific types of behavioral adaptation. a With patterns, is related increasing synchrony shift to the delta frequency spectrum, tranquillization, sedation and and decreased agitation become prominent, while desynchronization and a shift to beta frequencies are associated with excitement, illusions and delusional ' ideation. These studies are also consistent with numerous reports of the neuroand physiologic effects of these compounds (15-20), and specifically support amplify those of Wikler who concluded, in his studies of morphine and mescaline, that "regardless of the nature of the drug administered, shifts in the pattern of the electroencephalogram in the direction of desynchroniza- tion occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness" (21). This hypothesis, and the electrographic measure of neurophysiologic change, lends itself to application in the assay of the rational application of pharmacotherapy (lb), new psychotropic drugs and as a (2% basis for further experimental study of neurophysiologic-behavioral relationships in psychiatry. �SUMMKRI AND CONCLUSIONS: The relation between electroencephalographic change and behavioral response was determined on acute and chronic administration of a variety of psychopharmacologic agents in voluntary, openoward, psychiatric patients. EEG patterns were classed according to effects on synchrony and frequency patterns. Behavioral and language pattern changes were noted as concurrent with Agents EEG response. that induced an alteration in neurophysiology manifest as increased synchrony and frequency slowing in EEG were associated with behavioral sedation, tranquillity, and minimization of symptoms. Increased synchrony and increased frequency were associated with sedation, euphoria, hypomania and decreased somatization. Desynchronization of frequencies was accompanied by increasing agitation, excitement, somatization, illusory phenomena and and hallucinatory delusional ideation. The neurophysiologiccadaptive hypothesis of the psychotropic drugs is supported; mode of action of and the value of electroencephalography in the behavioral assay of these agents is suggested. �-10REFERENCES and Weinstein, E.A.: Relation of Amobarbital Test to Clinical Improvement in Electrashack, A.M.A. Arch. Neural. & Psychiat. 1Q: 23-29, 1956. l. Kahn, R.L. , Fink, 2. Fink, 3. Fink, h. Fink, M., Kahn, R.L. and Green, M.A.: Experimental Studies of the Electroshock Process, Dis. Nerv. . 12: 113-118, 1958. M.: A M. Unified Theory of the Action of Physiodynamic Therapies, J. Hillside Hosp. é: 197-206, 1957. Balatian of EEG Delta Activity to Behavioral Response in ElectraShock: Quantitative Serial Studies, A.M.A. Arch. Neural. & Psychiat. 1.8.: 516-525, 1957. M. and Kahn, R.L.: a Fink, , Kahn, R.L. and Karin, H.: Relation of Tests of Altered Brain Function to Behavioral Change Following Induced Convulsions, Prac. Int. Cong. Neural. Sci,, 1957, Brussels, (in press). M. Strauss, , Ostaw, ography, Grune H. Kahn, R.L. and M. & and Greenstein, L.: Diagnostic Electroencephal- Stratton, N.Y., 1952. Fink, M. : Changes in Language During Electroshock and Therapy, in Psychopathalgg of Comunication eds. Hoch, P. Zubin, J., Grune & Stratton, NJ. 1958, 33-139. Jai‘fe, J .: An J. Hillside Hosp. é: 207-215, 1957. - Pfeiffer, C.C. et a1.: Stimulant Effect of 2 - dimethylaminoethanal _12__§: 610-611, views, 9. 10. Objective Study of Communication in Psychiatric Inter- Precursor of Brain Acetylcholine, Science Pogsible 19 7. Pennes, H. and Hach, P.: Psychatomimetics, Clinical and Theoretical Considerations, Amer. J. Psychiatn 113: 887-892, 1957. Abaod, L.G., Osti‘ield, A.M. and Biel, J.: mimetic Agents, Proc. Soc. Exp. Biol. A New Group of Psychoto- Med. 21: h83-h86, 1958. Effect of Anti-Cholinergic Agent, Diethazine, on ER} and 12. Fink, 13. Fink, M.: Effect of Anti-Cholinergic Compounds an Post-convulsive EEG and Behavior, EEG. Clin. Neurophysiol. (in press). 14.: Behavior: Significance for Theory of Convulsive Therapy, A.M.A. Arch. Neural. & Psychiat; (in press). �-11.. REFERENCES Fink, M. and Jaffe, J.: Drug Induced Changes in Interview Patterns: and Neurophysiologic Indices, in Conference on amic A ects of Neurole tic D 3, ed. 3. Sarwer- Linguistic P chc oner in press . 150 Verdeaux, G. and Marty, R.: Action sur L'Electroencephalogramme de Substances Pharmacodynamiques D'interet Clinique, Rev. Neurol. ............._.. 2;: 1.05-4.27, 195a. 16. Andermann, K.: Electroencephalographic Evidence of Personality Change Produced by Ataractic Drugs in Mentally Disturbed 17. Bradley, P.B. and Elkes, J.: The Effects of Some Drugs on Electrical Activity of the Brain, Brain, g9: 77-117, the 1957. 18. Garattini, S. 19. Jorgensen, R.S. and wulff, M.H.: The Effect of Orally Administered Chlorpromazine on the Electroencephalogram of Man, EEG. Clin. ' and Ghetti, V., Amsterdam, .1957. eds.: Psychotropic Drugs, Elsevier, Neuroghysiol. 39: 325-329, 1958. 20. Winfield, D.L. and Aivazian, G.H.: EEG. Changes Associated with Sparine Therapy, EEG. Clin Neurophysiol. $9: 575, Inégnsive 19 . Wikler, A.: Clinical and Electroencephalographic Studies on the Effects of Mescaline, N-allynormorphine and.Morphine inLMan, J. Nerv. Ment. Dis. 120: 157-175, 19Sh. �-12.. FIGURES 1. Chlorpromazine, oral (male, age 15). 2. Chlorpromazine, oral (female, age 3b). 3. Amobarbital, intravenous (male, age 31). Win-2299, intravenous (female, age bl). ﬂectroconmllsive Therapy (female, age 55). Amobarbital, intravenous (female, age 36). Win-2299, intravenous (female, age 51). �ACKNOWEDGEMENT are grateful for the cooperation of the following laboratories who made supplies of the various psychopharmaceuticals We fully available: Ciba Pharmaceutical Prods. (reserpine), Lakeside Laboratories (JB—318, 336), Eli Lilly 8: Co. (amobarbital), Merck Sharpe 8c Dohme (benactyzine), Riker Laboratories (Deanol), Roche Laboratories (iproniazid), Sandoz Pharmaceuticals (LSD-25), Schering Corp. (perphenazine), Smith, Kline 8: French Laboratories (chlorpromazine, diethazine), E.R. Squibb & Sons (triflupromazine), Winthrop Laboratories (Win-2299) and Wyeth Laboratories (promazine, meprobamate ) . � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource EEG and behavioral effects of psychopharmacologic agents. In P. B. Bradley, P. Deniker, and C. Radouco-Thomas (eds.), Neuro-Psychopharmacology. Elsevier, Amsterdam, 1959, 1: 441-46. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-37b-003 Date A point or period of time associated with an event in the lifecycle of the resource 1959 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint and [preprint]. Reprint from Neuro-Psychopharrnacology Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/c1a1aa6de811d0a1630b2188051d512d.pdf a467aa19b75ccf3c7353e27cd875e8ef PDF Text Text M. FINK From the Department of Experimental Psychiatry, Hillside Hospital 7 Glen Oaks (N. Y.) Meeting on the Techniques for the Study of Psychotropic Drugs Bologna 1960 DISCUSSION OF THE REPORT OF Prof. MARCEL MONNIER Reprinted from the: of Acta of the International Meeting on the Techniques for the Study Psychotropic Drugs» - Bologna June 26-27th 1960 « MODENA —>SOCIETA TIPOGRAFICA MODENESE �Dr. Monnier‘s excellent review presents a vivid picture of neurophysiologic techniques in the study of drug effects. From monosyna‘ptic and poly— synaptic to organismic patterns the methods of study appear rich in promise. One phase of these studies, that of cortical EEG analysis, has been of considerable interest to our laboratory, Changes in EEG patterns induced by pharmacologic agents are generally considered to be poorly related to changes in clinical behavior. Yet, from the extensive experience with anesthetics, alcohol. sedatives and convulsants, and the theoretical views ascribing to brain function a central role in conscious behavior we would expect that psychotropic drugs may also have signiﬁcant electrographic behavioral relations. The difﬁculties in such studies lie in inter—species differences in physiologic response, the range of inter-individual and intra—individual variability in both neurophysiologic and behavioral parameters, and the wide variety of events which must be measured to obtain a reasonable image of mammalian interactive behavior. A further difﬁculty has been a lack of reasonable theo— retic models of brain function-behavioral interrelations. Recent suggestions, however, may be helpful, including the synaptic models of Marrazz‘i (l) amongst others; the brain stem models of Magoun, as elaborated by Hi‘mwich (2): and the general neuro‘physiovloglic~adaptive views of Wlikler (3), Weinstein (4‘) and our laboratory (5). In 1954. Wikler (6) stated that drugs that alter human behavior in the direction of EEG desynchronization are associated with behavioral excite— ment. alertness, illusory sensations, and hallucinations; while drugs which induce EEG synchronization, with or without increased slowing, are associa— ted with sedation. tranquillization and decreased excitement. In our studies in psychiatric patients, this hypothesis has been substantiated. The following compounds administered in physiologic dosage ranges have been shown to decrease synchronization of the EEG: mescaline, LSD—25, amphetamine; anticholinergics as diethazine, benactyzine. JB—318, JB-336; and local anesthe— tics as cocaine, procaine, and lidocaine. The following agents increase synchronization of the EEG: barbiturates, chlorpromazine and similar pheno— thiazines. meprobamate, and anesthetics as ether, chloroform. etc. In addi— — tion, various compounds without signiﬁcant clinical behavioral eﬁ'ects have been studied, including phenyltoloxamine, WY-3149 and deanol - and these have inconsistent or indeﬁnable EEG effects. In these studies we have observed. however, that the continuum of synchronization-desynchronization is an oversimpliﬁed generalization. In our present view, two other EE‘G pattern changes have assumed considerable prominence. One is a shift of dominant frequencies either to the slow (theta or delta) or the fast (beta) ranges; and the second, the presence of such ﬁgures .as burts, spikes or spindling. These latter two patterns were signiﬁcant in �2 describing the EEG behavioral relations of imipramine (7). Examples of these paterns may he found in publications from this laboratory and elsewhere (8. 9, 10, 11). It is our impression, therefore_ that further EEG analyses of new compounds in man is indeed warranted. We would suggest that the number of quantiﬁcation procedures be extended to include, in addition to frequency analysis, the techniques of topographic analysis, chronologic analysis - and these techniques may be augmented by computer techniques of summating evoked potentials. In studies of drug effects. not only is it important to deﬁne neurophysiologic parameters, but the behavioral parameters are equally signiﬁcant. The equation of change in rates of animal pole-climbing. bar pressing or jiggleand is inaccurate and excitation human with tranquillization movement cage inappropriate. There is no evidence that such tasks in experimental animals and of to interaction physicians human in signiﬁcance related to changes are psychologists. Indeed, if one impression dominates the session today, it is that the behaviors studied by pharmacologists are not the behaviors of inte— rest to the clinicians. Further study of the relations between the laboratory tasks highlighted today and human behavioral measures are needed. In this regard multivariate pattern analyses of behavior and the newer applied psycholinguistic techniques may be helpful in deﬁning the changes in human behavior patterns. In conclusions. I wish to reenforce Dr. Monnier’s review, and indicate that increased attention to EEG analyses may be proﬁtable in understanding the mode of action and the signiﬁcant differences and similarities in psycho— pharmacologic agents. REFERENCES 1) 2) 3) 4) 5) 6) 7) 8) Marrazzi A. S., Science 118, 367 (1953). Himwich 11., Rinaldi F., Brain Mechanism and Drug Action, 115-44 C. C. Thomas, Springﬁeld, 1957. Wikler A., The Relation of Psychiatry to Pharmacology. Wm. Wilkins, Baltimore, 1957. Weinstein E. A., and Kahn R. L., Denial of Illness: Symbolic and Physiological Aspects. C. Thomas, Springfield, Ill. 1955. Fink M., A Uniﬁed Theory of the Action of Physiodynamic Therapies. J. Hillside Hospital 6, 197 (1957) Wikler A., J. Nerv. Ment. Dis., 120, 157 (1954). Fink M., Canad. Psych. Assoc. J. 4, 1668 (1959). Fink M., Neuro-Psychopharmacology, ed. Bradley, P., Elsevier, Amsterdam, 441446, 1960. 9) Kink M., EEG. Clin. Neurophysicl. 12, 359 (1960). 110) Verdeaux G., Marty R., Rev. Neurol., 91, 405 (1954). 11) Bradley P. D., Elkes J., Brain. 80, 77 (1957). �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource EEG techniques in study of psychotropic drugs. Acta of the International Meeting on the Techniques for the Study of Psychotropic Drugs, Bologna, 1960. Societa Tipografica Modenese, Modena, 1961: 3pp. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-55-021 Date A point or period of time associated with an event in the lifecycle of the resource 1961 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource DISCUSSION OF THE REPORT OF Prof. MARCEL MONNIER. Reprinted from the: Acta of the International Meeting on the Techniques for the Study of Psychotropic Drugs, Bologna June 26-27th 1960 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/ab4087755279fc01b94c0135ed348fc4.pdf b42318ee79fcb2ebd0a6f398dbb0a0b0 PDF Text Text EFFECT OF ANTICHOLINERGIC COMPOUNDS (IN POST CONVULSIVE ELECTROENCEPHALIIGRAM AND BEHAVIOR 0F PSYCHIATRIC PATIENTS MAX FINK, M.D. Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L.I., N.Y. Reprinted from "Electrrrrrephalography and Clinical Neurophysiology Ioumal" Vol. 12, No.2, May 1960. �EFFECT OF ANTICHOLINERGIC COMPOUNDS ON POST CONVULSIVE ELECTROENCEPHALOGRAM AND BEHAVIOR OF PSYCHIATRIC PATIENTS 1 MAX FINK, M.D. Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L.I., N.Y. (Received for publication: March 11, 1959) Demonstrations of the significance of high voltage EEG delta activity in the convulsive therapy process (Roth et al. 1951, 1957; Fink and Kahn 1957) and the report that this delta activity was blocked by the administration of atropine and scopolamine (Ulett and Johnson 1957) provided the basis for these studies. As there were attendant unpleasant systemic effects with the administration of these agents, reports describing diethazine as an antieholinergic compound with potent neurologic but minimal systemic effects (J enkner and Lechner 1955; Lechner 1956) led us to undertake studies similar to those of Ulett and Johnson using this compound (Fink 1958). Observa— tions with diethazine led to the investigation of other experimental anticholinergic agents. This report describes clinical and electroencephalographic observations incident to the intravenous administration of various anticholinergic agents in psychiatric patients at various stages of convulsive therapy and relates the observations to hypotheses concern— ing the mode of action of convulsive therapy and of hallucinogens. Patients have been observed at various stages of the treatment process. The observations were made in the EEG laboratory, using a standard 8 channel EEG recorder and needle electrodes applied in 17 lead placements following Strauss et al. (1952). In each trial, the compound under study was administered intravenously at a set rate per minute until clinical behavior or electrographic changes were observed. The compounds studied have been dietha— zine (Heymans et al. 1949), Win-2299 (Pennes and Hoch 1957), benactyzine (Jacobson 1955), JB-318 and JB-336 (Abood et all. 1958) and atropine. Diethazine was administered at 25 mg. per minute for a total of 175-250 mg. (2.5-5.0 mg/kg.) ; Win-2299 and benactyzine at 0.5 mg. per minute for 2 to 5 mg. (0.02-0.15 mg/kg.) ; and JB-318, JB-336, and atropine at 0.4 mg. per minute for 1.2 to 4.0 mg. (0.01-0.10 mg/kg.). OBSERVATIONS (a) Diethazine. The administration of diethazine in 15 patients prior to convulsive resulted in a decrease in EEG volttherapy SUBJECTS AND METHOD ages an-d a desynchronization of all freThe subjects were 90 psychiatric patients quencies. Prevailing rhythmic patterns bereferred for convulsive therapy. Ages ranged came less pronounced. In some instances, symfrom 18 to 67 years, and diagnoses included metric low voltage 6—7 c/sec. activity appeared schizophrenic reactions and manic-depressive and was most apparent in frontal and anterior and involutional-depressive psychoses. A va— temporal leads (Fink 1958). ried number of subjects were studied for each In 25 patients with varying degrees of induced high voltage delta activity during compound for a total of 107 observations. convulsive therapy (Fink and Kahn 1957), 1Aided, in part, by grants M-927 and MY-2092 there was a significant decrease in voltage and of the National Institute of Mental Health, National in per cent time of slow wave activity. From Institutes of Health, US. Public Health Service. 45 of in frontothe delta cent an average per Atlantic Read at the American EEG Society, occipital leads, there was a reduction to a City, June, 1958. [359] . �MAX FINK 360 mean of 20 per cent. Both random and burst delta activity diminished. Low voltage alpha and beta frequencies became more prominent. The usual increase in per cent time and in voltage of slow wave activity with hyperventilation was no longer apparent. These electrographic effects appeared during drug administration and persisted for 1 to 5 hours (Fink 1958). Concurrent with these electrographic effects, we observed distinctive systemic and complaints of abdominal griping. Such effects were generally less prominent than the electrographic or behavioral. Behaviorally, patients became irritable, restless, tense and excited, and it was difficult to maintain eyelid closure. They complained of feelings of unreality and of tingling, weakness and heaviness of the extremities. Complaints that colors were pale or more intense, halos about lights and changing shadows were accompanied by delusional thoughts about W W W mm W W W W W W W W W W WWWW PRE-DRUG LF-LO WWW/(WWW RF—RO + 40 MINS. AFTER 3.2 mg. WM + 80 MINS. wwwwvuwwmm WWWM wwwmmmw LAT-LF MAM-«Mm RAT-RF LF-RF LPT-LO 0-0 RPT'RO SouVLlsﬁ- #2016 HH Fig.1 Effect of i.v. Win-2299. Note desynchronization of frequencies after behavioral changes. The initial systemic effects were episodes of coughing and complaints of dryness of the mouth. Skin remained dry and the heart rate increased by 5 to 10 per cent. This increase was rarely noted by the subject, and was not accompanied by precordial distress. There was no change in pupillary size, and constriction in response to light was prompt. There were occasional 3.2 mg. (Female, age 41). their illness, the setting of the test procedure or the examiner ’s identity. (1)) Win-2299. The report by Pennes and Hoch (1957) that Win-2299 induced illusory and hallucinatory states in man, led to this next study. On intravenous administration of Win-2299, both electrographic and behavioral effects similar to diethazine were observed. In 5 patients without EEG slow wave �ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG activity, desynchronization of frequencies and a decrease in voltages were noted in four (fig. 1). In 11 patients with high voltage delta activity there was a decrease in amplitude and per cent time of slow wave activity with an increase in the per cent time of alpha and beta frequencies. The mean delta activity dropped from 50 to 23 per cent (fig. 2). Associated with these electrographic effects were clinical patterns of restlessness and excitement, and minimal systemic effects. PaPRE-DRUG 361 rate was unaffected except in patients who became. overtly excited and fearful, in whom tachycardia appeared during this excitement period. Dryness of the mouth was reported only on direct inquiry. (c) Benactyzine. Reports that benactyzine induced EEG desynchronization (Coady and Jewesbury 1956), its anticholinergic nature, and the structural similarity to diethazine and to Win-2299 led to our testing of this compound. Intravenous administration in 12 subjects elicited similar clinical and + 40 MINS. AFTER 2.0 mg. + 60 MINS. LF-LO W WW W” W WW W WWWW Wm Wm M W MW RF- R0 Wm WM RAT-RF WWW WNW LPT-LO 0-0 RPT-RO 50ml I SEC. # 1977 HH Fig. 2 Effect of i.v. Win-2299 on post—convulsive delta activity. Record taken 24 hours after convulsion #8. Note desynchronization of frequencies and persistence after 2.0 mg. (Female, age 51). tients became fearful and tense. Visual illusory sensations were reported and were associated in these subjects with delusional elaborations about their hospital experience. Excitement was accompanied by ideas of reference, and in two subjects, intravenous chlorpromazine was administered to halt this process. These behavioral changes appeared during drug administration or within 10 min, and disappeared within 2 to 3 hours. Systemic effects were slight. There were neither cough nor respiratory distress. Heart electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, desynchronization was prompt. Delta activity decreased from a mean time of 39 to 16 per cent in 8 subjects (fig. 3, 4). These electrographic patterns were again accompanied by clinical restlessness, irritability and excitement. Artifact-free recording was more difficult. The illusory sensations and delusional thoughts seen with the initial compounds were not noted at these dosage �MAX FIN K 362 levels. Systemic effects were similar to Win2299. activity and clinical somnolence, we administered this anticholinergic agent intravenously in 15 subjects, in dosages of 0.8 to 4.0 mg. (.01-.10 mg/kg.). In 6 subjects without EEG delta activity, there were no changes in EEG pattern during drug administration nor for 10-20 min. thereafter. During a period of lassitu-de, decreased voltages, minimal desynchronization, and an increase in per cent time delta were noted. In subjects with delta activity, there was (d) Piperidylbenzilates. Following recent reports by Abood et al. (1958) that various piperidylbenzilates with measurable anticholinergic activity induced hallucinations in psychiatric subjects, we tested JB-318 and JB— 336 in 24 subjects. The electrographic patterns were identical with the other experimental anticholinergic compounds. Desynchronization of frequencies was noted during W W W W WM W W W WWW WWW WW PRE-DRUG LF-LO + 30 l0 MINS. AFTER |.5 + 50 MINS. MINS. mg. RF-RO LAT-LF RAT-RF LFTRF .. LPT-LO .. "A“... WWW/w WWW/WW 0'0 RPT-RO WM 50ml— WNWMNW‘AMAM. I Fig. SEC. WWW # |922 HH 3 Efftct of i.v. benactyzine. Note persistent decrease in voltages and desynchronization after 1.5 mg. (Female, age 34). the injection or within 15 min. and persisted for one to 4 hours (fig. 5). In each instance in which desynchronization was observed, clinical restlessness, excitement, illusory and hallucinatory activity were noted, and were concurrent with the electrographic changes. In two instances the behavioral changes were halted by the intravenous administration of chlorpromazine. (e) Atropine. Considering the numerous reports that atropine induced EEG slow wave an apparent initial decrease in voltage and per cent time of such activity during the first 10 min. after administration, followed by a return to original values during the period of quietude. In neither period were the changes significant (fig. 6). Systemic effects were prominent during the injection with increased respiratory rate, pallor, dry skin and dry mouth, precordial complaints and an increase in heart rate up to 100 per cent. Subjects became restless and �ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG recording became difficult. Within 10 min. these symptoms subsided and the subjects became drowsy and relaxed. 363 atropine under similar experimental condi- tions. These observations can be related to theories of the mode of action of convulsive DISCUSSION therapy; to concepts of the basis of experIn these studies, various experimental imentally induce-d hallucinations; and to recompounds with measurable anticholinergic ports of the effects of atropine on EEG patactivity have been observed to have similar terns. electrographic and behavioral effects. Elec(a) Convulsive therapy process. Earlier trographically, each agent induced a desyn- studies indicated that the development of high PRE-DRUG LF-LO RF-RO LAT-LF W + l0 2 MINS.AFTER MINS. |.5 mg. M +50 MINS. WW Wm «MW—MAW .AWNV'VW W W W WM W W W WW WW RAT-RF LF-RF LPT-LO Wm MWM'W 0-0 WWW/v RPT-RO WW4{)0qu #ZOIB HH Fig.4 Effect of i.v. benactyzine on post-convulsive delta activity. Record taken 24 hours after convulsion # 7. Note desynchronization of frequencies after 1.5 mg. (Female, age 33). chronization of frequencies and a decrease in voltages, which was most prominent in subjects with delta activity following convulsive therapy. Behaviorally, these electrographic patterns were associated with stimulating, excitatory, illusory and hallucinatory activity. To a lesser degree, minimal systemic changes in heart rate, salivation and sweating were noted. These latter systemic effects were more prominent in patients given intravenous voltage slow wave activity was a neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement (Fink and Kahn 1957). In summarizing the observations of numerous authors on the relation of acetylcholine metabolism to trauma of the central nervous system and to convulsions (Fink 1958) it was suggested that a biochemical concomitant of the induced EEG slow �MAX FINK 364 WWW WWVWWWW PRE-DRUG LF-LO AFTER 2.4 MG.IV l0 MINUTES AFTER WWW mm WWW WWW W W WWW W PR=|08 PR=96 .18 318- N-ETHYL, 3-PIPERIDYLBENZILATE PR=84 SOuvL—_ # 2|50 HH ISEC. Fig. 5 Effect of JB-318 on post-convulsive delta activity. Record taken 24 hours after convulsion #9. Note desynchronization of frequencies, decreased voltages after 2.4 mg. Cardiac rate shows 10 per cent increase. (Female, age 27). Similar records observed with PRE- DRUG JB—336. AFTER 2.0 MG. IV AFTER 30 MINUTES LAT-LF # 2|90HH HR=78 HR=|50 Fig. 50va__ l 6 SEC. Effect of small doses of i.v. atropine on post-convulsive delta activity. Record taken 24 hours after convulsion #6. Note minimal effect on delta activity and associated increase in heart 2.0 mg., 025 mg/kg.) rate, with persistence. (Male, age 18. Atropine : �ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG wave activity was an increase-d level of acetylcholine-cholinesterase activity of the central nervous system. The present observations of alterations in the slow wave activity of convulsive therapy by these experimental anticholinergic compounds are consistent with this suggestion. That the problem is more complex is indicated by reports of compounds with other biochemical activity also affecting slow wave activity in a similar fashion. Amphetamine (Lennox et al. 1951), Mescaline (Merlis and Hunter 1955; Denber 1955), lysergic acid diethylamide (Bente et al. 1957 a, b) and diphenhydramine (Diaz—Guerrero ct al. 1956) also reduce-d post-convulsive slow wave activity. In these reports, such a reduction was accompanied by excitatory and stimulating effects on behavior. These compounds, how— ever, are primarily sympathomimetic and antihistaminic in pharmacologic activity and not anticholinergic. The similar effects of these diverse biochemical agents on electrographic patterns and on clinical behavior may be considered within theoretic constructs of the relation of synaptic activity to behavior as expressed by Marazzi (1953, 1957), Bradley and Elkes (1957), Evarts (1958 a, b), Sherwood (1958) and Woolley (1958). These authors suggest that two types of interacting chemoresponsive receptors exist within the nervous system which are selectively responsive to cholinergic or to adrenergic agents. Where such receptors exist, they exert opposing stimulatory or inhibitory action. Thus, repeated induced convulsions may lead to a change in synaptic cholinergic activity, reflected in surface electrodes as high voltage slow wave activity. Administration of anticholinergic agents may alter synaptic activity, resulting in a decrease in the manifest cortical electrical activity to preconvulsive levels. Administration of sympathomimetic agents may achieve the same electrical effects by increasing the level of adrenergic activity. The manifest slow wave activity, so prominent and so persistent in the post-seizure EEG, may thus be viewed as resulting from a persistent alteration in the synaptic activity of large numbers of cells of the central nervous 365 system. The delicate nature of this balance is seen in the ready reversibility with alerting, time, and the wide variety of pharmacologic agents noted here. While an alteration in synaptic activity may underlie the behavioral changes in convulsive therapy, the mechanism by which such alteration is developed or sustained is unclear. The observation by Aird et al. (1956 a, b, 1958), that an increase in permeability of the blood brain barrier followed repeated induced convulsions suggests one way in which synaptic changes may be mediated. The consistent nature of these neurophysiologic observations makes an exclusively psychologic explanation of the mode of action of convulsive therapy less tenable. These studies are consistent, however, with the neurophysiologic-adaptive view of the convulsive therapy process which suggests that neurophysiologic changes provide the substrate for alterations in all aspects of the subject’s clinical behavior; the type of behavioral alteration being dependent upon the type and degree of neurophysiologic change, the personality of the subject and the expectations and tolerance of the milieu (Weinstein and Kahn 1955; Fink and Kahn 1957; Fink 1957). (b) Neurophysiology of hallucinogenic activity. The effects of anticholinergic compounds-on EEG and behavior may also be related to the understanding of experimental hallucinogenic activity. Each of these experimental compounds induced excitatory behavior, including illusory and hallucinatory phenomena. Here, too, a synaptic model may be applicable. Sympathomimetic agents, as Mescaline, LSD and amphetamine, and anticholinergic agents as those described here, are also potent hallucinogens. A neuropharmacologic basis for such behavior may be characterized as an alteration in the level of synaptic activity in the direction of increased inhibition (decreased transmission) of stimuli. The clinical efficacy of convulsive therapy in modifying hallucinatory activity may lie in alterations at this neurophysiologic level. The effects of such hallucinogenic blocking agents as chlorpromazine and Reserpine on EEG electrical activity are consistent with such a view. Both compounds induce EEG �366 MAX FINK hypersynchrony in man (Bente and Itil 1954, 1958) and block the EEG desynchronization effects of LSD and Mescaline (Schwartz ct al. 1955). Chlorpromazine was found equally potent in aborting the excitatory activity of the experimental anticholinergic compounds in these studies. (0) Relation to atropine. Comparison of the systemic and neurologic effects of experimental anticholinergic compounds with atropine reveals differences in initial focus of action. Experience with atropine at physiologic and toxic levels in man indicate that the predominant effects are focused at peripheral nervous structures. Initial bradycardia, followed by tachycardia, loss of sweating and salivation, pupillary dilation, intestinal relaxation and decreased motility are amongst the effects at low (0.2-1.2 mg.) dosages. At higher dosages (2-5 mg), the neurologic effects of ataxia, irritability, disorientation, and delirium are observed (Goodman and Gilman 1955). In contrast, the experimental anticholinergic agents in dosages sufficient for central nervous system effects manifest little peripheral activity. The central effects are observed early and may continue for extensive the dosage of atropine varied from 0.5 to 7 mg/ kg. — a range roughly comparable to the dosages used in atropine coma therapy (Forrer and Miller 1958) . In the present studies, the EEG effects of low dosages of intravenous atropine (0.01 to 0.10 mg/kg.) were minimal and systemic effects considerable, confirming similar observations by Verdeaux and Marty (1954) and by Danielopolu et al. (1955). The slow wave activity so prominent in animals and man at high dosages of atropine, may not be a manifestation of the initial or direct effects of atropine, but a reflection of a more widespread alteration in body physiology. Thus, while considerable speculation as to central neurophysiology has been based on studies with atropine, such observations provide a special case of anticholinergic effects. The anticholinergic activity established in observations in vitro and in the peripheral nervous system, may not be the effective physiologic activity in the large doses necessary to affect central structures. The experimental compounds, however, provide more suitable agents for the study of central neurophysiologic (anticholinergic) patterns than atropine, as, for example, in a re-evaluation of the studies of craniocerebral trauma and epilepsy. Ward’s (1950) reports of the efficacy of high doses of atropine in altering the clinical manifestations of head trauma indicated that effective doses brought with them severe systemic effects. The failure of atropine and scopolamine to affect epilepsy may be related to the inability of these compounds to reach the central nervous system in adequate quantity. It would seem advisable, therefore, to repeat these studies utilizing such more centrally active anticholinergic compounds as used in the experiments reported here. periods without gastrointestinal, cardiac or pupillary changes. It is within the context of the focus of activity in relation to dosage that the apparent discrepant EEG observations of the effects of atropine (in inducing slow wave activity) and these experimental anticholinergic compounds may be reconciled. Wescoe et al. (1948) administering 1.0 to 3.0 mg/kg. atropine in curarized cats and monkeys and Fun— derburk and Case (1951) using 0.4 to 1.2 mg/ kg. in curarized cats, observed high voltage EEG slow wave activity. Wikler (1952, 1957) reported that 7.2 mg/kg. atropine on SUMMARY unanesthetized, uncurarized dogs produced 1. Experimental anticholinergic comslow similar to wave” sleep. “spindle patterns Rinaldi and Himwich (1955 a, b) reported pounds (diethazine, Win-2299, benactyzine, JB-318 and administered to JB-336), psy0.5 2.0 of doses to that atropine in mg/kg. chiatric patients at various stages of convulin curarized rabbits exaggerated EEG sleep sive associated with: therapy, were of the inhibited and the alerting patterns EEG to peripheral stimuli. Similar observa- (a) desynchronization of EEG rhythms with tions have been reported by Bradley and Elkes a blocking of post-convulsive delta activ(1953) in the conscious cat. In each instance ity ; �ANTICHOLINERGIO COMPOUNDS AND POST CONVULSIVE EEG 367 (a) des effets systémiques de faiblesse musculaire, sécheresse buccale, sécheresse cutanée et tachycardie. Les effets de comportement, électrographiques et systémiques étaient concurrents. 2. Ces observations sont consistentes avec The electrographic, behavioral and systemic la suggestion qu’un concomittant neurophysiologique de la thérapie convulsive soit l’augeffects were concurrent. 2. These observations are consistent with mentation de l’activité cholinergique du systéme nerveux central. the suggestion that a neurophysiologic conco3. Des observations sur le fait que le LSD, mitant of convulsive therapy is an increase in central nervous system cholinergic activity. l’amphétamine, 1e Mescaline, et le diphenhy3. Observations that LSD, amphetamine, dramine — agents sympathicomimétiques et Mescaline and diphenhydramine —- sympatho- antihistaminiques — induisent également une mimetic and antihistaminic agents — also in— désynchronisation EEG, le blocage de l’acti— duce EEG desynchronization, blocking of vité delta post-convulsive et l’activité clinique post convulsive delta activity and clinical excitatoire, soutiennent la suggestion que des excitatory activity support the suggestion that variations de comportement et electrographibehavioral and electrographic patterns may ques puissent étre basées sur des alterations be based on alterations in synaptic activity. de l’activité synaptique. On suggere que l’acIt is suggested that increased synaptic activ- tivité synaptique augmentée (effets cholinerity (cholinergic, sympatholytic effects) is giques, sympatholytiques) soit associée a l’hyassociated with EEG hypersynchronization, persynchronisation EEG, la sé-dation clinique and clinical sedation and euphoria; while de- et l’euphorie; tandis que l’activité synaptique creased synaptic activity (anticholinergic, diminuée (anticholinergique, sympathomimesympathomimetic) is associated with EEG tique) soit associée a la désynchronisation desynchronization and clinical excitatory and EEG et des états cliniques excitatoires et hallucinogéniques. hallucinogenic states. 4. Des observations contradictoires avec 4. Discrepant observations with atropine are related to significant differences in dosage. atropine sont en relation avec des differences Re-assessment of the role of anticholinergic signifi'catives de dosage. Une reevaluation du role d’agents anticholinergiques dans les trau— is seizure and in head states trauma agents matismes craniens et les états comitiauX semsuggested. 5. These observations amplify the neuro- ble étre indiquée. 5. Ces observations amplifient l’hypothese physiologic-adaptive hypothesis of the mode of action of convulsive therapy and of exper- neurophysiologique-adaptive du mode 01 ’action de la thérapie convulsivante et des états halluimental hallucinogenic states. cinogenes expérimentaux. (b) alerting, excitatory behavioral response with illusory, delusional and hallucinatory i-deation; and, (a) systemic effects of muscular weakness, dryness of the mouth, dry skin and tachycardia. RESUME Des composés anticholinergiques eXpérimentauX (diethazine, Win-2299, benactyzine, JB-318 et J 13-336), administrés a des patients psychiatriques a des étapes différentes d’une thérapie convulsivante, étaient associés avec: ZUSAMMENFASSUNG 1. (a) une désynchronisation des rythmes EEG, avec un blocage de l’activité delta postconvulsive; (b) une réponse de comportement excitatoire, vigilante, avec de l’idéation illusoire, délusionnelle et hallucinatoire, et Mischungen von experimentellen anticholinergischen Stoffen (Diethazine, Win2299, Benactyzine, JB-318 und J 13-336) wurden psychiatrischen Patienten verabreicht welche sich in verschiedenen Stadien der konvulsiven Therapie befanden. Hierbei wurde folgendes beobachtet: 1. (a) Eine Desynchronisierung der EEGRhythmen mit Blockierung der postkonvulsiven Delta-Aktivit'at. �MAX FINK 368 (b) Eine Weckreaktion mit erregtem Benehmen, welches mit Illusionen, Halluzinationen und Wahnideen einherging. (c) Allgemeineffekte charakterisiert durch Muskelschwache, Trockenheit des Mundes und der Haut und Tachykar-die. Die elektrographischen- und Allgemeineffekte, sowie die Veranderungen des Benehmens erfolgten gleichzeitig. 2. Diese Beobachtungen stehen nicht in Konflikt mit der Theorie, wonach eine Erhahung der cholinergischen Aktivit'at im zentralen Nervensystem eine neurophysiologische Folgeerscheinung der konvulsiven Therapie darstellt. 3. Die Beobachtungen, dass LSD, Amphetamin, Meskalin und Diphenhydramin sympathomimetische und antihistaminische Stoffe —— ebenfalls die EEG-Desynchronisation herbeifiihren, die postkonvulsive DeltaAktivitat blockieren und die klinische Erregtheit dampfen, unterstiitzen die Annahme, dass elektrographische Veranderungen sowie solche des Benehmens auf Anderungen der synaptischen Aktivit'at zuriickgefiirt werden konnen. Es Wird angenommen, dass eine erh'ohte synaptische Aktivitat (cholinergische, sympathikolytische Effekte) assoziiert ist mit Hypersynchronisierung des EEG’s, mit klinischer Sedation und Euphorie, W'ahrenddem eine verminderte synaptische Aktivit'at (anticholinergische, sympathikomimetische Effekte) assoziiert ist mit Desynchronisierung des EEG und mit klinischen halluzinatorischen Erregungszustanden. 4. Abweichende Beobachtungen mit Atropin stehen mit signifikanten Differenzen in der Dosierung in Beziehung. Die Rolle, welche anticholinergische Stoffe bei Kopftrauma und Anfallszust'anden spielen, sollte erneut in Betracht gezogen werden. 5. Diese Beobachtungen unterstiitzen die neurophysiologische Hypothese ﬁber die Aktionsart der konvulsiven Therapie und der experimentellen halluzinatorischen Zust'ande. I am grateful for the technical assistance of Mrs. Hannah Mosquera in EEG recording and analyses. Supplies of the various pharmaceuticals were made freely available by Lakeside Laboratories (JB318 and JB—336), Merck Sharpe &Dohme (benactyzine), Sandoz Pharmaceuticals (LSD-25), SterlingWinthrop (Win-2299) and Smith, Kline and French Laboratories (diethazine, chlorpromazine). REFERENCES ABOOD, L. G., OSTFELD, A. M. and BIEL, J. A new group of psychotomimetic agents. Proc. Soc. Exper. Biol. Med., 1958, 97: 483—486. AIRD, R. B. Clinical correlates of electroshock therapy. A.M.A. Arch. Neural. Psychiat, 1958, 79: 633- 639. AIRD, R. B., STRAIT, L. A., PACE, J. W., HRENOFF, M. K. and B‘OWDITCH, S. Neurophysiologic effects of electrically induced convulsions. A.M.A. Arch. Neurol. Psychiat., 1956, ’75: 371-378. BENTE, D. und ITIL, T. Zur Wirkung des Phenothiazinkorpers Megaphen auf das Menschliche Hirnstrombild. Arzneimittelfarschg, 1954, 7: 418-423. BENTE, D. and ITIL, T. A comparison of the action of various phenothiazine compounds on the human EEG. Trans. Int. 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Cholinergic mechanism involved in function of mesodiencephalic activating system. A.M.A. Arch. Neural. Psychiat., 1955, 73: 396-402. ROTH. M. Changes in the EEG under barbiturate anesthesia produced by electro-convulsive treatment and their significance for the theory of ECT action. EEG Olin. Neuraphysial., 1951, 3: RINALDI, 261-280. ROTH, M., KAY, D. W. K., SHAW, J. and J. GREEN, Prognosis and Pentathal induced electroencephalographic changes in electroconvulsive treatment. EEG Olin. Neuraphysiol., 1957, .9: 225—237. SCHWARZ, B. E., BICKFORD, R. G. and ROME, H. P. Reversibility of induced psychosis with chlorpromazine. Prac. Maya Olin., 1955, 30: 407-417. SHERWOOD, S. L. Central cerebral chemicals and their relation to psychoses. Chemical Concepts of Psy- chosis. McDowell, Oblensky, N.Y., 1958, 268-276. STRAUSS, H., OSTOW, M. and GREENSTEIN, L. Diag— nostic Electroencephalography, Grune & Stratton, N.Y., 1952. ULETT, G. A. and JOHNSON, M. W. Effect of atropine and scopolamine upon electroencephalographic changes induced by electroconvulsive therapy. EEG Olin. Neurophysiol, 1957, 9: 217—224. VERDEAUX, G. et MARTY, R. Action sur l’électroencé- phalogramme de substances pharmacodynamiques d’intérét clinique. Rev. Neural, 1954, .91: 405-427. WARD, A. Atropine in the treatment of closed head injury. J. Neurosurg., 1950, 7: 398-402. WEINSTEIN, E. A. and KAHN, R. L. Denial, of Illness: Symbolic and Physiological Aspects. C. Thomas, Springfield, 111., 1955. 0., GREEN, R. E., MCNAMARA, B. P. and KR-OP, S. The influence of atropine and scopolamine on the central effects of DFP. J. Phar- WESCOE, W. macol, 1948, .92: 63-72. WIKLER, A. Pharmacologic dissociation of behavior and EEG “sleep patterns” in dogs: morphine, N’allylnormorphine and atropine. Prac. Soc. Exper. Biol. Med., 1952, 79: 261—265. WIKLER, A. The Relation of Psychiatry ta Pharmacology. Wm. Wilkins, Baltimore, 1957. WOOLLEY, D. W. Serotonin in mental disorders. Res. Publ. Ass. nerv. ment. Dis., 1958, 36': 381-400. Reference: FINK, M. Effect of anticholinergic compounds on post convulsive EEG and behavior of psychiatric patients. EEG Olin. Neuraphysial., 1960,12: 359-369. W w IN �ANNOUNCEMENT WEEK—END COURSE IN "EEG AND CLINICAL NEUROPHYSIOLOGY IN PAEDIATRIC PROBLEMS” Institute of Child Health, Hospital for Sick Children, University of London, London, England Saturday, June 18th, 1960 9.45 a.m. Introduction. 10.00 a.m. Electrocorticography During Operations for Partial Epilepsy. 11.15 a.m. Coffee. 11.30 a.m. Motor Function and The Basal Ganglia. 1.00 p.m. Lunch. 2.00 p.m. Behaviour after Cerebral Lesions in Children and Adults. 3.15 p.m. Tea. 3.30 p.m. Diffuse Systems in the Brain: Physiological and Pharmacological Mechanisms. Dr. Otto Magnus, Head EEG Dept, St. Ursule Clinic, Wassenaar and “Meer en Boslk’ ’, Hemsteede, Holland. Dr. John A. V. Bates, Neurological Research Unit (M.R.C.), The National Hospital, Queen Square. Prof. H. L. Teuber and Dr. R. Rudel, Dept. of Psychiatry and Neurology, New York University, Bellevue Medical Centre. Dr. Philip Bradley, Dept. Experimental Psychiatry, University of Birmingham, Hon. Director M.R.C., Neuropharmacology Research Group Sunday, June 19th, 1960 10.00 a.m. Circulatory Arrest. 11.15 a.m. Coffee. 11.30 a.m. The Clinical Physiology of the Lower Motor Neurone. Dr. G. Pampiglione, Dept. Clinical Neurophysiology, Hospital for Sick Children, Lecturer Institute of Child Health, University of London. Dr. J. A. Simpson, Neurology Unit, Northern General Hospital, and University Department of Neurology, Edinburgh. ��,. ,r" . 7/ Editor-imChief E L E C T R O E N C E p H A LO G R A p H Y Montreal Neurological Institute 3801 University Street Montreal 2' Canada AND HERBERT H. JASPER CLINICAL Editorial Assistant Montreal IItlleurological Institute 3801 niversity Street “m“l 2. R' S. SCHWAB . Massachusetts General Hospital Boston 14. Mass” U.S.A. H. FISCHGOLD 9 ans “élP‘FQ‘” . rance l NEUROPHYSIOLOGY PIERRE GLOOR M Associate Editors Clinical and Laboratory Notes can“ d ° . An International )ournal European Office Managing Editors W. STORM VAN LEBUWEN OTTO MAGNUS THE E.E.G. JOURNAL Aid. Electro-Neurologie Academisch Ziekenhuis Leiden, Holland. StreEt Montreal 2' Canada . 3801 univerSity my 6 , 1959 a Technical Notes _H. {WM 3,1111%??? D.lVlSlon o e rca ec romcs College of Medicine Iowa City. Iowa. LI.S.A. F. BUCHTHAL Universitetets Izeurofysiologiske Institut Copen aaen. Denmark _ _ Index and Review of Literature C. E. HENRY Institute of Living 200 Retreat Avenue Hartford, Conn., U.S.A. Dr. Max Fink, Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L. N. Y. Dear Dr. Fink: I., - Effect of Anticholinergic Compounds on Post Behavior of Psychiatric Patients Convulsive I am pleased to inform you that the above manuscript has been reviewed by members of our Editorial Board and recommended for publication with some revision. < .. ”by/ﬁnwﬁlw... l , Re: MS 981 EEG & In the first place, I am sorry to have to ask you to condense the manuscript to about two thirds of its present size, since we have had to institute a more stringent regulation regarding the length of manuscripts, due to an excessive amount of material for publication. I should think that this condensation could well be made in your study by reducing the length of your discussion and trimming up descriptions in places where elaboration of drug action is perhaps not necessary, as such information may well be available in current pharmacological literature. also that you consider alternative hypotheIt is recommended modes and of action. Reference to the work by Aird, other possible see; on Cerebro-vascular Permeability, to be found in the Archives of 1956, the Journal of Nervous and Mental Disease of 1956, the Archives of 1958 and the Journal of Neurosurgery of 1952 might be worthwhile. Your synaptic theory would be stronger if it was not over-emphasized and made clear that it is only a tentative hypotheses throughout, perhaps particularly in the conclusions where it should be quite clear that your statements are hypothetical rather than proven, since the relationship between the EEG patterns and synaptic activity is a very tenuous one and may, at times be inverted. We also would like to have some legends for your illustrations make them to clear and independent of the text. Official organ of the International Federation of Societies for Electroencephalography and Clinical Neurophysiology, Inc. �ELECTROENCEPHALOGRAPHY Editor—in-Chief HERBERT H. JASPER Montreal Neurological Institute 3801 University Street Montreal 2. Canada R. S. SCHWAB Massachusetts General Hospital Boston 14. Mass.. U.S.A. AND C LI N I C A L Editorial Assistant H. FISCHGOLD NEUROPHYSIOLOGY PIERRE GLOOR Montreal Neurological Institute 3801 University Street Montreal 2. Canada H. W. SHIPTON THE EEG. JOURNAL Division of Medical Electronics College of Medicine Iowa City, Iowa. U.S.A. F. BUCHTHAL Universitetets Neurofysiologiske Institut Copenhagen. Denmark 3801 University Street. Montreal 2, Canada Index and Review of Literature EurOpean Office Managing Editors OTTO MAGNUS Afd. Electro-Neurologie Academisch Ziekenhuis Leiden, Holland. 1 rue Lu Cases Paris VII. France Technical Notes An International Iournal W. STORM VAN LEEUWEN Associate Editors Clinical and Laboratory Notes C. E. HENRY Institute of Living 200 Retreat Avenue Hartford, Conn.. U.S.A. _ 2 _ to your illustrations, we compliment you on their clarity and clean presentation; but there is some question as to whether they are all needed to make your points. If you can find some way of reducing their number to enable further condensation of your presentation, it would be adWith regard visable. sorry to cause you this extra trouble with your manusa splendid piece of work; but we feel that due to our own publication problems, and for the benefit of the clarity and conciseness of your presentation, the above alterations would be advisable. cript, which I am is obviously Yours sincerely, / Wt Herbert H. Ja Editor-in-Ch' f e rmrx HHJ/nb Official organ of the International Federation of Societies for Electroencephalography and Clinical Neurophysiology. Inc. �lurch 9, 1959. the Editor, EEG Journal, 3801 University Street, Hentranl, 2, Clnldl. Dear Dr. Jasper: I :1 enclosing a copy of a report entitled Effect of Anticholinargic Compounds on PostOonvulaivc EEG tad Behavior of Psychiatric Patients“ for your consideration for publication in the EEG Journal. Ran: thanks for yam: consideratiun. “The Sincortly yours, m Junk, 31:33 14.». �Hay 20, 1959. Dr. Herbert H. The EEG 3801 Jasper, Editorain-Chier, Journal, University Street, Montreal, 2, censda. Re: as 981 Jasper: I as pleased.to return the enclosed manuscript which has been edited according to your suggestions. I found your comments and reoosnendatiens helpful and have been able to condense the manuscript oonsidersbly. I trust that it will still read intelligibly. Dear Dr. by I have reduced the nnnber of illustrations 1958 the since the tee diethasine deleting cots, report has adequate pictures. I have also taken out one each or the piperidylbensilate and atropine figures, leasing but six figures for the final manuscript. Legends for each of the illustrations are eppended after the rersr~ CBCOEe I had seas difficulty in encespassing the obsersetiens or iird in this report, since he has not attempted a generalisation of nenrophyeiologic change and behavior. As I interpret his studies, he has observed changes in distribution of large molecules in spinal fluid after convulsive therapy. This observation say or say not be consistent with changes in cholinergic, adrenerxio or synaptic relationships but in no wise excludes the concoaitsnt changes suggested by our studies. In any case, I have screed that the synaptic theory has been rather strongly pot and have modified the language considerably, including what I believe is a relevant reference to iird's studies. Except for the hypotheses suggested by Roth and Blett, which I believe are consistent with the suggestions or this report I know or no other systeaatio atteapt to relate nenrophysiologic and behavior changes after convulsive therapy. I would be pleased to include such studies. �Dr. Earhart H. and Jaipur, (Contd) #2 I an grateful for your vary kind caaoidcratioa nest £hut¢htrul criticism. I stunt that this copy a: the unnuseript any aunt with your approv:1. Sincoruly yours, an aran Fink, rm. �Anticholinergic Hellucinogene and Post Convaleive' EEG From and Behavior the Department of Experimental Psychiatry, Hillside Hoepitel, Glen Oaks, L.I., N.I. Aided, in part, by grant M~927 and HY~2092 of the National Institute of Mental Health, National Institutes of Health, 0.8. Public Health Service. Read at the VII: 1/59 - American EEG EEG Society, Atlantic City, June, 1958. �Anticholinergic Hellucinogens and Post Convuleive EEG and Behavior In 1956 Ulett and Johnson ( ) reported that atropine and scopolanine blocked the eppesranee ot the high voltege activity usually induced by convulsive therapy. that the dose of atropine necessary to affect the They EEG delta also noted EEG was such es to be associated with unpleasant systemic effects. Reports by Jenkner compound & Lechner ( ) describing diethaeine es en enticholinergio with potent neurologic but minimal systemic effects led us to undertake studies using this compound ( similar to those of Ulett and Johnson ); and these observations, in turn, led to an investigation of other experimental anticholinergic agents. It is the purpose of this report to describe clinical and electro- encephalographic observations incident to the intravenous administrao tion of various anticholinergic agents in psychiatric patients at verious stages of convulsive therapy and to relate these observations to hypotheses concerning the node of action of convulsive therapy ( ) and of exogenous hellucinogene ( ). �-2SUBJECTS AND METHOD: subjects were consecutive referrals for convulsive Our therapy in an open ward volunhry psychiatric hospital. While varying numbers of subjects have been studied for each compound, subjects in 106 experiments have been essayed. 88 Iron 18 Agesranged to 67 years, and diagnoses include schizophrenic reactions, manioudepressive and involutional depressive psychoses. Patients have been studied at various stages of the treatnent process. EEG The observations were laboratory, using a made standard 8 in acute experiments in the channel EEG recorder and needle electrodes applied in 17 lead placements following Strauss 33_5l ( ). In each experiment, the compound under study was administered intravenously at a set rate per minute, until clinical behavioral or electrographic changes were observed. have been atropine. diethasine, Each is a Win~22§9, The compounds studied benactysine, JB-318, JB-336, and potent enticholinergic agent in vitro. Diethasine (diethylaminoethylwxwdibensoparathiazine), for example, induces nydriasis end hypotension, suppresses salivation and blocks the bradycardia, salivation and seizures of acetylcholine and �-3fluorophclphntc ). ( win-2299 (2-diethylnninoethyl cyclopcnty1-2, thienyl-glycolnte) end benactysine (2-diethy1nninocthy1 benzilnte) are synthetic nnticholinergic agents with potent central neurologic effects nininal peripheral systemic effects and cnd JB~336 two ). Diethazine 175-250 ninnte for ). JBnBlB 2 to of a recent series of synthetic antichclinergic central potency compounds or high total of , (N-ethyl-3~piporidy1benzilatc, X-nethy1o3~piperidy1~ bennilcto) are ( ( was mgm; and high administered at hallucinogenic activity 25 mgm. Win-2299 and benactyzine 5 mgm.; and per minute for a at 0.5 mgm. JB-318, JB~336, and atropine :31. per minute for 1.2 to h.0 mgm. at per O.h �OBSERVATIONS: (a) Diethaeine: As previously reported administration of diethacine in 15 ), the ( patiente prior to convulsive therapy resulted in a decrease in voltages and a deaynchronisation of all frequencies. Prevailing prominent. instances, symmetric In some activity appeared, temporal leede. rhythmic patterns beoane leee most prominent in the The low voltage 6;? cps frontal and anterior alpha frequency ﬁes not altered, but the build-up in voltage and the slower frequencies induced by hyper- ventilation vere blocked (Fig. 1). -Q-‘-Fig. 1 UUUUU Q-ﬂO-u-n--In 25 patients during convulsive therapy, with varying degrees of induced high voltage delta activity significant decrease both in voltage slow wave hSﬁ neon activity. From an and in 20%. ) there was a per cent time of average per cent tine delta of in the {route-occipital leads, there per cent time or ( was a Both random and reduction to a burst delta �-5- activity diminished became prominent. slow wave activity increase in per cent time and voltage of The on voltage alpha and beta frequencies hyperventilation was no longer apparent. clectrographic effects appeared during drug administration These persisted for and and low one to five hours (Fig. 2). ‘ﬂ’--“---yig. 2 ﬁ‘-‘~“---Concurrent with those electrographic effects, distinctive systemic effect was an and S The observed initial systemic episode of coughing and the occasional spontaneous complaint of dry mouth. by behavioral changes. we to 10 per cent. Skin remained dry and-heart This increase was rate increased rarely associated by pron cordial awareness. Baring the period of observation pupils were not altered, and responded pronptly to light and near vision. were There occasional complaints of abdominal griping. These effects, however, were generally or behavioral. less prominent than the electrographic �-6. Beheviorelly, patients became more irritable and restless. They became tense end excited, end it use difficult to neintein eyelid closure. They complained of feelings of unreslity and of dysthesias of the extremities. Visual illusory phenomena and delusional thoughts about their illness, the setting or the test procedure or the examiner's identity were also reported. were cherecteristic in behavior. chenges in lenguege There sssocieted with this change Syntectic language patterns ( altered in ) were 1 fashion opposite to that previously described for amobarbitel ( ) so node and that verbal denial, minimization, cliches, third person past tense became less prominent. nese of speech, measured by dyadic TTR, The degree of repetitive- decreased )whieh ( eltered opposite to that described for convulsive therapy (b) Win-2299: Reports by Pennes enticholinergic men ( ) compound, Uin~2299, induced led to this next study. 0n that an is ( en ). eXperinentel excitetory states in intravenous edninistretion of 2—5 n3n., both elsctrogrephic end behavioral effects similar to diethesine were observed. In five petients without EEG slow were �-7- ectivity, deeynohroniaetion of frequencies and a decrease in voltages were noted in four (Fig. 3). -‘h‘-----‘ ‘-0-----~~ In 11 patients with high voltage delta activity there wee a decrease in amplitude and per cent time or slow wave activity with an increase in alpha and beta frequencies. The noun cent tine delta activity dropped from (Fig. h). 50% to 23% per ‘—-~..—“--‘ Fig. h -~--~-~-“Associated with these electrographie effects were minimal systemic effects but prominent clinical patterns of restlessness and excitement. Patients became fearful and tense. Visual eeneetione were reported and in three subjects, delusional eleboretiene about their hoepitel experience were prominent. These beheviorel chengee Appeared during drug administration or within ten ninetel, end disappeered, at theee doeege levels, within two to three hours. �-8Reports that beneetyzine induced Benectzzine: (C) deeynchronizeticn ( and ) EEG its structural similarity both to diethanine end Win-2299 led to our testing of this compound. Intrevenoue adminiatretion in 12 subjects elicited similar clinical end electrogrephic patterns. Both in the well modulated alpha record and in the recerd with high voltage delta activity, deeynchronieetion wee prompt. Delta activity decreased from a teen per cent time of 39% to 16% in subjects (Figs. 5, 6). 8 n--ﬁ-¢-----Figs. 5, 6 ”0.“--“u-ﬁ'ﬂﬁu- These electrcgraphic patterns were again accompanied by clinical restlessness, irritability tree recording wee here difficult. delusional thoughte seen with the noted et these dceege levels. orienteticn ( wee an excitement. Artifact- The illusory eeneeticne initiel compounds were and not In patients with nenifeet die- end language changes ), however, there end associated with convulsive therepy alerting petterne, as noted with diethezine. and a reversal cf the language �-9(d) Piperioylbensilstesz Following recent reports by Abood ( ) that verious piperidylbensilates both manifested cnticholinerzic activity tested and induced two of hallucinations in psychiatric subjects, these, JB-318 end JB~336 in 2h subjects. we The electrographic patterns were identical to these other experimental Onset of desynchronizetion was during coupounds; injection or within 15 minutes and persisted for one to four hours (Fig. 7, 8). .n...‘..“... Figs. 7, 8 ---0------uIn each instance in which desynchronizetion was observed, restlessness and clinical excitement, illusory and hallucinatory activity iwere noted, and were concurrent with the electrogrsphic changes. In two instances the beheviorel chenges were halted by the subsequent intravenous edninistretion of chlorpronesine. (e) itrogine: Continuing our study of enticholinergic compounds, we administered atropine intravenously inlh subjects, in doseges of 0.8 to h.0 ngn. Systemic effects were prominent during the iniection with increased respiratory rate, pellor, dry skin end dry mouth, precordiel complaints and nerked techycerdie �-10- (Pig. 9). Subjects became restless and fearful and recording became and the difficult. Within ten minutes these symptoms subsided subjects became drowsy and relaxed. In six subjects without delta activity} no change in pattern was seen during drug administration or for minutes thereafter. During the period of voltages and ninisal desynchronisetion was no was EEG 10—20 lassitnde, decreased observed, but there significant difference in per cent tine delta. Fig. 9 -ﬁ.--‘.& In subjects with delta activity, there was an apparent initial decrease in voltage and per cent time of such activity during the first ten minutes after administration, followed by a return to original values during the period of quietude. period were the changes significant (Fig. 10). “-~-“---~ In neither �-11DISGUSSIOH: Various experinentel compounds with measurable enti— cholinergie activity have thus been shown to have similar electrographic and behavioral effects. Electrogrephicslly, each agent induces a desynchronizstion of frequencies and s in decrease Ind voltages, which is most prominent in subjects with delta activity following therapeutically induced convulsions. Beheviorally, these electrogrsphic patterns are associated with stimulating, excitstory, illusory and hallucinatory ectivity. To e lesser degree, nininsl systemic heart rate, sslivetion, sweating letter systenic effects ere and changes in ptpil are noted. more prominent in These patients given intravenous atropine under sinilsr experimental conditions. These observstinns can be relsted to theories of the node of action of convulsive therapy and the basis for the induced slow were activity; to concepts of the besis of experimentally induced hallucinations; and to the conflicting reports of the effects of atropine on nervous ectivity. �-12- (a) Convnlsive therapyuprocees: In earlier studies we indicated that the develcpnent of high voltage slow wave activity was the neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not eufficient, condition for clinical improvement ( ). During the past ten years, numerous authors including Bernstein, Tower and chachern, Ward, Sachs and Huge have reported similarities in the biochenical changes of the central nervous system in convulsive therapy to that seen in crania— cerebral trauna ( ). They observed an increase in cholinergic activity, nanirested by an elevation of free acetylcholine and pseudocholineaterase in the spinal fluid, and associated with high voltage slow wave activity. Sinilar high voltage slow wave activity has been reported after the administration of the cholinesterase blocking agent (di-isoprcpylfluorophoephate),I with attendant increase in cholinergic activity. In addition, the increase in central nervous system cholitergic activity by topical administration of acetylcholine induces high voltage ~ bursts and spike activity ( ). blocking of the behavioral and electrographic effects of convulsive therapy by the antichelinergic actiyity of atropine and scopolanine (Ulett and Johnson) are replicated by these observations on diethazine, Win-2299, benactyzine and the piperidylbensilates. The potent anticholinergic activity or The cent!!! each of these compounds (with apparent predominant locus or activity in the central nervous system) supports the �suggestions that the biochenioal basis for the induced activity of convulsive therapy results slow wave from an increased level of central acetylcholine~cholinestereos activity; While these observations demonstrate that anti— choliuergic compounds are effective in reducing slow activity, reports of other compounds with have also appeared. ( ), nescaline similar effects Agents such as anphetanine (Bensedrine) ), lysergic Acid diethylanide“ ( wave and diphenhydrasine (Benedryl) convulsive slow wave ectivity. ( ) ( ) also reduce poet~ These compounds are primarily synpathoniuetio and antihistaminic in pharmacologio aytivity, yet each has excitstory and stimulating effects ( and , , , ). The on behavior relations of these various anticholinergic synpathoninetic agents say be related within constructs of synaptic activity. observations have been confirmed in this laboratory. Intravenous adainistration of So~1oo genus LSD in subjects withoutldelta activity induced EEG desynchronisation one to two hours after administration. In subjects with delta activity there is a marked reduction of delta with the re-essertion of proainont, high voltage alpha frequencies. These �~1h- In a study or the effects or various agents on the EEG and the behavior of unaneethetised cats with chronic implanted electrodes, Bradley and llkes ( ) postulsted the existence of two, or possibly three, types of interacting chenoreeponsive receptors within the central nervous system: cholinergie, nonucholinergic susceptible to anphetaeine, nonucholinergic susceptible to Harassi and Hart pathways in the on evoked ( ) LSD eXplondng and tryptaminie derivatives. intercortical (transcellosal) cat, described the effects of various potentials on end oonpounds direct electrical stinulation. They postulated the presence or two chenoreceptive potentialities of the synapse - cholinergic and edrenergic - with opposing stimulatory and inhibitory ectien. been described by Hoolley ( Similar constructs have ), Evarts ( ( ) and Sherwood ). According to these models, the administration of snticholinerzic agents, or of sympathoninetic agents, results in equivalent synaptic electrical effects, and nresnnebly, similar electrogrsphic and snpethnine, nescaline end behavioral effects. LSD Thus adrenaline, inhibit the level of electrical �-15- activity at synapses as effectively as the blocking or inactivation of acetylcholine by atropine end other enti~ cholinergic compounds. In the light of these scggesticns, the present eXperinents permit a mere specific hypothesis regarding the phernacclcgic basis cf the convulsive therapy process. Repeated induced convulsions lead to an increase in the synaptic or xyxplttl cholinergic activity which voltage slow wave activity.; electrical activity (and of is reflected in surface electrodes level ) as angnented high Administration at anticholinergic agents reduces the level of synaptic activity, resulting in a decrease in the manifest cortical electrical activity to precenvulsive levels. may also achieve the Administration or synpathcmisetic agents same electrical effects, not by eltering the level of cholinergic activity but, by increasing the level of adrenergic activity. The nsnirest slow wave prominent and so persistent in the waking state ( ) nay thus be viewed as a EEG activity, so or the pcst~seisure persistent alteretion in synaptic transmission activity or large numbers of cells of the �central nervous system. is seen in the ready ( ) and The delicate nature or this balance reversibility with alerting ( ), tine the wide variety of pharmacologic agents noted here. Repeated induced convulsions may thus be described as a device to create biochemical changes in the brain for their resulting behavioral effects. view a Such/formulation that convulsive therapy is process ( a is consistent with the nonuspecifio therapeutic ). the initial suggestion ( ) basis for the convulsive therapy process that the pharaaeologio may lie in an alteration in acetylcholine-oholinesterase relationshipsban thus be focused on the alteration in the level of synaptic activity. In this regard, the observation that diphenhydranine, primarily an anti-histaminic agent, also reduces slow induced convulsions ( ), and the wave activity of observations by Sachs ( ) that increased amounts or serotinin appear in the spinal fluid after convulsions suggest that this image in convulsive therapy is oversimplified. ’ 0; synaptie activity Further studies or the effects or various drugs on the postcseiaure electrical ‘ �activity are warranted. (b) Iearophyeiolggy or hallucinogenic These EEG activity; observations of anticholinergic compounds delta activity also related to concepts of eXperinental may be hallucinogenic activity. Each of these compounds induced excitatory behavior including illusory and Here, too, synaptic models phenomena.* on hallucinatory may be applicable. Synpathoninetic egents, ae mesoaline, LSD, and amphetamine, and anticholinergic agents as those described here, are equally potent hallucinogens. i necrophareacologic basis for such behavior nay be characterised as an alteration in the level of synaptic activity in the direction of increased inhibition (decreased transmission) of stimuli. The clinical efficacy hallucinatory activity biochemical level. ester: ( The may of convulcite therapy in modifying thus In the doses used, higher dosage ( A in alterations at this effects or hallucinogenic blocking agents ), as chlorpronarine for benactysine. lie and reserpine, on EEG electrical hallucinatory phenomena were not observed report of such activity was reported at ). �~18~ ectivity are consistent with EEG hypersynchrony in non effects of LSD end LSD and such a View. ), block the ( nesculine ), ( and Both compounds induce EEG desynchronizetion in animal studies, block neeceline behavioral and electrographic effects ); ( Chlorpronaoine was found equally potent in abutting the excitatory activity of these experimental anticholinergics in these studies. (c) Relation to atropine: Comparison of the oystenic and central effects or these experimental anticholinergic conponnda with atropine reveals significant differences. Extensive experience with atropine at physiologic end toxic levels in men indicate that the predominant Initial effects are focused at peripheral nervous structures. bradycnrdia, followed by marked tachycardia, loss of sweating and salivation, papillary dilation, intestinal relaxation and decreased motility are amongst the effects at physiologic (O.2~l.2) dodagee. At higher dosages (2-5 mg), the central nervous irritability, disorientation, oyeton effects of ataxia, delirinn ( may be observed ( ), anonnta ranging Iron ). In the atropine 32 to 212 some end studies 33:. injected intra- �.19nuacularly into psychiatric petiente resulted in the following ( sequence )t ”There is an induction period or 15 to minutes 20 after adninietretion characterised by restlessness, occasionally mild exoitenent, confusion, and at times nausea and vomiting. This proceeds, smoothly and predictably, to muscular inooordinetion, ataxia, weakness, vertigo and difficulty in articulation. An acute brain syndrome with memory disturbance, disorientation, elouded consciousness, illusions and most frequently visual hallucinations vergee into delirium come... ' Thus and rapidly proceeds to central nervous system effects are preoedodhnd accompanied by marked peripheral effects. In contrast, these experimental enticholinergic agents, in equivalent dosage ranges, manifest and lurked central. The are observed early and effecto may on little peripheral effects the central nervous system continue for extensive periods and in higher dosages with minimal peripheral nervous effects. It ie within this context of central tarsus peripheral predominant sets or activity that the apparent discrepant EEG observations of the etteete of atropine (in inducing elow wave �.20- activity) these experimental enticholinergic compounds and be reconciled. The variable EEG effects, like the verieble behavioral effects are dose related. adminietering l~3 mg/Kg may Weeeae exist 33‘3l ( ) atropine in curarized cats and monkeys using O.h to 1.2 mg/kg in curerized and Funderburk and Case ( ) cats, produced high voltage slow wave activity. Wikler ( ) reported that 7.2 mg/kg atropine in unanosthetized, ancnrarized patterns strikingly similar to dogs produced "epindle slow wave" sleep. 'Rinaldi and Himwioh ( ) reported that atropine in doeee of 0.5 to 2.0'mg/kg in cnrarized rabbits exaggerated patterns and inhibited the electing of the EEG EEG sleep to various peripheral stimuli. _Sinilar observations have been observed by Bradley and Bikes ( ) in the conscious oat. In each instance the dosage of atropine varied from 0.5 g 3 mg/kg- a range roughly comparable to the massive dosages need in atropine coma therapy. Yet what of the electrographie eitects in lower In our observations, the EEG effects of dosage? low dosages of intravenous atropine (006‘ .06 ng/kg) were minimal. Similar obeervatione have been reported by Danielopelie, Guirgee end Drooen �021-: ( ) who specifically releted the effects to dosage level. EEG with high doeeges of atropine (h-B ng/kg) in rabbits einiler high voltage nixed slow and feet (21-30 ope) activity was observed, while with low deeegee (2h~.8 ng/kg) the original rapid rhythms remained unehenged. These authors thus suggested ! ﬂat atropinegs effects were multiple end doee determined, and related the observations to similar findings with regerd to EEG heart rate. Denielopelu atropine slow down ( ( observed that small doses of cardiac rhythm nine while larger doses cenee eexeklteiien acceleration. been confirmed ) These obeervetiene have recently ). Thus, while oonsidereble speculation as to central neurophysiology he: been related to observations with atropine, these observations provide e special case of atropine effects. The entiohelinergic activity, so prominently established in observations in vitroI end in the peripheral nervoue system, may not be the effective physiologic activity in the large doses neeeeee y to reach central structure. It is poeeible that the experimentel entichelinergic compounds used in the present studies �-22protﬁe more suitable experimental tools fer the elucidation of central neurophysiologic nativity than atropine. In part, these differences may be related to difference- in etrnctnrel chemistry. Each of these experimental cenponnde contain a tertiary canine linkage, while atropine (and ecopolemine) quaternary centnin a qxxtx:xznx linkage. Such differences may be clearly observed in the structure~ectivity relationships or the piperidyl- bennilatee ). ( While Hwnethyl-B-piperidylbenzilete and Nsethyla 3-piperidxlbeneilate have potent enticholinergic and hallucinogenic potency, Hedinethyl~3~piperidylbeneilete - the quaternary conpennd - has considerable in vitro anticholinergic activity, and no hallucinogenic property. The significance of tertiary amine linkage for central neurophysiolcgic effect: he: been repeatedly affirmed by numerous observers, and neat recently by Pennel Denber; ( ), Theee e Hake ( ) and Plodnerk ( ). structure~aetivity relations lend theneelves to re-eveluation or studies or creniccerebrel trenne Ward's ( ) ( and epilepsy. reports orﬁthe efficacy of high doses of etrepine in altering the clinical manifestations of head trauma indicated ), �-23- that effective dose: brought with Thu them severe systemic effects. failure of the oxtohaive studies a: the efficacy or atropinc and soopalunine in epilepsy ( ) any be related to : failure of these quaternary compounds to reach the central nervous syntax in adequate quantity. It would noun advisable, therefore, to, ropoat those studies utilizing such more potent, more centrally specific, antieholinorgic canpaunds as used in the eXporixonts reported here. �lj MS 981 W Mel 3;..." EFFECT OF ANTICHOLINERGIC COMPOUNDS EEG AND BEHAVIOR OF Max (Received ON POST CONVULSIVE PSYCHIATRIC PATIENTS Fink M.D. for publication: march 11, 1959) v v-u-u. From the Department of Experimental Psychiatry, Hillside Hospital, L.I., Glen Oaks, Aided, in Institute N.Y. M-927 and MY-2092 of the National Health, National Institutes of Health, by grants part, Mental of U.S. Public Health Service. Read at the American W-EEG 3§5357k? EEG Society, Atlantic City, June, 1958. �MS 981 ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG �Effect of Anticholinergic EEG and Behavior of Compounds on Post Convulsive Psychiatric Patients Mcsfl—vsﬂswﬁ kg 76.: gagiﬁsignificance of high voltage EEG delta activity in the convulsive therapy process (Roth gt_gl, 1951, 1957; report that this delta activity was blocked by the administration of-eniiehnlinersic ealﬁiﬁiaa atropine and scopolamine (Ulett and Johnson, 1957) provided the basis for these studies. As there were attendant unpleasant systemic effects with the administration of these agents, reports describing diethazine as an anticholinergic Fink and Kahn, 1957) and the with potent neurologic but minimal systemic effects (Jenkner and Lechner, 1955; Lechner, 1956) led us to undertake studies similar to those of Ulett and Johnson using this compound (Fink, 1958). “@bservations with compound diethazine led to the investigation of other experimental anticholinergic agents. This report describes clinical and electroencephalographic observations incident to the intravenous administration of various anticholinergic agents in psychiatric patients at various stages of convulsive therapy and relates the observations to hypotheses concerning the mode of action of convulsive therapy and of hallucinogens. �SUBJECTS AND METHOD: subjects were ninety psychiatric patients referred for convulsive therapy. Ages ranged from 18 to 67 years, and diagnoses included amcaai-t!=s£ schizophrenic The reactions‘ and manic-depressive and involutional—depressive varied number of subjects were studied for each compound for a total of 107 observations. Patients have been observed at various stages of the treatment process. The observations were made in the EEG laboratory, using a standard 8 channel EEG recorder and needle electrodes applied in 17 lead placements following Strauss gt_§l (1952). In each trial, the compound under study was administered intravenously at a set rate per minute until clinical behavior or electrographic changes were observed «a -'w ‘M psychoses. Www'” mam. "4”,...“ A." A Hm , ‘5 was”“My HM A r-m new M, -J:,M-,_.m,..\. "was... “A...“ i, ,1“. The ine, JB3l8 JB~336, and atrOpine.{ Each is a potent “p' a: icholinergic agent in vitro. Diethazine (lgﬂgéwdaetﬁyl- \\ ‘H‘benact v. __~ ‘ (2-diethylamipdéthyl ﬁgnzilate) are synthetic anticholinergic '- 3‘ .h u k‘ ‘ ‘ �W [M ﬁW/émgw (m w 1,?de //h)1 (Maw (WW. a /¢‘¢¢) ’ f ﬂux-322.497“ f E (W . 7’6’33“ wit/4&4, xiJ'C) 7 I (W ﬁg?) 17”} M .7313”: W �agents with potent neurologic effects and minimal peripheral P’w ‘nwV""' systemic effects W JB- 318 and JB~336(N~et§gl~3ﬂwiperidylbenzilafe N-methyl-~3two of a new series of syntﬁébiq piperidylbenzilataﬂ (Pennes and Hocn%wl9§7?“§:c9bson, 1955) """ ‘m‘,’ anticholiHErgic compounds w'th a»? éﬁmm‘ distinct hallucinogenic 1958). et a1, g Diethazine administered at _activity __ ’ total (Abood was mac?“ 25 mg per minute for 2.5-5.0 mg/kg); Win-2299 and mg per minute for 2 to 5 mg (0.020.15 mg/kg); and JB-318, JB-336, and atropine at O.h mg per minute for 1.2 to h.o mg (0.0l~0.10 mg/kg). of 175-250 benactyzine at 0.5 a mg ( �OBSERVATIONS: administration of diethazine in fifteen patients prior to convulsive therapy resulted in a decrease in EEG voltages and a desynchronization of all frequencies,€¥$§3;=;$§8%. Prevailing rhythmic (a) Diethazine: patterns became The less pronounced. In symmetric low voltage 6-? cps most apparent in W frontal and some activity appeared and was _ (F3416 anterior temporal leads. ammmmmwmmm~.w fequencyas not send, ”Mm“ Thz“‘;“i”;“n. instances, ,, .1. >u-L—‘7‘? mm»- ,.... .14.“ mm“. We they”; In twenty~five patients with varying degrees of induced high voltage delta activity during convulsive therapy (Fink and Kahn, 1957), there was a significant decrease in voltage and in per cent time of slow wave activity. From an average-pal—Icnt-ttne delta of h5% in the front-occipital leads, there was a reduction to a mean uggzggntntine of 20%. Both random and burst delta activity voltage alpha and beta frequencies became more prominent. The usual increase in per cent time and in voltage of slow wave activity with hyperventilation sans-no diminished. Low 51, \} "it; 2’ lfJ?e>» �-5longer apparent. These electrographic effects appeared during drug administration and persisted for one to five hours Mﬁﬂ (Fun/t} xqs’f) Concurrent with these electrographic effects, we observed distinctive systemic and behavioral changes. The initial systemic effects were episodes of coughing and complaints of dryness of the mouth. Skin remained dry and the heart rate increased by S to 10 per cent. This increase was rarely noted by the subject, and was not accompanied by ,n» precordial distress. -9ar&ng—tho—peried~e£w- , Gems/haﬂhv observationnﬁhere was no change in pupillary size, and their response to light was prompt. There were occasional complaints of abdominal griping. Ihﬁégweffects were generally less prominent than the electrographic or behavioral. Behaviorally, patients became irritable, restless, tense and excited, and it was difficult to maintain eyelid closure. They complained of feelings of unreality and of tingling, weakness and heaviness of the extremities. Complaints that colors were pale or more intense, halos about lights and changing shadows were accompanied by delusional thoughts about their illness, the setting of the test procedure or the examiner's identity.4p . AM �-7(b) Win-2299: The report by Pennes and Koch (1957) that Win-2299r—aaother_axparamoatalwaatieholinergée~eempound1 induced illusory and hallucinatory states in man, led to this next study. 0n intravenous administration of Win-2299, both electrographic and behavioral effects similar to diethazine were observed. In five patients without EEG slow wave activity, desynchronization of frequencies a decrease in and voltages were noted in four;éi§igggg; {Vfgf / ), In eleven patients with high voltage delta activity there was a decrease in amplitude and per cent time of slow wave activity with an increase in the per cent time of alpha and beta frequencies. dropped from 50% to 23% The mean pea—eoat—tine (Fig.1;3. Fig.3 delta activity 3" Associated with these electrographic effects were clinical patterns of restlessness and excitement, and effects. Patients became fearful and tense. Visual illusory sensations were reported and were minimal systemic associated in these subjects with delusional elaborations �-3about their hospital experience. Excitement was accompanied by ideas of reference, and in two subjects, intravenous chlorpromazine was administered to halt this process. These behavioral changes appeared during drug administration or within ten minutes, and disappeared within two to three hours. effects were slight. There were neither cough nor respiratory distress. Heart rate was unaffected except in patients who became overtly excited Systemic fearful, in and whom excitement period. on ' tachycardia appeared during this Dryness of the mouth was reported only direct inquiry. (c) Benactyzine: Reports that benactyzine induced EEG desynchronization (Coady and Jewesbury, 1956), its anticholinergic nature, and the structural similarity to diethazine and to Win-2299 led to our testing of this compound. Intravenous administration in 12 subjects elicited similar clinical and electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, desynchronization was prompt. Delta activity decreased in 8 subjects from a mean pti—OUI$ time of Wﬁﬁ/d} 39% to 16% �-9These electrographic patterns were again accompanied clinical restlessness, irritability and excitement. Artifact-free recording was more difficult. The illusory by sensations and delusional thoughts seen with the initial compounds were not noted at these dosage levels. Systemic effects were similar to Win-2299. (d) Piperidylbenzilates: Following recent reports by Abcod et a1 (1958) that various piperidylbenzilates with measurable anticholinergic activity induced hallucina- tions in paychiatric subjects, we tested JB-318 and JB-336 in 2h subjects. The electrographic patterns were identical with the other experimental anticholinergic compounds. —¥he— ur ng e njection or Wafﬂes ync hroniza ti onA? ?- duufdtvthhfhﬂ within 15 minutes and persisted for one to four hours (Fig. 5: t). ‘ , Figs. 5f In each instance in which desynchronization was observed, clinical restlessness, excitement, illusory and hallucinatory activity were noted, and were concurrent with the electrographic changes. In two instances the behavioral changes were halted by the intravenous administration of chlorpromazine. �-10Considering the numerous reports (e) Atropine: that atropine induced EEG slow wave activity and clinical somnolence, we administered this anticholinergic agent intravenously in 15 subjects, in dosages of 0.8 to h.0 In six subjects without EEG delta mg (.01-.10 mg/kg). activity, there were no changes in EEG pattern during drug administration nor for 10-20 minutes thereafter. During a period of lassitude, decreased voltages, minimal desynchronization, and an increase in per cent time delta were noted. In subjects with delta activity, there was an apparent initial decrease in voltage and per cent time of such activity during the first ten minutes after administration, followed by a return to original values during the period of quietude. was» In neither period (@3925) were the changes significanta �-11- Systemic effects were prominent during the injection with increased respiratory rate, pallor, dry skin and dry mouth, precordial complaints and an increase in heart rate up to 100%. Subjects became restless and recording became difficult. Within ten minutes these symptoms subsided and the subjects became drowsy and relaxed. �-12- arious experimental compounds with measurable anticholinergic activity have been observed to have similar electrographic and behavioral effectsignmthnsematudiOOVM Electrographically, each agent induced a desynchronization of frecuencies and a decrease in voltages, which was most prominent in subjects with delta activity following convulsive therapy. Behaviorally, these electrographic patterns were associated with stimulating, excitatory, lesser degree, minimal systemic changes in heart rate, salivation and sweating were noted. These latter systemic effects were more prominent in patients given intravenous atropine under similar experimental conditions. These observations can be related to theories of the mode of action of convulsive therapy;and-oﬁrthevastS“fvr' illusory and hallucinatory activity. ‘thauaadnoedﬁaiew—wamowaewévttyj To a to concepts of the basis of experimentally induced hallucinations; and to.thv reports of the effects of atropine on EEG patterns. (a) Convulsive therapy process: Earlier studies indicated that the development of high voltage slow wave activity was 4:; neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement (Fink and Kahn, 1957). In summarizing the observations of numerous �-13the relation of acetylcholine metabolism to 1;” 4o $vuuna andAconvulsions (Fink, central nervous system Ckxcxnurnsd'éjf 5L biochemical bootseinn the the 1958) it was suggested that induced EEG slow wave activity lay-ﬁn an increased level of acetylcholine-cholinesterase activity of the central authors on nervous system. in the slow wave 1? present observations of tin alterations_ activity of convulsive therapy by these The experimental anticholinergic compounds are consistent with this suggestion. is indicated by reports of compounds with other biochemical activity also affecting slow wave activity in a similar fashion. Amphetamine That the problemis more complex gt_§l, 1951), mescaline (Merlis and Hunter, 1955; ‘Ib (Bente gt_§1, %§?b§i$ 1955), lysergic acid diethylamide ”iuuéig,snd diphenhydramine (Diaz-Guerrero et a1,1956) also reduced post-convulsive slow wave activity. In these reports, such a reduction was accompanied by excitatory and stimulating effects on behavior. These compounds, however, are primarily sympathomimetic and antihistaminic in pharmacologic activity and not anticholinergic. The similar effects of these diverse biochemical agents on electrographic patterns and amuauibusﬁ be behavior may rat-ind within theoretic on clinical (Lennox «K2~Kssrsr'6247 ‘ﬁtﬁix “ﬁ’ constructs of synaptic activity;r— mm w The existence oftwo, or possibly three, Mypee cf interact~ 'AQ/ 1. m.“- ing chemo~re§poﬁsive receptors withinthd‘central ner::gg,system �/ (I W24: L M7? 5 ,7 v M/ ’46; MW w- M} Arm/a; Ail/”M Wag .- f �“Jamal-un- h awmh'auu: gnaw“WWW WU“we ' lead to a change in synaptic cholinergic activityywhésh—és— reflected:h11llhsurface electrodes as augusntsd high voltage slow wave activity. Administration of anticholinergic agenggijltenﬂ'synaptic activity, resulting in a decrease in the manifest cortical electrical activity to preconvulsive levels. Administration of sympathomimetic agents 3f-lg-‘Leja-‘ﬁieve/ the same electrical effectsr-s-s-t-by—ns4tssang—tha—1saol—sfrehoiénsrgss—sstinitanbat by increasing the level of adrenergic activity. The manifest slow wave A activity, so prominent and so persistent in thsfﬁ::;ng£§;:& -ss«the—pust-setzure-statej may thus be viewed as tho resulttnf persistent alteration in the synaptic tssssméssésn activity of large numbers of cells of the central nervous system. The delicate nature of this balance is seen in the ready reversibility with alerting, time, and the wide ~qﬂra variety of pharmacologic agents.nntsdwhaner-m~m~"~"“ ’jiﬁ/ér\:;> The consistent nature of these neurophysiologic observations all. makes an exclusively psychologic explanation of the mode of action of convulsive therapy less tenable. These studies are consistent, however, with the neurophysiologic-adaptive view of the convulsive therapy process which suggests that neurophysiOlogic chanazMs provide the substrate for alterations in all aspects of cligical behavior} fg’h" �Ma . ,W‘ w, .M Won/7w AC ,W W hyLWM MWMWM'W“ W 5 I414} 2‘5 Maxwu 4; ’ :73? (/ija; Z; W Wag a, WM7£ ILL-«44.1“ 04”), MLIMK W; ”W MW; “4344: a' WM W I a; a. L « �-17- we, of~the—oabaeetp"{ﬂn type of behavioral alteration ts ﬁsvwig dependent upon the type and degree of neurOphysiologic change, the personality of the subject and the expectations and tolerance of the milieu (Weinstein and Kahn, 1955; Fink and Kahn, 1957; Fink, 1957). (b) Neurophysiology of hallucinogenic activity: The effects of anticholinergic compounds on EEG and behavior may also be related to the understanding of experimental hallucinogenic activity. Each of these/tzzgfunds induced illusory excitatory behavior, including 4L phenomena. m Here, too, the synaptic and hallucinatory model] may be applicable. Sympathomimetic agents, as mescaline, LSD and described amphetamine, and anticholinergic agents as those here, are 01-‘3iv potent hallucinogens. A neuropharmacologic basis for such behavior may be characterized as an alteration in the level of synaptic activity in the direction of increased inhibition (decreased transmission) of stimuli. ‘The clinical efficacy of convulsive therapy in modifying hallucinatory activity may lie in alterations at this neurophysiologic level. . The effects of such hallucino- genic blocking agents as chlorpromazine and reserpine on EEG electrical activity are consistent with such a view. Both compounds induce EEG hypersynchrony in man (Bente and Itil, 19Sh, 1958) and block the EEG desynchronization effects of LSD and mescaline (Schwarz et al, 1955). �-19Chlorpromazine was found equally potent in aborting the excitatory activity of the experimental anticholinergic compounds in these studies. (0) Relation to atropine: Comparison of the systemic and neurologic effects of eXperimental anticholinergic with atropine reveals signi£ieaat differences.«av ax/Aaf compounds {pH/95 s:%bé§i£3§§§§2::ence with atropine at physiologic and toxic levels in man indicate that the predominant effects are focused at peripheral nervous structures. Initial bradycardia, followed,by tachycardia, loss of sweating and salivation, pupillary dilation, intestinal relaxation and decreased motility are amongst the effects at low (0.2-1.2 mg) dosages. At higher dosages (2-5 mg), the neurologic effects and delirium are of ataxia, irritability, disorientation, Mgr...“ observed (Goodman and Gilman, 1955). In atrop' e coma therapy, 7amounts ranging from 32 to 212 g injected int amuscularly into psychiat ic patients resul s in the fell wing sequence (Forrer and Miller, 1958): "Th re is an induc ion period of 15 to 20 minufes after adminis ration charactkrized by V mm:Wm..- ! 2 I . Jonfusion, and . restlessnessg ceaselonally mil excitement, at times naufca and rarely vo ting. This p oceeds, smoothly and predictably, to muscular coordination, ataxia, weakness, vertigo and ifficulty in artffulation. An cute brain syndrome wit. memory dis turbanhe, disorienta ion, clouded illusions and mtst frequently kisual hallucinaconsciousnesf, tions mergesa into delirium and§.:;rapid1y proceehs to coma. ..." I ‘ I ’ ; �-20.. Thus/central nervous system effects arevprecededwwv accompanied by marked peripheral effects?” contrast, the experimental anticholinergic agents in dosages sufficient for central nervous system effects manifest little peripheral activity. The central effects are observed early and may continue for extensive periods without gastrointestinal, cardiac or pupillary changes. It is within the context of the focus of activity and w. -din relation to dosage that the apparent discrepant EEG observations of the effects of atropine (in inducing slow wave activity) and these experimental anticholinergic In reconciled. Wescoe gt_al (l9h8) administering 1.0 to 3.0 mg/kg atropine in curarized cats and monkeys and Funderburk and Case (1951) using O.h to 1.2 mg/kg in curarized cats, observed high voltage EEG slow wave activity. Wikler (1952, 1957) reported that 7.2 mg/kg atropine on unanesthetized, uncurarized dogs produced "spindle slow wave" patterns at-ihiugiy similar to sleep. Rinaldi and Himwich (1955a, b) reported that atropine in doses of 0.5 to 2.0 mg/kg in curarized rabbits exaggerated EEG sleep patterns and inhibited the alerting of the EEG to unit-l: peripheral stimuli. Similar observations have been reported by compounds may be Bradley and Elkes (1953) in the conscious cat. In each instance the dosage of atropine varied from 0.5 to 7 mg/kg - a range roughly comparable to the dosages used in atropine (me'w‘ Md: We’rfrfg. “ma therapy! �: M 4% 1mg,» Jyyzmw f)”; r gag“; m mﬂﬂ/w 1:; @c‘jf jaw/(4,4,2... W a; 351,, fgﬂzﬂ, �-21'éoueraduuage? Auéf In thelzn;tudies, the ‘g’ ﬂﬁmal EEG effects of low dosages of intravenous atropine (0.01 to 0.10 mg/kg) were minimalaasﬁ CMMHKM éﬁ, iﬁkbﬁ iconfirming similar observations by Verdeaux anglﬂgrﬁzw (195h) and by Danielopolu et al (1955)., Danielopolu et a1” Wmmwﬂwawmqum specifically related the EEG effects to dosage levelvfw” ith high dosages of atropine in rabbits ( h to ﬂfﬁg/kg) . W wa‘ianMu-‘rm‘m. -W«m««uw~w ~w-wwmw~wmmw .; m W. ..,..-..g., , m ,u . swan-bani" .twmi-mc”1; ~11.»- . man. ; they observed similar high voltage mixed sloﬁfand fast activity, while with low dosage (.Zh t9 id mg/kg) the original apid rhythms remained hgphanged. These authors It fy~”' thus sugges d that atropinetg effects were multiple and“ related the EEG ob rvationgxtg similar findings with rega dﬁtﬁ heart rate. Danie ported earlier that s 11 doses of atropinesloqed cardiac rhythms while/larger dose caused acceleration. These dose determine ’ and cardiac observations have recentlyxbeen confirmed (Morton 232;; ‘ Thus, while considerable speculation as to central neurophysiology has been based on studies with atropine, té§LL——— special case of anticholinergic effects. The anticholinergic activity,—eo—pnonéaeatky established in observations in vitro and in the peripheral nervous system, may not be the effective physiologic activity in the large doses necessary to affect central such observations provide a �.. 2 2 - Th3’2xperimental compounds z:::=zm—the~preeontm the ﬂﬂﬁgw provide more structures. s-‘bu-d‘éoo ﬂow/M)“: udtuoédubéon of suitablewe} Wfor central neurophysiologic (anticholinergic) patterns than atropine] M, #AMcuu/eml AM» In part, these physiologic differences may be re to differences in structural chemistry. Each of the experimental compounds contains a tertiary amine linka e, while atropine contains a quaternary linkage. The e fect of structure on in vivo pharmacology may be clea y observed in the structure-activity relationships of e piperidyl- benzilates (Abood 22.21:.1953)' While -methyl-3-piperidylbenzilate and N-ethyl-B-piperidy enzilate have potent anticholinergic and hallucinoge \c-potency, N—dimethyl-B-piperidylbenzilate - the quate ary compound - has considerable in vitro anticholinergic tivity but no hallucinogenic property. nd Hoch (1957), Denber (1958), Naka (1958) and Flodmark i (1958). f_ _-‘_ , f - . in.a re-evaluation 05‘studies ,_”4 , 1 7 ,. _éwr of craniocerebral trauma and epilepsy. Ward's (1950) reports of the efficacy of high doses of atropine in altering the clinical manifestations of head trauma indicated that effective doses brought with �-23- effects. The failure of atropine to affect epilepsy may be related to the them severe systemic and scopolamine inability of these quota-unis compounds to reach the central nervous system in adequate quantity. It would seem advisable, therefore, to repeat these studies utilizing ardﬁuf such mere-paten%7~more centrally speeésée..anticholinergic , compounds as used in the experiments reported here. �'Zh' SUMMARY: 1. EXperimental anticholinergic compounds (diethazine, Win-2299, benactyzine, JB-318 and JB—336), administered to psychiatric patients at various stages of convulsive therapy, were associated with: (a) desynchronization of EEG rhythms with a blocking of post-convulsive delta activity; (b) alerting, excitatory behavioral reaponse with illusory, delusional and hallucinatory ideation; and, (c) systemic effects of muscular weakness, dryness of the mouth, dry skin and tachycardia. electrographic behavioral and systemic effects were The concurrent. that an ﬂ; 2. observations are consistent with the suggestion “faxmufaui These We!) thug,” ” ' of convulsive therapy'iilllllr.4ﬂ increase in central nervous system cholinergic activity. 3. Observations that LSD, amphetamine, mescaline and diphenhydramine - synpathomimetic and also induce desynchronization, blocking of post convulsive EEG delta activity antihistaminic agents - and clinical excitatory activity support the suggestion that bUth-hhu behavioral and electrographic based on alterations in synaptic activity,, sis Patterns Increased synaptic activity (cholinergic, sympatholytic effects) we ,4 �-25- hypersynchronization, and clinical sedation and euphoria; while decreased synaptic activity (anticholinergic, sympathomimetic) is associated with EEG desynchronization and clinical excitatory and hallucinogenic is associated with EEG states. Discrepant observations with the-entéehottnergiﬁ agent? atropine are related to significant differences inrﬁéfvﬁfygw’ h. .thawnantzalMnenuensmsaatanmaiﬂactsmoﬁmhighudeaagamainapineﬂ Re-assessment in_man_maxanataha4nninanil¥_anaiahnlinargis. of the role of anticholinergic agents in head trauma and seizure states is suggested. 5. These observations amplify the neurophysiologicadaptive hypothesis of the mode of action of convulsive therapy and of experimental hallucinogenic states. �ACKNOWLEDGEMENT: I Hannah {Eﬂ grateful for the technical assistance of Mrs. Mosquera in EEG recording and analyses; and—to— am Supplies of the various pharmaceuticals were made freely available by Lakeside Laboratories (JB-318 and JB-336), Merck Sharpe & Dohme (benactyzine), Sandoz Pharmaceuticals (LSD-25), Sterling—Winthrop (Win-2299) and Smith, Kline & French Laboratories (diethazine, chlorpromazine) �:f/ébétp/g 04M¢MW71M£04¢ W, 2: wow f/éétdi./g.7 JAM/47 7249.; ’9‘” M MW «044ml. W,- m; {fJZ/ E.- 37I-370‘ �-27Abood, L.G., W4} “E:ZLE:D Ostfeld, A.M. and Biel, J. new group of A psychotomimetic agents. Proc. Soc. Exper. Biol. Med., 1958’ 21: hq'é‘h86o Bente, D. and Itil, T. Zﬁr Wirkung des Phenothiazinkorpers Megaphen auf dasuMehschliche Hirnstrombild. Arzneimittelforsch§:“l95h, Z: h18-h23. Bente, D. and Itil, T. A comparison of the action of various phenothiazine compounds on the human EEG. Trans. Int. Cong. of NeurgpsychOpharm., 1958, (in press). Itil, Electroencephalographic studies concerning the action of LSD-25. EEG Clin. Bente, D., T. and Schmid, E.E. Neuroghysiol., 1957, 2: Bente, D., Itil, 359 (abst.). T. and Schmid, E. E. Elektroencephalon graphische Studien zur Wirkungsweise des LSD-25. Psychiat. et Neurol., 1958, $25: 273-28h. Bradley, P.B. and Elkes, J. The effect of atropine, hyoscyamine, physostigmine and neostigmine on the electrical activity of the brain of the conscious cat. J. thsiol., 1953, lﬁg: 1h_-15; Bradley, P.B. and Elkes, J. The effects of some drugs on the electrical activity of the brain. Brain, 1957, g9: 77-117. Coady, A. and Jewesbury, E.C. A clinical trial of benactyzine hydro<3hlcride ("Suavitil") as a‘physical relaxant. Brit. Med. Jour., 1956, l: h85-h87. �-2&- Danielopolu, D., Giurgea, C. and Drocon, G. 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MW~;:-a‘ ST MW own—VT“ mam»Warmest“ “: “NM“ 2,1958 13131315 HIM-~14“ humumwnhaartwrat? emfancet Naka, u. Effect of atropineon thew if , ..:. ¢~w m«w. v,;<w~1»~ww-.. Aﬂoé:§€ﬁ?bpgychopharm., 1958, wammwa Pennes, H.E. and Koch, P.H. ,1 I"; anununnwwnmsu ”N; . Trans. Int. Cong. wunme:::;::ZZZZZZZw (in press) Psychotomimetics, clinical theoretical considerations: Harmine, Nalline. Amer. J. Pszghiat., 1957, 112: and Win-2299 and 887-892. Rinaldi, F. and Himwich, H.E. Alerting responses and actions of atropine and cholinergic drugs. ﬁ;ﬂ;§. Arch. Neurol. and Psychiat., 1955, 12: 387-395. Rinaldi, F. and Himwich, H.E. Cholinergic mechanism involved in function of mesodiencephalic activating system. A.M.A. Arch. Neurol. & Psychiat., 1955, 12: 396-h02. Roth, the EEG under barbiturate anesthesia produced by electro-convulsive treatment and their significance for the theory of ECT action. §§§_ Clin. Neurophzsiol., 1951, 2: 261-280. M. Changes in Roth, M., Kay, D.W.K., Shaw, J. and Green, J. Prognosis pentothal induced electroencephalographic changes in electroconvulsive treatment. EEG Clin. Neuro- and �-32Schwarz, R.E., Bickford, R.G. and Rome, H.P. Reversibility of induced psychosis with chlorpromazine. Mega 2522. Clin., 1955, 29: h07-h17. Central cerebral chemicals and their relation to psychoses. Chemical Concepts of Sherwood, S.L. Pszchosis. McDowell, Oblensky, N.Y., 1958,v268-276. Strauss, H., Ostow, M. and Greenstein, L. Diagnostic Electroencephalography, prune Ulett, Stratton, N.Y., 1952. & Effect of atropine and scopolamine upon electroencephalographic changes induced by electroconvulsive therapy. EEG Clin. G. A. and Johnson, M.W. Neurophzsiol., 1957, 2: 217-22h. Verdeaux, G. and gramme de _4kum..u“W" clinique. WhamWmmw uwm “my echovsky, M. Marty, R. Action sur l'electroencephalo- substances pharmacodynamiques Rev. A d'interet Neurol., l95h, 91: hOS-h27. psych031s caused intoxicgtlonwWwAgggBayohiat by benactyzine Wmmwaw 'et www.mo.‘w:_mh‘”w mu... W NW. grams ”KM—i ““"C;L;ww ”w Mes-mm Neurol. Scand. M ﬁ,‘ "”§2}&, A. Atropine in the treatment of closed head injury. J. Neurosurg., 1950, 1: 398-h02. Weinstein, E.A. and Kahn, R.L. Denial of Illness: Symbolic and physiological aspects. Springfield, 111., 1955. C. Thomas, R.E., McNamara, B.P. and Krop, S. influence of atropine and scopolamine on the Wescoe, W.C., Green, The central effects of 63-72. DFP. J. Pharmacol., l9h8, 22: �-33. dissociation of behavior and EEG "sleep patterns" in «iogs: morphine, N-allylnormorphine and atropine. Proc. Soc. Exper. Wikler; A. Pharmacologic Biol. Med., 1952, 12: 261—265. Wikler, A. The Relation of szghiatry to Pharmacologz. Wilkins, Baltimore, 1957. Woolley, D.W. Serotonin in mental disorders. Res. Publ. Ass. Nerv. Ment. Dis., 1958, 2g: 381-h00. Wm. �On this sheet please prepare for publication in BIOLOGICAL ABSTRACTS a typewritten (double spaced) abstract of your paper and attach it to your corrected proof. Since proof cannot be furnished, check your abstract critically—especially the citation, scientiﬁc names, formulas, chemicals, and technical terms. An abstract should be an informative digest of the signiﬁcant content and conclusions of the paper, not a mere description. It should be intelligible in itself, without reference to the original, but is not intended to substitute for it. It should be brief (preferably less than 3% of the original), written in whole sentences, not telegraphic phrases. For directions, please see the reverse. Sample Citation: DOE, JOHN J. (U. Commonwealth, Capitol City), and RICHARD ROE. Metabolism of phosphorus in rats. Jour. Pest Control Res. 37(4): 152-165. 1957. Detach here and return lower portion only �A GUIDE FOR THE PREPARATION OF ABSTRACTS CONTENT—Include: 1. Name of organism, and objective of the study. 2. Materials, manner of use, or route of administration, principal ﬁndings, and results. 3. New techniques, their uses and qualities. 4. New apparatus, its intended use, and if commercially available, name and address of its manufacturer. 5. New or veriﬁed data of permanent value, e.g., absorption spectra, chromosome numbers, constants, mathematical or chemical formulae. 6. New genera of animals/ plants, new classiﬁcations, new distribution records. (For systematic data, see below.) ,7. New theories, new interpretations, evaluations, if possible; if not, reference to them. ‘ -Omit: Information contained in the title. 2. Additions, corrections, or any information not contained in the original published paper. 1. FOR SYSTEMATIC PAPERS—Additional instructions. FORM: 1. Write the name of a subgenus, genus, or any supergeneric taxon, if old, in small letters with a capital initial; if new, all in capitals. The name of a species, subspecies, variety, or form is never capitalized. 2. Alwa rs underline the name of a genus, subgenus, s ecies, su species, variety, and form: with a straight ' e if old, with a wavy line if new. No other group name is ever underlined. Write the name of a new combination of a species from one genus to another) transfer ‘ (e5: a straight line under the old and a wavy line under the new or shifted part, followed by the basonym and its author in parentheses. CONTENT: Be alert to information other than the formal, strictly taxonomic and nomenclatural. Summarize or men— tion new data in any biologic ﬁeld—life history, morphology, biogeography, cytology, ecolo , evolution. (Nontaxonomists welcome such information. NEW TAXA. Omit detailed descriptions, long synonymies and ~ �DEC 7'5 3.959 m, x. (mm. Hume-1. mm m, a. 1.). mm or MWo W m m. W on Wu But EEG mum- and 101. mm mummrm mm (cu-mum. win-2299‘. administer“ to mum-'10 patent- ﬂung, are «minted with n blocking Wtua Fatima. . JB~318 and 38-1336). Wu of of. with! It various «mutation a: mm, than at EEG rhythm pelt—amid” delta wtivity; darting, mum-y illusory. donning: and mnucinatory mum; and attacks of Ins-mm mimosa, drynosa of the mouth, dry akin md can— halyard“. The cloemgraphic, behaviml and manic offsets behavioral We mt.The“ mom. with m ' Mmtiam suggest. that. a «mimosa: ﬁlm is an 1mm in mtml mama “timers What at convulsive dim Mastic” that LSD, «momma, 30mm and aynpumm and awakening agomm -. also mam EEG deaymhnoniuum, blocking of post «mun delta activity and clinical Quinton? nativity support. the suggestion hand on that behavioral and durum in mm scum“ mug activity ehctmgnphie panama any be It is suggest“ that. increased (ahelinorzia, mamas atom) 1: associated mm EEG and cumin}. mum and euphoria while Mmud Widen, �‘_ W", . ”-77 .V . ,. . . ,, .. .. w. . ..‘Vr._.wum“.mmm————__——_q‘_ 02¢ mm activity (autumn-31¢, metie) is associated ﬁlth Em WWﬁan and clinical .33th and WWW: cum. Wampum; observations with atropine are round to significant hmmmnt a: the role of mtichonmme agents in head tram md «ism auto-n in mggaltad. no” chain-tum mpnfy the mmyhyaiologimﬁnptin Wham at the m or motion of cmlsiv. thorny and of ”puma hallucinogenic out». Mfume” in damage. �HS 981 33130? 0! ANTIGBOLINERGIG GOHPGUIDS OI P03? GOHVULSIVE EEG AID BEHAVIOR OF PSIGEIATRIG PATIENTS nux Fink H.D. (Rocoivod for publication: larch 11, 1959) Iron tho Departnont of Exporinonttl Psychiatry, Hillaid. Ronpitnl, Glon Oaks, L.I., 3.1. purt, by grant. H-927 and 31-2092 at the Nationtl Mental Hotlth, lutionul Institutes of Health, 3.8. Public Konlth Serviel. Icad at tho Alcricun EEG ﬁocioty, Atlantic City, June, 1958. Aided, 1n Institute of 11: 5/59 �HS 981 AlfialﬂLIlElGIG GOHPOUIDS AID POST GOIVULSIVE EEG �Ettact or Anticholinargie Compounds on Post Convulaiva EEG and Bohavior at Psychiatric Patients BIG Daaanatrationa or the aignificanea or high voltage dolta activity in the gonvulsive therapy procaaa (Roth w, this delta activity report that was blocked by the adniniatration or atropina and acopolanina (Ulatt and Johnaon, 1957) provided the basis for than. studioa. A: there were attendant nnplaaaant ayatoaic effects with the adniniatration of than: agents, report: describing diethalina as an antiehalin~ crgic compound with potent neurologic but minimal systolic affects (Janknor and Lcehnar, 19553 Laehnar, 1956) led an to undartaka studio: similar to those of Blott and Johuaon using this coapound (link, 1958). aboarvationa with diathasine lad to the invaatigation of othar experimental anticholinargic 1951, 1957; Fink and Kahn, 1957) and thc agonta. report daaeribac clinical and olactrooncaphalo» graphiu observations ineidant to the intravenous adniniatration at various anticholinarzie agent: in psychiatric patients at various stage: of convulsive therapy and relates the obaarvationa Thia to hypotheaaa eonaerning tho and. or action a! canvulaivc therapy and of hallucinogcna. �SEBJEGTS LIE KETKODi subjects were ninety psychiatric patients referred for convulsive theraoy. ages ranged from 18 to 67 years, and diagnoeee included schizophrenia reactions end nanio-deoroeaive end involutiona1~depreaeive peyohoeeo. a varied number of eubjeote were etudied for eaoh oonpoond for a total of 107 observations. Patients have been obeerved at variooe etagea or the treatment prooeee. The obeervatione were made in the EEG laboratory, using a standard 8 channel EEG recorder and noodle oleotrodee applied in 17 lead placements following Streuee £t_2; (1952). In eeoh trial, the compound under study we: administered intravenously at a set rato per uinnte until clinical behavior or electrogrephio changes were The obeerved. The compounds et a1, 19h9), studied have been diethezine (Reynane Win-2299 (Pennee and Hooh, 1957), benactyoine (Jacobeon, 1955). JB~318 end JB~336 (Abood ££_5;, 1958) end atropine. Diethaoine was administered at 25 mg per minute for a total or 175-250 I: (3.5-5.9 nelkg); w1n~2299 and bonaotyeine at 0.5 mg per ainute for 2 to 5 e3 (0.02~0.15 eg/kg)3 and JB~318, JB~336, and atropine et O.h mg per minute for 1.2 to h.0 mg (0.01~0.10 mg/kg). �OBSERVATIOHSa- (a) Diethaeine: administration of diethaeine in fifteen patients prior to convulsive therapy reaultea in a decrease in EEG voltages and a deeynchronieaticn of all trequenciee. Prevailing rhythmic patterne becane leee pro» nuanced. In acne inatanoee, symmetric low voltage 6-7 epa activity appeared and wee aoet apparent in frontal and anterior temporal leade (gink, 1958). In twentyative patiente with varying degreee of induced high voltage delta activity during convulsive therapy (rink and Kahn, 1957), there was a significant decreaae in voltage and in per cent tine of aloe wave activity. Iron an average delta or hSS in the trontnoeeipital leade, there was a reduction to a mean of 201. Both render and beret delta activity dininiehed. Low voltage alpha and beta frequencies became more prominent. The usual increase in per cent tine and in voltage or slow wave activity with hyperventilation was no'lenger apparent. Theee electrographic effects appeared during drug administration and pereieted for one to five houra (link, 1958). The . Concurrent.vi}h these electregraphic effecte, we cbeerved dietinctive eyetemic and behavioral changes. The initial eyetenie effects were episodes of coughing and complaints of dryneee of the mouth. Skin reaained dry and the heart rate increased by 5 to 10 per cent. this increase �-5- rarely noted by the preoordial'dietraea. not aoconpahied There was no change in papillary by sine, and constriction in response to light wan prompt. There were occasional oozplainte or abdominal griping. Such effects were generally less prominent than the electrographio or behavioral. was eubja ot, and was lehaviorally, patients hooano irritable, restless, tense and excited, and it was difficult to maintain eyelid closure. they oonplained or feelings of unreality and or tingling, weakneee and heavineea or the extremities. Oonplainte that color: were pale or more intenea, halos about lights and changing shadows were accompanied by delusional thoughts about their illness, the setting of the test procedure or the axaainer'e identity. (h) that Win—2229: Win-2299 induced The report illusory by Pennee and Hoch (1957) hallucinatory states in intravenone aaniniatration and led to this next etudy. 0n o: win-2299. both electrographic and behavioral attests einilar to diethaeine were obaerved. In five patients without EEG aloe wave activity, deeynohronisatien of frequencies and a deoreaee in voltagee were noted in four (Fig.1). “QC“.-.‘-- man, fig. 1 In eleven patiohto with high voltage delta activity there was a decrease in amplitude and per oent time of slow wave activity with an increase in the par cent tine of alpha and �.5beta trequcnciee. tc 235 (Fig. 2). The neen delte ectivity dropped tron Fig. 50$ 2 ,ieeccietcd with these clectrcgrephic effecte were clinicel patterns of reetlceeceee end excitement, end minimal eyetcuic effecte. Petiente becene teertul end tense. Vieuel illuecry eeueeticne were reported end were ececcieted in theee eubjecte with deleeicnel elebcreticne about their hospital experience. Excitenent yea ecccnpenied by ideas of reference, end in two chjecte, intrevencue chlcrprcnesine wee edainietered to halt this process. Theee behevicrel chengee eppeered during drug eduinietreticn or within ten minutes, end disappeared within two to three hcnre. systenic effects were alight. there were neither cough nor rcepiretcry dietrccc. Scert rete wee unettected except in petieate who becene overtly excited and teertcl, in vhcn techycerdie eppeered during thie excitement peried; Dryneee cf the ecuth wee repcrted only on direct inquiry. (c) Benectieine: Reports that bonectyeine induced EEG deeynchrcniseticn (Ccedy end Jeweebury, 1956), its enti~ chclinerzic nature, end the etrccturel cinilerity to dietheeine and to Win-2299 led to our touting ct thin ccnpcund. Intrevencne edninietreticn in 12 subjects elicited similar clinical and electrcgrephic petterne. Bath in the well ncduleted elphe record and in the reccrd with high vcltege delte ectivity, deeynchrcnieeticn wee prompt. Dclte ectivity decreased trcn - �.5a mean time of 391 to 165 in 8 Fig-t, These electroxraphic by subjects (Fig. 3, h). 3, h~ patterns were ngnin acconpuniod clinical roctlenlneol, irrittbility and oxeitcmont. Artifactwrree recording was nor; difficult.. the illusory sensitionl ind dblunional thoughts a¢en with the initinl aénpounds were hot notad at then. dongs. luvtla. Syatcnie effects wore niuilar to Win-229?. ‘ (d) Piparigylbanzilatoa: Following racont reports by Ahead 33_§; (1958) that various pipcridylbcnailatca with nynaurxblo antichoiincrgie activity induced hallucinations in psyehintrie subjects, we taut-d JB~318 and JB~336 in 2h vubjoets. Thu olectrogrnphic'pntterns wort identical with the other experihonttl antiehulinorgia compounds. Dosynchrenination of troquancios wan noted during the injectian or within 15-minute: and pornistod tar due tp {our hanrs (Pig. 5). O’Qﬂﬂﬁﬂw Fig. 5 In each inataneq in whieh duaynchronixation was obaarvad,‘ ainicnl restlolancau, excitcnont, illunary and hallucinatory activity were acted, and were eonuurrant with the nloetrographie changes. In two inatuneoa the behaviornl changoa wore haltcd by tho intravonoua administration or chlerprenasino. , �-7-(c) Atronins: Considering the numerous reports that atropine_indnced EEG elow wave activity and clinical eonnolence, we adninistered this anticholinergic agent intravenously in 15 aanecte, in dosages of 0.8 to h.0 as (.01~.1o ng/kg). In six snbjecte without EEG delta activity, there were no changes in EEG pattern during drug administration nor for 10-20 minutes theratter.. During a period of laseitude, decreased voltages, minimal desynchronication, and an increase in per cent tine'delta were noted. In subjects with delta activity, there nae an apparent initial decrease in voltage and per cent tine or each activity during the first ten ninutes after adainistration, followed by a return to original values during the period of quietode. In neither period were the changes significant,: (31:. 6). ﬁ Fig. 6 systemic effects were prominent during the injection with increased respiratory rate, pallor, dry skin and dry precordial complaints increase in heart rate up to 10oz. Subjects became restless and recording became difficult. Within ten ninntes these symptoms subsided and the subjects became drowey and relaxed. mouth, and an �-8DESGU$SION3 In those studies, varione experimental compounds with neaenrable anticholinorgic activity have been obeerved to have similar electrosrephic and behavioral effecte.' Electrographically, each agent induced a doeynchronination of frequencies and a decrease in voltages, which was most prominent in cubjocte with delta activity following convulsive therapy. Behaviorally, theee electrographic patterns were aceociated with stimulating, excitatcry, illusory and hallucinatory activity. To a leeeer degree, ainiaal oysteaic changes in heart rate, eelivetion and eweating were noted. Theeo latter eyeteaic cffccte were lore prominent in patiente given intravenous atropine under einilar experimental conditione. Thceo obecrvatione can be related to theories of the node of action of convnleive therapy; to concepts of the basic of experimentally induced hallucinatione; and to roporte of tho effocte of atropine on EEG patterns. (a) Convaleivo thcrggy process: Earlier etndieo indicated that the development of high voltage slow wave activity wee a nenrophyeiologic correlate of behavioral changc in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement (Pink and Kuhn, 1957). In enanarieing the obeervationc of nuaerone authors on the relation of acetylchcline metabolic: to trauma of the central nervous eycten and to convnleione (Pink, 1958) it wee enggeeted that a biocheaical concoaitant of the induced EEG �.9. alov wove ootivity to. an increased level or acotyicholinoo‘ oholinootorooo activity of tho central nervous system. Tho . pro-ant oboorvations of altorotiono 1n the slow wave activity at oonvnloivo thorapy by that. oxporiuontal antioholinorgic compounds or. oonaiatont with this suggestion. That tho problon 13 not. complex is indicated by reports or oonpoundn with other biochemical activity alto ottocting clot wave nativity in o aililor faahion. Alphotnnino (Lonoox‘:1_g;, 1951), nonoalioo (Karlia and Router. 19553 Dunbar, 1955), lyoorgio acid diothylonido (Dante gg_g;, 1957 a,b) and diphonhydranino (Bios-Guerrero £3;=;, 1956) olso reduced post-convulsive slow wave activity. In these reports, such a reduction vac aooonpnniod by excitntory nod stinuloting effects on bohtvior. Those conponndo, hovovor, are prinarily oynpathoninotio and antihistoninio in pharﬁaoologio activity and not antioholinorgie; 81n113r_oftocto of those divoroo bioohomical ngontt on olootrographio patterns and on cliniool behavior may be oonoidorod within thoorotio oooatruota of the relation of synaptic ootivity to behavior on oxproauod by Harolsi (1953, 1957), Brndloy and Blkool(1957), Evarts (1958 .,b), Sherwood Tho thono author: nnzgoot thot tvo ohonoroopon-ivo roooptorl oxiot within (1958) and Hoolloy (1958). typos or interootiog the nervous oyston which or. Iolootively roopoouivo to oholioorgio or to udrenorgio agonto. whore ouch rocoptorl oxilt, they oxort oppoaiog ntinolotory or inhibitory ootioo. �-10Thus, repeeted induced oeuvuleione mey lead to e choose in eyneptio eholiaergio activity, reflected in surface electrodes on high voltage slew wove activity. Administration or enticholinergio egente may alter eyneptie nativity, resulting in e decrease in the manifest aortioel electrioel eotivity to preoenvuleivo levels. Adeinietretion of eyupethoeinetio egente eey eohievo the gene electrical effects by inoreeeing the level of edrenergie activity. The neoiteet elov weve activity, so proninent end so pereietent in the poet~eeisure 328, any thne be vieved ee resulting from n persistent elteretion in the synaptic activity of large hunters of cello of the control rnervone eyeten. The delicate netnre or this balance is seen in the reedy reversibility with alerting, tine, and the wide variety of phernnoologio agents noted here. While an alteretion in synaptic activity may underlie the behavioral changes in coovulsive therapy, the neoheniel elteration is developed or eueteinod is uncleer. The obeervation by iird gt~gl‘(l956 e,b, 1958), that an inoreeee in permeability of the blood brain barrier followed‘ by which such repeeted indooed convulsion: euggeeta one sz in which synoptic ehengee eey be mediated. coneietent neture or these neurophysiolozio observation: nekee en exclusively payehologic explenetion e: the node or action of convulsive therapy lees teneble. These etudiee ere ooneietent, however, with the neurunxmyeiologio~‘ adoptive view or the convulsive therepy preoeee whioh eugzeete The �«11 an that nenrcphyeielcgic chengee provide the enbetrate for alterations in all aepecte cf the enbject'e clinical behavior; the type or behavieral eitereticn being dependent upon the type and degree of neurophyeiclcgic change, the personality or the eubject and the expectations and tolerance of the milieu (Weinetein and Kahn, 1955) link and Kahn, 1957; Pink, 1957). (b) leurcphyeialegy c: hallucinczenic activity: The effects of antichelinergic ccnpcnnde on EEG and behavior nay alec be related to the underetandinz or experinental hellucin» ct theee experinental ccnpcunde induced excitatery behavior, including illneery and hallucinatory phenomena. Here, tee, a synaptic nedel any be applicable. cgenic activity. Each sympathceinetic agente, ae neecaline, LSD and anphetanine, and anticheiinergic agente ea thcee described here, are alee potent hallucinogene. i necropharnacelcgic basis for each behavior nay be characterised ae an alteration in the level or eynaptic activity in the direction of increased inhibition (decreeeed tranenieeicn) or etincli. The clinical efficacy of ccnvnleive therapy in modifying hallucinatcry activity nay lie in alterations at thie nenro~ physiologic level, The effects or ench hallucinogenic blocking agents ae chlcrprenacine and rceerpine on EEG electricl activity are ccneietent with each a View. Both ccnponnde induce EEG hypereynchreny in nan (Bente and 339 deaynchrcnicaticn effects of 1955). Chlorpromazine was Itil, 195k. 1958} and b10¢k thd neeceline (Schware gt_3;, found equally potent in aborting the LSD and �-12. exoitatory activity of the experimental anticholinergic coupouoda in these etudiea. (c) Relation to atropine: Goapariaon or the eyetenic land neurologio effects of experimental anticholioergie compounds with atropine reveals ditterencea in initial focus of action, Exoerienco with atropine at physiologic and toxic levela in nan indicate that the prodoainant effects are :ocuaed at peripheral nervooe ctroctnroa. Initial bradycardia, followed by tachycardia, lose or creating and ealivaticn, papillary dilation, intestinal relaxation and decreased motility are. aaonget the effects at low (0.2-1.2'ug) dooagoa. At higher doaagea (ans :3), the neurolggic effects of ataxia, irritability, disorientation, and delirium are observed (Goodlla and Gilnan, 1955). ‘ In contrast, the experimental anticholinergic agents in doaegoo sufficient for central nervous system effects manifest little peripheral activity. The central effects are observed early and may continue for exteneive periods without gaetro~ intentinal, cardiac or pupillery changes. It ie within the context of the tocue or activity in relation to dosage that the apparent discrepant EEG observations or the effects or atropine (in inducing aloe wave activity) and the-e experimental antioholinergic coapounda nay be reconciled. I weecee 33_g; (19h8) administering 1.0 to 3.0 ag/kg atropine in curariadd cata and monkeys and funderbuzk and Ceae (1951) using 0.h to 1.2 ag/kg in curarised cata, observed high voltage EEG �.13.. aloe wave activity. Hitler (1952, 1957) reported that 7;! Ig/kg atropine on unaneethetiaed, uncurarieed deg: produced "spindle slow wave” patterns eiuilar t6 sleep.) Rinaldi and 'Hinwich (1955a, b) reported that atropine in doses of 0.5 to 2.0 mg/kg in curarized rabbits exaggerated EEG sleep patterns and inhibited the alerting or the EEG to peripheral stimuli. Sinilar observations have been reported by Bradley and Elkee (1953) in the cenecione cat. In each instance the doeage at atrepine varied tree 0.5 ta 7 ng/kg . a range roughly eoeparable te the deaagea need in atropine coma therapy (Ferret and Miller, ; 1958). In the present etudiee, the EEG effects at low deeagee of intravenous atropine (6.01 to 0.10 mg/kg) were minimal and systemic éfteete censiderable,cenriraing einilar observations by Verdeaux and Hartylfl95h) and by Danielepalu g§_3; (1955). the slow wave activify an prominent in animals and man at high doeazea at atropine, may not be a manifestation of the initial or direct effects at atropine, but a reflection of a more widespread alteration in body yhieialogy. Thee, while eeneiderable epeeulatien aa ta central neurophysiology has been based on studiee with atreyine, each abeervatione provide a epecial'caee at anticholinergic affects. the anticholinergic activity eetabliehed in observation: in vitro and in the peripheral nervous eyitee, may net be the effective physiologic activity in the large deaea necessary to affect centraldr‘cturee, rhe experimental cenpounde, however, provide mere euitahle �“15- for thu study of cantrnl nturaphysiologic (tnticholinargic) patterns thnn stropine, as, for oxunplc, 1a a ra~ovu1uut1an or the studio: at ertnieeorcbral trauaa :nd dpilcpay. Wtrd'l (1950)'r¢p¢rtl or the otticney a: high do... of atrepino in altering the clinical n‘n1£0ltatienl of hoad trnuau indicutod that effective dose: brought with than Invor¢ systolic ortoctl. the tntluro of ntgopino and scopolnninc to affect cpilcpny any be rolatod to th; inability agontn that. to rcgah thu cintral norvoua system in tdnquato quanlty. It would stun ndviugblo, thoroforo, to rcpuat that. Studio: utilising inch ﬁorc ccntrnlly active of eoupounda anticholinargic hora. compound; 18 used in the oxporimonta rapartud �-15SUHNARI: _ 1. Experinontsl natiohclincrgic compounds (dicthntinc, .Win«2299. bannctysino, JB~318 and JB~336), adainintorcd to paychiutric patients nt variant stcgcs c: convulsive therapy, wcro aascciated tith: (a) dcnynchrcniunticn of EEG rhythm: with a blocking of paltnccnvulcivo delta activity! (b) alurtina, cxcitatcry bahtvicral rolpcnao with illnlcry, delusional and hallucinatory idonticng and, (c) systemic Ottocts of muscular Icahn-cs, dryncun of thc month, dry skin cad tcchycardia. 2h. oltctrcgraphic bohavicral and systemic nrfncts were ccn~ current. 2. Thou. obscrvnticna are consist-at with tho auggonticn thut a nourcphysiclczic ccnconitant or convulsive therapy is ca incroulo in contral norvcul Iynton cholinorgic activity. Obscrvctionn that LSD, anphotuninc, nouculinc and diphonhydranino - tynpnthouinctic tad antihiatnninic agents . 31:0 induco BEG dcnynchrcniuaticn, blocking of part convullivc 3. doltn activity an; clinicsl cxcitntcry activity cuppcrt‘thc luggcsticn thut behavioral and clectrographic patterns may be bclud on altcrcticns in syntptic activity. )It is nuggclt that incrca-od synaptic activity (cholinorgic, aynpnthclytic ctructa) in calccintod with EEG hypornynchrcnisaticn, Aka clinicul �~16~ Itdgtion and ourhoria; whilo dtcrtasod synaptic activity (untieholinorgie, uynpathoninottc) is associated with EEG doayuchronization and clinical Ixeitatory and hulluainocanic stutou. nascrcpunt obscrvatiana with gtropinu art rulattd ta significant difroruncca 1n doaagc. Ronaasoaununt or tub h. rain or anticholinorcic taunts state: 1n hild truunt 3nd noisurn luggoatod. 5. These obaurvations amplify the neurophysioloxtcw tdaptivo hypothonia a: the and. at tcticn or convulsive thcrupy and of experinontnl hallucinogenic Itaton. 18 �-17“ AGKEOULBDG§§§§ga I u: gr‘totul far the tcchnicul auuiutanee of Bra. Etnnnh ﬁbuquorn in recording and nnulyaoa. Supplici ot‘tho various pharnncauticals were and. froely availtblc by Lake-1d. Laboratories (JD-318 and JB-336), Herck sharps & Donna (bounctyzinc); Sand»: Pharnnconticaln (nan-25). Sturlingwmthrup (win-2299) sud Smith, x11" und Preach Lnboratorica (ditthnsino, chlarpronastna). EEG �-18REFEREIOEB Ahead, L.G., Oottuld, A.H. and 31.1, J. A now group of psyohotominutic agonta. Proc. Soc. Expor. Biol. 804., 1958, 21: h83~h86. 11rd, 3.3. c11.1..1 oorrolnton o: clootroahook thorapy. 5:5:5: Arch. laurel. & quohiat., 1958, 12; 633-639. Lira, 3.8., Strait, L.A., Puoc, J.W., Hronott, 3.x. and Bowditch, 8. Neurophysiologic ottootn of olootrioolly induood convulsions. A.n.;. Aroh. lourol. & Pglghiot., 1956, 15: 371-»3'28. Dante; D. and Itil, T. Zur Hirknng do: Phonothiuninkorporo out do: Honaohlicho Hirnatronbild. Arsnoinittoltoroogg, 195k, 1} h18~h23. Bantu, D. and Itila I. A conporilon of tho action of various nogaphon phonothhsino compounds on tho human EEG. Trans. Int. Gong. of Houroagycggzyarm., 1958, (in gross). lonto, 9., 1%11, I. and Schnid, 3.3.. Eloctrouncophalographtc atndioo ooncorning the action or LSD-25. lourozhzliol., Bonto, D., I Itil, !. EEG Olin. 1957, 2} 359 (ubo£.) and Schnid, 3.x. Eloktrooncopholoo graphilcho studion our Wirkungauoiuo do: L8D~25. ggyohiut. at louro1., 1958, £25: 273~28h. Bradloy, P.B. and Bikes, J. the ottoct of atropine, hyosoynnine, phyooottgnino and noosttguino on the oleotriool ontivity of tho broin of the conscious cutoo J. thl1o1., 1953, ggga 1h~15. �‘19Bradley, P.B. and Bikes, J. effects of drugs on the electricel activity of the brain. gggég, 1957, ﬁg:' The some * 77~117. 3.0. A clinical trial of benectysine hydrochloride ('8uev1t11') as e phyeiael relexent. gggg. andy, 1. end Jewesbnby, Hed. ‘Ben1e10pelu, Jean, 1956, y 1.85—1.87. 9., Giurgee, c. end Brocan, G. Eleotroencephele~ grephic study at the,non~epoeitic phernecedynenice of the etimnlnigry effect at etrnpine on ths corebrel cortex. Iiiieégggcheekly Zhurnel 8858,'1955. g5: 601~611. Deﬁber, 3.6.3. Stud1ee on neecelinec III. letien 1n epileptice. 3933.,1955, 29: h33~h38. mm. Die.2~auerrero, R., re1nete1n, R. and eettlieb, J. a. EEG finding: following intrevenoue injection of d1phenhydramine hydrachloride (Benadrylr). Ema. Olin. Beure» 2n;.1.1., 1956, g; 299-306. Everte, E.V. Heurophysiologicel correlates of pherueeologicelly induced behavioral disturbencee. Ree. Publ. lee. xerv. .uent. 91... 1958, 29: 3h7-38o. Everte, 3.7. Chemical bases for peyohoeee. Chenicel Conceggg e! Pezphoeee. XuBovell, Dbleneky Inc., H.!. 1958, k1~62. link, a. A unified theery of the ection or phyeiodyuenic y therapies. J. Hilleide leep.. 1957. g; 197-206. l1nk, K. Efreet e: entichelinergic egent, dietheeine, an EEG and behevier: 81¢n1t1cence for theory at convulsive therapy. I 1.3.1. laurel. a Peyehiet., 1958, 80: 380~3873 end Biologicel Peyvhiet_z, ed. J. neeeernen, Grune & Stretton I. 3., Arch. 1959’ 1811*19he �-20- rink, Rnlation or olectrocncophnlogrqphic delta activity ta bohuvioral rulponao in aloctrolheck. H. and Kuhn, R.L. A.H.A. Arch. tartar, a. lourol. and 3111:», J.J. & szuhint., 1957, 13} 516~525. Atropiuo cont: A‘Ionatic therapy in psychiatry. Lu. J. quehint., 1958, $35; h55~£58. rundcrburk, w.n. 1nd Onto, !.J. rho affect of ntropino an cortical pot-ntiuln. EEG Olin. lburophlniel. 1951, g: 213~223. L.8. and Gilnnn, A. Pharmacolqlgcll Basin of Thorazcntieu. Kacxillan, I.!. 1955. Hoynans,.c., Establo, J.J. and dc Bonncvnanx, 3.6. sir 1: Boodnan, I - pharmacologio d0 11 phonothiaz1ny1-oth71d10thylnninc (2987 R.P.). Arch. Int. Pharmacoﬁzg; 19h9, 12; 123-138. Ito: ltd spacitik virkning p: contruluorvoayltonot. g‘plkritt far Lqugg, 1955, 3E2: Jacobson, E. Susvitil, at nyt ' 11h7~1151. Jonknor, 1.2. tad Lochnor, a. Th0 offset or diparoel on tho olcctrooncophnlogran in tho nnrnul Inhaoct und in than. with corobral iguana. BEG Olin. lenrophyniol., 1955. 1; ' 303-305. Lochnor, the influence or naticholinorgic drugs on the EEG Clin. EEG at rcchnt OIOIId crtniccrobral injuries. lourenhyliol., 1956, g. 71h'71§.' a. 0n Lonnox, H.A., Ruck, 1.0. :nd Gutornnn, B. The the postuoloctroshock lourozhza1a1., 1951, g: 63~69. boas-aria. on oft-ct EEG. EEG of 0113. �-21. 'Hereeei, A.$.- Sene indicetiene e: oerebrel hnnerel necheniene. science, 1953, 1;81 367-370. lereeei, A.8. Etteete ;;“peycheten1eet1c druxe eynepeee. Egyehotrepie Bragg. on cerebrel Eleevier, Aneterden, 1957, 283~28h. Herlie, 3. end Hunter, 7. Studies en eeecelinee II. Electra. eneephelegren in echieephreniee. fezghiet. 93ert., 1955, Pennee, 8.3. mum”. end neck, P.H. Peychetonimetice, clinicel end theoretical eeneideretiene: Hernine, w1n~2299 end leiline. Amer. J. Pelehiet., 1957, ;;3: 887~892. Rineldi, 7. end ninwich, 3.3. Alerting repeneee end ectione or etrepine end chelinergic drnge. A.H.A. Areh. Neural. end Rineldi, I. Pezehiet., 1955, 12: 387-395. Cholinergie nechenien involved in functien of neeodieneephelic ectiveting eyeten. ena ninwieh, H.E. leurel. e Peychiet., 1955. 1;: 396-h02. 3. Chengee 1n the nu unau- bubttnrete mu...“ produced by electroaeonvuleive treetnent end their significance fer the theory or E0! eetien. BEG clin. leureghzeiel., 1951, 3: 261-280. A.H.A. Arch. Roth, 30th, l., D.W.l., Sher, J. end Green, J.‘ Pregneeie end pentethel induced.electroencephelegrephie changes in Key, electreeenvemlve treeteent. E36 6113. leereggzg}el. 1957, 2: 225-237. �a22- 3.2., Bicktord, 3.0. Schwarn, and Rona, H.P. inducod psycho-it with ohlorpronasino. 1955. 2Q; h07oh17. Bhorvood, 3.x. Contrul oorohrol ohoniools dud Rovoroihility or Proc. Hiya Clin.. their rolation to paychonol. chonioal Gonoopto or £329hoaiu. xenowoll, Oblonlky, 3.2., 1958, 268~276. Btrnuol, 3., Ootov, H. and are-nutoin, L. Diagnostic Electroonccpholggrtphz, Gruno & Strntton, R.I., 1952. Vlott, 6.1. and Johanna, u.w. Ettoct o! ntropino and acopolonino upon alootrooncophalogrnphio changos induced by olootroconvulaivo thorapy. EEG Olin. lonrophzgiol., 1957,‘2: 217-22h. a. and Harty, R.‘ Action our l'oloctroonoopholocronno do ouhstancol phnrnacodynauiquoo d'intorot cliniquo. Vordoaux, Rev. Word, A. lourol., 195k, 2;:‘hosuh27. Atropino in the troatnont of cloood hood injury. J. lourouur‘., 1950,‘ls 398-h02. Uninstoin, 3.A. ond Kuhn, R.L. Doniol of Illness: aznholie and_phyoio1o§ict1 oqpooto. c. rhonal, Springfield, 111., 1955. Roscoe, nonunora, B.P. and Krop, 8. Tho influonco of atropine and aeopolonino on tho control ottooto of 91?. J. Phnrnaeo1., 19h8, 23: 63~72. w.c., Groom, E.B. Uiklor, A. Pharnocologic dissociation of behavior and EEG ”sloop pattorns' in dogs: morphine, l'nllylnornorphino and atropine. Ptoc. Soc. up». 31.31. 14“., 1952, 12: 261-265. �«~23. the 1.1915593 or P£Ich1utrl to thaaoLg‘z. Wu. Wilkins, Bathe", 1957. Woollcy, BAY. Scrotum”: in maul disorders. Ru. Pub]... Hitler, A. A". new. Hunt. 913., 1953, 29 381-4400. �aasaaaa '13. 1a Effiﬂt or :1 313.1299. was. anuyuchraaiiattua a! troqucaatnu nXtur 3.! 3:. (Fig.1.. 88' kl). 11:. 3. Efrhet at 1' Reward satin 31n~2299 an pottueoavu131Vt 2h hoard dulta :ettvtiy: artor aouvulsiau #8. ﬂat. dauznchrinilatioa at tvcguuueaou and yursiniana. nttor 2.0 is. ("l‘l’ﬁ ago 51). ‘ attooz a: It nuuuutwtaaot uni. perutntaut apero¢ac 1n rol‘agu: and duawachviatnntsaa art-r 1.5 It. (Filtllg “. 3’4). Ettoct at 1V aunuotrtﬁn- an yaatuoauvulatvo.doltt nottvaty. accord tokua 2£ hctru arch: cauvuzntau I7. lot. tetrachruntnttton or {toquuuclco urtor 1.5 ug. (tumult. It! 3)). 9“. 5. . Rttcat I: Jimﬂlﬁ an yout~¢¢uvulliau Rigord takun 2% hour: ¢¢I%& tttnr cunrulttan #9. nativity: lat. duarunhroattttiua a: Irvquuuotnn, ﬁneronagd rulingslttar !.h It. eur‘taa vita 330'! 101 tuartalt. (vaunlo. ago :7). 5&l11lr run-van thwarted math £I~336. �’1‘. 6. ”net or «$11 «Inn 62 I? “up“. an ”anemia" «In «an». nun mm: 2!; hour. um amass.» #6. 30%: man an.“ an delta “tint: and ”min“ menu. in heart an, with partition“. (mo. :3. “mam . 2.0 In. «025 Int/u). 18. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effect of antichlolinergic compounds on post convulsive electroencephalogram and behavior of psychiatric patients. Electroencephalogr Clin Neurophysiol. 1960 May; 12:359-69. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-34b-013 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 6 items. 1: Reprint from Electroencephalography and Clinical Neurophysiology JournalVol. 12, No.2, May 1960. 2: Letters. 3: [preprint]. 4: [Post print?]. 5: Publication submission info. 6: Drafts. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/78017191476d8e778612e5c61eff422b.pdf 82ede86cdae7bcc77cb09f6c0bbd0389 PDF Text Text Mammal in studios of Germain ﬁnd Drug max-span mun-ya Theoﬁtio Imitation! In swans a: aonvnluivo, payohophumcmgic and inaulin a» therapist, msalon of "idem tar a mmphysiolozimpuve W011! or the and. of these ﬂux-apt!» has wwmhtod. This hypotmsia “crib“ the officwy 01' each therapy in the trantaont of wohma to their ability to induae a persistent alternates: in cerebral function. mien provides the am“: for u changa in adaptation of the subject to his anviroment. In those studies, in Em have been and as indie» of uttered brain tumuom In convulsive thong, the shift in EEG tmuoneias to the delta range has been directly rented to the behavioral changa (AMA, Arch, Emmi. and analyses at r3;chiat. (J: com be (n) «hangs: 16;: 516, 1957). A maid. H292. 5: “1&1;in has been observed 31:11.: Bk. 1955). classified ascending to their EEG From ﬂat fnqucncios, with in- (mpmbmu, barbiturates); and (c) (domains, bemctysine and asp-nine). then analyses, a shirt in unused synchronisation tnnquiliutim m EEG mggasmd sedation. 1.957): mums». pruning, perphenaame, reserpine); (b) indueo a ahiﬂ. to crewod synchronization frequencies Viviana psychophameologe uganta can offsets: (J. Hillside Ham. 9; 197, mum a mm to delta frequenciu and high dose to insulin «mama frequencies to delta range and in» u the nmrophysiologic concomitanta mmphyaiologimdaptim hypothoais hm applicatim to the ammonia of physiodymmic mempiee, acmning or psychoplumeologic agents and as a trans of refemnce for the study a: bmior arid of and The mmphyaiology. From L010, the Dayna-meat “at; or Workman. rm. Hemlogical Society, MAR 2 6‘85 Why, Hillaido Hospital, Glen mks, March 11, 3.958. �«W W WWW AFTER 225 mg. PRE-DRUG LF-LO RF-RO WIN/WWW SOyvl _ #I64IHH �PRE- DRUG AFTER 150 mg �W WW ”“va W W W WW WW WW + PRE-DRUG + 25 mm 200 mg. LF-LO WWWNVMMJVW RF R0 NWvaw-AAW “T'RWWJWMM H ”ﬁn. MM LF-RFNWWN WWW” LPT'LO WWWM 50 )Lvl I $|631 NH �PRE-DRUG @. AFTER 250 mg. W W W W W W W W W W WW 50pvl_ SEC. 1 #IZQS NH �Effect of Anti-Cholinergic Agent, Diethazine, Significance for Theory of Max From the Department of Experimental L015, NJ. Fink, on EEG and Behavior: lesive Therapy 14.1). Psychiatry, Hillside Hospital, Glen Oaks, in part, by grant M-927 of the National Institute of Mental Health, National Institutes of Health, U.S. Public Health Service. Aided, (in part) at the meeting of the Eastern Association of Electroencephalographers, N.Y., December 1957,‘ 4.7444417 Jazz; Read 33?: 3-58 /“ a M 14/11.” 050,?wa �3.3-58 Effect of Anti-Cholinergic Agent, Diethazine, on EEG and Behavior: Significance for Theory of Convulsive Therapy Recent investigations of convulsive therapy have emphasized EEG delta activity as the neurophysiologic basis for the induced behavioral change (1,2,3,h,5). Little study, however, has been given to the biochemical effects of this therapy, except in the course of investigations of head injuries. In investigations of head trauma significance has been ascribed to in the acetylcholine-cholinesterase systems both for the behavioral and the electroencephalographic effects. An increase in free acetylcholine (6) and an alteration of the ratio of cholinesterases (7) in the spinal fluid have been positively correlated with the degree of EEG abnormality changes and degree of heurologic improvement deficit. in clinical status The EEG patterns were "blocked," and was reported following atropine (7,8). In convulsive therapy, atropine observed to block the appearance of delta some the administration of and scopolamine were activity, (9) although the systemic effects of the large doses of these agents were marked. Recent reports (10) noted that EEG and behavioral effects similar to atropine {were achieved in patients with head trauma by intravenous diethazine a phenothiazine compound systemic effects. with anticholinergic properties - with minimal In our continuing studies of the role of delta activity in electroshock (3), the effect of diethazine was studied. It is the purpose of this report to describe the effects of diethasine on EEG patterns and on behavior of patients during electreconvulsive therapy; and to relate these observations to the present neurophysiologic-adaptive hypothesis of the mode of action of convulsive therapy. �SUBJECTS AND METHODS: Forty psychiatric patients, at various stages of electroshock therapy in an open-ward, voluntary psychiatric hospital have been studied. All observations have been Following a routine at the rate of EEG made in acute experiments in the laboratory. recording, diethazine was administered intravenously 25 ngm per minute, upon the behavioral EEG effect. for a total of Dosage varied from to 250 mgn, depending 2.8 to h.0 mgm per kilogram 175 body weight. Diethazine is a soluble phenothiazine compound with pharmacologic properties similar to atropine. In experimental animals, diethazine blocks the bradycardia, bronchospasm, salivation, fasciculation and seizures induced by acetylcholine, di-isopropyl fluorophosphate and pilocarpine. suppresses salivation, and induces mydriasis and hypotensicn EEG It (ll). Anilxses: Recording was continuous for the duration of the observation period, except during interview periods. Needle electrodes, and an Moderaft instrument were used. All records were analyzed delta activity (3); the per cent time the relative amount of fast activity. measured in anterior temporaldvertex, and The and 8 channel for the degree of principal alpha frequency; and alpha and delta activity were parietal-ear ldbe lead coMbinations. Behavior measures: Prior to drug administration an unstructured psychiatric historical interview and a structured questionnaire period (12) were tape recorded. Following drug administration, periods of recorded interview were alternated �~3- with EEG recording periods, until the me had again manifested the pre- injection pattern on visual inspectioné Two estimates of behavioral effects were used: clinical descriptions subject, interviewer and technician - of the changes occurring during the drug period, and language analyses of the recorded interviews. Changes in language were evaluated by a syntactic analysis (12) and an analysis of the variability in verbal interaction in the dyad (13,1h).* by the participants ~ Both measures have been shown to be sensitive to induced by changes in the central nervous system. * Detailed analyses of these observations DPS. J. Jaffe alterations in behavior and Re In Kahn. will be reported separately by �OEERVATIONS: (a) Clinical: Within two to five minutes of the start of the injection, subjects manifested spontaneous coughing follow ed by a dryness of the of speech. and a thickness They reported a feeling of lassitude, mouth and a heaviness and weakness of extremities which was soon succeeded by increased difﬁculty in maintaining eyelid closure. Reports of visual and haptic illusory sensations, feelings of unreality distance, and delusional thoughts about their illness, the setting of restlessness and and test procedures or identity were voiced Spontaneously in eighteen subjects in the period between 15 and 60 minutes after drug adninistration. the our In three instances, increasing agitation and panic led to a cessation of the In two subjects withdrawal and negativism was the prominent recording. behavioral response. Such patterns of behavior were transient and had disappeared in (b) EEG 1% - h hours in all subjects. Patterns: Alteration in the EEG patterns was concurrent with the behavioral effects. In all records, changes occurred during drug administration and were sustained, with gradual diminution and restitution of the pre-injection patterns, in one to five hours. The initial response was a decrease in voltage and desynchronization of all frequencies. There prominence of prevailing rhythms. was a decrease in In patients without delta activity (pm-electroshock), desynchronization and voltage decrease was occasionally activity, symmetric and prominent in frontal and anterior temporal leads (Figure l, 2). The alpha frequency was not altered. accompanied by low voltage 5-? cps �~5The build-up in voltage and appearance of slower frequencies with hyper- ventilation was blocked. In patients with varying degrees of high voltage delta activity there was a prominent decrease in voltage and desynchronization of the record. burst delta activity diminished or disappeared, and irregular voltage alpha and beta frequencies became prominent (Fig. 3, h). The Both random and low hyperventilation response was no longer apparent. (c) Language Patterns: In previous studies, an intimate relationship between changes in syntactic language patterns and the behavioral response in electroshock had been reported (12). With alteration in brain function, increased use of third person, veroal denial, qualification, displacement and cliches became prominent. These effects could be enhanced by the administration of intravenous amobarbital (1h). In the subjects in the present study, syntactic analyses demonstrated a reversal of the patterns noted in electroshock. Use of third person, qualification and displacement decreased. Explicit verbal denial was modiﬁed and replaced by minimization and displacement, or by a reiteration of complaints of illness. In dyadic analyses, the verbal interaction was characterized by a greater diversity of vocabulary and less variability in the diversity scores for 25 word units. qualitative nature of these changes in the language patterns is opposite to that of amobarbital and electroshock. The duration of language changes was concurrent with the changes in the electroencephalogram. The �DISCUSSION: These observations confirm the report of Jenkner and Lechner of the effects of diethazine in "nonmal" subjects (10). Diethazine also alters electroshock induced delta activity in a fashion similar to atropine and sncpolamine, as described by Ulett and Johnson (9), with minimal unpleasant symptoms. EEG The effects of intravenous diethazine are immediate, both and behavior, and thus provides a cholinergic" properties. Two on the useful experimental agent with "anti- aSpects of these experimental observations warrant discussion: the role of acetylcholine-choldnesterase in the electroconvulsive therapy progress, and the significance of die thazine "alerting" for concepts of hallucinogenic activity. 1. Biochemical Basis of the Convulsive Therapy‘l’rocess: While there has been considerable study of the psychologic neurophysiologic aspects of convulsive therapy, biochemical processes is available. The little and infomation concerning studies of biochemical changes following head trauma and spontaneous seizures provide some analogic data. Bernstein (6), in a classical experimental study of head trauma in cats, that within a few minutes after trauma, free acetylcholine appeared in the Spinal fluid and persisted for periods up to 148 hours. He further demonstrated a positive relation between the severity of head trauma demonstrates and the quantity of free acetylcholine, degree of electroencephalographic the severity of the behavioral changes. The electroencephalographic records initially showed short periods cf high voltage fast activity, alteration and transient period of flattening of electrical activity, followed by prolonged periods of high amplitude sharp waves in the delta frequencies. Concomitantly, a �-7alteration in consciousness, changes in reflexes seizures EEG change. Tower and HbEachern (7) confirmed studies in man. In post-traumatic highest concentrationSOf free acetylcholine were most prominent with and greatest degree of and 112 neurologic these observations in clinical patients, free acetylcholine was found in the cerebrospinal fluid only in patients following head trauma and recent grand mal seizures; and the level of free acetylcholine varied directly with the degree of cerebral damage. In addition, these authors assayed the cholin- esterase activity of the spinal fluid, (7, 16). In patients following head trauma, they noted a sharp rise in non-specific cholinesterase (benzqylcholine- in.the specific cholinesterase (meoholyl-splitting) activity of the spinal fluid. No such inversion was noted in fluids containing splitting) and a drop free acetylcholine following spontaneous seizures. Electroencephalograms were taken at varying intervals following correlation of the extent of EEG trauma, and demonstrated a direct abnormality and the appearance of free acetylcholine in the spinal fluid. Tower and MhEachern also reported observations in six patients In patients after 3-7 induced convulsions, they noted free acetylcholine in the spinal fluid in two, and an increase in non-Specific cholinesterase with reversal of the cholinesterase ratio in five receiving electroconvulsive therapy. of the six. They concluded that the spinal fluid changes in electroshock are more like those of craniocerebral trauma than those found in epilepsy. * patient of the six who failed to show either free acetylcholine or a reversal of the cholinesterase ratio, they noted: “It is interesting that this patient was the only one of the six to show no * Regarding the one response to treatment." �-8recently, Sachs (17) confirmed the reports of free acetylcholine in the spinal fluid after head trauma and after electroshock. In his studies, Bornstein (6) administered 0.5-1.0 lug/kg atropine Mcre effects, and a modiﬁcation of the behavioral and neurologic signs. Atropine also blocked the EEG and clinical signs induced by intracisternal acetylcholine. and demonstrated a reversal or a blocking of the Ward (8) applied these observations with varying degrees of head trauma. atropine induced both clinical EEG to the treatment of Subcutaneous doses of 0.1 mg/kg of improvement and reversal of These observations were recently confirmed by Sachs Hughes (19). Based on subjects human these observations, Ulett (l7), EEG effects. Rugs (16) and and Johnson (9) noted the effect of atropine and scopolamine in blocking the Em changes of electroshock tharapy, without noting the effect on clinical behavior. Concurrently, Jenkner and Lechner (10) reported effects similar to those of Ward, in studies of diethazine in cases of head injury. Another group of investigations complete the available data. Studies of anticholinesterases, as DFP (di-isopropyl fluorophosphate) and (tetraetlwl-pyrophosphate), which block the enzymatic TEPP breakdcvm of acetyl- choline, demonstrate the development of high amplitude rapid frequency mac patterns similar to status epilepticus as well as lesser degrees of abnormality as noted in post-tramnatic states (20, 21, 22, 23). In these studies, atropine blocked both the electroencephalographic and the clinical toxic effects. Thus, both from experimental and trauma we may assume clinical studies of craniccerebral that (a) the acetylcholine activity of the spinal �-9- fluid increases; (b) pseudo-cholinesterase activity increases with a reversal of the ratio of cholinesterases; (c) slowing agents From parallel these biochemical alterations; may EEG tamer-synchrony and and (d) anticholinergic block both the electroencephalographic and the clinical effects. it is probable that the biochemical basis the data available convulsive therapy is similar to that of craniocerebral trauma. of Convulsive therapy results in free aoetylcholine in the spinal fluid (7, l7) and a reversal of cholinesterase ratios (7, 16). The electroencephalographic effects of repeated induced convulsions is the developnent of high voltage, activity, occasionally with spike activity (3, 2h, 25), which is similar to that observed in severe head trauma (26, 27). In symmetric slow wave previous studies we have reported the relationship between the degree of activity and behavioral reaponse (3). The studies reported here and that of Ulett and Johnson (9) demonstrate a reversal of the EEG and the behavioral effects of convulsive therapy by antiinduced slow wave cholinergic In each characteristic, convulsive therapy is thus compounds. similar to cerebral trauma. While the acetylcholine-cholinesterase system is highlighted (17). These studies, other enzyme systems may also be altered studies also suggest that convulsive therapy provides an by these excellent experimental method for studies of craniocerebral trauma. Studies of the brain stem activating system by Jasper and DroogleverFortuyn (28) and Lindsley gt a}, (29) had laid the foundation for the prevailing conclusion that symetric EEG slow wave activity has its origin in mesencephalic structures, and that these structures intimately affect the states of "alerting" and "drowsiness." More recently, Rinaldi and �-10- site of action of atropine and cholinergic to this mesodiencephalic activating system. It is also probable that Himwich drugs (30, 31) have related the these structures may be selectively affected by the convulsive therapy process, and that both the clinical and electrographic effects may be intimately related to changes in this systan. 2. Diethazine "Alerting" The and Hallucinogenic Activity: behavioral effects of diethazine provide information regarding another aspect of the convulsive therapy processxs. In patients without prior convulsive therapy, illusory phenomena and feelings of unreality were observed. These were similar to the hallucinogenic effects of and mescaline (33). Again analogic data about the of these agents may provide some no change, (31;) clinical and EG effects noted that the intermittent or continuous increase in alpha frequency. (32) information about convulsive therapy. In studies of mescaline, Wikler either LSD low voltage EEG danonstrated fast activity or Denber and Merlis (35) noted a similar acceleration of alpha frequency, decrease in per cent tine alpha including its disappearance, and non-specific random beta activity. Delta activity did not occur. In patients with delta activity induced by electroshock, Merlis and Hunter (38) noted that intravenous mesoaline markedly diminished the amplitude and per cent time delta activity with an increase in per cent time alpha activity. The effects of LSD on EEG are similar. Gastaut at g. (36) noted an acceleration of alpha frequency of 0.5 to of beta rhythms. Rinkel gt 9;... 14.0 (37) confirmed cps with an aocentuation this observation and noted, �-11- in addition, a reduced reaponsivity to hyperventilation.* In summarizing his studies Wikler (3h) concluded that " . . . regardless of the drug administered, shifts in the pattern of electroencephalogram in the direction of desynchnonization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness." This generalization provides a meaningful construct may be assessed. Agents that in which these agents evoke EEG desynchronization tend to be are clear examples. Agents that synchronize frequencies, such as barbiturate and meprobamate in the beta delta frequency range, and chlorpromazine, promazine and hallucinogenic, and mesoaline and LSD Wainthe frequency range (39) tend to be sedatives, euphoriants and relaxants. 'Ihe observations on diethazine reported here are consistent with this hypothesis. In patients without delta activity, the EEG demonstrated desynchronization of frequencies, and this was associated with clinical illusory phenomena. In patients with delta activity desynchronieation occurred, and alerting and reversal of the speech patterns induced by electroshock were observed. Electroconvulsive therapy We *- have previously noted a may also be understood in this framework. direct relationship between clinical evaluations Studies are now in progress of the effects of LSD, Win-2299, benactyzine and other anticholinergic compounds on post-convul sive EEG delta activity. Initial experiments m. ah intravenous ISD (50-100 gamma) demonstrated marked diminution in per cent time and amplitude of delta activity. �of improvement and the degree of conditions, sedation Under these EEG slowing induced by electroshock (3). and euphoria are most prominent and hallucinatory activity diminished. In patients in not induced, behavioral change is limited whom hypersynchrony and 'improvement' does is not occur (in) . Previously that the we have concluded therapies is based on the mode of action of convulsive induction of a state of altered cerebral function, in which changes in adaptive interpersonal behavior occur, preted as 'improvement' (3, h, 39). The inter- present studies amplify two aspects of. this neurophysiologc-adaptive hypothesis. substrate of the behavioral change and are is reflected by an The biochemical alteration in the acetylcholine-cholinesterase relationships of the central nervous system. It is also probable that EEG basis of the milieu change euphoria and mpersynchrony provides the neurophysiologic which is evaluated as is clinically manifest as sedation and 'imprcvement.‘ The neuropklysiologi.C-adaptive hypothesis of convulsive therapy has provided a meaningful basis for studies of other physiodynamic therapies (39) . In this study, it has been possible to amplify our understanding of neurophysiologic aspects of hallucinogens as well. �SUMMARY: effect of an anticholinergic agent, diethazine, on the behavior and language patterns was observed in to psychiatric patients, 1. EEG, The at various stages in the course of electrooonvulsive treatment. (a) Behavior: Increased restlessness and agitation, haptic and visual illusory sensations, and delusional thoughts about their illness or examiner's identity were observed. (b) Egg; Alteration in There was a decrease in voltage EEG was concurrent with behavioral changes. and desynchronization of In patients with delta activity, the per cent time all frequencies. and voltage of delta activity decreased. (c) Language: Syntactic patterns described for convulsive therapy were reversed. Use of third person, qualification and displacement decreased. In dyadic analyses, there was a decrease in the coefficient of variation. 2. These observations are discussed in the framework of the neuro— physiologic-adaptive hypothesis of the action of convulsive therapy; and it is concluded that: (a) the biochemical basis for convulsive therapy is similar to that of craniocerebral trauma; (b) changes in acetylcholine-cholinesterase metabolism are intimately related to the behavioral effects; (c) EEG desynchronization may be and a physiologic concomitant of hallucinogenic activity; and EEG-hypersynchrony associated with euphoria and sedation. �.m. W 1. Weinstein, E. and Kahn, R.L.: Denial of Illness, 0.0. Thomas, Springfield, I110, 1955. 2. Roth, M., Kay, D.W.K., Shaw, J. and Green, J.: Prognosis and Peutdzhal Induced Electroencephalographic Changes in Electroconvuleive Treatment, EEG 225‘237’ 1957. Clin. Neurophxsiol. 2: and Kahn, R.L.: Relation of Electroenecephalographic Delta Activity to Behavioral Response in Electromock, A.M.A. Arch. Neurol. and Psychiat. 1Q: 516-525.. 1957. 3. Fink, h. Fink, 24., Green, M.A. and Kahn, R.L.: Experimental Studies of the Electroehock Pracess, Dis, Nerv. SE . (in press). 5. Ulett, G.A., Smith, 6. Bornstein, M.: Presence and Action of Acetylcholine in Experimental Brain Trauma, J. Newcphzsiol. 2: 3113-366, 191:6. 7. Tower, 13.3. and McEachern, D.: Acetylcholine and Neuronal Canad. J. Research, 3.1: 105-131, 191:9. 8. Ward, A.: Atropine 9. Ulett, M. K. and Glaser, G.C.: Evaluation of Convulsive and Subconvulsive Shock Therapies Utilizing a Control Group, Am. Jo Pszghia‘b. gala-3 795’802, 1956c in the Treatment of Closed Neurosurg., 1: 398—102, 1950. G.A. and Johnson, M.W.: Head Effect of Atropine Injury, Activity, ,1. and Scopelamlne Electroencephalographic Changes Induced by Beetroconvulsive Therapy, EEG Olin. Neurophlsiol. 2: 217-2224, 1957. Upon 10 . Jenkner, F.L. and Lechner, H.: The Effect of Diparcol on the Electroencephalogram in the Normal Subject and in Those with Cerebral Trauma, EEG Olin. Neuromzsio . _7_: 303-305, 1955. 11. Heyman, Sur la 0., Estable, J.J. and de Bonneveaux, 8.0.: de la menothiazinyl-Etlnrldiethylandne (2987 R.P.) , Pharmac 12. in Language During Electroshock in {exchomthologg of Communication, pp. 126-139, Stratton’ NoYo 9 o Kahn, R.L. and Fink, 11.: Changes Therapy, Gr‘me 13. . 12: 123-138, 1919. Pharmacologie Arch. Int. Jaﬁ‘e, 8C Objective Study of Comuuﬁcation in Psychiatric Interviews, J. Hillside Hospital, é: 207-215, 1957. J.: An �.15.. Jaffe, J.: Language of the Dyed: A Method of Interaction Analyses in Psychiatric Interviews, mchiatgy, (in press). 15. 16. Weinstein, E.A., Kehn, R.L., Sugarman, L.A. and Linn, 1...: Diagnostic Use of Amobarbital Sodium in Organic Brain Disease, Am.J. mchia . 1-}.2.‘ 889-8911, 1953. Tower, D.B. and McEechern, D.: The Content and Characterization of Cholinesterases in Human Cerebrospinal Fluids, Canad, J . Research, 21: 132-115, 19349. 17. Sachs, E.: Acetylcholine and Serotonin in the Spinal Fluid, Neurosurg., 11*: 22-27, 1957. 18. Rugs, D.: The Use of Cholinergic Blocking Agents Cranio-Cerebral Injuries, J. Neurosurg., ,1. in the Treatment of I_l._1_: 77-83, 19514. Injury, J. Neural. of Acetylcholine in Head 1957. chia . g9; p.70, 19. Hughes, B.: The Role Neurosur . and 20. Freedman, A.M., Bales, P.D., Willis, A. and Himwich, H.E.: Experimental Production of Electrical Major Convulsive Patterns, 21. Am. J. @8101” ﬁg: 117-1214, 19149. GrOb, Do, Harvey, A.M., Iangworthy, 00R. and Lilienthal, Jolie 3 The Adminis tration of Di-Isopropyl Fluorophosphate (DFP) 257.266, 19,47. Man, B11110 Jo H0215. Hogan, to a: 22. McCauley, A. and Hinmich, H.: Effects of Di-Isopropyl Fluorophosphate (DFP) on mectroencephalogram Hampson, J., Essig, C.F., EEG 23. 01in. 3: 141448, Neuropﬂsio . Activity, angocmlinesterase 19 . Himwich, H.E., Essig, C.F., Hampson, J.L., Bales, P.D. and Friedman, A.M.: Effect of Trimethadione (Tridone) and Other Drugs on Convulsions Caused by Di-Isopropyl Fluorophosphate (DFP), J. Psychiat., 106: 816-820, 1950. Am. 2h. Callaway, E.: Slow Wave Phenomena in Intensive Electroshock, Egg. Clin. Neurophysiol., g: 157-162, 1950. 25. Green, 26. Jasper, H.H. , Kershman, J. and Elvidge, A.: Electroencephalographic Studies of Injury to the Head, Arch. Neural“: Psychiat” 1A: Significance of Individual Variability in EEG Reaponse to Electroshock, J. Hillside Hosp” _6_: 229-2ho, 1957. M. : 328~3h8’ 19,400 �~16~ W Ostow, M. and Greenstein, L.: Dia Gmne 8: Stratton, N.I., ostic $35. Electro- 27. Strauss, H., 28. Jasper, H.H. and Droaglever-Fortuyn, J .: Experimental Studies on the Functional Anatonw of Petit Mal Epilepsy, Res. Publ. A. Nerv. Mt. Dis. 2-6-3 272-298’ 19117. Lindsley, 1)., ‘Schreiner, L.H., Knowles, W.B. and Magoun, H.W.: Behavioral and EG Changes Following Chronic Brain Stem Lesion in the Cat, EEG Olin. Neuropmsiolu 2: 1:83-1:98, 1950. Rinaldi, F. and Him-rich, H.H.: Alerting Responses and Actions of Atropine and Cholinergic Drugs, A.M.A. Arch. Neural. and 29. - PﬁzChiate, 123 387-395) 19530 31. Himwich, H. and Rinaldi, F.I:'The Effect of Drugs on Reticular System, in Brain Mechanism and Dru Action, 15-4411, C.C. Thomas, Springfie d, 19 7. 32. Stall, W.: Lysergsaure Phantaetikum aus der Arch. Neurol. PsEhiat. , §_Q: diethylamid, ein -Schweiz Mutterkomgruppe, 1-h7, 19m. ' Neural. Psychiat., 1-315, 33. Beringer, K.: Der 'Meskalinrausch Springer, Berlin, 1927. 3h. Wikler, A.: Clinical and Electrencephalographic Studies on the Effects of Mescaline, N-allylnarmorphine and Morphine in Man, J. Nerv. Wilt. 1318., 120: 157-175, 19%. i Monog. on Mescaline I: Action in Schizo~ Psychiat. Quart., g2: 1.21-1.29, 1955. 3.: Studies 35. Denber, H. and Merlis, 36. Gastaut, H., Ferrer, S. and Castello, 0.: Action de la diethylamide de l'acide d-lysergique (LSD 25) sur lee fonctions psychiques at l'electroencephelograxme, Conf. Neuro1., 12: 102-120, 1953. 37- Rinkel, H., DeShon, H.J., Hyde, R.W. and Solomon, H.C.: Experimental Schizophrenia-Like Symptoms, Am. J. Psychiat., 108: 572-578, 1953. 38. Merlis, S. and Hunter, W.: Studies on Mesaaline II: nectroencephalogram in Schizophrenics, Psychiat. Quart. , g2: 1:30-4:32, 1955. 39. Fink, M.: ha. Fink, phrenic Patients, A Unified Theory of the Action of Physiotbmamic Therapies, J. Hillside Hosp. , {3: 197—206, 1957. and Green, M.A.: Electroencephalographic Correlates of the Electroshock Process (in proparation). M. ‘ ��~24... 1m 1955. mm:- and WM )mpwm that EEG and human-n oﬂam swim to abopinn were achieved by mm mama in paﬁenta with head trauma. Fran thaw report in mute“. the ayatemic attacks of We at ( am- theme and diam nppamd mam. intamt in the nativity 1n enmeshed: r613 of 6311;: ), an immigauon a: the «that of dint-hum, in patients manning eomlain therapy wmsuport to describe the oft-hats bazwiw sf pitienta mm in was both m EEG and behavior, mama. 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Ins/k8 1» wording to m ram, (SW mm mm 2.8 b0 Int/ks. mum is a column Wino W: with am to “reprint. “perineum the Wen. bmnehm, Wmtim, rummum lawman «mm by mﬁylmolm, «1»:meth 15W “Maiden, M and «1 and ‘ A mum: in» (DFP and plum-pins. new Wis 1nd momma (Raymu- 19189): All records were unlisted the por car animals, 22:: We mi: time and fast nativity. far the: dams of dolta aébiviw principal 31pm “ﬂuency; Drug errata were emailed ﬁnd the relative meant as synchronising (I) or Warning (n) «@0ng to the mam mama by um» ( In In W, mm, tapers]. both and 81m parietal and )3 ( ). mu nativity was mum in natal-ion» m m m mum. War Wm: Prim to drug twain-rattan an mmzmmd psychiatric historical �.3;- intern“ and a structmd Wm 1?ng drug achinistmtian, pat-1363 altamted with ma EEG mm. period 1mm tape 31’ taps new 13me m ”cording parieda, until the again. manifested EEG 1236 Macaw pattern 0213131231 inspection. 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It in also probable that. mmmmmmummmmimmmmamwm momwaammnwmummmmmmummm u ’Wﬂt’ ., �WWW at cm“ thirty form mWanu blathuamdnitmmlmuﬁhtonwxym ﬂmmdodynnue thanpﬁu( mammamotmmmsunn. �Effect of Anticholinergic Agent, Diethazine, on EEG and Behavior Signiﬁcance for Theory of Convulsive Therapy MAX FINK. M.D.. GLEN OAKS. N. Y. �Reprinted from the A. Ill. A. Archives of Neurology 6“ Psychiatry September 1958, Vol. 80, pp. 380—387 Copyright 1958, by American ﬂiedical Association Effect of Antieholinergic Agent, Diethazine, on EEG and Behavior Signiﬁcance for Theory of Convalsive Therapy MAX FINK, M.D., Glen Oaks, N. Y. Recent investigations of convulsive therapy have emphasized EEG delta activity as the neurophysiologic basis for the induced behavioral Changel"5 Little study, however, has been given to the biochemical effects of this therapy, except in the course of investi— gations of head injuries. In investigations of head trauma signiﬁ— cance has been ascribed to» changes in the acetylcholine—cholinesterase systems both for the behavioral and for the electroencephalo— graphic effects. An increase in free acetyl‘6 choline and an alteration of the ratio of cholinesterases 7 in the spinal ﬂuid have been positively correlated with the degree of EEG abnormality and degree of neurologic deﬁ— cit. The EEG patterns were “blocked,” and some improvement in clinical status was reported following the administration. of atropine.“8 In convulsive therapy, atropine and scopolamine were observed to block the appearance of delta activity,9 although the systemic effects of the large doses of these agents were marked. Recent reports 10 noted that EEG and behavioral effects similar to atropine were achieved in patients with head trauma by intravenous diethazine—a phenothiazine compound with anticholinergic properties— Submitted for publication March 24, 1958. From the Department of Experimental Psy— chiatry, Hillside Hospital. Aided, in part, by Grant M-927 of the National Institute of Mental Health, National Institutes of Health, U. S. Public Health Service. Read (in part) at the meeting of the Eastern Association of Electroencephalographers, New York, December, 1957. Awarded A. E. Bennett Psychiatric Research Award of the Society of Biologic Psychiatry, May, 1958. 380 with minimal systemic effects. In our con— tinuing studies of the role of delta activity in electroshock,3 the effect of diethazine: was studied. It is the purpose of this report to describe the effects of diethazine on EEG patterns and on behavior of patients during electroconvulsive therapy, and to relate these observations to the present neurophysiologic— adaptive hypothesis of the mode of action of convulsive therapy. Subjects and Methods Forty psychiatric patients, at various stages of electroshock therapy in an open-ward, voluntary psychiatric hospital were studied. All observations were made in acute experiments in the EEG lab— oratory. After a routine EEG recording, diemhazine was administered intravenously at the rate of 25 mg. per minute, for a total of 175 to 250 mg, depending upon the behavioral effect. The dosage varied from 2.8 to 4.0 mg. per kilogram of body weight. Diethazine is a soluble phenothiazine compound with pharmacologic properties similar to those of atropine. In experimental animals, diethazine blocks the bradycardia, bronchospasm, salivation, fasciculatio-n, and seizures induced by acetylcholine, ﬂuorophosphate, and pilocarpine. It suppresses salivation and induces mydr‘iasis and hypotension.11 EEG Analyses.~—Recording was continuous for the duration of the observation period, except dur— ing interview periods. Needle electrodes, and an eight—channel Medcraft instrument were used. All records. were analyzed for the degree of delta activity,3 the per cent time and principal alpha frequency, and the relative amount of fast activity. The alpha and delta activities. were measured in anterior temporal—vertex, parietal-ear lobe, and frontal-occipital lead combinations. Behavior Mensures—Prior to drug administra— tion an unstructured psychiatric historical interview and a structured questionnaire period” were tape-recorded. Following drug administration, �EFFECT OF ANTICHOLINERGIC AGENT ON EEG periods of recorded interview were alternated with EEG recording periods, until the EEG had again manifested the preinjection pattern on. visual inspection. Two estimates of behavioral effects were used: clinical descriptions by the participants—subject, interviewer, and technician—of the changes oc— curring during the drug period, and language analyses of the recorded interviews. Changes in 1“ evaluated by a syntactic analysis language were and an analysis of the variability in verbal interaction in the dyad?"14 * Both measures have been shown to be sensitive to alterations in behavior induced by changes in the central nervous system. W W W W WW W WW AFTER I50 mg. PRE-DRUG LF-LO RF.“ LAT‘LF RAT-RF LF-RF LPT-LO 0-0 RPT-RO WWW-MN WWW“ MWVVUWVV’WMWM 50va___ SEC. l Observations (a) C1inicwl.—Within two to ﬁve minutes of the start of the injection, subjects mani— fested spontaneous coughing followed by a dryness of the mouth and a thickness of speech. They reported a feeling of lassi— tude and a heaviness and weakness of the extremities, soon succeeded by increased restlessness and difﬁculty in maintaining eye— lid closure. Reports of visual and haptic illusory sen— sations, feelings of unreality and distance, and delusional thoughts about their illness, the setting of the test procedures, or our identity were voiced spontaneously by 18 subjects in the period between 15 and 60 minutes after drug administration. In three instances increasing agitation and panic led Detailed analyses of these observations will be reported separately by Dr. J. Jaffe and Dr. R. L. Kahn. * AFTER 225 mg. PRE-DRUGI 0-0 W {Wyn-— SEC. =0? IGQI HH 1 Fig. 1.—Effect of intravenous diethazine prior to electroshock in a man aged 27. Fin/e #1125 NH Fig. 2.——Effect of intravenous diethazine prior to electroshock in a woman aged 57. to a cessation of the recording. In two subjects withdrawal and negativism were the prominent behavioral response. Such patterns of behavior were transient and had disappeared in one and one~half to four hours in all subjects. (I?) EEG Potterns.——Alteration in. the EEG patterns was concurrent with the be— havioral effects. In all records, changes oc— curred during drug administration and were sustained, with gradual diminution and resti— tution of the preinjection patterns, in one to ﬁve hours. The initial response was a decrease in voltage and desynchronization of all frequencies. There was a decrease in prominence of prevailing rhythms. In patients without delta activity (preelectro— shock), desynchronization and voltage decrease were occasionally accompanied by low—voltage 5—7 cps activity, symmetric and prominent in frontal and anterior temporal leads (Figs. 1 and 2). The alpha frequency was not altered. The build—up in voltage and appearance of slower frequencies with hyperventilation were blocked. In patients with varying degrees of high— voltage delta activity, desynchronization of the records became prominent, with a sig— niﬁcant decrease both in voltage and in per cent time of slow wave activity. From an average per cent time delta of 45% in frontal—occipital leads, there was a reduction to a mean of 20%. Both random and burst delta activity diminished or disap‘ 381 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY PRE-DRUG AFTER 250 mg. W W ”W W W W W WW W W WW WW W LAT-LF/W RAT WWWW‘ WWWW RPM/MW LF- +5HRS. +|.HR WVJMWWVV' LPT'LQ’W’W‘VWW 0 ° ”WNW RPT—RW WMw/V *1249 SOpv [TEE—C HH Fig. 3.—Effect of intravenous diethazine on delta activity after electroshock. peared, and irregular low—voltage alpha and beta frequencies became prominent (Figs. 3 and 4). The hyperventilation response was no longer apparent. (c) Language Patterns.——In previous studies, an intimate relationship between changes in syntactic language patterns and the behavioral response in electroshock had been reported.” With alteration in brain function, increased use of the third person, verbal denial, qualiﬁcation, displacement, and cliches became prominent. These: ef— fects could be enhanced by the administra— tion of intravenous amobarbital.15 In the subjects in the present study, syntactic analyses demonstrated a reversal of the patterns noted in electroshock. Use of the third person, qualiﬁcation, and dis— placement decreased. Explicit verbal denial was modiﬁed and replaced by minimization and displacement, or by a reiteration of complaints of illness. In dyadic analyses, the verbal interaction was characterized by a greater diversity of vocabulary and less variability in the diversity scores for 25 word units. The qualitative nature of these changes in the language patterns is opposite that of amobarbuital and electroshock. The duration of language changes was concurrent with the changes in the electroencephalogram. Comment These observations conﬁrm the report of Jenkner and Lechner of the effects of di— ethazine in “normal” subjects.10 Diethazine also alters electroshock—induced delta activity in a fashion similar to atropine and scopolamine, as described by Ulett and Johnson,9 with minimal unpleasant symptoms. The effects of intravenous diethazine are immediate, both on the EEG and on W W “MW MN “$wa W W WM W W W W “”wa PRE-DRUG + 200 mg. +25 min. + 70min. LF-LO Rm MWWW st UT'LWMW ”NM-«MW WVMW“ LF-RF LPT~LO °'° WWW WWW/“M 5°}‘VL._. ISEC. WWW/WWW #l637 HH Fig. 4.—Effect of intravenous diethazine on delta activity after electroshock. 382 Vol. 80, Sept, 1958 �EFFECT OF ANTICHOLINERGIC AGENT ON EEG behavior, and thus provide a useful experi— mental agent With “anticholinergic” proper— ties. Two aspects of these experimental observations warrant discussion: the role of acetylcholine-cholinest‘erase- in the electroconvulsive therapy process, and the signiﬁ— cance of diethazine “alerting” for concepts of hallucinogenic activity. 1. Biochemical Basis of the Convulsive Therapy Process.——While there has been considerable study of the psychologic and neurophysiologic aspects of convulsive therbiochemi— information little concerning apy, cal processes is available. The studies of biochemical changes following head trauma and spontaneous seizures provide some analogic data. Bornstein,‘6 in a classical experi— mental study of head trauma in cats, demonstrated that within a few minutes after trauma free acetylcholine appeared in the spinal ﬂuid and persisted for periods up to 48 hours. He further demonstrated a posi— tive relation between the severity of head trauma and the quantity of free acetylcholine, the degree of electroencephalo— graphic alteration, and the severity of the behavioral changes. The electroencephalographic records initially showed short peri— ods of high—voltage fast activity, and a transient period of ﬂattening of electrical activity, followed by prolonged periods of high—amplitude sharp waves in the delta frequencies. Concomitantly, alteration in consciousness, changes in reﬂexes, and post— traumatic seizures were most prominent with highest concentrations of free acetylcholine and greatest degree of EEG change. 7 Tower and McEachern conﬁrmed these observations in clinical studies in man. In 112 neurologic patients, free acetylcholine was found in the cerebrospinal ﬂuid only in patients following head trauma and re— cent grand mal seizures, and the level of free acetylcholine varied directly with the degree of cerebral damage. In addition, these authors assayed the cholinesterase activity of the spinal ﬂuid.7’1‘6 In patients following head trauma, they noted a sharp rise in. nonspeciﬁc cholinesterase (benzoylcholine— Fink splitting) and a drop in the speciﬁc cholin— esterase (methacholine—splitting) activity of the spinal ﬂuid. No such inversion was noted in ﬂuids containing free acetylcholine following spontaneous seizures. Electroen— cephalograms were taken at varying inter— vals following trauma and demonstrated a direct correlation of the extent of EEG abnormality with the appearance of free acetylcholine in the spinal ﬂuid. Tower and McEachern also reported ob— servations in six patients receiving electro— convulsive therapy. In patients after three to seven induced convulsions, they noted free acetylcholine in the spinal ﬂuid in two pa— tients and an increase in nonspeciﬁc cholinesterase with reversal of the cholinesterase ratio in ﬁve of the six. They concluded that the spinal ﬂuid changes in electroshock are more like those of craniocerebral trauma than those found in epilepsyj' More re17 Sachs conﬁrmed the reports of cently, free acetylcholine in the spinal ﬂuid after head trauma and after electroshock. In his studies, Bornstein6 administered 0.5—1.0 mg/kg. of atropine and demonstrated a reversal or a blocking of the EEG effects and a modiﬁcation of the behavioral and neurologic signs. Atropine also blocked the EEG and clinical signs induced by intra— cisternal acetylcholine. Ward8 applied these observations to the treatment of human subjects with varying degrees of head trauma. Subcutaneous doses of 0.1 mg/kg. of atropine induced both clinical improvement and reversal of EEG effects. These observations were recently conﬁrmed by Sachs,17 Ruge,18 and Hughes}9 On the basis of these observations, Ulett and Johnson 9 noted the effect of atropine and scopolamine in blocking the EEG changes of electroshock therapy. Con— 10 currently, ]enkner and Lechner reported ' Regarding the one patient of the six who failed to show either free acetylcholine or a re— versal of the cholinesterase ratio, they noted: “It is interesting that this patient was the only one of the six to show no response to treatment.” 1‘ 383 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY effects similar to those of Ward, in studies provides an excellent experimental method for studies of craniocerebral trauma. of diethazine in cases of head injury. Studies of the brain—stem—activating sys— Another group of investigations complete the available data. Studies of anticholines— tem by Jasper and Droogleever-Fortuyn 28 terases, such as fluorophosphate, and tetra— and Lindsley et al.2‘9 had laid the founda— ethylpyrophosphate (TEPP), which block tion for the prevailing conclusion that sym— the enzymatic breakdown of acetylcholine, metric EEG slow—wave activity has its demonstrate the development of high-ampli— origin in mesencephalic structures, and that tude rapid—frequency EEG patterns similar these structures intimately affect the states to those of status epilepticus, as well as of “alerting” and “drowsiness.” More reslighter degrees of abnormality, as noted in cently, Rinaldi and Hivaich 30"” have re— post—traumatic states.”23 In these studies, lated the site of action. of atropine and atropine blocked both the electroencephalo— cholinergic drugs to this mesodiencephalic activating system. It is also probable that graphic and the clinicaltoxic effects. these be structures may selectively affected clinical and both from experimental Thus, studies of craniocerebral trauma we may by the convulsive therapy process, and that both ef— clinical the and the of electrographic the that acetylcholine activity (a) assume the spinal ﬂuid increases, ([9) pseudo- fects may be intimately related to changes in cholinesterase activity increases, with a re— this system. 2. Diethazine “Alerting” and Hallucinoversal of the ratio of cholinesterases, (c) EEG hypersynchrony and slowing parallel gem'c Activity—The behavioral effects of these biochemical alterations, and (d) anti— diethazine provide information. regarding cholinergic agents may block both the elec— another aspect of the convulsive therapy troencephalographic and the clinical effects. process. In patients Without prior convul— From the data available, it is probable that sive therapy, illusory phenomena and feelthe biochemical basis of convulsive therapy ings of unreality were observed. These is similar to that of craniocerebral trauma. were similar to the hallucinogenic effects of Convulsive therapy results in free acetylcho— lysergic acid diethylamide (LSD32) and line in the spinal ﬂuid 7'17 and a reversal of mescalinef“3 Again, analogic data about the clinical and EEG effects of these agents cholinesterase ratios.”6 The electroencepha— information provide about some con— may induced effects of con— repeated lographic vulsive therapy. is the development of high—voltage, vulsions 34 noted In studies of Wikler mescaline, symmetric, slow—wave activity, occasionally that the EEG demonstrated no change, or is which similar to with spike: activity,3"24’25 intermittent continuous low—voltage fast or trauma..2627 that observed in severe head increase in activity, or alpha frequency. In previous studies we have reported the Denber and Merlis 3'5 noted a similar accel— relationship between the degree of induced eration of decrease in per alpha frequency, slow—wave activity and behavioral response.3 cent time alpha, including its disappearance, The studies reported here and, the work of and random beta nonspeciﬁc activity. Delta 9 Ulett and Johnson demonstrate a reversal activity did not occur. In patients with of the EEG and the behavioral effects of delta activity induced by electroshock, Mer— convulsive therapy by anticholiner‘gic com— lis and Hunter 38 noted that intravenous pounds. In. each characteristic, convulsive mescaline markedly diminished the ampli— therapy is thus similar to- cerebral trauma. tude and per cent time delta activity with While the acetylcholine—cholinesterase sys— an increase in per cent time alpha. activity. tem is highlighted by these studies, other The effects of LSD on EEG are similar. enzyme systems may also be altered.17 These Gastaut et al.3‘6 noted an acceleration of studies also suggest that convulsive therapy alpha frequency of 0.5 to 4.0 cps, with an 384 Vol. 80, Sept, 1958 �EFFECT OF ANTICHOLINERGIC AGENT ON EEG accentuation of beta rhythms. Rinkel et al.3‘7 conﬁrmed this observation and noted, in addition, a reduced responsivity to hyper— ventilation: In summarizing his studies, Wikler 34 concluded that “regardless of the . . drug administered, shifts on. the pattern of elec— troencephalogram in the direction of de— . synchronization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness.” This generalization. provides a meaningful construct in, which these agents may be assessed. Agents that evoke EEG desynchronization tend to be hallucinogenic, and mescaline and LSD are clear examples. Agents that synchronize frequencies, such as barbiturate and meprobamate in the beta frequency range, and chlorpromazine, pro— mazine, and perphenazine in the delta fre— 39 tend to be sedatives, quency range euphoriants, and relaxants. The observations on diethazine reported here are consistent with this hypothesis. In patients without delta activity, the EEG demonstrated desynchronization of f requen— cies, and this was associated with clinical illusory phenomena. In patients with delta activity desynchronization occurred, and alerting and reversal of the speech patterns induced by electroshock were observed. Electroconvulsive therapy may also be understood in this framework. We have previously noted a direct relationship be— tween Clinical evaluations of improvement and the degree of EEG slowing induced by electroshock.3 Under these conditions, seda— tion and euphoria are most prominent, and hallucinatory activity diminished. In, pa— tients in whom hypersynchrony is not in— of iStudies are now in progress on the effects LSD, Win—2299 (2~diethylarminoethy1-cyclo— pentylhydroxy—Z-thienylacetate), benactyzine, and other anticholinergic compounds on postconvulsive EEG delta activity. Initial experiments with these compounds have demonstrated marked diminution in per cent time and amplitude of delta activity associated with behavioral changes similar to those seen with diethazine. Fin/a duced, behavioral change is limited, and “improvement” does not occur.4 Previously we have concluded that the mode of action of convulsive therapies is based on the induction of a state: of altered cerebral function, in which changes in adap— tive interpersonal behavior occur, and are interpreted as “improvement.” 3'4'39 The present studies amplify two aspects of this neurophysiologic-adaptive hypothesis. The biochemical substrate of the behavioral change is reﬂected by an alteration in the acetylcholine—cholinesterase relationships of the central nervous system. It is also prob— able that EEG hypersynchrony provides the neur‘ophysiologic basis of the milieu change, which is clinically manifest as sedation and euphoria and is evaluated as “improvement.” The neurophysiologic-adaptive hypothesis of convulsive therapy has provided a meaningful basis for studies of other physiody— namic therapies.39 In this study, it has. been possible to amplify our understanding of neurophysiologic aspects of hallucinogens as well. Summary and Conclusions The: effect of an anticholinergic agent, diethazine, on the EEG, behavior, and lan— guage patterns was observed in 40 psychiat— ric patients, at various stages in the course of electroconvulsive treatment. (0) Behavior: Increased restlessness and agitation, haptic and visual illusory sensa— tions, and delusional thoughts about their illness or the examiner’s identity were ob— served. (b) EEG: Alteration in EEG were con— current with behavioral changes. There were a decrease in voltage and desynchroni— zation of all frequencies. In patients with delta activity, the per cent time and voltage of delta activity decreased. (c) Language: Syntactic patterns de— scribed for convulsive therapy were re— versed. Use of third person, qualiﬁcation, and displacement decreased. In dyadic analyses there was a decrease in the coefﬁ— cient of variation. 385 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY These observations are discusSed in the framework of the neurophysiologic—adap— tive hypothesis of the action of convulsive therapy, and it is concluded that (at) the biochemical basis for convulsive therapy is similar to that of craniocerebral trauma; (1)) changes in acetylcholine-—cholinesterase metabolism are intimately related to the be— havioral effects, and (c) EEG desynchroni— zation may be a physiologic concomitant of hallucinogenic activity, and EEG hyper— synchrony, associated with euphoria and sedation. Mrs. Hannah Mosquera gave technical assistance in the EEG recordings, and Dr. Joseph Jaffe and Dr. Robert L. Kahn made the analyses of the tape recordings. Diethazine was made available through the courtesy of Smith, Kline & French Laboratories, Philadelphia. Hillside Hospital, 75—59 263d St. REFERENCES Weinstein, E. A., and Kahn, R. L.: Denial of Illness: Symbolic and Physiological Aspects, Springﬁeld, 111., Charles C Thomas, Publisher, 1. 1955. 2. Roth, M.; Kay, D. W. K.; Shaw, J., and Green, J.: Prognosis and Pentothal Induced Elec— troencephalographic Changes in Electroconvulsive Treatment, Electroencephalog. & Clin. Neuro— physiol. 9:225—237, 1957. 3. Fink, M., and Kahn, R. L.: Relation of Electroencephalographic Delta Activity to Be— havioral Response in Electroshock, A. M. A. Arch. Neurol. & Psychiat. 78:516—525, 1957. 4. Fink, M.; Green, M. A., and Kahn R. L.: Experimental Studies of the Electroshock Process, Dis. Nerv. System, 19:113—118, 1958. 5. Ulett, G. 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M.: Effect of Trimethadione (Tridone) and Other Drugs on Convulsions Caused by Di—Isopropyl Fluorophosphate (DFP), Am. J. Psychiat. 106:816—820, 1950. 24. Callaway, E.: Slow Wave Phenomena in Intensive Electroshock, Electroencephalog. & Clin. Neurophysiol. 2:157-162, 1950. Vol. 80, Sept, 1958 �EFFECT OF ANTICHOLINERGIC AGENT ON EEG M.: Signiﬁcance of Individual Variability in EEG Response to Electroshock, J. Hillside 25. Green, Hosp. 6:229-240, 1957. 26. Jasper, H. H.; Kershman, J., and Elvidge, A.: Electroencephalographic Studies of Injury to the Head, Arch. Neurol. & Psychiat. 44:328-348, 1940. 27. Strauss, H.; Ostow, M., and Greenstein, L.: Diagnostic Electroencephalography, New York, Grune & Stratton, Inc, 1952. 28. Jasper, H. H., and Droogleever—Fortuyn, J.: Experimental Studies on the Functional Anatomy of Petit Mal Epilepsy, A. Res. Nerv. & Ment. Dis., Proc. 26 :272-298, 1947. 29. Lindsley, D. B.: Schreiner, L. H.; Knowles, W. B., and Magoun, H. W.: Behavioral and EEG Changes Following Chronic Brain Stem Lesion in the Cat, Electroencephalog. & Clin. Neurophysiol. 2 :483-498, 1950. 30. Rinaldi, F., and Himwich, H. H.: Alerting Responses and Actions of Atropine and Cholinergic Drugs, A. M. A. Arch. Neurol. & Psychiat. 73 :387395, 1953. 31. Himwich, H., and Rinaldi, F.: Effect of Drugs on Reticular System, in Brain Mechanism and Drug Action, edited by W. S. Fields, Springﬁeld, Ill., Charles C Thomas, Publisher, 1957. Fink 32. Stoll, 'W. A.: Lysergsaure—Diathylamid, ein Phantastikum aus der Mutterkorngruppe, Schweiz. Arch. Neurol. u. Psychiat. 60:279—323, 1947. 33. Beringer, K.: Der Meskalinrausch, Seine Geschichte und Berlin, Erscheinungsweise, Springer—Verlag, 1927. 34. Wikler, A.: Clinical and Electroencephalographic Studies on the Effects of Mescaline, N— Allylnormorphine and Morphine in Man, J. Nerv. & Ment. Dis. 120:157—175, 1954. 35. D‘enber, H., and Merlis, S.: Studies on Mescaline: I. Action in Schizophrenic Patients, Psychiat. Quart. 29:421-429, 1955. 36. Gastaut, H.; Ferrer, S., and Castells, C.: Action de la diéthylamide de l’acide d—lysergique (LSD 25) sur les fonctions psychiques et l’électroencéplhalogramme, Conﬁnia neurol. 13:102— 120, 1953. 37. Rinkel, M.; DeShon, H. J.; Hyde, R. W., and Solomon, H. C.: Experimental Schizophrenialike Symptoms, Am. J. Psychiat. 108:572—578, 1953. 38. Merlis, S., and Hunter, W.: Studies on Merscaline: II. Electro—Encephalogram in Schizophr‘enics, Psychiat. Quart. 29:430—432, 1955. 39. Fink, M.: A Uniﬁed Theory of the Action of Physiodynamic Therapies, J. Hillside Hosp. 6: 197—206, 1957. 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I; 5' 47.5'rﬁ Bulaefﬂuq J’ a 352.6% 9 / g 5/ LSD r ﬂ'f/JXQIWLJ “,3 j in U 9'5. . A m, 4., « 20.3”]; 2.2.00; 4.474 As“. (1 ��Effect of Anticholinergic Compounds on Post Convulsive EEG and Behavior In 1956 Ulett and Johnson (1) reported to this society that large doses of atropine or scopolamine blocked the appearance of the high voltage delta activity usually induced by convulsive therapy. They also noted that the dose of atropine necessary to affect the EEG-was such as to be associated with unpleasant systemic effects. The reports describing diethazine as an anticholinergic by Jenkner and Lechner (2) compound with potent neurologic but minimal systemic effects led us to undertake studies similar to those of Ulett and Jehnson; and these observations, in turn led to an investigation of other similar agents. clinical and EEG It is correlations the purpose of this report to describe the on the intravenous administration of various hallucinogens and anticholinergic agents in psychiatric patients it various stages of convulsive therapy; and to relate these observations to the recently expressed neurophysiologic-adaptive hypothesis of the mode of action of convulsive therapy and of hallucinogens. Subject and Mathod: Our subjects were consecutive referrals for convulsive therapy in an open ward voluntary psychiatric hospital. Patients have various stages of therapy, with observations being in the 17 EEG laboratory. Following a standard leads using needle electrodes, the intravenously at a made been studied in acute experiments 8 channel EEG compound under at recording from study was administered set rate per minute, until clinical behavioral or �electrographic changes diethazine, were observed. Win 2299*, LSD-25, benactyzine, Diethazine was administered at 25 mgm;'Win-2299 and benactyzine at 10 gamma per minute per minute for 1.2-3.6 mgm. at 0.5 for 50-150 studied The compounds JB—318* and JB-336.* per minute, for a mgm gamma; have been total per minute for 2-5 of 175-250 mgm; LSD-25 and JB~318 and JB-336 at 0.h mgm mgm. Observations: the administration of diethazine, in 15 patients prior to convulsive therapy, there was a decrease in voltage and a desynchronization of all On frequencies. Prevailing rhythmic patterns some instances, symmetric prominent in the was not hy frontal altered, but the became low voltage 6-? cps and less prominent. In activity appeared, most anterior temporal leads. in voltage build—up The alpha frequency and slower frequencies induced hyperventilation was blocked (Fig. 1, 2). In 17 patients during convulsive therapy, with varying degrees of induced high voltage delta activity, there was a significant decrease both in voltage and in per cent time of slow wave activity. From an average per cent time delta of h5% in the fronto-occipital leads, there was a reduction to a mean of 20%. Both random and burst delta activity diminished voltage alpha and beta frequencies became prominent. response was no longer apparent. hyperventilation electrographic effects persisted for is 2-diethy1aminoethyl cyclopentyl (2-thienyl) ggycolateg is n-ethyl-B-piperidylbenzilateg JB-336 is memethyl-3-piperidy1benzilate. ”'Win-2299 JB-313 These The and low �one to five hours (Fig. 3, h). Concurrent with these Patients changes. EEG became more effects, we observed irritable and distinctive behavioral restless and complained of sensations of unreality with dysesthesias of the extremities. Visual illusory phenomena and delusional thoughts about their illness, the setting of the test procedure or the examiner's identity were described. Their language patterns were characteristically altered in a fashion opposite to that previously described for amobarbital (3), so that verbal denial, minimization, cliches, third person mode and past tense became less prominent. The These changes were concurrent with maximum electrographic change. behavioral observations with diethazine led to a review of the effects of hallucinogens on EEG activity. In 1955 Denber and Merlis (h) had reported that mescaline altered EEG delta activity induced by electroshock, in a fashion similar to diethazine. They described a marked reduction in amplitude and per cent time of high voltage symmetric slow wave bursts with an increase in alpha per cent time and in low voltage, random leW'wave activity. Reports by fennes (5) that an experimental compound, Win-2299 manifested both potent anticholinergic activity and induced hallucinations in to our study of this compound. The effects were (Fig. 5). led similar to that observed in the diethazine group. In patients pre-convulsive therapy, desynchronization and decrease in voltages of man all frequencies EEG were induced In eleven patients with high voltage delta activity there was a decrease in amplitude and per cent time of slow wave activity with an increase in alpha and beta frequencies. activity dropped from 50% to 23% The mean per cent time delta in these subjects. Associated with these �-helectrographic effects and hallucinatory and clinical patterns of restlessness, excitement, illusory activity (Fig. 6). As the hallucinogenic were activity of LSD-25 was well established, these studies were next repeated with this compound. Here, too, the behavioral and electroencephalogrgphic effects, was a administration, on intravenous were similar to diethazine. There difference in the time constant in that the behavioral effects occurred 1% to 2 after hours drug administration, but the electrographic changes were concurrent with the behavioral change. While there was desynchronization with Mean LSD, less the delta activity was significantly repressed. fell per cent time delta activity in five subjects from h7% to 16% (Fie- 7, 8, 9). Recalling reports that benactyzine, a potent anticholinergic compound, induced EEG desynchronization next administered this we compound intravenously in eleven subjects, and again observed similar clinical and electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, desynchronization was prompt. Delta activity decreased from a subjects (Fig. 10, ll).’ clinical restlessness same per cent time of electrographic patterns 39% to 17% we in 8 were accompanied by and excitement. While we did not observe hallucinatory activity, in the These mean illusory or did note that the language patterns were altered fashion as with the other agents tested. Lately, following reports by Abood (6) that various piperidylbenzilates had potent anticholinergic properties and induced activity, we patterns were tested two of these, clinical hallucinogenic JB~318 and JB-336. identical to those of Win-2299 and The electrographic in each instance in which desynchronization was observed, clinical restlessness and hallucinatory �~5- activity for l to (Fig. 12, 13). was noted 3 The hallucinatory activity persisted hours, and during this period, electrcgraphic alteration was prominent. Thus, six compounds have been shown to have similar electrographic and behavioral effects. Each has definitive anticholinergic activity. Each induces hallucinogenic or excitatory activity; and these behavioral changes are accompanied by desynchronizaticn. compounds have a vamine EEG Furthermore, these similar chemical structure (Fig. 1h). The tertiary in a substituted diethylaminethanol is prominent, corroborating the recent reports by Denber (7) on the hallucinogenic activity of tertiary amines, and amplifying his studies by the common concurrent electrographic patterns. These observations amplify our understanding of the convulsive therapy process. In earlier studies high voltage slow wave activity we indicated that the development of was the neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical years, studies improvement (8). During the past ten by Bernstein, Tower and MeEachern, ward, Sachs, Bugs and others have noted similarities in the biochemical changes in convulsive therapy to craniocerebral trauma (9). They reported an elevation of free acetylcholine and pseudonholinesterase in the spinal fluid during convulsive therapy. In addition, topical administration of acetylcholine induces high voltage bursts uni spike activity. Ulett and Johnson emphasized the blocking of these cholinergic effects by the anticholinergic activity of atropine and scopolamine. The obsumvaticns on this report on �~6- diethazine, Win-2299, benactyzine and the piperidylbenzilates ISDbZS, support their observations. Each of these compounds has potent anticholinergic clinical behavioral and language effects areqpposite to those described for convulsive therapy. we may thus amplify the earlier conclusion that the neurophysiolegic basis for behavioral change in activity and the convulsive therapy by noting is that this the development of high.voltage slow wave EEG change activity reflects an alteration in the acetylcholine- cholinesterase relations of the nervous system, probably in the direction of increased cholinergic activity. These observations lend themselves to application in studies of craniocerebral trauma. .ward's (10) reports of the efficacy of high doses of atropine in altering the clinical manifestations of head trauma also indicated that effective doses brought with It would more them severe systemic be advisable to repeat these studies, neurologically specific anticholinergic utilizing such effects. more compounds as used potent, in these experiments. Finally, these observations, and our earlier reports significance of EEG on the delta activity in convulsive therapy, support the his report on mescaline, morphine with the comment that: "... regardless observation of Wikler (11) n-allylnormorphine and who concluded of the drug administered, shifts in the pattern of the electroencephalogram in the direction of desynchronization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness." This conclusion, supported by our observations, permit a more meaningful �.7- ._ generalization of the recently expressed neurophysiologicuadaptive twpothesis of the mode of action of somatic therapies in psychiatry. We may infer that agents that synchronize EEG in the beta frequency range frequencies, like barbiturate and and chlorpromazine, promazine and perphenazine in the delta frequency range, tend to while agents that evoke hallucinogenic, as EEG meprobamate be sedative, euphoriant and relaxant; desynchronization tend to be excitant and was noted for diethaaine, mescaline, and the piperidylbenzilates. LSD-25, Win-2299, benactyzine, �~8~ In summary, and the effects of various hallucinogenic we have observed anticholinergic compounds on the electroencephalogram and behavior in psychiatric patients at various stages of convulsive therapy. Behaviorally, these compounds induced increased restlessness, haptic and visual illusory sensations and delusional thoughts about the illness or the examiner's identity. The subject's syntactic language patterns described for convulsive therapy and barbiturate were reversed. Concurrent with these changes were a decrease in voltage and a desynchronization of all freQuencies in the In patients with high voltage delta EEG. activity, the per cent time and voltage of the delta activity were markedly decreased. These observations have been discussed common in the framework of the biochemical structure and anticholinergic properties of these agents with the conclusion that: (a) The biochemical basis for convulsive therapy and for>high alteration in the acetylcholinecholinesterase relation of the nervous system, probably in the direction voltage EEG delta activity may be an of increased cholinergic activity. (b) of the mode The recently expressed neurophysiologic-adaptive hypothesis of action of somatic therapies in psychiatry is amplified to encompass the action of hallucinogens. It is cholinergic more recommended compounds that further studies of the effects of anti- in creniocerebral trauma to neurologically specific Win-2299. compounds be undertaken, utilizing as diethazine, benactyzine and �REFERENCES 1. .2. Ulett, Effect of Atropine and Scopolamine Electroencephalographic Changes Induced by ElectroOlin. Neuro aio . 2; 217-22h, 1957. convulsive Therapy, G.A. and Jehnson,1MJﬂ.: Upon Jenkner, F.L. and Lechner, H.: wig; 19 3. 5. ,6. Effect of Diparcol on the . in Kahn, R.L. and Fink, M.: Changes Therapy, In Grune ,h. The Electroencephalogram in the Normal subject and in Those Cerebral Trauma, EEG Olin. ' NeuropQXSiol. I; 303-305, & EEZOhOEEthOlOEY Stratton, Denber, H. and marlis, N.Y. 19 8. 8.: Studies Language During Eleotroshook of Communication, pp. 126-139, on Nescaline I: Action in Schizophrenic Patients. Eﬁychiat. Quart., g2; h21-h29, 1955. Pennes, H. and Koch, P.: Paychotomimetics, Clinical and Theoretical Considerations, Amer. J. Psychiat. _1_1_;: 887-892, 1957. Abood, L.G., Catfield, A.M. and Biel, J.: A New Group of Psychotomimetic Agents, Proc. Soc. Exp. Biol. Mad. 21: h83‘h861 1958 o 7. Denber, H.C.B.: Drug-Induced States Resembling Naturally Occurring Paychosee, in ggzchotrogic DEEES: eds. Garattini, S. and .8. - , l9 7. Fink, M. and Kahn, R.L.: Relation of EEG Delta Activity to Behavioral Response in Electroehock: Quantitative Serial Studies, A.M.A, Arch. Neurol. & Psychiat. 1Q} 516-525, 1957. Ghetti, V., Elaevier, 9. Fink, M.: Effect of Anti-Cholinergio Agent, Diethazine, on EEG and Behavior: Significance for Theory of Convulsive Therapy, A.M.A. Arch. Neurol. a Psychiat. §Qr W88, 1958. 10. Ward, A.: Atropine in the ”heatinent of Closed 398.).‘02’ 1950. 7: Neurosurg., Head Injury, ,1. Clinical and Electaoencephalographic Studies on the Effects of Mescaline, Nealkylnormorphine and Morphine in ‘Wikler, A.: Man, J. Nerv. Ment. 1318., 120: 157.175, 195h. �Effect of Anti-Cholinergic Agent, Diethazine, on EEG and Behavior: Signiﬁcance for Theory of Omleive merepy Max From LOI.’ Fink, 14.1). the Department of Experimental Psychiatry, Hillside Hospital, NOYI Glen Oaks, in part, by grant M-927 of the National Institute of Mental Health, National Institutes of Health, U.S. Public Health Service. Aided, Read (in part) at the meeting of the Eastern Association of Electroenceplmlo- graphers, N.Y., December 1957. SBP: 3-58 �3-3-58 Effect of Anti-Cholinergic Agent, Diethazine, Significance for Theory on EEG-and Behavior: oi Convulsive Therapy Recent investigations of convulsive therapy have emphasized EEG delta activity as the neuroprxyaaoiogic basis for: the induced behavioral change (l,2,3,h,5). Little study, however, has been given to the biochemical effects of this therapy, except in the course of investigations of head injuries. In investigations of head trauma significance has been ascribed to in the acetylcholine-cholinesterase systems both for the behavioral and the electroencephalographic effects. An increase in free acetylcholine (6) and an alteration of the ratio of cholinesterases (7) in the spinal fluid have been positively correlated with the degree of EEG abnormality changes and degree of neurologic improvement deficit. in clinical status The EEG patterns were "blocked," and was reported following some the administration of atropine (7,8). In convulsive therapy, atropine and scopolamine were observed to block the appearance of delta activity, (9) although the effects of the large doses of these agents were marked. Recent reports (10) noted that EEG and behavioral effects similar to systemic atropine were achieved in patients with head trauma by intravenous diethazine a phenothiazine compound with anticholinergic properties - with minimal systemic effects. In our continuing studies of the role of delta activity in electroshock (3), the effect of diethazine was studied. It is the purpose of this report to describe the effects of diethazine on EEG patterns and on behavior of patients during electroconvulsive therapy; and to relate these observations to the present neurophysiologic-adaptive hypothesis of thexnode of action of convulsive therapy. �SUBJECTS AND METHODS: Forty psychiatric patients, at various stages of electroshock therapy in an open-ward, voluntary psychiatric hospital have been studied. All observations have been made in acute experiments in the EEG laboratory. Following a routine recording, diethazine was administered intravenously per minute, for a total of 175 to 250 mgm, depending the behavioral effect. Dosage varied from 2.8 to h.0 mgm per kilogram at the rate of upon EEG 25 mgm body weight. Diethazine is a soluble phenothiazine compound with pharmacologic properties similar to atropine. In experimental animals, diethazine blocks the bradycardia, bronchospasm, salivatim, fasciculation and seizures induced by acetylcholine, di-isopropyl fluorophosphate and pilocarpine. It suppresses salivation, and induces nwdriasis and hypotension (11). me An ses: Recording was continuous for the duration of the observation period, except during interview periods. Needle electrodes, and an Medcraft instnnnent were used. All records were analyzed delta activity (3) 5 the per cent time the relative amount of fast activity. measured in anterior temporal-vertex, and The and 8 channel for the degree of principal alpha frequency; and alpha and delta activity were parietal-ear lobe lead combinations. Behavior Measures: Prior to drug administration an unstructured psychiatric historical interview and a structured questionnaire period (12) were tape recorded. Following drug administration, periods of recorded interview were alternated �+3- with EEG recording periods, injection pattern on until the EEG had again manifested the pres visual inspection; No estimates sf behavioral effects were used: clinical descriptions by the participants - subject, interviewer and technician - of the changes occurring during the drug period, and language analyses of the recorded interevaluated by a syntactic analysis (12) views, Guanges in language were .* and an analysis of the variability in Verbal interaction in the dyad (13.11:) Both measures have been shown induced by changes in the to be sensitive to alterations in behavior central nervous system. * Detailed analyses of these observations Drs. J. Jaffe and R. L. Kahn. will be reported separately by I �OBSERVATIONS: (a) Clinical: Within two to five minutes of the start of the injection, subjects manifested spontaneous coughing followed by a dryness of the anzl a thickness of speech. They reported a feeling of lassitude, mouth and a heaviness and weakness of extremities which was soon succeeded by increased difﬁculty in mintan eyelid closure. Reports of visual and haptic illusory sensations, feelings of unreality distance, and delusional thoughts about their illness, the setting of restlessness and and test procedures or identity were voiced Spontaneously in eighteen subjects in the period between 15 and 60 minutes after drug aduinistration. the our In three instances, increasing agitation and panic led to a cessation of the recording. In two subjects withdrawal and negativism was the prominent behavioral response. Such patterns of behavior were transient and had disappeared in (b) EEG 1% - 14 all subjects. hours in Patterns: Alteration in the EEG patterns was concurrent with the behavioral effects. In all records, changes occurred during drug administration and were sustained, with gradual diminution and restitution of the pre-injection patterns, in one to five hours. The voltage and desynchronization of initial response was a decrease in all frequencies. praninence of prevailing rhytlms. There was a decrease in In patients without delta activity (pm-electroshock), desynchronization and voltage decrease was occasionally activity, symmetric and prominent in frontal and anterior temporal leads (Figure l, 2). The alpha frequency was not altered. accompanied by low voltage 5—7 cps �~5The build-up in voltage and appearance of slower frequencies with hyper- ventilation was blocked. In patients with varying degrees of high voltage delta activity there was a prominent decrease in voltage and desynchronization of the record. burst delta activity diminished or disappeared, and irregular voltage alpha and beta frequencies became prominent (Fig. 3, h). The Both random and low hyperventilation response was no longer apparent. (c) Language Patterns: In previous studies, an intimate relationship betwaen changes in syntactic language patterns and the behavioral response in electroshock had been reported (12). With alteration in brain function, increased use of third person, verbal denial, qualification, displacement and cliches became prominent. These effects could be enhanced by the admirﬁstration of intravenous anobarbital (1h) . In the subjects in the present study, syntactic analyses demonstrated a reversal of the patterns noted in electroshock. Use of third person, qualification and displacement decreased. Explicit verbal denial was modified and replaced by minimization and displacement, or by a complaints of illness. In dyadic analyses, the verbal characterized by a greater diversity of vocabulary and reiteration of interaction was less variability in the diversity scores for 25 word units. qualitative nature of these changes in the language patterns is opposite to that of amobarbital and electroshock. The duration of language changes was concurrent with the changes in the electroencephalogram. The �DISCUSSION: report of Jenkner and Lechner of the effects of diethazine in "normal" subjects (10). Diethazine also alters electroshock induced delta activity in a fashion similar to atropine and These observations confirm.the s cpolamine, as described by Ulett and Johnson (9), with minimal unpleasant symptoms. EEG The effects of intravenous diethszine are immediate, both and behavior, and thus provides a on the useful experimental agent with "anti- aspects of these experimental observations warrant discussion: the role of acetylcholine-cholinesterase in the electrocholinergic" properties. The convulsive therapy progress, and the significance of diethasine "alerting" for concepts of hallucinogenic activity. 1. Biochemical Basis of the Convulsive Therapy Process: While there has been considerable study of the psychologic neurophysiologic aSpects of convulsive therapy, biochemical processes is available. The little and information concerning studies of biochemical changes following head trauma and spontaneous seizures provide some analogic data. Bernstein (6), in a classical experimental study of head trauma in cats, demonstratadthat within a few minutes appeared in the Spinal fluid and after trauma, free acetylcholine persisted for periods up to h8 hours. He further demonstrated a positive relation between the severity of head trauma and the quantity of free acetylcholine, degree of electroencephalographic alteration and graphic records the severity of the behavioral changes. initially showed short periods The electroencephalo- of high voltage fast activity, transient period of flattening of electrical activity, followed by prolonged periods of high amplitude sharp waves in the delta frequencies. Concomitantly, a �.7 - alteration in consciousness, changes in reflexes and post-traumatic seizures were most prominent with highest concentrationsof free acetylcholine and greatest degree of EEG change. Tower and HbEachern (7) confirmed studies in man. In 112 neurologic these observations in clinical patients, free acetylcholine was found in the cerebrospinal fluid only in patients following head trauma grand mal seizures; and the level of free acetylcholine varied the degree of cerebral damage. and recent directly with In addition, these authors assayed the cholin- esterase activity of the spinal fluid, (7, 16). In patients following head trauma, they noted a sharp splitting) and a drop rise in non-specific cholinesterase (benzoylcholine- in the specific cholinesterase (mecholyl-splitting) activity of the spinal fluid. No such inversion was noted in fluids containing free acetylcholine following spontaneous seizures. Electroencephalograms were taken at varying intervals following correlation of the extent of EEG trauma, and demonstrated a direct abnormality and the appearance of free acetylcholine in the spinal fluid. Tower and MbEachern also reported observations in six patients receiving electroconvulsive therapy. In patients after 3-7 induced convulsions, they noted free acetylcholine in the spinal fluid in two, and an increase in non-specific cholinesterase with reversal of the cholinesterase ratio in five of the six. They concluded that the spinal fluid changes in electroshock are more like those of craniocerebral trauma than those found in epilepsy. * patient of the six who failed to show either free acetylcholine or a reversal of the cholinesterase ratio, they noted: "It is interesting that this patient was the only one of the six to Show no response to treatment." * Regarding the one �-8recently, Sachs (17) confirmed the reports of free acetylcholine in the spinal fluid after head trauma and after electroshock. In his studies, Bernstein (6) administered 0.5-1.0 mg/kg atropine More and demonstrated a reversal or a blocking of the EEG effects, and a modification of the behavioral and neurologic signs. Atropine also blocked the EEG and clinical signs induced by intracisternal acetylcholine. Ward (8) applied these observations with varying degrees of head trauma. atropine induced both clinical to the treatment of subjects human Subcutaneous doses of 0.1 mg/kg of improvement and reversal of EEG effects. recently confirmed by Sachs (1?), Huge (18) and these observations, Ulett and Johnson (9) noted the These observations were Hughes (19). Based on in blocking the Em changes of electroshock therapy, without noting the effect on clinical behavior. Concurrently, Jenkner and Lechner (10) reported effects similar to those of Ward, in effect of atropine and scopolamine studies of diethazine in cases of head injury. Another group of investigations complete the available of anticholinesterases, as DFP data. Studies (di-isopropyl fluorophosphate) and (tetraethyl-pyrophosphate), which block the enzymatic TEPP breakdown of acetyl- choline, demonstrate the development of high amplitude rapid frequency EEG patterns similar to status epilepticus as well as lesser degrees of abnormality as noted in post-traumatic states (20, 21, 22, 23). In these studies, atropine blocked both the electroencephalographic and the clinical toxic effects. Thus, both from experimental and trauma we may assume clinical studies of craniocerebral that (a) the acetylcholine activity of the Spinal �-9- fluid increases; (b) pseudo-cholinesterase activity increases with a reversal of the ratio of cholinesterases; (c) EEG hypersynchrony and slowing agents From parallel these biochemical alterations; may and (d) anticholinergic block both the electroencephalographic and the clinical effects. the data available convulsive therapy it is probable that the biochemical basis is similar to that of craniocerebral trauma. of Convulsive therapy results in free acetylcholine in the spinal fluid (7, 17) and a reversal of cholinesterase ratios (7, 16). The electroencephalographic effects of repeated induced convulsions is the development of high voltage, symmetric Slow wave activity, occasionally with spike activity (3, 2h, 25), which is similar to that previous studies we have observed in severe head trauma (26, 27). In reported the relationship between the degree of activity and behavioral response (3). The studies reported here and that of Ulett and Johnson (9) demonstrate a reversal of the EEG and the behavioral effects of convulsive therapy by anti- induced slow wave cholinergic compounds. In each characteristic, convulsive therapy is thus similar to cerebral trauma. While the acetyloholine-cholinesterase system studies, other enzyme systems may also be altered studies also suggest that convulsive therapy provides an is highlighted (17). These by these excellent experimental method for studies of craniocerebral trauma. Studies of the brain stem activating system by Jasper and DroogleverFortuyn (28) and Lindsley gt|§l. (29) had laid the foundation for the activity has its origin in mesencephalic structures, and that these structures intimately affect the states of "alerting" and "drowsiness." More recently, Rinaldi and prevailing conclusion that symmetric EEG slow'nave �-mrelated the site of action of atropine and cholinergic drugs to this mesodiencephalic activating system. It is also probable that Himwich (30, 31) have these structures may be selectively affected by the convulsive therapy process, and that both the clinical and electrographic effects may be intimately related to changes in this system. 2. Diethazine "Alerting The and Hallucinggenic Activity: behavioral effects of diethazine provide information regarding another aSpect of the convulsive therapy processt. prior convulsive therapy, illusory phenomena and In patients without feelings of unreality were observed. These were similar to the hallucinogenic effects of and mescaline (33). Again analogic data about the of these agents may provide some no change, (31;) noted that the intermittent or continuous increase in alpha frequency. (32) and EG effects information abmt convulsive therapy. In studies of mescaline, Wikler either clinical LSD low voltage EEG demonstrated fast activity or Denber and Merlis (35) noted a similar acceleration of alpha frequency, decrease in per cent time alpha including its disappearance, and non-specific random beta activity. Delta activity did not occur. In patients with delta activity induced by electroshock, Merlis and Hunter (38) noted that in travenous mescaline markedly diminished the amplitude and per cent time delta activity with an increase in per cent time alpha activity. similar. Gastaut gt g. (36) noted an acceleration of alpha frequency of 0.5 to h.0 cps with an accentuatim of beta rhythms. Rinkel 33 al. (37) confirmed this observation and noted, The effects of 151) on EEG are �4L1- in addition, a reduced responsivity to hyperventil‘aﬁon.* In smnmariaing his studies Wikler (3h) concluded that " . . . regardless of the drug administered, shifts in the pattern of electroencephalogram in the direction of desynchnonization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness.“ This generalization provides a meaningful construct may be assessed. Agents that hallucinogenic, and mascaline in which these agents evoke EEG desynchronization tend and 1813 to be are clear examples. Agents that synchronize frequencies, such as barbiturate and meprobamate in the beta frequency range, and chlorpromazine, promazine and pezﬁmaz‘mainthe delta frequency range (39) tend to be sedatives, euphoriants and relaxants. The observations on diethazine reported here are consistent with this hypothesis. In patients without delta activity, the EEG demonstrated desynchronization of frequencies, and this was associated with clinical illusory phenomena. In patients with delta activity desynchronisati.on occurred, and alerting and reversal of the speech patterns induced by electroshock were observed. Electroconvulsive therapy We ~31- have previously noted a Studies are now may also be understood in this framework. direct relationship between clinical evaluations in progress of the effects of LSD, Win-2299, benactyzine other anticholinergic compounds on post-convul sive EEG delta activity. Initial experiments w- ah intravenous LSD (SO-100 gamma) demonstrated marked dinﬁnution in per cent time and amplitude of delta activity. and �of improvement and the degree of Under these conditions, sedation EEG slowing induced by electroshock (3). and euphoria are most prominent and hallucinatory activity diminished. In patients in whom hypersynchrcny is not induced, behayicral change is limited and 'imprcvement' does not occur (hO) . Previously we have concluded therapies is based on the that the mode of action of conVulsive induction of a state of altered cerebral function, in which changes in adaptive interpersonal behavior occur, and are inter» preted as 'hmprovement' (3, h, 39). The present studies amplify two aspects of this neurcphysiologic—adaptive hypothesis. The biochemical substrate of the behavioral change is reflected by an alteration in the acetylchcline-cholinesterase relationships of the central.nervous system. It is also probable that EEG basis of the milieu change hypersynchrony provides the neurophysiologic which is clinically manifest as sedation and euphoria and is evaluated as 'imprcvement.‘ The neurophysiologic-adaptive hypothesis of convulsive therapy has provided a meaningful basis for studies of other physiodynamic therapies (39). In this study, it has been possible to amplify our understanding of neurophysiologic aspects of hallucinogens as well. �SUMMARY: effect of an anticholinergic agent, diethazine, on the behavior and language patterns was observed in to psychiatric patients, 1. EEG, The at various stages in the course of’electroconvulsive treatment. (a) Behavior: Increased restlessness and agitation, haptic and visual illusory sensations, and delusional thoughts about their illness or examiner's identity were observed. (b) pg: Alteration in There was a decrease EEG was concurrent with behavioral changes. in voltage and desynchronization of all frequencies. In patients with delta activity, the per cent time and voltage of delta activity decreased. (c) Language: Syntactic patterns described for convulsive of third person, qualification and displacement decreased. In dyadic analyses, there was a decrease in the coefficient therapy were reversed. Use of variatian. 2. These observations are discussed in the framework of the neuro- physiologic-adaptive hypothesis of the action of convulsive therapy; and it is concluded that: (a) the biochemical basis for convulsive therapy is similar to that of craniocerebral trauma; (b) changes in acetylcholine-cholinesterase metabolism are intimately related to the behavioral effects; (c) EEG desynchronization of hallucinogenic activity; and and sedatidn. EEG may be a and physiologic concomitant hypersynchrony associated with euphoria �.Ih~ REFERENCES 1. Weinstein, E. and Kahn, R.L.: Denial of Illness, C.C. Thomas, Springfield, 111., 1955. 2. Roth, M., Kay, D.W.K., Shaw, J. and Green, J.: Prognosis and Pentcthal Induced Electroencephalographic Changes in Electroconvulsive Treatment, EEG 225-237. 1957. Clin. Neurophysiol. 2: R.L.: Relation of Electroenecephalographic Delta Activity to Behavioral Response in Electromock, AMA. Arch. Neurol. and Psychiat. '_?_8_: 516-525, 1957. 3. Fink, h. Fink, M., Green, M.A. and Kahn, R.L.: Ehcperimental Studies of the (in press). Electroshock Process, Dis. Nerv. 5. Ulett, G.A., Smith, 6. Bornstein, M.: Presence and Action of Acetylcholine in Experimental 7. Tower, D.B. and McEachern, 13.: Acetylcholine and Neuronal 8. Ward, A. : Atropine 9. Ulett, M. and Kahn, st. K. and Glaser, 6.0.: Evaluation of Convulsive Shock Therapies Utilizing a Control Group, Subconvulsive and m. J. chhiat. 1.2-: 795‘802, 19560 Bra-in Jo Neurophym:01. 2.: 3:49.366, 19,460 Tram, Canad. J. Research, g1: 105-131, 19h9. in the Treatment of Closed Neurosurg., 1: 398-1102, 1950. Head Injury, Activity, ,1. Effect of Atropine and Scopolamine Induced by Electroconvulsive Upon Electroencephalographic Changes 1957. Therapy, EEG Clin. Neurophysiol. 2: 217-221;, G.A. and Johnson, M.W.: 10 . Jenkner, F.L. and Lechner, H.: The Effect of Diparcol on the Electroencephalogram in the Normal Subject and in Those with Cerebral Trauma, EEG Olin. 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Ruge, D.: The Use of Cholinergic Blocking Agents in the Treatment of Cranio-Cerebral Injuries, J. Neurosurg., 2.3;: 77-83, 1951;. 18. Cerebrospinal Fluids, Canad, J. Cholinesterases in Research, 21: 132-115, 19h9. Human 19. Hughes, B. : The Role of Acetylcholjne in Head Injury, his . _2_9_: p.70, 1957. Neurosur . and 20. Medman, 21. Grob, 1)., Harvey, A.M., Langworthy, 0.11. and J. Neurol. Bales, Pens, Willis, A. and HiRMiCh, HeEe: Ehrperimental Production of Electrical Major Convulsive Patterns, Am. J. @5101 a , 1146: 11.7.1211, 19,49 0 AoMo, Lilienthal, J.L.: The Administration of Di-Isopropyl Fluorophosphate (DFP) 257.266, 191,7. Man, Bull. J. H025. Hosp., to §_:_L_: 22. McCauley, A. and Hinmich, H.: Effects of Di-Isopropyl Fluorophosphate (DFP) on Electroencephalogram Hampson, J., Essig, C.F., andsoCholinesterase Activity, l9 . EEG Olin. Neuropgxsio . _2_: Bales, PUD. and Friednlan, A.M.: Effect of Trimethadione (Tridone) and Other Drugs on Convulsions Caused by Di-Isopropyl Fluorophosphate (DFP), Am. J. PSyChiat., 106: 816‘820, 1950. 23. Him-1°11, HQEQ, E55518, CeFe, Hampson, Jolie, 2h. Callaway, E.: Slow Wave Phenomena in Intensive Electroshock, Clin. Neurophysiol., a: 157-162, 1950. 25. Green, 26. ’41-'48, 3133. Significance of Individual Variability in EEG Response to Electroshock, J. Hillside Hosp., 9: 229-2ho, 1957. hic Jasper, H.H., Kershman, J. and Elvidge, A.: Electroencephalogra:£1; : Neurald: Arch. Psychiat. Head, the to of Studies , Injury M. : 328-3h8, 19h0. �W ~16- Ostow, M. and Greenstein, L.: Dia ostic Grune & Stratton, N.Y., 1935. Electro- 27. Strauss, H., 28. Jasper, H.H. and Drooglever-Fortuyn, J .: Experimental Studies on the Functional Anatomr of Petit Mal Epilepsy, Res. " " A.' Nerv. " Publ. 29. 30. Lindsley, D., Schreiner, L.I-I., Knowles, W.B. and Magoun, H.W.: Behavioral and EG Changes Following Chronic Brain Stem Lesion in the Cat, EEG Olin. Neuroplgsiol” _2_: h83-h98, 1950. of Rinaldi, F. and Himwich, H.H.: Alerting Responses and Actions and Atropine and Cholinergic Drugs, A.M.A. Arch. Neurol. ngchiatu 1;: 31. ' ' Ment. Dis. gg: 272-298, 191.7. 387-395, 1953. Himich, H. and Rinaldi, F.: The Effect of Drugs on Reticular System, in Brain Mechanism and Dru Action, 15-1114, C.C. Thomas, Springfield, 1937. aus der 32. dietmrlamid, ein Phantastikmn Stoll, W.: Lysergsaure - Schweiz Neurol. 33. Beringer, K.: Der Meskalinrausch Springer, Berlin, 1927. 35. Wikler, A.: Clinical and Electrencephalograwic Studies on the Effects of Mescaline, N—allylnormorphine and Morphine in Man, J. Nerv. mnto D180, 120: 157-175, 19%. Denber, H. and Merlis, 3.: Studies on Mescaline I: Action in Schizophrenic Patients, PsEhiat. Quart. , 2_9_: 1421-1429, 1955. Gastaut, H. , Ferrer, S. and Castello, 0.: Action de la diethylamide de l'acide d-lysergique (LSD 25) sur lee fonctions psychiques at l'electroencephalogranme, Conf. Neum1., 3;: 102-120, 1953. 36. Pslchiat. , Arch. Mutterkomgruppe, 1-h7, 19m. Monog. §_Q: Neural. Psychiat., 1-315, 37. Rinkel, M., DeShon, H.J., Hyde, R.W. and Solomon, H.C.: Experimental Schizophrenia-Like Symptoms, Am. J. Pszchiat" 108: 572-578, 1953. 38. Merlis, S. and Hunter, W.: Studies on Mescaline II: Electroencephalogram in schizophrenics, Psychiat. Quart., g2: 1.30-1.32, 1955. 39. Fink, M.: ho. Fink, A Unified Theory of the Action of mysiodynamic Therapies, J. Hillside M. Hosp. , é: 197-206, 1957. and Green, M.A.: Electroencephalographic Electroshock Process (in preparation). Correlates of the ��j: q-»-\’X mm or mumma manganese» w Panama“ m and Behavior 4" tho abmﬁm at W Fm;black-d the W mek, m mathem- diam!” induced «synchronization of ma fmquamisa and in ”mums. In ptﬁent! with dais: activity, voltage ﬂowed, nativity diuppeumd. muﬁms, m, amt mm mm function. ath an was amt alpha and beta and bdnvioral changes Wynn in mm“ therapy. the behavioral wager? airﬂow}: 11:01:16.6 mm o! the language patterns indicative psychotonmotio nativity nf 2299, um mm frame“: increased WV Mutton and withdrawal, immaod asthma, in maintaining eyelid closure, of 1115”“ and W muuhdmrgic comm, amine. tine of delta nativity and burnt. “W that «It: w’dﬂty .méucad by convulsiw mum, studies mm max-tutu: with a and Jamie»: 419mm led 1» may of Mme sum or cmlsive for ml: of mu W: In recordings of compounds 1:: tbs dons matreutmt, each MOW. m amt induced memmauon at can record with momma in beta “unity, mm, par-1103.06 mm md 1n fmuemy and per-cent time at alpha. m nativity, both the mug. and ppm meat. was “at Imam" mm, nativity. In ”cards with 01w was of thin: activity and ﬁlm alpha Wan}. Bombwnt of mm: W58 APR 2 :5: tummy immacd. (many: new concurrent with than ehctmgnphic manages, use both mm inhibited by Pram the mm, mtmm WW mummsim. Psychiatry, Hillside Kama, Cam Oaks, LL, NJ“. �nﬁa‘ m alumna” are Mar ta thwa of Dunbar a}. 3;. tor Winn. Wt Michalimmio prawn", and signiﬁcanaa structurally, each contain: 1 mm nitrogen linkage. Each of theme compounds have The 01’ than ﬁanrapy of amatima far the theazy of ﬁlm made of nation at convulsiw mama‘s. as will u tor the wommbmr and Wing $.13 1:311qu 1:111 b0 discusud. K �new cat Antichollnergle Game at mmmm me and Bob-71w * 3mm the observations 2: 217, 1957) by cumin ergie (W. ﬁle“ and Johnson um. atropine and 309130le blocked the delta wtiuty induced than”, dMlar studies were undemken with another madmanof diet-henna. Prenloe’oroehock, dietbuine induced demahrmiution tuuuaned.“ end a decrease/1n voltages. In peasants with delta. activity, compound, of ER; voltage md pennant time of delta emvity hemmed, frequencies increased and burst activity diuppeared. dam all” end beta . Concurrent behavioral mum, illusory maid ideetion and withdrawal, increased restlessness, difficulty in maintaining eyelid closure, and reversal of the language patterns «scouted with altered eerebml function after canvulsive changes included therapy (m amt. tholog 9; Gomniggtion, _ The Gram a: Sure/atom, pg. 126, 1958) psychotoulmtle aunt}; of diethuim led to the study at hear-ac and diethyhﬂde, Win 2299 and bemtysim in voluntary momma patients at venous stages of convulsive ﬁrm-aw. These antichaunerglo compounds were Metered intmenously in amounts! of 50-150 gm, 2 to S m and 1.5 m respectively, dung“ mder continuous and language mum-es mutmtmt, nah compound EEG mm. ‘For «ch compound the behavioral peremled those of diethuine. In ma meanings induced EEG demchmieeuon with an increase in beta activity and in the alpha fmqueney. In renews with slow wave activity, both the voltage and pop-neat time of this activity decreased, pement time feet rmuemlea manned, and the alpha frequency increased. Behavioral ahmgea mm concurrent with these ehctrographlc changes, and both were inhibited by intravenous uhlorpmmine. A it Fm: the 61.1}. m. Amos Mia/SB ﬂuent of Experimnbal Psychiatry, Hillside Hospital, .1. NW York. �«a. 3mm ahauntim for muslin. we boon reported by Dunbar. We and (W. W want]. the 33: m. 1955). of postoonvulain Em and bah-uric: pattoma by these potent “mallow «unwound: “was“ a naumphyuiologic but: for comma“ thorupy. Purim 39mm acted that. the clinical ropoma to manned comm m «peach; m the dmlemﬁt af Wain hiya voltnga aim: we nativity (W. my than be 19,: 516.. mmiaud with ma 1957). An 1mm in ahalinorgic nativity Wchrazv and clinical sedation and whom. SWy. a decrease in choumrgia activity may bu associated with EEG «syncing-am mum and 6111:1031 psychotmuc nativity. as therapy or the mad. or whim of amulaiu ”exam and tho mou- phyamlogic «ﬂoat: of mﬁebalmergic command- will be dismantled. �\\ "v Mint: of Ant-1011mm: W311: Minimums on Wm E39 and neopolmim blocked the dclta activity induced by convulsive therapy, studies are Wart-ken with moflar mama“ 0136th dinthuim «cram in voltages. induced compound, diothuine. m. «mm-m on of frequencioa and In putianta with delta activity, volﬁge and pen-mt m of delta nativity acct-cu», tramway immune and law“ activity disappears. Concurrent behavioral chanson: 11:01am imam and withdrawal, illusory sensations, paranoid incmaod ”ﬂatleusnass, difficulty in maintaining mud. of the ham patterns indicative of altered The apparent. hallucinogenic activity m to any of eyelid cio'sum, and «mm. ﬂirtation. various Wu inoluang The of hmetysim LSD. Win 2299, bohuvionl changes in the dam dawns. In m6 Hoarding intizm at the record with an employed were mutmhaant, «eh mousse in '58" parallel to those agent indmd «manom- an fmuemiu, max-cue in alpha Inquency, and alpha voltaga tad para-mt 601%: and masculine. tins. In records mm activity, both the valtagc md pox-«mt tins of delta. activity duel-sand, �duh 4..., par-43m tine fut {maintains Manama, Behavioral (changes were ugd both wm inhibited by and. alpha Inquancy increased. emmnt with than electramphie mung», intramm «human-um. 00de hm patent mticholimrgic properties a wall as n W tertiary W W... Wm“ or them absent»Each at then The um 29:: thus timery :5 of thg an“ a: nation or combs.” therapy in payments, all «a fur the mumphysialogy and pinmcology of hallumogana 61mm. 11.111 be �Effect of Anticholinergic * Compounds an Post—Convulsive EEG and Behavior Following the observations of Ulett and Johnson (EEG Clin. Neurophysiol. 2; 217, 1957) that atropine and scopolamine blocked the delta by convulsive therapy, similar studies were undertaken with ergic of compound, EEG activity induced snail-l anticholin- diethazine. Pre-electroShock, diethazine induced desynchronization frequencies and a decrease in voltages. In patients with delta activity, voltage and per-cent time of delta activity decreased, donﬁnant alpha and beta frequencies increased and burst activity disappeared. Concurrent behavioral illusory sensations, paranoid ideation and withdrawal, increased restlessness, difficulty in maintaining eyelid closure, and reversal of the language patterns associated with altered cerebral function after convulsive changes included therapy. The apparent psychotomimetic activity of diethazine led to the study of lysergicl;:dudiethylamide, benactyzine in voluntary psychiatric Win 2299 and patients at various stages of convulsive therapy. were administered intravenously mgm in reSpectively, under continuous These anticholinergic amounts of 50-150 gamma, EEG recording. 2 EEG 5 mgm and 1:5 For each compound the behavioral changes and language measures paralleled those of diethazine. pre—treatment, each compound induced to compounds In EEG recordings desynchronization with an increase in in the alpha frequency. In records with slow wave activity, both the voltage and per—cent time of this activity decreased, per~cent time fast frequencies increased, and the alpha frequency increased. Behavioral beta activity and changes were concurrent with these electrographic changes, and both were inhibited by intravenous chlorpromazine. % From the Department Glen Oaks, AEEG: L.I. u/3/58 New of Experimental Peychiatry, Hillside Hospital, York. ' . H.“ as... �a-2-n Similar observations for mscaline have been reported by Denber, Merlis and Hunter . w» “inhuman“. ﬁJ/A‘revious reportstzgoted that the clinical response to induced convulsions the development of extensive high voltage was dependent upon slow wave,activity.QAaH7k7~Aznh.aNauroi7v9SyChtat?"j§7"516?“t959}n The reversal of postconvulsive cholinergic compounds suggcrests and euphoria ’ WC ﬁes G The EEG and behavior “patterns thatEEmersynchrony by these potent and anti- [clinical sedation {increase in cholinergic acti@ desynchronization and clinical psvchotomimetic activity,ere 4:. decrease in cholinergic activl$291 5M7 Wild relation of these observations to studies of head trauma, and to the neurophysiologic-adaptive hypothesis of the convulsive therapy will be discussed. mode of action of �Effect of Anti cholingeric Compounds on Post Convulsive EEG and Behavior , In 1956 Ulett and Johnsgon repcrted to this society that large doses (jig of atropine erscopolamine blocked the appearance of high voltage delta ,. Its-their—smdyzhey noted 6? activity usually induced by convulsive therapy. that the dose! of atropine necessary to affect the W" ' with“ carried m unpleasant W5 mic ”We effects. ‘ ' Jenkner and Lechner M compound. It is m were these-sthet—else— Following. £23 reports by Modiethazine 4 a—peten-‘t (Mf‘iam facts aw cw. anticholinergic compound with minimal systemic 9 those of Ulett and Johnson EEG W. 1' Mi! W XMMA‘.‘ ”ﬁr/félcm studies to similar W Our observations with led to an investigation of other anticholinergic this. the purpose of this report to describe the clinical and EG correlations on intravenous A administration of LSD-25, Win-2299, benactyzine and diethazine . n Z; in pSychiatric patients at various stages of convulsive therapy; and relate and these observations to thekneurophysiolog'c-adapative hypothesis of the mode of action of convulsive therapy and of hallucinogens. Subject and Method: Our km subjects ass consecutive referrals for convulsive therapy in an open ward voluntary I psychiatric hospital. Patients have been studied at �.2— [ll observations mg: made in acute is? laborah'y. Following a standardﬁrecording from experimnts in the W 17 leads, the compound under study #8 administered intravenously at a W various stages of therapy, EEG 1-: rate per minute , until clinical behavioral or electrographic changes m I observed. The compounds studied have been diethazine, Win-2299, LSD-25 p and benactyzine . Fig. I- Diethazine was administered at Win-2299 and benactyzine mgm; 10 gamma Chemistry structure 25 mgn. per minute, at 0.5 per minute for 50-150 mgm for a total of 175-250 per mimte for 2—; men; and )5atI LSD gamna. Observations: ‘ low If; patients (Q Wm ' there decrease in voltage and a desynchronization of rhythmic patterns became less prominent. In all frequencies. Prevailing some voltage 6-7 cps activity appeared, most prominent temporal leads. m The alpha frequency was not 993 $9321; Wm was a instances, symmetric in low the frontal and anterior a; altered, and? the build-up an by hyperventilation was blocked, �-u-u— -- .— --- —-.— --—--- Fig. 2’ \‘V 93 \. W; Diethazine - EEG - g Pre-Cenvulsive Treatment vi; .........._.-- __ W , /7 “I at! 3 InApatients during convulsive therapy, with varying degrees ofﬂhigh ,5 (V significant decreaseA in voltage and in We}? ‘1‘! a W K%W W aways... Flusucu/ISlow per-cent time of delta activity. Both random and burst delta activity is voltage delta activity, there M a M 4 V - ~ I 0’3 diminished and low voltage alpha and beta frequencies The hyperventilation respoxaewas — no Fig. Diethazine --—---- .- EEG - Patients ’4, S Convulsive Treatment EEG effects, “wwwwww for irritable Mdysesthesias 1:3» and patterns were ‘ ,m to five hours. I Me dest-tive restless behavioral and complained of of the extremities. W. Visual illusory their illness, the setting of the test W1 46M! procedure; or the examiner's identity were MAM Myopposite one we observed phenomena and delusional thoughts about ‘ / #‘X became more sensations of unreality prominent. longer apparent. @hctrographic effects persisted changes. been .— Concurrent with these . l4» "— ' Their language L w to that previously described for amobarbital) 5 �- 80 W thatkdehial, minimization, cliches, third person were of 4:mode and less prominent. These behaVioral changes were pun-at. during the period 46W W W W W M maximum EG- chani gs. We: led to i. :qs's’ diethazine of other-imam hallucinogens Aru— m Denber and Merlis had W W mmdhﬁmmndm They WAWWM t-L similar to diethazine. «mt ﬁche-high voltage symmetric slow wave time and in w ”Mutant low voltage, ‘9” WW W wand M ”ma,”led to ‘x ’ril' ‘ ~ MWMJ MIM‘M? - MAM“? Fﬁfﬁw' W this compound. study ELIZA; —— 51/ bursts were-diminished WW activity. random slow wave //{/,{r_,,"" fa. etagrm with an increase in alpha per/cent ”.WMM @ports by Pennes and anticholinergic altered mescaline . it: EEG changes“induced by electroshock in a fashion The past tense M. ‘ x-Jyx'yﬂ effects were similar to that: in the diethazine group. Inpatients pres convulsive therapy, 4,.v‘. I EEG .4 ‘ '7 .“-' ’ ' , I desynchronizationéwas induced. Fig. Win 2299 - 6 Pm-Cpnvulsive Treatment .I‘.\ In patients with high voltage slow wave activity induced by convulsive therapy, �.5. P, . \B ‘2‘ 9 \C . there was of slow wave adecrease in amplitude and per-cent time " OLE, & WA. LC— "1L” . ”I , ‘ r '1‘.“ I activity ' with an increase in alpha and beta frequencies. AA‘ssociated with these electrographic effects were clinical patterns of restlessness, excitement, / _.__ , Win 2299 and hallucinatory and - Post Fig. 7 Convulsive Treatment We ﬁremeﬁkwawAﬂ illusory activity. . I, Th? studies yore7/"repeated with intravenous -' 4 LSD {if/(MW isWM inMcbwLW W MAL/”3‘ W. l /.I ( V W A’M/[F There m behavioral effects] W €265 a difference In the time constant bee—names In line/- M electrographio changes-.ﬂkhh 144. ’1» A—‘nﬁlvj 5—6796 mi there me less desynchronization 2-bit the delta activity WrepressedmMkw M “(p/7L “79% M7 miﬂlméw} __ (5‘; a I/L-v ‘ I, . Wﬁ‘ﬁ’Wxﬁi Mose-Al} Recalling the- reports that benactyzine induced l . “Mﬂx I)?“ ‘ EEG W '3 desy‘nchmnization 5 we / adninistered the- ccmpound intravenously: and again! observed similar clinical and is electrographic patterns. In the well modulated alpha record, desynchronization prcmpt. In the record with high voltage delta activity, desynchronization �~6- ' MWMKL Wdelta I790: V13. activity 3903+} __ Fig. 11,’ 12 Bemctyzine WWW These pattems were accompanied by While we did not observe - EEG clinical restlessness and excitement. illusory or hallucinatory activity, mguagew m and Mo diethazine, ‘éu-e ”,ij Cl w w IL: cc te-theé-r EEG M M M3 a: W desmchrmizWeWw, thﬁcue M compounds , an, Malt/71,) aaﬂwf/‘04 WM have In: W11 chemical structure W Jaw/554m these did note the Am to have similar electrographictand behavioral effects. minced I”) we Win-2299 and LSD. Thus, four compounds shown M awfﬁijfj d‘u a M M “by; have been {m W’MM 0’}; Ag,“ écfmmnmé’ é; 444-“ my 1“.” “In diethyl-anﬁno-ethyl organization. ' 7544.. (5y --------m-- ---~Repeat Fig __________________ WM”; WWWtK’L/océeuﬁﬂﬁnféawhhmva\ «a �. ' I I I These observations therapy process. In high voltage slow a; i Ii . site amplify our understanding of the convulsive earlier studies wave activity was . we indicated that the development of the neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement. During the past ten years, studies by Bornstein, Tower and McEachern, Ward, Sachs, Bugs and I“.— of convulsive therapy have noted similarities in the biochemical to craniocerebral trauma. acetylcholins They reported thatqguring convu Sl and pseudocholinesterase others erap free are-eiouated in the Spinal fluid. In addition, topical administration of acetyicholine induces high voltage burst and Spike activity. Ulstt and cholinergic effects ‘ The by the Johnson emphasized anticholinergic the blocking of these i::;::§§s;7:;ropine and 5v . . observation in this report on dietha21ne,‘Win-2299, support their observations. Each of these activity and the clinical behavioral 6 AldAbév‘ that the neurophvsiologic eerreiate compounds has and language thfse described for convulsive therapy. LSD-25 and thus scopolamine. benactyzine potent anticholinergic effects are apposite to we may/amplify the earlier conclusion behavioral changes in convulsive therapy �.5- is the development of high voltage slow wave activity, by this EEG tag—ion that reflects an alteration.in the acetylcholine-cholinesterase change "L”! J‘ relation of the basin, probably in the direction of increased cholinergic activity} [Tl' These observations lend themselves to application in studies of cranio- h9,41;r17§ cerebral trauma. The-repeat—ef Ward ll“ e clinical efficacy of high doses of atropine in altering the clinical manifestations of head trauma/also noted that effective doses brought with be advisable them severe peripheral effects. to repeat these studies, utilizing such neurologically Specific anticholinergic more potent, It would more compounds as Win-2299, diethazine or benactyzine. Finally, these observations, of EEG (l95h) and our earlier reports on the significance delta activity in convulsive therapy, support the observation of Wikler who concluded with the comment his report that: ".... on mascaline, n-allylnormorphine and morphine regardless of the drug administered, shifts in m the pattern.ofnelectroencephalogram.in the direction of desynchronization occurred in association with anxiety, hallucinations, fantasies, illusions or �tremors, and in the direction of synchronization with euphoria, relaxation M or drowsiness." This conclusion, supported by these observations, permit a more near meaningful generalization of the recently expressed neurophysiologic - adaptive hypothesis of the We may mode of action of somatic therapies in psychiatry. infer that agents that Synchronize frequencies, like barbiturate ”ﬂ . and meprobamate phenazine EEG in the in the be r ge and chlorpromazine , promazine and deltm; tend to be sedativel, while agents that evoke EEG euphoriant and relaxantl; desynchmnization tend to be excitant and halluc- inogenic, as was noted for diethazine, In smmnary, per- we have observed pf 161), Win- 2299, benactyzine and meccaline. the effects of various compounds as diethazine, ,x/ Win~2299, LSD, benactyzine and mescaline on the electroencephalogran and behavior? in psychiatric patients at various stages of convulsive therapy. Behaviorally, these compounds induced increased restlessness, haptic and visual illusory sensations and delusional thoughts about the subject's illness or the examiner' 5 identity. The syntactic language patterns described for Wham/C convulsive therapy were reversed. Concurrent with these changes were a decrease in voltage and a desynchronization of all frequencies in the EEG. In patients with high voltage delta activity, the per-cent time and voltage �.10.. of the delta activity were marhedly decreased. These observations have been discussed in the framework of the common biochemical structure - that of a substituted diethylanimoethanol thééIanticholinergic properties with the conclusion that: (a) The // - and £74kfzitiég‘ biochemical basis for convulsive therapy;may be an alteration in the acetylcholine-dholinesterase relation of the nyrvous system, probably in the direction of increased cholinergic (b) The (Z? encompass the activity. recently expressed neurophysiologic adaptive hypothesis of the mode of action of somatic therapies action of hallucinogens; studies of the effects of anticholinergic trauma be undertaken, utilizing more in psychiatry is amplified to t is recommended that further compounds in craniocerebral neurologically Specific as diethazine, benactyzine and Winr2299. lﬁfﬁg’ compounds �Effect of Antichelinergic Hallucinogen: on Post Convaleive EEG _and Behavior * tron the Department of Experimental Psychiatry, Hillside Hospital, GlQn OIkB, L010, 3.1. part, by grant H—927 and HI~2092 of the National Institute of Hental Health, National Institutes of Health, 0.8. Public Health Aided, in Service. Read at the v1: 1/59 ~ American EEG. EEG Society neeting, Atlantic City, June, 1958, �Effect of Anticholinergic Hellocinogens on Poet Convnleive EEG and Behavior In 1956 Ulett and Johnson ( ) reported that atropine and ecopolanino blocked the appearance of the high voltage delta activity usually induced by convulsive therapy. They that the dose of atropine necessary to affect the also noted EEG was each as to be associated with unpleasant systemic effects. Reports by Jenkner conponnd us 90 this J Leehner (r) describing diethaeine as an antioholinergic bet minimal eyatenic effects led vith potent neurologic endertake studies similar to those of Ulett and Johnson using compound ( )y and these observations, in turn, led to an investigation of other experiaental enticholinergic agents. is the purpose of this report to describe clinical and It electro~ encephalographic observations on the intravenous administration of various anticholinergic agents in psychiatric patients at various stages of convulsive therapy and to relate these obeervationa to hypotheses concerning the node of action of convulsive therapy and the physiology o: hallucinogens ( ). ( ) �-2SUBJECTS AND METHOD: Our subjects were consecutive referrals for convulsive therapy in an open ward voluntary psychiatric hospital. numbers of While varying subjects have been studied for each compound, Ages ranged from 18 in 10k eXperinents have been assayed. subjects 86 to 67 years, and diagnoses include schizophrenic reactions, manic-depressive and involutional depressive psychoses. Patients have been studied at various stages of the treatment process. observations were The laboratory. 1 standard 8 made channel EEG in acute experiments in the EEG recorder and needle electrodes applied in 17 lead placements following Strauss 22.2; ( ) were In each experiment, the compound under study was edninistered used. intravenously at a set rate per minute, until clinical behavioral or electrographic changes were observed. The compounds studied have been diethasine, Win-2299, benaetyaine, Each is a potent JB~318, JB-336, and atropine. anticholinergic agent in vitrc. Diethasine (diethylaaineethyl~n~dibensoparathiasine), for example, induces mydriesis and hypotension, suppresses salivatien and blocks the �-5. bradycardia, aalivation and soizuros cf acctylchcline and fluorophosphatc ). ( Win-2299 (2-diotylaminoothy1 cycloponty1—2-thieny1~ 1 (2-diethy1aninoathyl benzilato) are similar to atropine pcgﬂLt central offocts synthetic anticholinorgic agents/but with glycolatc) and minimal and benactyzino : peripheral effects ( , ). JBo318 and JB-336 (N~ethy1o3-piperidy1bensilate, H-nethyl~3-piperidy1bonsilato) , . are two at a rccant series or synthetic anticholinergic 33:3: coupounda of high ( ). Diathazino total or minute central potency was 2 to 5 hallucinogenic activity adminiatcrod at 25 ngn. per minute for a 175—250 ngn; Win—2299 for and high ngn.3 and anqbonactynine at 0.5 nan. par JB—BIB) ngnt per minute for 1.2 to h.o ngn. JB-336, and atropine at O.h �OBSERVATIOHS: (a) Diethezine: A: previously reported administration or diethezine in 15 ), the ( patients prior to convulsive ron therepy resulted in a decrease ib volteges and a deeychnnnization or all frequencies. Prevailing rhythmic patterns became lees In some inetences, symmetric low voltage 6-7 ope prominent. activity appeared, nest proninent in the frontal temporal leads. The and anterior elphe frequency was not altered, but the build-up in voltage and the slower frequencies induced by hyper- ventilation vere blocked (fig. 1). acetone-ounces- In 25 petiente during convulsive therapy, with varying degrees of induced high voltage delta activity significant decrease both in voltage slow wave activity. From an and in ( ) there was a per cent time or everage per cent tine delta or hSI in the £ronte~occipita1 lends, there was 1 reduction to e neen per cent tine of 201. Both random and burnt delte �-5- activity diminished became proninent. and low increase in degree of slow The hyperventilation was on effects persisted for voltage alpha and bets frequencies longer apparent. no one activity wave These electrographic to five hours (Fig. 2). ﬁ-‘-¢’---‘ Fig. 2 --‘------Concurrent with these electrographic effects, distinctive behavioral changes. Patients and restless and conplained of we observed irritable became more sensations of unreality and or dysthesias of the extremities; Visual illusory phenomena and delusional thoughts about their illness, the setting or the test procedure or the examiner’s identity were reported. syntactic language patterns a ( were Their . characteristically altered in fashion opposite to that previously described for snobarbital ), so that verbal denial, minimisation, cliches, third person node and past tense hsaanaﬂhax becane less prominent. changes were concurrent with maximum These electrographic change. �«6» (b) Win-2299: Reports by Pennee compound, Win 229?, manifested both and induced compound. excitetory etatee in The ( ) that an eXperimental potent anticholinergic actiity nan led to our study or this observations were einilar to those observed with diethazino. In five patients without slow wave activity, deeynchronisation of frequencies and decrease in voltages of all frequencies were noted in tour (Fig. 3). nooﬁﬂﬂ‘vw Pig. 3 ”------In 11 patients with high voltage delta activity there was a decrease in amplitude and per cent tine of slow wave activity with an increaee in alpha and beta frequencieec The mean per cent tine delta activity dropped from 50% to 23% (Fig. h). Fiz.\h -‘-‘---“ Associated with these electrographio effects were clinical patterne of reatleaeneea and and excitenent. Patients became fearful tenee. Visual seneatione were reported and in three subjects, delusional elaboraticne about their hospital experience were �-7. proninentdheee behavioral changee appeared during drug administrau tion or within ten minutes, ' levels, within to Reports that benactycine induced (c) Benactzaine: diethazine and disappeared, at these dosage tea three hours. two deeynchronization and ( its structural similarity both to and ) Win~2299 EEG led to our testing of this coupoond. Intravenous administration in 12 oubjecto elicited oiuilar clinical and electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, deeynchroniaation was prompt. Delta activity decreaeed from a mean per cent tire of to 171 in 391 ‘--“‘-C“--“ PigS. 5’ 8 cuhjecte (Figs. 5, 6). 6 ﬁ“-~--‘---These electrographic patterns were accompanied by clinical reetleeeoeee, irritability was more difficult. dittaanxt The thoughts econ with the dosage levels. In and excitement. Artifact-free recording illusory sensations initial compounds were and delusional not noted at these patients with manifest dieorientation language changee associated with convulsive therapy ( and ), however, �‘8‘ there wee en alerting and e revereal or the language patterns. (d) Piperiqzibenziletee: Abood ( ) that various piperidylbenziletea both manifested entioholinergic activity subjects, The Following recent reports by we tested and induced two or these, hallucinations in psychiatric JB-318 and JB—336 in 2b subjects. electrographio patterne were identicel to those other deeynohronination was during - Onset of inaynshxlaxxntx experimental oonponnde. injection or within 15 ninntee and persisted for one to four hours (Fig. 7, 8). -“Q.*.‘..--‘U.Figs. 7, 8 -nﬂ-~ﬁ--.‘-‘--animation was observed, In each instance in whioh deeynchrntxixx clinical restlessness activity changes. were and exoitenent, illusory and hallucinatory noted, and were concurrent with the electrographio In two inetanoee the behavioral changes were halted by the subsequent intravenous adninietration of chlorpronaaine. �(e) Atrozine: Continuing our etudy or enticholinergic compounds, we edniuietered atropine intraveneuely in 12 subjects, in dosages of 0.8 to h.0ngn. Systemic erreeta were prenineut during the injection with increased respiratory rate, puller, dial dry akin and dry mouth, preeorttxxx cenpleinte and eerked teehy~ eerdie (Figs. 9, 10). und.~¢...mnd.¢Figs. 9, 10 ‘b.-’~.ﬁ-‘----Subjects beenne reetleee end feertul (as did the obeervergp) end Seekxxxnptenxxunxnxpxenixentxlxxte recording became difficult. Within ten minutes these symptoms subsided and the subjects became drowsy and relaxed. In subjects without delta activity in the initial record, to leeeitude by decreased slowing (Fig. little be followed during change was seen the period at voltages, desychrenization and increased 9). Fig. 9 In subject: with delte activity, there wee en initial decreeee in voltage and per eent time or such activity during the period or �~10... reatlonancaa, following by an increaao during tho period of quiotudc (Fig. 10). --ﬁ---.-‘&-ﬂw Fig. 10 “.Q‘....‘.‘.‘ �-11DISGUSSIOH: i Various compound: with measurable anticholinorgic activity have that been effects. Thoco shown to have similar oloctrographic and bohovioralw oxporinontal compounds oxhibiting the greater facility in altoring cloctrcgraphic patterns structure oach containing a have a cannon tortiory nitrogen with linkage to varying roota (Fig. ll); a diothyl whilo atropine, rolativoly inpotont in altering oloctrcgraphic patterns contains a quaternary nitrogen. Bohaviorolly each compound induces stimulating, excitatcry and illusory and hallucinatory activity. Electro- graphically each induces dcaynchronication of frequencioa, and docroaac in voltages, most prominent in anhycta with delta activity c 7 following thoropcntically induced convulsions. (a) Convulsive theragy process: Those observations amplify our understanding of the convulsive therapy process and at the induced activity. In earlier studios or high voltoho slow wave ccrroloto or bohoviordl we slow wave indicated that the development activitr chango EEG woo tho nonraphyaiologic in convulsive therapy, and a �-12- - heceslary, though not sufficient, condition for clinical improvement ( ). During the past ten years, .1ncluding Bernstein, have reported numerous Tower and HoEachern, Ward, similarities in the biochednicsl authors Sachs, Rugs changes or the central nervous system in convulsive therapy to that seen in craniocerebral trauma ( ). They observed an inorease in cholnerzic activity as manifest by an elevation of tree acetylcholine and pseudocholinestereses in the spinal fluid. In addition, the direct increase in central nervous system acetyloholine activity by topical administration or eoetyloholine induced high voltage bursts and spike activity. Ulett and Johnson ( enphesised the blocking of the behevioral and electrographic effects by the antioholinergic activity of strapine The observations in this report on end scopolenine. dietheziue, Win-2299, benectysine and the piperidylbenziletes support their observations. The potent enticholinergic activity of such of these compounds (with apparent predoninant locus of activity in the central nervous system) expliries the suggestion that the beechenical basis for the induced slow wave activity of oonvulsivei therapy results from �an increased lova4tf control acetylcholine-cho1inesterase activity. Support for such a hypothesis considerable degrees of slow adniniotrotion of DE? wave is also seen in the activity observed after the (di-ioopropylrlnorophoophote) - a potent oholinootoraoo blocking agent. Uhilo these observations demonstrate that anticholinorgic compounds or. affective in reducing slow wovo activity,.roporto of othor compounds with similar effectihavo also appeared. ‘Anphotanino (Bonaodrino) ( acid diothylonido and diphenhydronino (Bonodryl) ( ) ), moocalino ), lyoorgic ( ( have been reported as rodncing post-convulsive slow wave These compounds ) activity. are primarily described as oymphthominotio and ontihiatoninio in phornncologio activity, yet each has exoitotory ond stimulating effoﬁoto on bahnvior ( , , , ). The relations or those observations to than. soon in this report are possibly boat assessed in relation to synaptic activity. In t study of tho effects or vorioua agonta on the EEG and behavior of unanosthotizod cats with chronic inpltnted electrodes, �-1hBradley and Elkee ( ) postulated the exietence of two, or pcesibly three, types of interacting chemoreaponeive receptors within the central nervous system: cholinergic, non~cholinergie eheeeptible to amphetamine, and nonecholinergic susceptible to LSD and tryptaminie derivatives. Marezei and Hart ( ) exploring intercortical-(transcollosel) partwaye in the cat, described the effects of various compounds on direct electrical stimulation. They on the evoked potentials postulated the presence of two chenoreeeptive potentialities of the synapse - cholinergic and adrenergic ~ with Opposing stimulatory and inhibitory aetien. In both constructs, the administration at antifcholinergie agents, or at eympatheniaetic agenta, results in equivalent eynaptic .electrieal effects. LSD Thus adrenaiine, amphetamine, meecaline inhibit the electrical activity recorded afcreee and a synapse. in ddentieal effect is achieved with atropine. In the light or these suggestions, the present experiments permit a.mere specific hypothesis regarding the pharmacologic baeie of the convulsive therapy preceee. Repeated induced convulsions leads to an increase in synaptic eheliaergie activity with an �-15- increase in the level at electrical activity of the central nerveue system, which 1e recorded by surface electrodes es augmented high voltage slow wave activity. Adainietratien of entieholinergic agents reduces the leveﬂef synaptic activity, resulting in a decrease in tbe manifest cortical electrical activity to pre-convulsive levels. The administration of ayapathomimetic agente, however, also achieve: the seme etiolate, not by altering the by increasing the aloe EEG uni“ chelinergic ectivity but level of adrenergic activity. activity, wave so preninent and so or the poet-seizure state electrical ( The manifest persistent in the ) may waking thus be related to a pereiatent alteration in synaptic transmission activity of large numbers of The delicate thin balance is seen in the ready reversibility with a! Venture or alerting calls at the centre‘rerveee system. ( ), tine agents neted hare. ( ) and the wide variety or pharmacologie Repeated induced convuleione nay thus be described an a device to creete bioeheaieal changes in the brain �.16. for their resulting behavioral effects. fornuletion is Such a consistent with the view that convulsive therapy is therapeutic process non~apecitic ). ( initial suggestion The a ( ) for the convulsive therapy process may that the pharmacologio basis lie in alteration in an acetylcholine-cholinaeteraeo relationships, can, thus on be focused the alteration in the level of synaptic activity. 11:? regard, the observation that diphonkydranine anti~hystaninic agent, also reduces slow convulciono amount of ), ( and wave Innzyknhni In this primarily an , activity of induced the observations by Sacha ( ) that increased cerotinin appear in the spinal fluid otter convulsion: cuggeet that this image of synaptic activity in convulsive therapy is oversimplified. Nevertheless, further animal studies or the effects of various drugs on the poat~seizure electrical activity are warranted. (b) Neurophysiologz;pf hallucinogenic activitz: These observations of anticholinergic compounds delta activity also nay activity. be on EEG related to concepts of hallucinogenic Each of the compounds studied induced excitatory �-17behavior including illusory and hallucinatory phenomena.* Here, - too, synaptic models nescaline, may be useful. Sympathomimetie agetts, as amphetamine, and LSD, and entieholinergie agents es those described here, are equally potent hellucinogene, The neurophermacologic basis for such behavior may be characterized ee en alteration in synaptic balance in the direction of increased inhibition (decreeeed.trenenieeion) of stimuli. clinical efficacy of convulsive therapy in The hallucinatory ectivity.ney the: lie in biochemical level. known alteration at this Equally eignifieent are the effects of other cin entiehellunuiogene, ee chlorpromezine end reserpine, electrical activity. in an modifying men ( nedceline ), block the ( ), and Both compounds induce EEG EEG on hypersynohrony deeynehronieing effects of LSC.end in animal studies, block behavioral and electrogrephic effects ( ,). LSD and mesoeline The nonospecific nature of the neurophysiologic basis of orperimental hallucinatory activity ia thus emphasized. In the doses need, hellucinetory phenomene were not observed for benectyeine. A report of such activity was reported at higher doeege ( ). � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effect of anticholinergic agent, diethazine, on EEG and behavior; significance for theory of convulsive therapy. AMA Arch Neurol Psychiatry. 1958 Sep;80(3):380-7 Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-29b-005 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 6 items. 1: Experimental Studies of Convulsive and Drug Therapies in Psychiatry: Theoretic Implications (one page). 2: Small graphs. 3: [preprint]. 4: Draft. 5: Reprint from the A. M. A. Archives of Neurology and Psychiatry September 1958, Vol. 80, pp. 380—387. 3: File copy. 4: Handwritten notes. 5: 8 drafts. 6: [preprint]. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/41d2ce5a639c29832746c6ec9a762f69.pdf be29ea3cfc0ebd057d49979acc6884d6 PDF Text Text �Reprinted from Biological Psychiatry Grunt & Stratton, Inn, 1959 Printed in (1.8.4. CHAPTER 14 Effect of An Anticholinergic Agent, Diethazine, on EEG and Behavior: Signiﬁcance for Theory of Convulsive Therapy By MAX FINK, M.D. of convulsive have therapy emphasized EEG RECENT delta activity as the neurophysiologic basis for the induced behavioral change.“5 In investigations of head trauma signiﬁcance has been ascribed to changes in the acetylcholine-cholinesterase systems both for the behavioral and the electroencephalographic effects. An increase in free acetylcholine6 and an alteration of the ratio of cholinesterases7 in the spinal ﬂuid have been positively correlated with the degree of EEG abnormality and degree of neurologic deﬁcit. The EEG patterns were “blocked,” and some improvement in clinical status was reported following the administration of atro8 pine.“ In convulsive therapy, atropine and scopolamine were observed to block the appearance of delta activity,9 although the systemic effects of the large doses of these agents were marked. Recent reports10 noted that EEG and behavioral effects similar to those produced by atropine were achieved in patients with head trauma by intravenous diethazine—a phenothiazine compound with anticholinergic properties—with minimal systemic effects. The effect of diethazine was studied in the course of our continuing studies of the role of delta activity in electroshock.3 It is the purpose of this report to describe the effects of diethazine on EEG patterns and on the behavior of patients during electroconvulsive therapy, and to relate these observations to the present neurophysiologicadaptive hypothesis of the mode of action of convulsive therapy. INVESTIGATIONS From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, Long Island, N. Y. Aided, in part, by grant M-927 of the National Institute of Mental Health, National Institutes of Health, U.S.P.H.S. Co-recipient of the 1958 A. E. Bennett Foundation Award for research in biological psychiatry. Reprinted by permission from the A. M. A. Arch. Neurol. & Psychiat. 8: 38 (Sept) 1958. I am indebted to Mrs. Hannah Mosquera for her technical assistance in the EEG recordings, and to Drs. Joseph Jaﬂ'e and Robert L. Kahn for their analyses of the tape recordings. Diethazine was made available through the courtesy of Smith, Kline and French Laboratories, Philadelphia, Pa. 184 �EFFECT OF AN ANTICHOLINERGIC AGENT 185 SUBJECTS AND METHODS Forty psychiatric patients, at various stages of electroshock therapy in an openward, voluntary psychiatric hospital have been studied. All observations have been made in acute experiments in the EEG laboratory. Following a routine EEG recording, diethazine* was administered intravenously at the rate of 25 mg. per minute, for a total of 175 to 250 mg., depending upon the behavioral eﬁ'ect. Dosage varied from 2.8 to 4.0 mg. per Kg. body weight. EEG Analyses: Recording was continuous for the duration of the observation period, except during interview periods. Needle electrodes and an 8 channel Medcraft instrument were used. All records were analyzed for the degree of delta activity,3 the of fast relative and the amount time and frequency, alpha principal cent per activity. The alpha and delta activity were measured in anterior temporal-vertex, and parietal-ear lobe lead combinations. Behavior Measures: Prior to drug administration an unstructured psychiatric historical interview and a structured questionnaire period12 were tape-recorded. Following drug administration, periods of recorded interview were alternated with EEG recording periods, until the EEG had again manifested the preinjection pattern on visual inspection. Two estimates of behavioral effects were used: clinical descriptions by the particithe drug of the during occurring and changes interviewer technician) (subject, pants period, and analyses of the language of the recorded interviews. Changes in language were evaluated by a syntactic analysis12 and an analysis of the variability in verbal interaction in the dyad 1" “1' Both measures have been shown to be sensitive to alterations in behavior induced by changes in the central nervous system. OBSERVATIONS Clinical: Within two to ﬁve minutes after the start of the injection, subjects manifested spontaneous coughing followed by dryness of the mouth and thickness of speech. They reported feelings of lassitude and heaviness and weakness of extremities, soon succeeded by increased restlessness and difﬁculty in maintaing eyelid closure. Reports of visual and haptic illusory sensations, feelings of unreality and distance and delusional thoughts about their illness, the setting of the test procedures or our identity were voiced spontaneously in 18 subjects in the period between 15 and 60 minutes after drug administration. In three instances, increasing agitation and panic led to a cessation of the recording. In two subjects withdrawal and negativism were the prominent behavioral had and transient of behavior disappeared Such were patterns responses. in one and one-half to four hours in all subjects. *Diethazine is a soluble phenothiazine compound with pharmacologic properties similar to those of atropine. In experimental animals, diethazine blocks the bradycardia, bronchospasm, salivation, fasciculation and seizures induced by acetylcholine, di-isopropyl ﬂuorophosphate and pilocarpine. It suppresses salivation, and induces mydriasis and hypotension.11 'j'Detailed analyses of these observations will be reported separately by Drs. J. J affe and R. L. Kahn. �186 BIOLOGICAL PSYCHIATRY WWW Wm mm PRE-DRUG LF-LO RF-RO 0-0 RPT-RO AFTER 225 mg. WWW/«WNW WWW WW 50ﬂVl—— l FIG. l.—-EHect SEC. of intravenous diethazine, pre-electroshock (male, age 27). PRE-DRUG 0-0 1r I64l HH AFTER I50 mg. WW 5°)‘VL— SEC. I FIG. 2.—Eﬁ'ect of we I725 HH intravenous diethazine, pre-electroshock (female, age 57). �187 EFFECT OF AN ANTICHOLINERGIC AGENT PRE-DRUG W W ”W W W W W W W W W W W WW + 200 mg. + 25 min. 4- 70min. “WWW- 50 )‘VI I SEC. #l637 HH 3.—Eﬂect of intravenous diethazine after electroshock (note especially effect on delta) . FIG. PRE-DRUG +|HR AFTER 250 mg. W W W W W W W W W W WW SGML...— I FIG. 4.——-Effect of on delta) . SEC. + 5 HRS. WwL/M *l249 HH intravenous diethazine after electroshock (note especially effect EEG Patterns: Alteration in the EEG patterns was concurrent with the behavioral effects. In all records, changes occurred during drug administration and were sustained, with gradual diminution and restitution of the preinjection patterns in one to ﬁve hours. The initial response was a decrease in voltage and desynchronization of all frequencies. There was a decrease in prominence of prevailing rhythms. In patients without delta activity (pre- �188 BIOLOGICAL PSYCHIATRY electroshock), desynchronization and voltage decrease were occasionally accompanied by low voltage 5 to 7 cps activity, symmetric and prominent in frontal and anterior temporal leads (FIGS. 1 and 2). The alpha frequency was not altered. The build-up in voltage and appearance Of slower frequencies with hyperventilation were blocked. In patients with varying degrees of high voltage delta activity there was a prominent decrease in voltage and desynchronization of the record. Both random and burst delta activity diminished or disappeared, and irregular low voltage alpha and beta frequencies became prominent (FIGS. 3 and 4) . The hyperventilation response was no longer apparent. Language Patterns: In previous studies, an intimate relationship between changes in syntactic language patterns and the behavioral response to electroshock had been reported.12 With alteration in brain function, increased use Of third person, verbal denial, qualiﬁcation, displacement and clichés became prominent. These effects could be enhanced by the administration of intravenous amobarbital.“ In the subjects in the present study, syntactic analyses demonstrated a reversal of the patterns noted in electroshock. Use of third person, qualiﬁcation and displacement decreased. Explicit verbal denial was modiﬁed and replaced by minimization and displacement, or by a reiteration of complaints of illness. In dyadic analyses, the verbal interaction was characterized by a greater diversity Of vocabulary and less variability in the diversity scores for 25 word units. The qualitative nature of these changes in the language patterns is Opposite to that of amobarbital and electroshock. The duration of language changes was concurrent with the changes in the electroencephalogram. DISCUSSION These Observations conﬁrm the report of Jenkner and Lechner of the effects Of diethazine in “normal” subjects.10 Diethazine also alters electroshock-induced delta activity in a fashion similar to atropine and scopolamine, as described by Ulett and Johnson,” with minimal unpleasant symptoms. The effects of intravenous diethazine are immediate, both on the EEG and behavior, and it is thus a useful experimental agent with “anticholinergic” prOperties. Two aspects Of these experimental Observations warrant discussion: the role of acetylcholine-cholinesterase in the process of electroconvulsive therapy, and the signiﬁcance Of diethazine “alerting” for concepts of hallucinogenic activity. Biochemical Basis of the Convulsive Therapy Process: Bornstein,6 in a classic experimental study of head trauma in cats, demonstrated that within a few minutes after trauma free acetylcholine appeared in the spinal ﬂuid �EFFECT OF AN ANTICHOLINERGIC AGENT 189 and persisted for periods up to 48 hours. He further demonstrated a positive relation between the severity of head trauma and the quantity of free acetylcholine, degree of electroencephalographic alteration and the severity of the behavioral changes. The electroencephalographic records initially showed short periods of high voltage fast activity and a transient period of ﬂattening of electrical activity, followed by prolonged periods of high amplitude sharp waves in the delta frequencies. Concomitantly, alteration in consciousness, changes in reﬂexes and post-traumatic seizures were most prominent with highest concentrations of free acetylcholine and greatest degree of EEG change. Tower and McEachern7 conﬁrmed these observations in clinical studies. In 112 neurologic patients, free acetylcholine was found in the cerebrospinal ﬂuid only in patients following head trauma and recent grand mal seizures; and the level of free acetylcholine varied directly with the degree of cerebral damage. In addition, these authors assayed the cholinesterase activity of the 16 ﬂuid.“ spinal They noted a sharp rise in nonspeciﬁc cholinesterase (benzoylcholine-splitting) and a drop in the speciﬁc cholinesterase (mecholylsplitting) activity of the spinal ﬂuid in patients following head trauma. No such inversion was noted in ﬂuids containing free acetylcholine following spontaneous seizures. Electroencephalograms were taken at varying intervals following trauma, and demonstrated a direct correlation of the extent of EEG abnormality and the appearance of free acetylcholine in the spinal ﬂuid. Tower and McEachern also reported observations in six patients receiving electroconvulsive therapy. ’In patients after three to seven induced convulsions, they noted free acetylcholine in the spinal ﬂuid in two, and an increase in nonspeciﬁc cholinesterase with reversal of the cholinesterase ratio in ﬁve of the six. They concluded that the spinal ﬂuid changes in electroshock are more like those of craniocerebral trauma than those found in epilepsy.* More recently, Sachs17 conﬁrmed the reports of free acetylcholine in the spinal ﬂuid after head trauma and after electroshock. In his studies, Bornstein6 administered 0.5 to 1.0 mg./ Kg. atropine and demonstrated a reversal or a blocking of the EEG effects, and a modiﬁcation of the behavioral and neurologic signs. Atropine also blocked the EEG and clinical signs induced by intracisternal acetylcholine. Ward8 applied these observations to the treatment of human subjects with varying degrees of head trauma. Subcutaneous doses of 0.1 mg./Kg. of atropine induced both clinical improvement and reversal of EEG effects. These observations were recently conﬁrmed by Sachs,17 Ruge,18 and *Regarding the one patient of the six who failed to show either free acetylcholine or a reversal of the cholinesterase ratio, they noted: “It is interesting that this patient was the only one of the six to show no response to treatment.” �190 BIOLOGICAL PSYCHIATRY Hughes.19 Basing their study on these observations, Ulett and Johnson" noted the effect of atropine and scopolamine in blocking the EEG changes of electroshock therapy. Concurrently, Jenkner and Lechner10 reported effects similar to those of Ward, in studies of diethazine in cases of head injury. Another group of investigations complete the available data. Studies of anticholinesterases, such as DF P (di-isopropyl ﬂuorophosphate) and TEPP (tetraethyl-pyrophosphate) , which block the enzymatic breakdown of acetylcholine, demonstrate the development of high amplitude rapid frequency EEG patterns similar to status epilepticus as well as lesser degrees of abnormality as noted in post-traumatic states.”23 In these studies, atropine blocked both the electroencephalographic and the clinical toxic effects. Thus, both from experimental and clinical studies of craniocerebral trauma we may assume that (a): the acetylcholine activity of the spinal ﬂuid increases; (b) that pseudo-cholinesterase activity increases with a reversal of the ratio of cholinesterases; (c) that EEG hypersynchrony and slowing parallel these biochemical alterations; and (d) that anticholinergic agents may block both the electroencephalographic and the clinical effects. From the data available it is probable that the biochemical basis of convulsive therapy is similar to that of craniocerebral trauma. Convulsive therapy results in free acetylcholine in the spinal ﬂuid“ 17 and a reversal of cholinesterase ratios.“ 16 The electroencephalographic effects of repeated induced convulsions is the development of high voltage, symmetric slow wave activity, occasionally with spike activity,3' 24’ 25 which is similar to that observed in severe head trauma.” 27 In previous studies we have reported the relationship between the degree of induced slow wave activity and behavioral response.3 The studies reported here and that of Ulett and Johnson" demonstrate a reversal of the EEG and the behavioral effects of convulsive therapy by anticholinergic compounds. In each characteristic, convulsive therapy is thus similar to cerebral trauma. While the acetylcholine-cholinesterase system is highlighted by these studies, other enzyme systems may also be altered.17 These studies also suggest that convulsive therapy provides an excellent experimental method for studies of craniocerebral trauma. Studies of the brain stem-activating system by Jasper and DroogleverFortuyn28 and Lindsley et al.29 had laid the foundation for prevailing conclusion that symmetric EEG slow wave activity has its origin in mesencephalic structures, and that these structures intimately affect the states of “alerting” and “drowsiness.” More recently, Rinaldi and Himwich30’ 31 have related the site of action of atropine and cholinergic drugs to this mesodiencephalic activating system. It is also probable that these structures may be selectively affected by the process of convulsive therapy, and that �EFFECT OF AN ANTICHOLINERGIC AGENT 191 both the clinical and electrographic effects may be intimately related to changes in this system. Diethazine “Alerting” and Hallucinogenic Activity: The behavioral effects of diethazine provide information regarding another aspect of the convulsive therapy process. In patients without prior convulsive therapy, illusory phenomena and feelings of unreality were observed. These were similar to the hallucinogenic effects of LSD32 and mescaline.33 Again, analogic data about the clinical and EEG effects of these agents may provide some information about convulsive therapy. In studies of mescaline, Wikler34 noted that the EEG demonstrated either no change, intermittent or continuous low voltage fast activity or increase in alpha frequency. Denber and Merlis35 noted a similar acceleration of alpha frequency, decrease in per cent time alpha including its disappearance, and nonspecific random beta activity. Delta activity did not occur. In patients with delta activity induced by electroshock, Merlis and Hunter38 noted that intravenous mescaline markedly diminished the amplitude and per cent time delta activity with an increase in per cent time alpha activity. The effects of LSD on the EEG are similar. Gastaut et a136 noted an acceleration of alpha frequency of 0.5 to 4.0 cps with an accentuation of beta rhythms. Rinkel et a1.37 conﬁrmed this observation and noted, in addition, a reduced responsiveness to hyperventilation.* In summarizing his studies Wikler34 concluded that “ . . . regardless of the drug administered, shifts in the pattern of electroencephalogram in the direction of desynchronization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness.” This generalization provides a meaningful construct in which these agents may be assessed. Agents that evoke EEG desynchronization tend to be hallucinogenic, and mescaline and LSD are clear examples. Agents that synchronize frequencies, such as barbiturate and meprobamate in the beta frequency range, and chlorpromazine, promazine and perphenazine in the delta frequency range89 tend to be sedatives, euphoriants and relaxants. The observations on diethazine reported here are consistent with this hypothesis. In patients without delta activity, the EEG demonstrated desynchronization of frequencies, and this was associated with clinical illusory phenomena. In patients with delta activity desynchronization occurred, and alerting and reversal of the Speech patterns induced by electroshock were observed. *Studies on the effects of LSD and such anticholinergic compounds as Win-2299, benactyzine, and hallucinogenic piperidyl benzilates (JB-318, 336) demonstrated marked diminution in per cent time and amplitudes of delta activity, associated with behavioral changes similar to those seen with diethazine.“ �192 BIOLOGICAL PSYCHIATRY Electroconvulsive therapy may also be understood in this framework. We have previously noted a direct relationship between clinical evaluations of improvement and the degree of EEG slowing induced by electroshock.3 Under these conditions, sedation and euphoria are most prominent and hallucinatory activity diminished. In patients in whom hypersynchrony is not induced, behavioral change is limited and ‘improvement’ does not occur.‘1 Previously we concluded that the mode of action of convulsive therapies is based on the induction of a state of altered cerebral function, in which changes in adaptive interpersonal behavior occur, and are interpreted as 4’ 39 ‘improvement’F" The present studies amplify two aspects of this neurophysiologic-adaptive hypothesis. The biochemical substrate of the behavioral change is reﬂected by an alteration in the acetylcholine-cholinesterase relationships of the central nervous system. It is also probable that EEG hypersynchrony provides the neurophysiologic basis of the milieu change which is clinically manifest as sedation and euphoria and is evaluated as ‘irnprovement.’ The neurophysiologic-adaptive hypothesis of convulsive therapy has provided a meaningful basis for studies of other physiodynamic therapies.39 In this study, it has been possible to amplify our understanding of neurophysiologic aspects of hallucinogens as well. SUMMARY The effect of an anticholinergic agent, diethazine, on the EEG, behavior and language patterns was observed in 40 psychiatric patients, at various stages in the course of electroconvulsive treatment. Behavior: Increased restlessness and agitation, haptic and visual illusory sensations, and delusional thoughts about their illness or examiner’s identity were observed. EEG: Alteration in the EEG was concurrent with behavioral changes. There was a decrease in voltage and desynchronization of all frequencies. In patients with delta activity, the per cent time and voltage of delta activity decreased. Language: Syntactic patterns described for convulsive therapy were reversed. Use of third person, qualiﬁcation and displacement decreased. In dyadic analyses, there was a decrease in the coefﬁcient of variation. 2. These observations are discussed in the framework of the neurophysiologic-adaptive hypothesis of the action of convulsive therapy; it is concluded that: (a) the biochemical basis for convulsive therapy is similar to that of craniocerebral trauma; (b) changes in acetylcholine-cholinesterase metabolism are intimately related to the behavioral effects; and (c) EEG desynchronization may be a physiologic concomitant of hallucinogenic activity; and EEG hypersynchrony may be associated with euphoria and 1. sedation. �EFFECT OF AN ANTICHOLINERGIC AGENT 193 REFERENCES . Weinstein, E. A., and Kahn, R. L.: Denial of Illness, Illness: Symbolic and Physiologic Aspects, Springﬁeld, Ill., C. C. Thomas, 1955. Roth, M., Kay, D. W. K., Shaw, J. and Green, J.: Prognosis and pentothalinduced electroencephalographic changes in electroconvulsive treatment. EEG & Clin. Neurophysiol. 9: 225-237, 1957. Fink, M. and Kahn, R. L.: Relation of electroenecephalographic delta activity to behavioral response in electroshock. A.M.A. Arch. Neurol. & Psychiat. 78: 516—525, 1957. Green, M. A. and Kahn, R. L.: Experimental studies of the electroshock, process. Dis. Nerv. Sys. 19: 113-118, 1958. Ulett, G. A., Smith, K. and Gleser, G. C.: Evaluation of convulsive and subconvulsive shock therapies utilizing a control group. Am. J. Psychiat. 112: 795-802, 1956. Bornstein, M.: Presence and action of acetylcholine in experimental brain trauma. J. Neurophysiol. 9: 349-366, 1946. Tower, D. B. and McEachern, D.: Acetylcholine and neuronal activity. Canad. J. Research. 27: 105-131, 1949. Ward, A.: Atropine in the treatment of closed head injury. J. Neurosurg. 7: 398-402, 1950. Ulett, G. A. and Johnson, M. W.: Effect of atropine and scopolamine upon electroencephalographic changes induced by electroconvulsive therapy. EEG & Clin. Neurophysiol. 9: 217-224, 1957. Jenkner, F. L. and Lechner, H.: The effect of Diparcol on the electroencephalogram in the normal subject and in those with cerebral trauma. EEG & Clin. Neurophysiol. 7: 303-305, 1955. Heymans, CL, Estable, J. J. and de Bonneveaux, S. 0.: Sur la pharmacologie de la phenothiazinyl—ethyldiethylamine (2987 R. P.). Arch Int. Pharmacodyn. 79: 123-138, 1949. Kahn, R. L. and Fink, M.: Changes in language during electroshock therapy. In Hoch, P. and Zubin, J. Eds: Psychopathology of Communication. New York, Grune & Stratton, 1958, pp. 126—139. J affe, J.: An objective study of communication in psychiatric interviews. J. Hillside Hospital. 6: 207-215, 1957. : Language of the dyad: A method of interaction analyses in psychiatric interview. Psychiatry. 21: 249-258, 1958. Weinstein, E. A., Kahn, R. L., Sugarman, L. A. and Linn, L.: Diagnostic use of amobarbital sodium in organic brain disease. Am. J. Psychiat. 112: 889-894, 1953. Tower, D. B. and McEachern, D.: The content and characterization of Cholinesterases in human cerebrospinal ﬂuids. Canad. J. Research. 27: 132-145, , 10. 11. 12. 13. 14. 15. 16. 1949. 17. Sachs, E.: Acetylcholine and serotonin in the spinal ﬂuid. J. Neurosurg. 14: 22-27, 1957. 18. Ruge, D.: The use of cholinergic blocking agents in the treatment of craniocerebral injuries. J. Neurosurg. 11: 77-83, 1954. 19. Hughes, B.: The role of acetylcholine in head injury. J. Neurol. Neurosurg. and Psychiat. 20: p. 70, 1957. 20. Freedman, A. M., Bales, P. D., Willis, A. and Himwich, H. E.: Experimental production of electrical major convulsive patterns. Am. J. Physiol. 146: 117124, 1949. �194 BIOLOGICAL PSYCHIATRY 21. Grob. D., Harvey, A. M., Langworthy, O. R. and Lilienthal, J. L.: The administration of di-isopropyl ﬂuorophosphate (DFP) to man. Bull. the Johns Hopkins Hosp. 8]: 257-266, 1947. 22. Hampson, J. L., Essig, C. F ., McCauley, A. and Himwich, H. E.: Effects of diisopropyl ﬂuorophosphate (DF P) on electroencephalogram and cholinesterase activity. EEG & Clin. Neurophysiol. 2: 41-48, 1950. 23. Himwich, H. E., Essig, C. F., Hampson, J. L., Bales, P. D. and Friedman, A. M.: Effect of trimethadione (tridone) and other drugs on convulsions caused by di-isopropyl ﬂuorophosphate (DFP). Am. J. Psychiat. 106: 816-820, 1950. 24. Callaway, E.: Slow wave phenomena in intensive electroshock. EEG. & Clin. Neurophysiol. 2: 157-162, 1950. 25. Green, M.: Signiﬁcance of individual variability in EEG response to electroshock. J. Hillside Hosp. 6: 229-240, 1957. 26. Jasper, H. H., Kershman, J. and Elvidge, A.: Electroencephalographic studies of injury to the head. Arch. Neurol. & Psychiat. 44: 328-348, 1940. 27. Strauss, H., Ostow, M. and Greenstein, L.: Diagnostic Electroencephalography. New York, Grune & Stratton, 1952. 28. Jasper, H. H. and Drooglever-Fortuyn, J.: Experimental studies on the functional anatomy of petit mal epilepsy. Res. Publ. A. Nerv. Ment. Dis. 26: 272-298, 1947. 29. Lindsley, D., Schreiner, L. H., Knowles, W. B., and Magoun, H. W.: Behavioral and EEG changes following chronic brain stem lesion in the cat. EEG & Clin. Neurophysiol. 2: 483-498, 1950. 30. Rinaldi, F. and Himwich, H. E.: Alerting responses and actions of atropine and cholinergic drugs. A.M.A. Arch. Neurol. & Psychiat. 73: 387-395, 1953. 31. Himwich, H. and Rinaldi, F.: The effect of drugs on reticular system. In Brain Mechanism and Drug Action. Springﬁeld, 111., C. C Thomas, 1957. 32. Stoll, W.: Lysergsaure—diethylamid, ein Phantastikum aus der Mutterkorngruppe. Schweiz Arch. Neurol. Psychiat. 60: 1-47, 1947. 33. Beringer, K.: Der Meskalinrausch, Monog. Neurol. Psychiat. Berlin, Springer, 1927. 34. Wikler, A.: Clinical and electroencephalographic studies on the effects of mes35. 36. 37. 38. 39. 40. caline, N-allylnormorphine and morphine in man. J. Nerv. Ment. Dis. 120: 157-175, 1954. Denber, H. and Merlis, 8.: Studies on mescaline. I: Action in schizophrenic patients. Psychiat. Quart. 29: 421-429, 1955. Gastaut, H., Ferrer, S. and Castello, 0.: Action de la diethylamide de l’acide d-lysergique (LSD 25) sur les fonctions psychiques at l’electroencephalogramme. Conf. Neurol. 13: 102-120, 1953. Rinkel, M., DeShon, H. J., Hyde, R. W. and Solomon, H. 0.: Experimental schizophrenia-like symptoms. Am. J. Psychiat. 108: 572-578, 1953. Merlis, S. and Hunter, W.: Studies on mescaline. II: Electroencephalogram in schizophrenics. Psychiat. Quart. 29: 430-432, 1955. Fink, M.: A uniﬁed theory of the action of physiodynamic therapies. J. Hillside Hosp. 6: 197-206, 1957. Effect of Anticholinergic Compounds on Post-convulsive EEG and . Behavior, EEG and Clin. Neurophysiol. 10: 776 (Abst.) 1958. #3....” � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effect of anticholinergic agent, diethazine, on EEG and behavior; significance for theory of convulsive therapy., In JH Masserman (ed.), Biological Psychiatry. Grune and Stratton, New York, 1959, 1:184194. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-29c-006 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprinted from Biological Psychiatry Grune & Stratton, Inc., 1959 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/96ce3f4b6be961e4eabd7724c9d19da6.pdf a0a4da54e32427732cf5206a7a8e7ac6 PDF Text Text m: 603.29% (f/ 3 mammowmmmwmwm MW“ * m an W8 at mm. mm, mm- mm, am am, L.,I.. m. and u. tho mung a: u:- mrim m Mum Atlantic any, m 31;. 3.958. �’umwuummcmmmmoommm “We! mmsémwwmmmwwmumduymmmu 02-00%de mammuotmhighwltago doltn ants-upon: nativity woolly mm by convulsive tux-spy. may also noted mm the M 91‘an mammary to affoettm Rem mob an tuba “mama with mutant music: aﬁaou. m reporta by Janinar and W!“ mums W mmmcmquuammnmmmma-o mamummo u an miehonmme with patent MWtﬁnﬂW;mdthouMmﬁm,intumlodfamlmﬂgatm ofothormmnu. 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Mont activity and in M‘tomramm‘tmmdg 'moﬂmhuwwﬁntobw in ma «dawning group» m 1mm mound“ merma- m �Wﬁon We and in values: of :11 inguinal“ m 16.3.6 W351“ mm Win 2399 ~ A; A - m .W mam laments umwmuge stoma «unuymm mWMmGwcwt than of Ingram nativity nmmmm am and m tum-mu. mm m out w» mu minty to £35 in than mac/cm Manama with than patterns of aﬂoat: at” from 59$ w I 111W ”ﬁlthy. 1’18. an 8399 - Pelt 0:: u m hallucinogenic W dummwia mm, «amt, ﬁlm W . .; 111' ma Minotaur: ‘ 'i Win treatment ’ nativity at 1633-25 mmummum thine-mama. m an «um-had, that. am» Hm,m, wmmmm to manna, mm mmWax-:1 mmme struts, 1mm constant in ﬂat thin an amine. in: n “from” 1} to a ham mar There than m m :mmtmm, but an; clamping man we? Wt mam mm sham. was then! m m 9:er mad mmum 1%»:er tilll with LSD, m «an activity was mum mud. ma activity £8.13.- fmh‘ﬂ to 16$ infiw mm. as. a. 9. an m .. me �mm mom that mum, 0. mm mammary» ewgmmmmummwmmmw W a: 01m subjects. again mam mum 1::qu electromphic patterns. ma moan-d with high and 30th in 13119 1011 ma mm voltage done activity, ‘ , , z and Ilphn moot-dual! in m pmpt. mlmwuﬂtymumtmammmttmM39$to17$1n8 mm; . . mac-11:33 Warm anathema pttummmiodhymmﬁ mun-anon an! exam was It did not W mm or hallucinatory county, madmmtmmmpammmdummmmrmas 11% the am: mm W I �«6-: mrwmammummmwmmmmmc M m Miami” mtieholimrzio ”unity. M mam WW9 or mum-y “mum and m We}. and behavioral aﬂoat-I. Wm townpnnnd by ma ﬂan. ‘ ‘ ‘ Walton, that cmmaumumrommmmuwummmw Iigum‘q ﬁlo Mm min. in a whatihum 1110'!!!le is WanmmmwmmmmmW HIP!“ activity of ternary minus, and “£01 Wing his studies by tho s' * moan-ant chummphic patterns. ‘ mono ohumhimo may man. am- In «no» ohms we high voltage slow nu «ﬂaw no the thumps? Moratorium of tho eonmlaivo indicated hint. on. dwalomh of mmphyoiologic correlate or We in oomulain mum. and a mom, thought. not outﬂow, mum for clinical inpmh. During tho pat. hon yum, studies by mum, W wﬂommm, Word, 3m, Mo ma ommmmammmmmmmmcmummmw Monarch-cl mm. W «pom on almohim of 2m thumpy maintain. ”ho mwlohoum and in pummm In honed. W. tho spam. nun among mutation of mtylohoiim mum, W170 mummmlupwmmaapmm'my. MMJohnaon. Mind the blocking of thus «mac attach: w m W316 “tin? of atropin- Ind prolnnﬁmg- m own-ration. on this report on �#7419 ms m: Wyﬂm mm m Mmtm“ mammmmmmumacutmtymmo mm, Vin 2299.. 0113mm magnum ma m appoint to the” Market! thus with ﬂu urns: magnum that 11mg. 0&me tar commas.” than”. “6 may the Mumimnc built for mama}. m ”1m aw m Woman at high 336 Ghana! “than a: 0.1th in the the in activity convulsive“; therapy by noting tint this mam-mm Mattel: at W Mien of tin mmua ”an, probably in the $30le is nativity: M Mansions load mam to magnum in mam W dammnmmmm 01‘ WWI-'11 tum; 51.1%?! 91' tho efficacy of high “nu-stations of head do“! Walla indium tint struts.” do”: bmught men than 19mm mum streets. am mm: It would be mam, mamas such m potent, am neurologically mum: on and in mm awn m Ma mama mm“; our «311:: reports an tbs then ”osmium, m, tbs Mia-am at me delta activity W1” thcupy; we mama his “part. ”comm, Mmﬂm m:mm with tbs mm mm 1".“ or the drug mum, mu in pattern at a in the am at mmmum coma in mention mm: minty, in tho Was a: Mandamus, mm, mamas w mm, Wuﬁm um: smug, mm» or Wu.” ma mmm, Wbymmnm, Wtammgcmuﬁmo: and 1:: 01“ 01:13pm (1951:) an and mental-.033 that than 01 and �‘ Nu“ Mom.“ at the m at mug thumb; in mum. 1% any infer mat agents that unmatanu mamgmmmu frequenay my ad «thiamine, mam nad paramount!» in than and mutant;data rmuem mg» m to be mm“, which a: Mummm mm Mammanmmmmgmmtoummtm a... Mmimmu, u and W1; Mad m mwm. tan-25. m 2299, WW ' �«an». In m.cw WWW Win bum “rim them. untieholimm and u have We the «that: at "new m the psychiatnc putt-mt: at in and stages of convulsive mm, W mm mm than lame and vim]. Wood and 1mm math-mu, Musical sham“ about tin 1W gamma mm ﬁr 00mm“: therapy mums. mm. Commuthtm mammammmmwammum a: an. raw-mm m m m. In puma“ with man mango don: activity, the per mt m Velma at the ma activity are My mm. subject's illness or ti» W13 “entity. the syntactic and Item and 'mmwmmmmnwozmorm mmmm ommmmmmuﬂmmu that; nth the for (t) m Wad hum: far amulet" mm mwmwm ‘ evacuation and range m mu may m be an high dmtim 1n ﬂu mommmmuwmtm Winn Wmhuwd at utiviwu W We (b) me . ”Manama” somatic new}; means! mumdmmotacmor thumpiuiapayumnttyu of the WW. was m It in arm: was.» of m- ama upmud to M an ammo cmmds in Wet-am}. m Wally lip-01:10 W to h. Wn Moth-11m, or am... Mart-Jean, utilising Wynne mt! � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effect of anticholinergic compounds on post-convulsive electroencephalogram and behavior. Electroencephalogr Clin Neurophysiol.,10:776, 1958. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-34a-012 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [preprint]. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/ee9acc31c3d43280c2889e28c2a5cbdf.pdf bf2464ff0c5b85a41fb05f4bcfd6dfb6 PDF Text Text Inlnary tor All (—1143 . turner 0’ Ilill'lﬂﬁﬂﬁ IA‘IIIHIhTI 6' Pllﬁlpilﬂﬂ In: #13:. u.n.. Horton lathnnsoa. I¢E., villi: a. nits-an, I‘D. tad Harris I. laudmr, l.n. ottoat at antravuaona barbiturutu an tbs parcnptxen of Itltlpl. saunltunoauu antantoun atmnuli In. obsnrvud in lawn. groupa o: nor-s1 subjectt. puttantu with Iiitﬂlt and lawn! our.» bani 41:051., tptlul word 10-103. and psychoconic disordqu. Itch in. attain-d hetero and utter the :10! idltltltrtm ties of 2 1/25 uulution of Indian snytsl tn dost: o: 3‘15 to 6.50 an. to nyatusnnu. slurred upcoah, ‘ttxza and drauaantsu upponrcd, The haltnd tun simulttunoua tacit}. tints war. :9plind. 2h: assaincr ntunltaanounty tauahnd tn. lubjout In two plaacs - such ll tn. abbot and tho hand - and tutti his ta p.9ort that wt: ialt* ib3t§ tart rupaatnd with Vtrtoul boa: «ouhtlltiens. tad thu report: rueardod. It» ottcnts a! median atrial on Indul1:30: 0th.: than touch ‘Qf. sane inronttgntcd. In :11 labJoctn Indian ‘Iﬂt‘l etuuod arrow. in tin par~ caption a! tbs uisnltaaaaﬁn stimuli. Ibrﬂtl nuhjoats taunt tun tnxxuaact e1 tn. barbiturate trcqauntly rcportod only «In at tho two stinnlt (onttantton); a. ., tn tho acubtnutton at £30. and hand only the stimulus to tat tnao was royortud. It‘s. trrarn into tt3nsannt :nd tlnntuntod during tho parted a! «was :atton. tn. indoetlan was 31.11:: bohavtar van untod £3 »»1¢, duproauian. paticntniv1th paychoanatu dtnovdurn schisophrnntu)¢ - 1 u �In puttoats with acrobrnl disease, uaytul brought out anioets ant privaoualy appaiunt or oxnguuruttd oxinttng .113: of 63:1uautioa. In this group tun orrnru U‘t. not. pronounced, porstntcd tor lessor porleds, ind abound 1's: tluatuttlon thﬁn :3 ch. nor-n13. 1h 9&ttontc with~£oanl carohrul dlﬂitit with 00:50:: daftots continua to any urea at thn body. anytaz brought out utter: which var. ant apparcnm ova: vith Ixnnltnanou: test: Ind 1t daftnnd tort nightly tho oxtnnt of tho teaser: disturbanco. Qttiuntn with diffuse aorubrul dyntuantion rho pruvtounly and. no orroru on atuultnnnoun tnatllo tautg, lhﬂﬂid rcpoatod Otters a: cxttnntton tug diuplnecnnnt as both 314.: at tn. body utter anal: dalos o: a-wtal. Pntxonts who angina uxtinattan or displgoonnnt prior to tha anytnl pertornod attiarantly sitar tin drug tn: xtvcn. Errata heath» nypnrnnt in body part: which print to tho naytnl ‘DIO rupartad oarruatly. Furthnr-oru, tho phannuoa: o: oxouounuthnsia (displaoalant to astrupﬁrnoall apnea), allcun than (duplwmnt to tho «man. an) «mom» son: (incenplntc apailatcrsl displneoaunt) var. also ovidont. In ‘11 pationta with orgnnio unatll uyndron. tn. duration at tho porcoptuul otter: ‘3: troqunntly 1033.: than the OUOrt 31.3; of drug sattan. Th. porcuptuﬁl ahtﬂlhi lustod lancer thin in noruul m mt»: “suchctu attor stutznr downs tad var. norc canntstcat. :3 10310:. of tho aptnal nard, tho scanary dl£octn banal! not. ;ppnront: cutinntion could ho clxaitod «var : mutant unit and tho 1.?!1 at sonnet: 4.103: bouts» not. ﬂittinct. In two �inntsnoOI. hounvur, t prsvtounly duturnlnod tensor: 1:!31 could not be olinltod :ttur tho anytul. In tout. o: othor century functions, nystncuun on datcct torvnrd can. In: ‘holiuhod during the potion at drug n¢tten, tad ch. concomitsat vxlutl disturbunncn (blurring and oaalllopllu) use unwed. suzmu, ”that: an tiuitm «mm a shelttton uanll d1.1:ution of this syupton nttor tho insection at of unytul. ow downs val thorn ta ultor tho porcupttoa a! ntuult¢nooun tacttln stimuli in all nubjoots. Thar. was an nltaratson in annnrtl paracptutl tauntian as wall as th. 19¢t1~ laud porutptunl luantlout. ’laistzng nonuary dyltuactiau its oumutod with the ”actuation of «not: not previously mm at. it... slt-tntxonn 1n porecption var. 31.11:: to thou. lollowtax prolonsud unsuthnutn er cloctrolhuck thortpv. Intrsvonoun barw bituruto any to a «metal tdaunat in oltattin; or oxnggnrutlnc nournl dystunottun. that. routtnn nuanzaatiou yield: equivocal 53553513 rumults. Xutruvonoau unytul �\V‘ “I ' Reprinted from TRANSACTIONS AMERICAN NEUROLOGICAL ASSOCIATION 1953 NEIIRIIPHYSIIILIIEY LABZ’IIA'TII'W’ HILLSIDE HOSPITAL GLEN OAKS, N. Y. EFFECT OF INTRAVENOUS BARBITURATE ON PERCEPTION MAX FINK MORTON NATHANSON PHILIP S. BERGMAN AND MORRIS B. BENDER NEW YORK The effect of intravenous barbiturate on the perception of multiple simultaneous cutaneous stimuli was observed in large groups of normal subjects, patients with diffuse and focal cerebral disease, spinal cord lesions and psychogenic disorders. Each was examined before and after the slow administration of 2% per cent solution of sodium amytal in doses of 0.15 to 0.50 Gm. As nystagmus, slurred speech, ataxia and drowsiness appeared, the injection was halted and simultaneous tactile tests were applied. The examiner simultaneously touched the subject in two places—such as the cheek and the hand—and asked him to report what was felt. Tests were repeated with various body combinations, and the reports recorded. The effects of sodium amytal on modalities other than touch were also investigated. In all subjects sodium amytal caused errors in the perception of the simultaneous stimuli. Normal subjects under the inﬂuence of the barbiturate frequently reported only one of the two stimuli (extinction) ; e.g., in the combination of face and hand only the stimulus to the face was reported. These errors were transient and ﬂuctuated during the period of drug action. Similar behavior was noted in patients with psychogenic disorders (psychoneurosis, depression, schizophrenia). In patients with cerebral disease, amytal brought out defects not previ— ously apparent or exaggerated existing signs of dysfunction. In this group the errors were more pronounced, persisted for longer periods, and showed less ﬂuctuation than in the normals. In patients with focal cerebral disease with sensory defects conﬁned to one area'of the body, amytal brought out errors which were not apparent even with simultaneous tests and it deﬁned more clearly the extent of the sensory disturbance. Patients with diffuse cerebral dysfunction who previously made no errors on simultaneous tactile tests, showed repeated errors of extinction and displacement on both sides of the body after small doses of amytal. Patients who showed extinction or displacement prior to the amytal per— formed differently after the drug was given. Errors became apparent in body parts which prior to the amytal were reported correctly. Furthermore, the phenomena of exosomesthesia (displacement to extrapersonal space), allesthesia (displacement to the opposite side) and partial displacement . 244 5’) «L I �Fishman—Intracranial Pressure 245 (incomplete ipsilateral displacement) were also evident. In all patients with organic mental syndrome the duration of the perceptual errors was frequently longer than the Overt signs of drug action. The perceptual changes lasted longer than in normal subjects after similar doses and were more consistent. In lesions of the spinal cord, the sensory defects became more apparent; extinction could be elicited over a larger area and the level of sensory defect became more distinct. In two instances, however, a previously determined sensory level could not be elicited after the amytal. In tests of other sensory functions, nystagmus on direct forward gaze was abolished during the period of drug action, and the concomitant visual disturbances (blurring and oscillopsia) also disappeared. Similarly, patients with tinnitus reported an abolition or diminution of this symptom after the injection of small doses of amytal. Summary: Intravenous amytal was shown to alter the perception of simultaneous tactile stimuli in all subjects. There was an alteration in general perceptual function as well as the localized perceptual functions. Existing sensory dysfunction was exaggerated with the production of defects not previously apparent. These alterations in perception were similar to those following prolonged anesthesia or electroshock therapy. Intravenous barbiturate may be a useful adjunct in eliciting or exaggerating neural dysfunction, where routine examination yields equivocal results. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effect of intravenous barbiturate on perception. Trans Am Neurol Assoc. 1953; 3(78th Meeting): 244-5. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-001-12-016 Date A point or period of time associated with an event in the lifecycle of the resource 1953 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Nathanson, Morton; Bergman, Philip S.; Bender, Morris B. Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [Preprint] and reprint. Reprinted from Transactions American Neurological Association. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/f8b5cf3cf6b847561379d21a8181ceef.pdf 550c4683b921dafa008583e1e9dd5aff PDF Text Text ��COPY Clinical Release PRODUCT Combination of 'Thorazine' and Diparcol (SKF #1026-A) Diparcol alone 'Thorazine' mg/cag. ca . FORMULAS 50.0 mg. H01 2.0 Magnesium.Stearate Lactose 200.0 -__- ---- mg. mg. 300.0 mg. is. Restricted Medical Utility Studies - Dr. Herman Denber TOXICITY Acute Intravenous Toxicity The intravenous acute toxicity of a combination of SKF #1026—A ('Diparcol') and 'Thorazine' in the ratio of 5:1 was determined. Intravenous LD50'S in male mice (CFl) were determined for SKF #1026-A, 'Thorazine' and a combination of SKF #1026-A and ‘Thorazine' in the ratio of 5:1. The mice were observed for a 2h hour period, at which time all surviving mice appeared — normal. Combination significantly more toxic than SKF #1026-A (T.R. = 1.2) 'Thorazine' ngt_significantly'more toxic than combination. (T.R. 'Thorazine' significantly more toxic than - 1.36) SKF #1026-A (T.R. = 1.13) acute intravenous toxicity in mice of a combination of 'Thorazine' and ‘Diparcol', in the ratio of 1 part of 'Thorazine' to 5 parts of 'Diparcol', did not differ significantly from that of 'Thorazine' alone. Such a comparison is valid since the slopes of the toxicity curves are parallel. The combination is significantly more toxic than 'Diparcol' alone, but the comparison is subject to criticism.that the slopes of the toxicity curves are not parallel. The December 9, 1955 �DIPARCOL In answer to your request an attempt has been made to find data comparing the anticonvulsant activity of Diparcol (Diethazine, SKF #1026) with.that of other phenothiazine derivatives: Phenergan (SKF 1&98), 'Thorazine‘ (SKF 2601), Promazine (SKF 3h06), 'Compazine' (SKF h657), SKF 5277 and SKF 5116. No such studies have been done in our laboratory. The only SKF lab report on Diparcol gives its toxicity as LDSO * 31.2 mg/Kg I.V. as compared with 22.9 mg/Kg I.V. for 'Thorazine'. Balestrieri (1955) compared Diethazine, Phenergan, Parsidol and chlorpromazine with respect to their protective action against electroshock and Metrazol seizures in rabbits. Phenergan and chlorpromazine showed no anticonvulsant action against electroshock seizures; Diethazine, 5 mg/Kg I.V. protected 2/5 animals and at 10 mg/Kg I.V. 3/5 animals. Parsidol protected 2/5 animals at both doses. These results confirm SKF data obtained using maximal electroshock seizures in mice which showed no anticonvulsant activity for SKF lh98, 2601, h657 or 5116. SKF 3h06 did protect mice against seizures; the ED§Q was 155 mg/Kg p.o. SKF 5277 also demonstrated anticonvulsant activity with an oral ED50 of 71.0 mg/Kg. , Balestrieri snowed chlorpromazine to be Metrazol seizures. Phenergan was inactive inactive in protecting at 5 mg/Kg I.V. rabbits against but a 10 mg/kg I.V. protected h/5 animals. Diethazine protected h/5 animals at 5 mg/Kg and 5/5 at 10 mg/kg. ParSidol protected 5/5 animals at both doses. ’No similar SKF data are available. The experiments of Anticonvulsant action and molecular structure of phenothiazine derivatives. .krch. Int. Pharmacodynam. 103:1-11, 1955 Balestrieri, HLM:pz hc A. �COPY- PHARMACOLOGY REPORT November 8, 1956 10-(2'-Diethy1aminoethyl)-Phenothiazine Hydrochloride 0R (Diparcol) SKF No. 1026-A Compound: Code No. Lot No. 99 Structure: )W ii /” '\\ K\//h\§v/\ EV 1 9H2 l c H2.N-( 02H37~2 mignzim.R.T.Cmma' Tested for: Dose Range - .HCl Mmda Studies in mice after intravenous administration (11/10/55) Observations Dose rug/kg side effects 2.5 No 5.0 2/2 slight depression, loss of pinnal reflex 2/2 ataxia, sl. depression, loss of pinnal reflex, 'Thorazine' walk. 2/2 ataxia, marked depression, dyspnea, 'Thorazine' walk, loss of pinnal reflex. 10.0 15.0 6/6 clonic convulsions, apnea, prostration, ataxia after recovery, hypotonicity, 3/6 dead 2/2 clonic convulsions, apnea, prostration, ataxia after re- 20.0 25.0 . cover h otonicit Note-—all animals recovered from.prostration within 60 minutes.. Summary: exhibited 'Thorazine'-like side effects after intravenous administration in mice. Slightly higher doses were required to produce depression than with 'Thorazine' and the depression produced was of shorter duration. SKF #1026—A 'Thorazine'-like Activity: Charge: Biological screening GW/IB/m/mh �LILLY LABORATORY FOR CLINICAL RESEARCH INDIANAPOLIS GENERAL HOSPITAL INDIANAPOLIS 7, U. S.A. December 29, 1955 Max Fink, MOD. Hillside Hospital 75-59 263rd Street Glen Cake, New York Dear Dr. Fink: In answer to your recent request, Storey et a1. (Antibiotic Med. & Clin. Therapy, 2c258, September, I§§STI though they do not report electroencephalogram findings, do discuss the behavioral effects of cycloserine. There have been no publications, to my knowledge, reporting EEG findings in patients receiving 'Seromycin' (Cycloserine, Lilly). Veterans Administration hospitals have been doing EEG tracings but their reports have not yet been published. They will probably present their data at the Veterans Administration Conference on the Chemotherapy of Tuberculosis to be held in St. Louis in February. do be not we of further please may assistance, any If hesitate to w rite us. The Very truly yours, f th, M.D. ri Clinical esearch Division R. mlw 18760EIGHTIETH ANNIVERSARY-1956 �TELEPHONE: LEHIBH Form 90a-Adm. 4-1300 State of New York Department of Mental Hygiene MANHATTAN STATE HOSPITAL JOHN H. TRAVIS, M. D. DIRECTOR IN Ward’s Island, New York City 35, N. Y. ANSWERING REFER To ______.______._____ Dr. Max Fink June 20, 1957 Hillside Hospital 75-59 263rd Street Glen Oaks, N. Y. Dear Max: your findings on I should like very much to include Chloram on I that writing the final in paper the 'Diparcol' me send Could of you Treatment Depression. promazine-Diethazine diethazine I.V. of the effects in general, note indicating, a brief on the EEG? Were there any concomitant psychological effects? of "personal reference under the of note I will course, this, communication." Many thanks. Sincerely yours, [/7 HD:SS Herman C. B. Denber, M. D. Director of Psychiatric Research �4;:- x} June a?) 1957. Dr. Hem 6. B. Ember, Dimmr of Payehiatma Bsmmh, Mahatma; State ammm, ”55W"! 1818M, ”at. f: , Dear Hm Itwaaaplmto Atlantic city. I am aomr that mm we We withyouandymwﬁein mum could not. get. smother for "mucus“ much. Johanna and cmvisit. I social enjoyed bht very Mb: 5.3 who: moth with a wry Might. boy, But this yw' almdy may: Mahala, Ina 1mm. A9 fer our “parlance with your suggestion in 1 obtained some intmous manual from SKI. In the last 1w ‘mths we hm given it. to six ”news intmmly. Evin subject and tt. {um at" electroshock therapy and the trim of the I. of much. In sank instance high height. of m: mo 1n In: an the premix "mag abatmmphdogm u’mrity tam. the but situation, in which I and an we qmamm 3 and than remand after the parlour M the Watt-attests cf the d 50 2 of the The rate was mm. dosage drug gvmat smnmum. and than abuut for thirty ”cording a at. of the air. rate mast how the to for eight Manama unplug :pprmntnly mm hour. mm. mm mm, W 93.03th m m mm W» 6!me We: m. mum WW m W m ma Way m hiring the ministmtion, each patient Moped, batman the coma um fourth cc. m epdseda of waging. mare m macaw in breathing which an trunnion. This was the mat untoward attach a: m m alaotromcophnlosnphia ohms pared gradually but was mt. M: the: tho of minutes n injection. within tan 150 ace mm apparent. to thin tin mm veto mead rm a may a! than mansions 70 rum rmmyms toammcf in mm» Wt.- mmumm. tamper-u MWalimdzm;wnwegemmWofﬁmSma cent. tin 691th, however, mad about the sum. Mb 3:: «that peanut! far one to an hours and in :1]. WWW 1n the maples “loan about four to time: hours liter the Gilt: activity at at the pro-injection m1. In an. “outpatient:mdauutiﬂtymmotthaomrofhto66330.3“ caploﬁon of the Winn in value” of he to 70 UN. mm the delta activity am: ”My ma in pomnt tiny and in voltage u: that. m an: amount! mam- him he Waits. nun appeand stupor-impound ﬁlm �Dr» new at Bar mr, #2 a clearly defined 25 cpl. nativity... Tlmm records the the was an ”alerting? following. report Warmly animated by an incmaad methane” ai‘ we patient and a crust. “ibis greater difficulty in having the patient maintain his eyes gazed, ma tbs change in hm patients from: a "Home for this alerting phenm effect to a mgative am)... The changes in language after positive were the reverse of the changes in language which we have axperlmcod 131ml 1n the past after tho amatmtion a! mama-him. Since we use the identical w scone the changes in 11am in an Mammal fashion. In maimaim, three Mamas the questions prior to the of Dime}. wen 11-. and therefore to ovum.“ the changes in Imam. negative Waible & “manure" In one manna tha max-d changed in to an 1mm. mama clung» of the kind tkmt we see: with mbarbim. This dinmponcy I. cannot explain. m m m1 m 1mm W10 rm manna; am eontinning this study and I would 11m to pmmt the behavioral and electroeneephalog‘aphia effects My in the £111 to the Eastern EEG Association. Thaw observations are, of eourse, migratory and I am not 8m 8 UT the next batch or patients may not shot-7 us some other patterns. To tho ﬂat extent. that. this inmatigation has confirmed the observations of Leann”, I an moat yieased. Ha I have no objection to war reporting some of this itﬂ'omtian in outline. If is of any help ta you, I will be pleased to see the paragraph: as yen intend to report, them and give you my reaction as to how they reflect. it our axpoziemaa, Sincerely yours,Kn: Fink, Dani-haunt at MFtJB mammal Pnyuhiatry. H.130 �“,f ‘i? ziirect i v . i of Diethazine on EEG ’5‘ 0+3 qt I for and Significance Theory of Convulsive Therapy Mauougﬂwk.ﬂdb Previous studies of the role of EEG changes in convulsive therapy delta activity for have demonstrated the significance of the induced the behavioral re3ponse. Investigations concerning the biochemical substrate of delta in electroShock and convulsions EEG have indicated significance for the cholinesterase - acetylcholine system. reports on by Ulett concerning the effects of atropine and Recent 00’ scogﬁlﬂhine the delta response-efﬁhe-EEE-showed a reversal of the-induced patterns. Boncurrent iswmvaﬁ. reports by r and of diethazine on normal EEG and that following Lechner on the EEQ effects trauma provided the stimulus for the study of the effects of this drug in electroshock. Subjects: Twenty voluntary psychiatric patient in an openyward/psychiatric hospital have been tested to date. d " £5? During recording, at various maturing (Biparcol) is administred intravenously at per minuteI Maw “'5’57- £155; xi treatmen . rmi 94°" " the rate of 25 milligrams ‘1 250 milligrams, {My diethazime 70.,qu * �Observations : a) by the of All dryness cmgling, respond subjects Behavioral“ mouth and thickness of speech. Feelings of weakness of extremities illusory sensations are and There common. is an increase in rest- lessness and difficulty in maintaining eyes closed. In patients who have had sufficient electroshock to manifest syntactic and orientation language changes indicative of altered cerebral function, is there ‘ b) EEGSq a reversal of language patterns. . In all subjects there is desynchronization of frequencies \ and decrease in voltage. Alpha rhythms are less prominent. ! low Occasionally, \ -—-a c" In voltage “ILA 577’ frequencies appear. \ voltages-a25of delta with degrees varying activity, patients in decrease‘, frequencies decrease and burst activity disappears. Irregular alpha and beta frequencies of low voltage become c) The EEE and persist clinical effects consist for gradually disappear. one mmminent. to three hours, and �Discussion: The pharmacologic effects of diethazine are described as "anti- cholinergic" and "atropine-like," and in patients with altered brain function may be h described as "allert‘ electroshock induced m (Ulett). EEG delta is P The action of diethazine an 0 . scopﬂl ine similar to atropine and eeelpalemine (Zinc ﬂoss observations era‘similar to those in subjects with head injury (Jeéhker and Lechner). Conclusion: ‘1'“ Based on this data, as well as the cerebr¢{:§pinal ﬂuid cholin- esterase studies of Bornstein) and Tower and McEachern, . fuedJLb£1 diethazine hes-e ready that: (l) ' ' it is .: enter the central axrhnL; and trauma induced electroshock by by delta system3(2) a . concluded nervous 4' may similar A have biochemical substrate;(3) electroshock may be looked upon as a controlled 6F Alana; method tc.indnge ce ebral dysfunction for The its induced behavioral significance of these observations for EEG studies of head trauma and the mode of action of gin-ilpconvulsiVe therapy discussed. effects. will be �//— £3th at Diethuine on 3%: and Significance for Theory at Germanium mm Previous studies of the rule of have demtrnted EEG changes in convulsive thenpy the eigmfieam or the induced delta activity for the behwioral response. Imeatigetions containing the substrate of EEG 1:10ch delte 1n electroshock and convulsions have inﬂated significance for the eholinestemae - mtwlchonne system. reports Ulatt concerning the «treats a! atropine and by anthedalta patterns, response otheEEGshemdamml of napalm theinducedm Goncurrent reports by Jemkner and Lochner an the ofﬂiethum «1110;14:11me Recent. effects mtrmmmmmmm atimelua for the study of the effects or this drug in electmahock. Subagetet Twenty voluntary psychiatric patimte in en upward/psychiatric hospital have been tested to date. Electroencephalogm have been obtained mutant. During the recording, at. various ﬁnes during (limit) is administer! intmemualy per me until at. the 250 Milligrams have been rate of Metered. diethume 25 milligrams a an �¢2~ mumations: a.) Behavioral - 51]. subjects respand by coming, dryness (J the math and thickness of speech. Feelings of weakness of extremities and mm. illusory sensations are Mamas is news in mt. an difficulty in maintaining eyes closed. In pgtients 3nd who have had There Mficient ehctmhwk to manifest syntactic and onentation language changes indicative of altamd cerebral function, them in a reversal of language pattern» b) EEG ~ In all subjects than in Voltage. and decrease Damionﬂly, 10w is «synchronization Alpha W of Inqueneies are less prominent. tnqmncies appear. voltnga In pstinnta with varying dogma of delta activity, voltaga is deemed, tmquemiea in “cram am} burst wtivity disappears; Irregular alpha and but: fmqmnoioa of law voltage become more a) Tho W and liy clinical eﬂwta diuppnr. . pox-stat mm gamut. for om to than hours, and �A! mammalian The phnmaeolog'ic effects of diethuine are described as ”anti- cholinergia“ and “atmpimlﬂm,” and in patients with altered brain function may be doacribod an ”martini." The action of electroshock induced (Butt). EEG delta is 3min:- to atropine Also, than. observations with hast! 11131211 («bunker and m diothum 8nd n W napalm 51:11” to than in subdue“ Mr). 091191113th Band on this data, us all 0 as the carom spinal ﬂuid wanna «tea-am swarms of Bernstein and Tower and IicEnchem, it is minded that: (1) diothuine has a randy ability to enter the central nervous system (2) delta induud by electroshock and by trauma my have similar Mommioal substrate (3) electroshock my be loolwd upon as a controlled m’chod to induce cerebral dysfunction for Ema tm its induced behavim'al effects. hand for'EEG of atxﬁias of these obsamtiona significant: and the mode of discussed. act-.1031 of electmcomluvo therapy will. be �MM or blow swam m and Gmmlaim Therapy on m m, for 1119on of 24.13. me changes in wmulsive therapy have the signifiam of the induced delta actdxiw for the biochemm umoarning the Invasﬁgatlans tome. have EEG and indicated electroshock emulsions of delta in mutate nignﬁmm tor the ahonmuem - mmdcholine system mm. Pruvioua studies Wand 1:6de at the rails of. otatropdmandaoopolmo Wbymttcommmgmeﬂw EEG induced showed EEG or cloctrashook a moral in an pattom. am: Comm-rent reparts by Janka»: and Lechner an the: extent: of on mm]. EEG and that. following tram provided this stimulus far the study of the effects at this drug in electroshock. mm Salaam” treatment various during ht stages patina“ puma-lo in an open—ward voluntary psychiatric hospital have been tested to (Dimmol) is manicured date. "During EEG recording, int-.mwaly at the rate of 25 milligrams- por minute, for a total at 2% Twenty diam W0 Mmtionu ' : a) %: b) m m All subjects respond by coughing, dryness of the thickness of mach. Feelings of weakness of emu-mitten mm and illusory marathons are cam. more is an immune 1h restless. mas and mamty 1n maintaimng eyes clued. In patients who have had sufficient. electroshock to manila“ syntactic and orientation language changes indicative of album earabral function, there is a reversal of language patterns. more 13a doaynchrmiuuon of rmmdes down» in voltage. Alpha rhythms are less lament. Occasionally, 1m? voltage theta frequencies appear. In all subjects In patients with varying demos of delta activity, voltageand burnt increase frequencies activity disappears. Irregular decmo, alpha and beta Imumcies of low voltage become prominent. c) The EEG and clinical effects persist for one to three hours, and gradually disappear. Fm Department of men Oaks, ELY. than 1.1-6.5? - EAEEG mmm Psychiatry, Hillside Hospital, �‘5 of downbeat aﬂoat: dawn» m Wohgie u ”antiwhonmtgie" and 'ttropine‘uka," and in patina“ With slated brain imam any be 6030de as ”wrung.” the mum at on ahctroshack induced EEG delta is amm to atropine 610mm um! £39me (010%). mm ebmmﬁom an aim similar to ﬁrm in aubjccta with bud injury (Janina: and helmet). The cmcluaiam Mac! on this duh, as «11 as this cerebmspinal fluid cholimatamso studios of Ben-MW, and Tower and Wuhan, is wmludod that: (1) damn» mam entm the «antral nervous system; (2) delta nativity inducod kw alwtrodmck and and by tram may ham: 3 similar (3) mutate: mm be lookad upon an o. watt-0119c! ”that! of naming «mural to: its behaviaral affaa‘w. it mmwu m Wanna The «:1ng the or action of convulsive: therapy will trauma and node of thew than mamtiom for m ”adieu or had be animated. �v -r:‘V?\'(‘r.uv' w--w—ILW|>L‘»V‘V'~B—w"y:mm w—r-mw-vwn»vww.,u—A » v —.-.r. -- .vr. w—y ~ w — "av/\— <7 r ,rw-I'IWK . aw u 'mwl' - - - "a.“ AM'HV'Wwv _,,, A was �wan-my r'm ��Form 90-Adm. éhhft$nk jﬂuh ﬁsgrlﬁatrit gustitute 722 WEST 188'"! STREET. LAWRENCE B. KDLI, M. D. nlnlm'run NEW YORK December 4, 1957 Dr. Max Fink Dept. of Experimental PSychiatry Hillside Hospital 75—59 263rd Street Glen Oaks, New York Dear Max: feelings about Saturday night are reciprocal. Weihoroughly enjoyed the gracious company of you and Martha. With the intuitive perceptiveness of the female, Yetta informed me of a forthcoming event in your family, and we Wish you the best of everything. I indeed look forward to the reprints on your Work which you described in your letter and our discussing them together. The next edition of the Kalinowsky and Hoch will be expanded to include tranquilizers, and I would also appreciate any reprints of yours in this area. I have enclosed my own reprint on the clinical effects of Win-2299 and the basic paper by Luduena and Lands. As you will note, the compound is a peripheral anticholinergic and produces a "disorientative" reaction in cats by central action. Its psychotomimetic action in man appears basically to be an acute toxic reaction type. I would imagine that its central mech~ anism of action is similar to that of atropine (which also produces acute confusional states in high doses). Win—2299 is effective at much lower dosages than atro— pine. Possibly both atropine and Win—2299 both produce central effects by an anticholinergic action but, as far as I know, this modus operandi has not been pinned down crucially as far as the C.N.S. is concerned. I would not expect all anticholinergic agents to be psychotomimetic, of course. Win-2299 is a tertiary amine. Monodral is a closely related drug, differing only by quaternization of the terminal nitrogen in Win—2299. It is Win~4369 in the paper of Luduena and Lands (p.283), i.e. the methobromide form. According to Winthrop-Sterling, it is a peripheral anticholinergic in man in doses of 5-40 mg. per day. Central or psychic actions are not mentioned in their account. Presumably, quaternization reduces central activity by reducing permeability. Our �Dr. Max Fink (cont'd) ’ -2— I imagine that other agents in the Win series with central effects in cats might also be active as psychotomimetics in man. I am not familiar with the formula of diparcol and if you have it available would appreciate learning where to look it up. The drug is not covered by Goodman and Gilman. I would appreciate return of the Luduena and Lands paper when it has served your needs. We gave the Win—2299 the orally, The compound being drug was supplied as the supplied in tablet form. racemic mixture, the asymmetric carbon atom being terminal in the aliphatic chain. Sterling—Winthrop may have it for intravenous use and I suggest that you write M. L. Tainter, M.D., Director, Sterling-Winthrop Research Institute, Rensselaer, N.Y. about it. Our oral supply was used up in the study. As you know, all psychotomimetics not only create new symptoms in mental patients but also intensify or revive pre-existent symptoms. Best of luck. Cordially, ”2a Harry Pennes, H. HHP/ys Encl. M.D. �PA if .. _ * (on 1M5? I Effect of Diethazine on EEG and we Significance for Theory of Convulsh M Therapy MD Mow In a previous report to-this society we noted the relationship between the degree of induced delta activity during the course of therapy and the behavioral reSponse to electroshock. Those patients, in delta activity were induced early, and were degrees of behavioral change, as well as a significantly greater percentage W gm vial £64414a Law In. Box} EH: acetylcholine and in whom only low degrees were induced (Fink and Kahn, 1957). activity 1, (ii; '1.) high degrees of sustained, manifested the greatest of improvement and recovery than those patients of delta whom ,hML-wQA‘O‘ . a, W" , ‘Jawc‘z MM L Mkﬁl‘g‘f‘” ’M‘Af‘z‘ mv’efrff " in!“ (.4 Mﬁanges infree” ' a variety é‘fu‘reports, cholinesterase in the Spinal fluids of patients (Sachs, 9. Ward) and animals (Bdrnstein, Tower and McEachern) following head Wig; . . I the observations that by trauma M o (Bfrnstein, ﬂue/4% In 1956 .c‘ E agents liq—alter the EEG patterns induced Ward, Jenkner-Lechner) and by electroshock ( “knew“at?mp (Ulett)pu_l Ulett reported that atropine g’scbpolaminerwhea-aéiénéstered— / W, blocked the appearance of the delta wea»...have come to associate with - _,-.,..«-'V'F-r -v~ WWW ahaaul,” "‘4“qu w. traumalawﬂ electroshock therapy. A!” 791’] am’LlLJ/g/J M ’L “‘2‘“ 4“““4/ié’MWrrW ”“an“ j?” activity {lama/Wye? v» �-ebeervetions~ Previously, ward (193) following the suggestion of Bornsteiny (19h6) had noted that atropine altered both the EEG patterns and the neurologic signs induced in.man by head trauma. aﬁereT-tee, the side ZZ,AQA7V ~effects were marked. In 1955: Jenkner and Lechner reported that EEG behavioral effects similar to atropine were achieved by diethazine istered in patients with head trauma.‘ They and admin— also reported the effect‘of diethazine in normal subjects. It is the purpose of this report to describe the effects of intravenous diethazine on the EEG of patients during electroshock therapy; and to relate their these findings to the present neurophysiologic-adaptive hypothesis of the ndde of~action of convulsive therapy. w ‘ﬂwmwmﬂmwwwﬂ_ﬂ____.imm 3" Diethazine is a soluble phenothiazine compound with phamacologic properties similar to atropine. In experimental animals, (19h?) have noted that diethazine blocks vagal slowing of the heart‘) M suppresses the bradycardia, bronchospasm, salivation, and fasciculation and seizures induced by acetylcholine, DFP ‘‘‘‘‘ ‘wywwﬂﬁmgimww‘ﬁzoxsum-“:- w' ”mm—«MA..- and pilocaxxﬁxg and induces dry mouth, mydriasis and hypotension. L/——' / Heymans EE.E£ a“: nevus-aw» 4.: '2‘ YW',‘47"’~"5‘W1‘-05 Emma-gwhz - .— ' .~_4~:_MD~J �93" ”w W Subjects: Twenty-two psychiatric 42‘ patients,” various stages of electro- shock treatment in an open-ward, voluntary psychiatric hOSpital have been studied. the laboratory. Following a routine EEG administered intravenously at the rate of of 2630 to 250 mgm, the i Tl’br.‘ EEG 25 mgm per minute, for a total effects. Prior to the historical interview and a structured questionnaire period were tape-recorded. EEG recording, diethazine was depending upon the behavioral drug administration, an unstructured both EEG gubjects were tested in Following drug administration, recording‘ and recorded interview periods were continued until record again manifested.the pre-injection patterns on visual inspection. Mm New. ‘>IIVW~.. Qbservations: in Le ,, (a) Clinical: AH su jects manifesm Spontaneous coughing mutual-i33- @ followed by a dryness of the mouth and a thickness of speech. ﬂgrtrf They note‘, ' 3'37 a feeling of lassitude and weakness of the extremities? soon followed by increased restlessness and difficulty in maintaining eyelid closure. phenomena were PSymW/clearly between 15 and 30 minutes . manifested in after some subjects. In the rest period drug administration, six subjects spontan- ..,. _‘ ... _ A �4,. eously voiced feelings of unreality, visual and haptic illusions, and delusional thoughts about their illness, the setting of the test procedures or our identity. Such patterns were transient and had disappeared In by the termination of the experiment,-asaallyhiééﬁﬁurdﬁnnxrdnmzns. three subjects, increasing agitation . and panic led to a cessaﬁon of the recording. éHere7-tccy—restétation_a£—pme—énjenﬁﬁnnrdnﬁuuﬁuuaauua I 'li' g“, , I! i . ﬁilliwuwﬁ (b) In previous studies, the intimate relationship we had noted between changes in syntactic language patterns with alteration in cerebral function induced by electroshock. In subjects tested prior to electroshock, diethazine induced changes in syntactic pattern of an "alerting" variety. I - gal [5% In subjects with elta activity‘ with clinical syntactic patterns indicative of an alteration in cerebral function, diethazine induced a transient dis- appearance or minimzation of Such language in language (c) was concurrent with changes EEG Patterns: In all patterns. The period of changes in electroencephalogram. records, there is a decrease in voltage and desynchronization of frequencies. There is a decrease in prominence of prevailing rhythms. In patients without delta activity (pre-electrodhock)’ �-s5‘ 4/ this deéhronization and voltage decrease is occasionally accompanied by the appearance of small amounts of low voltage These are demonstrated in Slides 1, not appear to be altered. The and 2. The 5’7 '5' cps activity. basic alpha rate does build-up in voltages and appearance of thm slower frequencies with hyperventilation is blocked. In patients with varying degrees of induced high voltage activity voltage”, both random and 4 This change It and 3 dub is a decrease in burst delta activity disappears; and irregular, / low voltage alpha and beta frequencies become prominent. are noted in Slides delta These changes LL. 5W in is manifest in appears during drug administration, and all electroshock subjects. persists for awe. [WM ﬁlwwx 13% 2/1. ﬂoncurren WithAelectroencephalographic hours vtwv ‘ ”fly to three age MM» Wrens-em ﬁith the 8&3 17TH 770 n moustita—tion— of the pre-injectionEl'I} patterns, the pre-injection behavioral and language patterns again appeared. �DISCUSSION: report of Jenkner and Lechner of the t”t.¥£~£ dikd/“4lz‘ijzz7' effects of diethazine in"normal" subjects. 'Wa.alsa—nnta_tha§21iethazine These observations confirm the alters records-snd-ﬁith electroshock induced delta activity in‘a fashion similar to atropine and scopolamine, as described by Ulett, A Mada» W was. . 1%,. is apparent, therefore, thatngﬁ readily affects the central nervous and.é53 duration system, ofiactivity is most useful for experimental purposes. The-previeusiy—eitnd studies by numerous Observers of nervous system effects of head trauma point to an intimate relationship between the degree of neurologic dysfunction, the degree of EEG alterationjgand the level of free acetylcholine in the spinal fluid. The effect of atropine both the Echand ill on concomitantly on behavior in subjects with head trauma lends further support to the significance of ﬁgs: acetylcholine as the biochemical basis for the observed EEG patterns. In these studies of diethazine electroshock, the intimate relationship between EEG patterns and and behavior �-7have been reported. We note the parallel to the observations in head \ trauma. On the basﬁs of these observations, as well as studies of Spinal fluid Woholinesterase levels; (Tower we would and HoEachern, Fink and Goldenberg)‘ suggest that the biochemical substrate of the electroshock process. is isimilar to that of head controlled trauma.9 method of inducing ectroshock hLauri. may be looked upon cerebral dysfunction for its as a behavioral effects. Previous studies have demonstrated that alteration in cerebral function provides the physiologic basis for the behavioral changes in electroshock (Fink and Kahn, 1957). Such alteration in cerebral function provides the milieu for a change in the organism's adaptation to his environment. aSpects of behavior, as perception, language, mood, recall, memory, All affect, undergo change, and provide the basis for the therapist's evaluation of improvement. The studies of diethazine amplify this neurophysiologic 9.39.9. adaptive hypothesis of electroshock by suggesting the type of biochemical substrate that underlies both the physiologic and the behavioral changes. �Mm= 0 Diethazine, a pftent anti-cholinergic compound, u was experimentally introduced intravenously in psychiatric subjects,;ﬁ various stages of convulsive therapy. Electroencephalograms manifested a desynchmnization of frequenciesfue («C decrease in voltage records without prior delta activity. Records with delta activity showed similar changes with disappearance of delta burst activity. Concomitant with the electrographic patterns indicative of It is concluded a effects, behavioral reversal of the electroshock effect enters the central nervous System upon intravenous (b) The biodemical basis for that of head trauma; (c) therapy The may EEG compound that readily adninistration. changes in electroshock is similar and biochemical basis of the lie in were observed. that: (a) Diethazine is a Bitent anti-cholinergic to and language mode of action of convulsive the acetylcholine-cholinesterase system. a, �@ Research and Development Division SMITH, KLINE & FRENCH LABORATORIES PHILADELPHIA - I ESTABLISHED I84| December 11, 1956 Max Fink, M.D. Director of Research Hillside Hospital 75—59 263rd Glen Oaks, Street New York Dear Doctor Fink: associate, Mr. C. W, French, has referred your letter of November 12 requesting a supply of diethazine to me for reply. It has taken me a little While to uncover-sufficient supplies for the short clinical trial you want to conduct since our interest in diethazine alone and in come bination with 'Thorazine' isn't too great at this time. My not have this compound available in 500 mg. capsules as you requested. It is only available in 250 mg. tablets. A supply of this strength has been sent to you together with a supply of the intravenous we do material so that you is all the literature we this will be of some help. Enclosed hope the may Observe EEG effects on 10 have available on Sincerely yours, .\ to 15 patients. diethazine. I , J”, Meagan? Ms (,7 . John F. Buckley a Research Associate / ’ ' Medical Department JFB:hc Enclosures P.S. Will you kindly sign the enclosed FDA card and return so that we may keep our files up-to-date. it to us � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effects of Diethazine on EEG and significance for theory of convulsive therapy. Electroencephalogr Clin Neurophysiol. 10 207-208. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-29a-004 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 13 items. 1: Handwritten notes. 2: Clinical Release. 3: Diparcol. 4: Pharmacology Report. 5: Letter to Fink from R. S. Griffith. 6: Letter to Fink from Herman C. B. Denber. 7: Letter to Denber from Fink. 8: Draft with edits. 9: Two drafts. 10: Handwritten notes. 11: Letter to Fink from Harry H. Pennes. 12: Draft with edits. 13: Letter to Fink from John F. Buckley Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/86dcc852ef57150af5b9234a4c32a667.pdf 0ab52ac497e61e2b06bc38b78babd96f PDF Text Text EFFECTS OF DIFFUSE ALTERED BRAIN FUNCTION ON PERCEPTION BY MAX FINK, ROBERT L. KAHN and HYMAN KORIN ( Hillside Hospital, New York) PROBLEM Recent studies of the relation of perceptual alteration following brain damage have emphasized the role of focal damage. To determine the patterns Of perceptual changes with diffuse alterations in brain function, the following studies were undertaken. SUBJECTS AND METHOD Consecutive subjects in a psychiatric hospital referred for electroshock therapy were studied. Alteration in brain function was induced by varying the frequency, number and severity of the induced convulsions. The following tests were applied before treatment, at weekly intervals during, and two weeks after treatment terminated. A) Measures of altered brain function: Two quantitative indices were used to determine the degree of altered cerebral function: 1) the per cent time, amplitude and lowest frequency of the induced delta response in serial electroencephalograms; 2) changes in orientation and in language following the administration of intravenous amobarbital sodium. B) Perceptual Tests: 1) Tactile: Threshold perception (100 ‘X, point) of square wave electrical stimuli was determined for different body areas. Stimuli were then applied simultaneously to two body areas, with interspersed single stimuli in random fashion, and the subject was asked to report where he felt the stimulation. 2) Visual: a) Figure—Ground: Using embedded ﬁgures (Gottschaldt) of increasing complexity, subjects were requested to identify a simple geometric ﬁgure in a complex background. b) Tachistoscopic recognition: paired words were presented at rapid exposures to subjects. The words were matched according to tables of frequency in common usage, and were of two groups: relating to illness or to the body, and those not relating to illness. Words were matched \ randomly. ‘ �2 THEME 9 RESULTS With increasing degrees of altered brain function, there were increasing errors in reporting the simultaneous tactile stimuli. There was a concomitant rise in the threshold of perception. With high degrees of cerebral dysfunction, mislocalization of responses appeared, in addition to the persistent failure to report one of the stimuli. 2) The ability to isolate embedded ﬁgures was impaired in direct relation to the severity of the alteration in brain function. 3) Threshold for the perception of words increased and subjects were unable to identify two words with increasing degrees of cerebral dysfunction. 4) Changes in perception were highly correlated with other behavioral changes, indicative of an altered interaction with the environment. 1) CONCLUSION Diffuse alteration in brain function, as measured by electroencephalographic delta and orientation tests after amobarbital, results in alteration of perceptual patterns marked by an increase in threshold, impaired discrimination of stimuli, of which the ability to discriminate a ﬁgure from a complex background is a special example. 2) Alteration in perception represents one aspect of an altered behavioral interaction with the environment, rather than a speciﬁc physiological defect. This factor should be considered in perceptual studies in focal brain lesions as well. 1) ape. Inf. (Dong. ﬂieﬁoa E .- /f57 - gVH-SJa/S �3mm of Emma Altered Brain mum on Pomepticm m Fink, 11.13., mm; L. Kuhn, Bun. md than Karin, 31.33. mm gt the IV International Wrens of Psycholow, annuals, My 30, 3.957. �m at mm» Alton! Brain mum on Pauptian m of this study at alteration in Won fol-loving Mg» in «abut; mum ha been devoted to ram Mom u in nus-31m imam, dials 1!: head’ m md brain tumor. Litﬂn emphasis usually placed an the We effects of such hum on the pommml prom». In tha acme of this :tudiu in 1:ka therapy, we charred that may 13th aanaidonble neutral 0: the down at induce-d alteration of brain mum. In these studies we ware impressed with the wide variability in the behavioral and nmphyaiologie response 91‘ our subjects to apparent ‘ aquivalent mailbox-n of convulnima. madam We have Max:815? reported the a! the belaviaral napmsaa and the W: inter- dew of apparent new Widow-c manna-grandma mortistodowribgpomoptualchanmmrm conditions cf differing determine the down of diffuse alum brain relatiwahtp of the function, and 150 136th We to the indueed amm- physiologie change. I Three perceptual M113 Visual Visual mm mm utilised: perception of Gamma“ mm wave electriwl 1.3QO or mad gamma stimuli figure; :04»th of tachistooaopdcally presumed wows. �_...___.1 em: subjects were 2310 53 meetive hospitalized patients, rerun-ed fer electroshock. Brain mention was altered by meaning remitted grand m1 cemuleim under penteﬁml pmdicetim. a rmqwncy of three time per week. The convulsions were given For a control group, randomly eelected therapy; with equivalent umber of patients received eubeomalsivo Wimtim at pontothnl but with web» eonvuleive doses of electric current. All weluetiwe and same as in the experimental gmup at ~ and the type or each subject was not known to any of the tests were the thetmt in we fer investigator: until the experiment we ended. We Wmmgic indie“ were used. mameMz-ama, taken at weekly intervale an a day after an indueed maveleian, and mﬁtetively measured for the degree of incheed delta activity; and mobarbital taste for main disease. In this test, the language responses on a etenéandiled interview, are ”use“! after intravenous mobarbital. Mammal, 1W altered eembral fxemtice. denial, disorientation, and eyntuetieel as an 1nd!“ of Both changes have been enema these tests erem applied lure-armament and during the 2nd, are and 5th week: of treatment. The technique ef etch of the three pemeptual tasks will be doaeribad with the eomspmding results. For mm: a! thin mamtetien, the m mm to the quantitative «pacts only, and aa them is a wide variability in mangle response, we idu meant group data for obamatim apex-junta). and control groups wording to» the dogma at ﬁrst; mum ded- than were physiologic change. the observation: �__.____1 _. In this talk, isolated square WWW 1mm ma emu-ital atimuli were 81ml» We mmugh attnclwd 1 on .. dine electrodes. delivemd to two body point.) valwa were doteminod :or «ﬁx my part and $11“th the tasting, random single stimuli were interspersed to Meme errors due to ﬂuctuatien ef threshold. Subjects were whed to threshold (100% _ localim the npplieﬁ atimli. Slide 1 deem-1b“ the mean number of errors mtreament, and at the Widogic effect, which is manly after the 12th tram-b. The mzbeouvulsiw (mtml) group shes: a drop in the number of errors, the Mod pmotioa effect.» This canvulsivo group, tamer, Ihm height a? the induced & Meant increase in errors. patients with a who had first The immune in we: were _ manna. Pn-tmtnent,the In Slide 2, the group differences are diffemce in the number of more in the treatment course the difference: In Slide 3. the ineWimt, because ml. of the induced In the firm; section, the subjects in than Waive, and later m—tmtad been treated by a Waive course of thumpy. marked but at the height on? significant mum We is “tossed. who have had two new or thus positive to those with either no uobcrbitn tests during tmtmt are panties new. or only am. The number of errors: are higher in patients with mom positive moberbital responses. diffemnee 101' rm the pmmtmatmnt score, the group with the greater 601%! the Mm m aignificantlv different Wiologie avenge. In the second section, the encephalograpme Furthomom, in comparing the me melts response; and in physiologic inclines are oompared. ﬁlm are noted for the electro- third motion, the two new �«hm Errors in the 5:9er of ammo“ tactile mm 1mm with increasing degree: at altered brain function. 3: Bamegtim ‘01 W FM, 3: In true task, goo-atria figma embedded in a. complex dasigmd field are premtod «ml the subject is asked to tame the 9112913 figm. The slide 14 shown and subcmvulaive minim or Bath ﬁeld. simple figure is: simultaneously pmmted above thh complex the man manor warm». 'i'ha 91‘ art-era before and anhconvﬂaivo or control group, with no mnmphyaiologio change, thaws a drop Waive gramme show utter eumulaiva in the amber of an increase in true tugboa- or W mm. «mm. compared aide 5, the aubeomulaiw and Gamma” m bath befm am} mg the 5th week of treatment. man mamas, m difi'amwe in the who: of arrow is acted. It the height of tha cleara— In shock effact, the convulsive Wits We group makes aigzrii‘iomxtly more Change. the group. (31163 6) . visualized next tha in than calmly new am are divided warding to than degree of effect in Here, the Mrs than W a: the mutual to“, W Magic the oluctmonaaphnlngm, and tha mama data, there is a simficant diffemca in the mmbar of mm undo. Patients with higher dame: cf hummimgic chums mks ﬁn mt errant ”100th for their equivalence in fmmncy in mush matched, was mounted at rm. diffemnt speed: of mum Pairad words, usage and :3de taming from m to 250 rimmmdu 2130 of for a total mm. mum 13311607, the The mm m puma tn u wen-act morainewhgmupmpwmteﬁ. Harem, thumb- Wimt eonvulsive or control gmup ohm a amp in the number of while the group sham a much smaller practice effect. minim emu, �.59 In the are mud M 313.60 (8), the proutmtmat. and post-treatmnt «com The groups urination 1n the are 11611 More, untamed number of. arrears with alters-d and in both there is a brain function, Mt, the is greater than the convulsive. Thou are mt simifiaant. reduction in the aubconwlaive groups differences are and}. and In Slide 9, the role of neurophysinlagic change is again assess'eﬂ. toe, as in the wading slide,» them in a deem it: the pmtiae This is clearly effect with the greater the change in carebml now in tha canwlaxva Wagon seem, uhomtha patients with mm but Waugh Mags show a decrease in armra, while theme with the mam“. Hero, tam. Mainlogio change show a small umber of arrears. Ia this tank, in mtmat to the two pmeding on», the effect of altered 13min functim is not manifest in an increase in the umber or errors, but is seen only when the enacted immanent in performance fails WW1? mm thou-gum in «row mum In: m NM in psychiatric patients by the remand 92mm“). induction at grand m1 control Win emu perceptual in and experimental to chanson in degree when perceptual tasks, portion to the dogma er «smut-a1 cmlsim. in emu“ mp9, the mammalian) at on? «tubal ﬁguration hm baen obsozvod. increasing arrow" in pemaptian in pro- mm dwmﬁm in muréphyaiologic. indie” at mum m be observed. In addition to these pomeptual ml: changes, humor, there arm commmt altamtim in behavior, language. ariontatien, attitude and mad, and these am: highly Mama Mending upon individual 612mm“: 1n the subject“. ”the panorama). altemtima ducrihco’ here :3me but �we upset at tbs clung» in the Mom: 111th Farmer studiuﬁ cf this in ”spouse to mmbral lesions are mm hater in pmgrcsa. 91' tam. at” organism. indium mmw � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effects of diffuse altered brain function on perception. In Proc. XV Int. Congr. Psychol. North Holland, Amsterdam: 1959:15: 238-239. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-35-001 Date A point or period of time associated with an event in the lifecycle of the resource 1959 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Kahn, Robert L.; Korin, Hyman Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [preprint] and a publication copy. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/718a29ec15d25cbb6a477d3556be0fdd.pdf da7a7236e5d976ec8ac1cfd95b801264 PDF Text Text EFFICACY OF DIVIDED AND SINGLE DOSE SCHEDULES IN INSULIN COMA THERAPY ARNOLD G. BLUMBERG, M.D., PETER LADERMAN, M.D., AND MAX FINK, M.D.1 [Reprinted from THE AMERICAN JOURNAL or Vol. 116, No. 9, March, 1960] PSYCHIATRY, �1960 ] CLINICAL NOTES 839 EFFICACY OF DIVIDED AND SINGLE DOSE SCHEDULES IN INSULIN COMA THERAPY ARNOLD G. BLUMBERG, M.D., PETER LADEBMAN, M.D., AND MAX FINK, M.D.1 While many technics for the administration of insulin in insulin coma therapy have been advocated(3), recent reports(4) have assessed multiple divided doses as more effective and safer than other methods. Previous studies indicated that the production of coma was directly related to the level of hypoglycemia and its duration (1) and that deep coma for sustained periods was essential to the treatment result in insulin therapy(2, 3). It seemed reasonable to test the suggestion of increase-d efﬁcacy for a modiﬁed insulin administration by comparing the length and depth of coma and the blood sugar levels in patients treated both by single and divided insulin dose methods. If the divided dose schedule were more effective, it would be expected that the induced coma would be equal or greater in depth and duration; that the time for onset would be equal or shorter; and the blood sugar levels lower for divided dosage than single administration. the dose was increased in 10 unit incre— ments. At the time when coma was produced, a single dose equivalent to the 3 doses was given on the succeeding day. For each treatment, coma depth and the time of onset was determined. Coma was deﬁned as the loss of consciousness (failure to respond meaningfully to verbal signals), associated with the appearance of the Babinski reﬂex, and the loss of the lid reﬂex. An adequate coma treatment was deﬁned as the persistence of this depth of coma, or deeper (loss of pupillary or corneal reﬂexes) for at least one hour. At half-hour intervals true blood sugar levels were serially determined by the Somogyi method. The resulting blood sugar curves and their level at the time of onset of coma, were compared for each subject with the blood sugar curve and coma data obtained on a single administration of an equivalent dose. METHOD The blood sugar levels at various intervals after the administration of divided doses of insulin compared with a single dose of insulin in one patient is presented in Figure 1. This pattern has been reproduced in each of the patients studied. For each, the blood sugar curve drops rapidly in the ﬁrst hour without respect to the initial dose, and ﬂattens at progressively lower levels as the total dosage of insulin increases. Coma characteristically is reported in subjects in whom the blood sugar curve is below 21 mg.% for an extended period of time(1). The time of onset of coma and the blood sugar level at coma in each of the patients is presented in Table 1. In ﬁve of the 6 Consecutive patients referred for insulin coma therapy were given daily increasing amounts of insulin in 3 divided doses until a coma level was achieved. The same total dosage was then given in one injection. Six patients were studied in this manner. Each patient was started on the following insulin dose schedule : ﬁrst day—10 units; second day—10 units and 2 doses of 5 units each at intervals of one half hour; third day—3 doses of 10 units at half hour intervals ; and fourth day—20 units followed by 2 doses of 10 units. On each successive day From the Departments of Internal Medicine and Experimental Psychiatry, Hillside Hospital, Glen Oaks, L. 1., N. Y. 1 [Reprinted from THE OBSERVATIONS AMERICAN JOURNAL OF PSYCHIATRY, Vol. 116, No. 9, March, 1960] �' 'n' 9 Ir" : 840 CLINICAL NOTES [ March I % TRUE BLOOD SUGAR LEVELS FOLLOWING ADMINISTRATION OF INSULIN IN DIVIDED AND SINGLE DOSE SCHEDULES 9 9° ~7‘ 9; 8° 3 O \\ .- _ \\ I \ 7o \.\ as INSULIN DOSAGE IN UNITS 20.20.20... —---— 10.70.70... .......... 90.90.90“. ———-— ...q’ \ \\ '\ ———- AT auo MINJNYEuRVALS “ " “ I20,I20.I20u." —'-— 360u. IN " " " SINGLE DOSE E K <1 0D U) D oo _J with divided doses in 4 of the 6 cases. It was identical in one and lower with the divided dose in one. As there was no evidence in these studies that the divided dose method was more effective in the production of insulin coma than the single dose method, the divided dose technic was discontinued. m CONCLUSIONS MI 3 a: [— O 60 90 IZO I50 TIME IN MINUTES AFTER ADMINISTRATION 30 IBO ZIO OF INITIAL DOSE 240 cases, there was no difference in the time required to induce coma by either the single or the divided dose methods. In one subject (Sc) coma was observed in 132’) hours with a single dose as compared with 3 hours with divided doses. TABLE 1 ONSET OF COMA AND BLOOD SUGAR WITH DIVIDED AND SINGLE DOSAGE SCHEDULES PT D G H c So V Time for Coma Blood Sugar Value (minutes) (mg. %) Insulin Divided Single Divided Single U nit: Dore Dore Dose Dose 330 360 270 390 360 210 210 210 210 180 210 135 190 210 210 90 210 150 4 14 15 12 12 8 0 4 15 7 8 20 The average blood sugar at the time of coma was lower with the single doses than The coma produced with the divided insulin doses did not occur earlier and was not deeper than that produced by the single dose. The increased effort in divided dose schedules is justiﬁed neither by increased safety nor by increased depth or duration of the induced hypoglycemia. There was no, evidence that the initial dose of insulin sensitized the subject so that subsequent doses produced a greater hypoglycemic effect. The total hypoglycemic effect of divided doses appears to be less, if anything, than the effect of a single dose. BIBLIOGRAPHY 1. Blumberg, A. G., Cohen, L., Croghan, J., and Kelsey, D.: J. Hillside Hospital, 5: 41, 1956. 2. Fink, M.: J. Hillside Hospital, 6: 197, 1957. 3. Kalinowsky, L., and Hoch, P.: Shock Treatments, Psychosurgery and Other Treatments in Psychiatry. New York: Crune & Stratton, 1952. 4. Laqueur, H. P., and LaBurt, H. A.: Proc. Annual Meeting, American Psychiatric Association, Phila., 1959. �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Efficacy of divided and single dose schedules in insulin coma therapy. Am J Psychiatry. 1960 Mar; 116:839-40. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-43-009 Date A point or period of time associated with an event in the lifecycle of the resource 1960 Creator An entity primarily responsible for making the resource Blumberg, Arnold G.; Laderman, Peter; <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint from THE AMERICAN JOURNAL of PSYCHIATRY, Vol. 116, No. 9, March, 1960 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/e014a6afb9c7514b91c71748685499ca.pdf 9f4aefec5e8c130c970f3538c3603299 PDF Text Text ELECTROENCEPHALOGRAPHIC AND BEHAVIORAL EFFECTS OF TOFRANIL Max Fink, M.D. Reprinted from “CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL” Volume 4 Special Supplement, 1959 McGill University Conference on Depression and Allied States, Montreal, March 19-21, 1959 �ELECTROENCEPHALOGRAPHIC AND BEHAVIORAL EFFECTS OF TOFRKNIL MAX FINK* With the rapid increase in the number of potential psychopharmaceuticals, the need for screening technics has become more acute. In studies of the electro— graphic patterns of convulsive therapy, the hypothesis evolved that behavioral changes induced by new compounds could be related to their neurophysiologic effects as reﬂected by the type and degree of electrographic change (1, 2). This suggestion followed a similar one by Wikler (3) who stated that “regardless of the nature of the drug administered, shifts in the pattern of the electroencephalogram in the direction ofdesynchronization occurred in association with anxiety, hallucina— tions, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness.” Studies with various psychotropics (4) and anticholinergic hallucinogens (5, 6) supported such a relationship. It is the purpose of this preliminary report to describe initial behavioral and electrographic observa— tions with Tofranil'l, a new psychopharmaceutical, and to relate these observations to the neurophysiologic—adaptive hypothesis of the mode of action of physiodynamic therapies (1). Methods Two types of studies were undertaken in an open—ward, voluntary hospitalized population. In 28 acute experiments, consecutive patients referred for physiodynamic therapies were tested in the EEG laboratory at various stages of treat— ment. Tofranil solution (10 mg/ml) was administered intravenously at a set rate (1 ml/4O sec.) until electrographic or behavioral changes became prominent, for a total of 40—125 mg (0.5—mg/kg). Behavioral observation and electrographic record— ing continued for one to three hours. A second group of 16 patients manifesting depressive, withdrawn or retarded behavior were referred by their therapists for pharmacotherapy. The patients received daily oral Tofranil, 75—250 mg. Behavioral observations and EEG recordings were made prior to and during treatment. Patients ranged in age from 17 to 58, and were diagnosed as suffering from schizophrenia, manic-depressive and involutional depressive psychoses, and psychoneuroses. ' Observations I. dcute Studies: On acute administration, there was an initial restlessness, associated with dizziness, dry mouth, “faintness,” nausea, and on four occasions, vomiting. These symptoms persisted for 10—20 minutes, and were accompanied by lassitude, heaviness of the extremities and eventual drowsiness. Heart rate was un— changed or slowed. Subsequently, subjects were relaxed, quiet and disinclined to activity, even when returned to their ward. The electrographic patterns accompanying these behavioral changes were initiated by a gradual decrease in voltages during the injection. By ten minutes, the per cent time alpha and mean alpha voltage had been halved. In four patients with moderate amounts of beta activity, such activity increased in voltage and low behavioral with association lassitude, time. minutes, By in cent twenty per voltage (to 50 microvolts) random theta frequencies (5-7 cps) appeared (Figures 1 and 2). *Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L.I., N.Y. Aided in part by grants M-927 and MY-2092 of the National Institute of Mental Health, National Institutes of Health, U.S. Public Health Service; and by a grant from Geigy Pharmaceuticals. The technical assistance of Mrs. Hannah Mosquera in EEG recording is gratefully acknowledged. ’rTrade Mark. �Special Supplement pre-d rug WWW WWW LF-LO 8167 DEPRESSION AND ALLIED STATES W W after 75 mg after 30 minutes WNW RF-RO wWWv«w¢wanMV‘ I‘VWW LAT-LF RAT-RF k/\_Jl/L,Ah/L JL/\,JA/A,_JL/\, =72 #2638Hh WW W WWW HR after 45 minutes HR 50 Mv|—_l SEC. =74 HR =72 1 Fig. 1 Effect of intravenous Tofrinil on EEG delta (female, aged 46) pre—drug LF-LO «wwNWVHMWwNmN RF-RO WWW LAT-LF W W after 100 mg after 30 minutes hv after 30 minutes “NV“WJWWWWVVV¢ UWMerVkmeV4 WWW WWW RAT-RF LF-RF LPT-LO 0-0 EKG plvltul HR=84 #2138HH W MymMA/VW-WVN MWVWVWMN‘ HR=108 50/.1vl—__J 1 Fig. 2 HR=84 SEC. Effect of intravenous Tofrinil on EEG delta (male, aged 37) HR=9O �8168 Vol. 4, 1959 CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL In six records with post—convulsive delta activity, there was a marked decrease in voltages and per cent time of slow wave activity. These electrographic patterns persisted for half—an-hour to two hours (Figure 3). There was considerable individual variability in the EEG response. In patients who received 100 mg or more of Tofranil, EEG and behavioral changes were Observed in all but three. In six patients, dosage Of Tofranil less than 50 mg were not associated with either EEG or behavioral changes. 2. Chronic ﬂdministmtion Studies: Sixteen patients, manifesting depressive symptoms with varying degrees of insomnia, anorexia, withdrawal, and agitation, have received Tofranil medication for four weeks or longer. Medication was given in oral divided doses of 100—250 mg per day. Behavioral changes generally appeared during the second and were maximal during the third week of treatment. LF-lO after 100 mg pre-drug W W WW W W WWW RF-RO RAT-RF LF-RF . LPT-LO 0-0 #2348 after 30 minutes after 15 minutes iv HR=86 HR=84 ,_~,\_M, amw HR=75 50 uv HR=72 l_ 1 __ SEC. _J Fig. 3 Effect Of Tofranil on EEG delta (female, aged 41: 24 hours post convulsion no. 7) The most prominent behavioral adaptation was euphoric denial, which was noted in eight patients. The depressive attitude was nO longer apparent. They participated more fully in ward activities, complained less of somatic symptoms, and denied, minimized or displaced their illness on inquiry. Agitation decreased, and complaints of insomnia became less. It became increasingly difﬁcult to discuss signiﬁcant life relationships as the patients pressed for an early discharge from the hospital. In three patients somatization and restlessness increased, and depressive affect persisted. In two of these, restlessness, insomnia and vomiting led to cessation of therapy. Sweating increased in most patients, but became a focus of attention in these subjects. NO change in symptoms were noted in ﬁve patients after four weeks of therapy. While no serious complications of therapy were noted, nausea, increased sweating, vomiting, dryness Of the mouth, restlessness and excitement, and increasing �Special Supplement DEPRESSION AND ALLIED STATES $169 insomnia were reported. These were prominent early in therapy, and except for the vomiting and restlessness, did not limit the treatment. In three subjects medica— tion was initially administered parenterally without untoward effects. Abnormal motor patterns and seizures were not noted in these patients at these dosages. Electrographic studies on chronic administration showed minimal changes. Voltages became lower and record modulation became poorer. Well—defined fast activity became more prominent, and in four subjects low-voltage theta (5—7 cps) activity was noted. Discussion These observations indicate that Tofranil is an active central nervous system agent in man, both on oral and intravenous administration. The neurophysiologic effects are manifest electrographically as desynchronization of rhythms and a shift-in frequency spectrum to the slower range. In depressed retarded subjects, Tofrinil administration is associated with such behavioral changes as decreased depressive affect with increased participation in ward activities, increased use of denial patterns (7) and occasional excitement. In comparison to our previous experience with other physiodynamic therapies, the behavioral and electrographic patterns of Tofranil are most like those seen with central anticholinergic agents. We observed desynchronization of frequencies, with an increase in theta activity, to be prominent with experimental anticholinergic compounds such as diethazine and benactyzine* (5, 6). In those studies, electro— graphic desynchronization was associated with behavioral alerting, excitement and illusory and hallucinatory activity. On Tofranil administration, similar electrographic patterns of desynchronization were observed, accompanied by euphoria and increased ward participation. While we have not observed hallucinatory activity at our dosage ranges, Lehmann (it a]. (9) have reported hallucinations and hypomanic excitement in 7 of 84 patients receiving Tofra‘mil. In earlier reports, Wikler (3, 10) suggested that the electrographic patterns of synchronization and desynchronization reﬂected neuron systems distinct from those neuron systems subserving such functions as ‘sensation,’ ‘ideation’ and ‘level of awareness.’ While these systems were frequently interlocked, dissociation between EEG pattern and behavior was observable under a variety of drug—induced states. In our earlier studies we were impressed that the electrographic and behavioral patterns seen after induced convulsions, anticholinergic compounds and phreno— tropic agents were directly related. On acute administration of Tofranil, however, electrographic desynchronization was associated with clinical sedation. These studies are consistent with Wikler’s suggestion. These observations permit the classification of the neuropharmacologic activity of Tofrinil in the central nervous system as predominantly anticholinergic. However, we have noted aspects of the electrographic and behavioral patterns reminis— cent of increased cholinergic activity. These include the electrographic shift to slower frequencies and sedative, euphoriant behavioral effects. Such observations suggest that there may also be an effective degree of central cholinergic activity. Summary Intravenous administration of Tofranil in 28 voluntary, open—ward psychiatric patients elicited electrographic patterns of desynchronization and an increase of theta rhythms, associated with behavioral alerting, relaxation and lassitude. Chronic administration of oral Tofrinil in 16 depressed and retarded psychiatric subjects elicited behavioral adaptations of euphoric denial in eight, restlessness 'A recent report by Abood and Meduna (8) relates the behavioral. improvement in depressed patients with a new central anticholinergic agent which has Similar electrographic patterns. J B-329, H ” �8170 CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL Vol.4,1959 and somatization in three and no change in ﬁve. During the ﬁfth week of adminis— tration, electrographic desynchronization was manifest. It is concluded that Tofranil is an active central nervous system agent, with a Spectrum of activity most like experimental anticholinergic hallucinogens. The theoretic signiﬁcance for neurophysiologic-behavioral constructs is brieﬂy discussed. Résumé Nous avons étudié la relation existant entre les eﬁets du Tofrinil sur le com— portement et sur le tracé électrographique, chez des patients atteints de psychoses aigués ou chroniques. Mét/zode Cas aigus: les patients retenus étaient examinés avant le traitement physioin— celui—ci. Tofranil Le de administré était stades divers ainsi en qu’a dynamique, jections intraveineuses d’une solution a 10 mg/ml, jusqu’a un total de 40—125 mg (0,5_2,5 mg/kg), concurremment avec des examens électro—encé—phalographiques. Cas chroniques: des patients présentant de la depression et un ralentissement du comportement étaient mis a la dose de 75—250 mg de Tofrz'mil par jour. Les examens encéphalographiques et du comportement étaient effectués avant le début du traitement, et a intervalles d’une semaine au cours de celui—ci. Observations 1° Cas aigus a) Comportement: au cours de l’administration du medicament, sur 28 cas, nous avons noté des nausées, des vertiges et de la faiblesse. Quatre fois des vomissements sont survenus. Le rythme cardiaque est demeuré inchangé, ou s’est ralenti. En 10 minutes ces symptOmes diminuaient d’intensité et les patients se détendaient. b) Electro-mcéphalogmmme: pendant le traitement, il y a eu une diminution du voltage dans toutes les fréquences. En 10 minutes le pourcentage de temps alpha baissait et les voltages tombaient a la moitié de leurs valeurs initiales. Chez les sujets a activité béta (4 cas), celle—ci devenait plus importante. Au bout de 20 5—7 de lentes ondes des minutes, cps, atteignant 50 microvolts, apparaissaient ici et la. Dans les enregistrements avec activité delta postconvulsive (6 cas) nous avons noté une baisse marquee des voltages et des pourcentages de temps danS l’activité des ondes lentes. Ces tracés électrographiques persistaient pendant M-Z heures. 2° Cas chroniques a) Comporz‘emem: seize sujets ont été observes a ce jour. Les effets~initiaux de la medication furent des nausées, deS vomissements, de l’agitation et de l’excita— tion, une exagération de l’insomnie et une transpiration tres augmentée dont se plaignaient les malades. Le traitement a été interrompu dans deux cas avec agita— tion. Des 13 autres sujets, 6 ont vu leurs symptOmeS de depression S’amender et ont pu reprendre une plus grande activité; ils ont pu étre renvoyés chez euX, ou ont été prévus pour un prochain licenciement. Les autres n’ont guere présenté de chan— a la soumis été n’ont leurs thérapeutique que pendant dans symptOmes, ou gements un temps trop court. &) Electra—encéphdlogmmme: Les enregistrements obtenus pendant 1e traite— ment n’ont montré que peu de modiﬁcations. Leur modulation était appauvrie et leurs voltages abaissés. Une activité rapide bien caractérisée a pris de l’impor— 5—7 de a bas activité noté voltage 4 malades chez une cps. nous avons tance; Conclusion: 1° Chez les psychopathes, les effets electrographiques du Tofrinil sont une Ces a tracés has lentes d’ondes activité voltage. suivie une désynchronisation, par a alors ressemblent les traités, et dans chroniques moins cas prédominants sont ceux que l’on Obtient avec la benactyzine. ' �Special Supplement DEPRESSION AND ALLIED STATES 2° En ce qui concerne le comportement, nous constatons une $171 augmentation de la motilité, un changement dans l’humeur et un malade plus éveillé. 3° Ces observations concordent avec les hypotheses neuro—physiologico—adaptatives expliquant 1e mode d’action des traitements physiodynamiques des psychoses. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Fink, M.: Hillside Hosp. J. 6:197, 1957. Fink, M.: Alteration of brain function in therapy, in Kline, N. S.: Psychopharmacology frontiers, Boston, Little, Brown, 1959, pp. 325-333. Wilder, A.: J. Nerv. & Ment. Dis. 120:157, 1954. Fink, M.: EEG and behavioral effects of psychopharmacologic agents. Read at 1st International Congress of Neuro—psycho—pharmacology, Rome, September 1958. In press. Fink, M.: A. M. A. Arch. Neurol. 8: Psychiat. 80:380, 1958. Fink, M.: Electroencephalog. 8t Clin. Neurophysiol. 10:776, 1958. Weinstein, E. A., and Kahn, R. L.: Denial of illness: symbolic and physiological aspects, Springﬁeld, 111., C. C. Thomas, 1955. 'Abood, L. G., and Meduna, L. J.: J. Nerv. & Ment. Dis. 127:546, 1958. Lehmann, H., Cahn, C. H., and de Verteuil, R.: Canad. Psychiat. A. J. 3:155, 1958. Wikler, A.: Proc. Soc. Exper. Biol. & Med. 79:26], 1952. General discussion from the ﬂoor (summarized) The question was asked whether administration of a large dose of Tofranil once a day would not be as effective as multiple dosage. This would of course be a tremendous saving in the time of the nurses involved. In answer it was stated that Tofrénil is best given not in one large daily dose but in a series of small doses such as 2 tablets t.i.d. It was also brought out that Tofranil has a tremendous inﬂuence on transference phenomena and that these can be analyzed in dreams and symbolisms. While such observa— tions have been made, deﬁnitive results must await an extensive study. Another discussant asked what is the difference between the effect of barbiturates and anticholin— ergic drugs on the EEG. One discussant felt that the EEG was a poor tool, since it could be modiﬁed in only two ways, synchronization or desynchronization, and ﬁrm conclusions should not be drawn from such changes. He therefore felt that analogies between diethazine and Tofrénil were dubious and that nausea was not a specific effect of Tofranil. He wondered if EEG changes would always exist in the absence of nausea, and felt it important to correlate EEG changes with clinical changes. In replying to these comments, Dr. Fink stated that he considered Tofrﬁnil an anticholinergic drug because of its similarity to other anticholinergic drugs in regard to its EEG patterns. Dr. Fink recalled that Dr. Sigg’s paper had also indicated that Tofrﬁnil was an anticholinergic drug. Many anticholinergic compounds appear to have rather speciﬁc central effects, and some are also experimental hallucinogens. In his experience, barbiturates produce not desynchronization, but rather synchronization. This becomes clear if the factors of dosage and time are considered. Thus the initial effect is hypersynchronization; if the drug is continued, sleep is of course produced and the initial effect disappears. The author replied to the criticism of his use of EEG. He agreed that it is a poor tool in many respects, but that it is possible to analyze EEG records for synchronization, desynchronization and fre uency shifts. One obtains different patterns with different agents even in the same patient. Dr. Fink explained that he was making a long—term study, and hoped that more conclusive data could be offered at a later time. ��’*” EEG uni nahtviernl striat: .2 nu nah, Torranil 3...». * 2h: rulltion hotvtcu thc ﬁlcetragrcphie and behaviortl «Itcctt at retranil in velunthry paychintrie pationtt wan datarnincd in taut. and thrsnic ntudioa. _ Kathodnr latto: Ganaaeutiva patiants rcturrod for phytiodynunic thtrupiol ttntod not: prior to and at yariatu itngal Of therapy. With 330 rocordinc, retruail nelution (10 ng/oc) was adminintorud intruvanouuly for I total of h0~125 I; (0.S~2.5 ng/ks). chronic: Pttiontp annitslting duprctuivo tad rotnrdod bchlvior aura plnoud an rogiucua o: 7S~2oe lg renunil daily. EEG oxnniuntionn and hchuyiornl obsothtiaus war. and. prior to and It weekly int-yttla during troutncnt. Oblarvntianus 1. Acute Stadielt a. Buhﬁyiora Baring drug zduiniltrutiou in 25 albjoata, 3.13033, EIuIIncoo in! Ionknoan wort rcpcrtud. Viniting ocearrcd an tour oecaaicnc. ﬁctrt rgto was Inshtngod, tr nluvcd. In 1&3 Iinutca, th... aynptoun were 103:, und puticnta war. roluxod. b. EEG: During ndninistrttion thtrc was a dccruuuc in yoltagc a: all trcquonans. By tan minuttu, thc par cant tint alpha ducronsed, lad valtngea were halt at thc initial values. In pationts with sodurnto anonntn of but. uctiyity (h), auch activity hocuno morc yroxincnt. ﬂy taunty mintha, slow It?! nativity of k-7 apt, up to 50 uiarovclta upponrnd, rundouly. In roenrd: with poat~eenvulaiva daltg activity (6), thert in a nurkcd docrotio in voltngcn and in par tent tin. of claw wave nativity. tutu: electraartphic pattcrn: pcraictcd far 2. Chrunia I studioat _Bchnvi¢rn i. rittouu patient: hay. 2 hours.\ boon under ebccrvutiou to data. -Iai -n a van a at nodicntian inaludod nanaou (a) vaulting (a), roatlouuuocn lad axaitantnt (2), insomnin oxaggorntod (35, And aonplainta o: oxacstivo uwiating (11). In tha tun pationtn with roitlsasnoal, nedic;~. tit» at: diaoontinund. a: the thirtaon pntionts, nix Innitcttni In 3110'iatiun or symptoms a: doprnulion with incronnad pnrtiaipation in activitics, Ind hava Bean dilahargad or rccaunoudcd tar diuehnrga. Th: rcaaiuing buy. nhaun littlc engage in a tan. (3) at thcrapy ht! baan patitntl udniniltorud for too thort a ptriod (hgfp 3:. mm: In neat-d. «ht-sin“ during hottmnt, tiniaul change: taro obIcrvoa. ﬁeduiation a: rucordu was poortr with lcwor yoltncct. H011 dutinod rant activity bee... not. proninont; tad in tour subject. 10v waltago 5~7 cps activity VI! noted. conclusion. Ll Sloetrozrtphic extactn o: Totrunil in payehiutriu patiuntc are thus: of duayuehroniantion, tullowod by law voltngo slaw wtva nativity. * Iron thc Duplrtuant at magazinpnttl Payehintry, nilluidc Rhapital, glig ggk" L010 301% �.2th¢to pattorna arc 1.0: proninnnt an chrcnie udntnintrntiau, tad rononblo that. or bnunctynin0¢ 2) Dihtviornl offset: arc that; of alurtiuc, Iced ch¢n¢a and inurilnnd motility. «autistant with ﬁha nauraphyszolagtau :Athivu hypathuntu at :h: act. at action or physiodyuania thcrupion 3) Thnss abaorvution¢ nae of paychoucu. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Electroencephalographic and behavioral effects of tofranil. Can Psychiatr Assoc J. 1959;4(Suppl):166-71. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-38a-004 Date A point or period of time associated with an event in the lifecycle of the resource 1959 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint from CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL Volume 4 Special Supplement, 1959 McGill University Conference on Depression and Allied States, Montreal, March 19-21, 1959 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/6428428b2e8c8dd8c101b89ff0bcc16f.pdf 0dca1e713671d6e32179b0a6fd1afba3 PDF Text Text Electroencqahalographic Correlates of the Electroshock Process Max Fink MJJ. and Martin A. Green 14.3). ‘ .. From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L.I., in part, by grant M—927, National Institutes of Mental Health, National Institutes of Health, U.S. Public Health Service. Aided, Read at the meeting of the Eastern Psychiatric Research Association, February 6, 1958. V:3-l-58 New York, N.Y. �Electroencephalographic Correlates of the Electroshock Process During the past few years, renewed attention has been given to the relation between changes in measures of cerebral function, and the behavioral changes induced by electroshock (l, 2). Alteration in various aspects of the electroencephalogram has been emphasized by various observers (3, h) in cerebral function. In an initial study in this laboratory, a significant relationship between the degree and duration of induced delta activity and clinical evaluation of "improvement" was observed (6). Subsequent studies have focused on as a sensitive index of changes ' various parameters of the EEG changes including frequency of type of current, age of subject and pre-treatment record It is treatment,' characteristics. the purpose of this report to assess the relation of these aSpects of treatment to changes in the EEG and in clinical response; and to describe the role of serial electroencephalograms in the rational management and study of convulsive therapies. �-2- man: One hundred and seventy-three consecutive electroshock referrals have been studied. Electroencephalograms were taken before treatment, after treatment at weekly intervals during and following the course of therapy until the record had achieved its pre-treatment and on a day characteristics. Patients in whom demonstrated slow wave or spike All the EEG delta activity. the pre-treatment electroencephalogram activity were excluded from the series. records were quantitatively measured for the amount of On the basis of the per-cent time, slowest frequency, highest voltage and longest duration of bursts of slow waves, in selected lead combinations, the records were classified into "high," "moderate" and "low" degrees of delta activity, according to criteria previously published (6). Three convulsive techniques were employed: suprathreshold alternating current, threshold alternating current current methods. The and parathreshold unidirectional alternating current suprathreShold (7) and unidirect- ional parathreshold (8) treatments followed established techniques. In the threshold alternating current method, patients without prior sedation received small amounts of current (90 volts for 0.2 second), usually sufficient for a petit mal response. intervals voltage, and if necessary, duration.was increased until a grand mal convulsion was inAt 20 second voltage and duration necessary to induce a grand mal duced. The minimal was the threshold value. In addition, a convulsive-subconvulsive control study was instituted during a period of these observations. Randomly selected patients referred . �.3for electrotherapy received subconvulsive therapy instead of grand mal. In this technique, patients were given pentothal intravenously until asleep, and then either low voltage unidirectional current fbr 60 seconds alternating current of 80 to 120 volts for 0.2 second were administered for one to three applications, for a total of 2h to 36 petit mal (8) or responses. Of the 173 electrotherapy referrals, lh6 received grand threshold alternating current, 57 by current and 63 by 26 by suprathreshold mal therapy - alternating parathreshold unidirectional current methods. Twenty- seven subjects received a course of subconvulsive therapy. All treatments were given three times a week, for 12-20 treannents. failed to develop a significant behavioral or clinical response, or middle or high degrees of delta activity in the EEG, were subsequently Patients Who treated five to ten times per week. Evaluations of clinical reaponse were trist ment and resident therapists on two occasions. At the supervising psychia- the height of the treat- effect, the degree of behavioral change was scored as ”marked," "moderate," "minimal” orfhone." in behavior in interviews These made by after treatment was terminated. and were based on the ratings were estimates of the change and on the ward from the Ratings of "improvement" were also weeks made by pre-treatment patterns. these physicians two to three These ratings were value judgments four-fold classification of "recovered," "improved” and "unimproved or worse" (2, 6). "much improved," �RESULTS: 1. Variability in Delta Activity'with Convulsive Therapy: variability in the degree of induced delta activity reparted in the initial 2h patients {6) is confinned in these series of convulsive therapy referrals (Table I). While the number of high degree The wide records increases with treatment, fourth week, are still rated as 27% ”low" degrees of TABLE Degree of EEG in the third week, and 18% in the delta activity. I Delta Activity with Convulsive Therapy (Per-cent of Group) Treatment Period h 28 h6 60 Moderate Degree 12 21 27 22 Lou'Degree 68 h8 25 18 16 3 2 o High Degree No Delta Activity 2. Role of Convulsion in The EEG Response: significance of the convulsion per gg in the EEG and behavioral response was assessed in the convulsive-subconvulsive study. Of the h? subjects*'who received convulsive therapy in this study, 9 had * These included 28 subjects who received grand mal therapy on a random selection basis, plus 19 subconvulsive subjects referred for a "second course" of therapy. �-5high degree delta records in both second, third and fourth weeks of ment, 12 during two of the three weeks, and 13 during one of the periods. Thirteen of the h? subjects failed to show a treattest high degree delta record on convulsive therapy. Of the 27 subjects who received subconvulsive therapy, however, none demonstrated middle or high degree delta activity records during any week of treatment. Low degrees of delta activity were noted in three subjects during both the second and third weeks of treatment, and in 8 subjects during the fourth week. In concurrent behavioral ratings, 25 of initial 28 subjects in the convulsive group showed marked behavioral change; while of the subconvulsive group, Of the 21; of the 27 showed Bdnimal or no behavioral changes (Table latter group, 19 were referred II). for a second course of therapy. In 1h of these, grand mal electroshock induced high degree delta activity all significant behavioral change. Of the five who failed to demonstrate high degree delta activity on convulsive electroShock, all and showed a showed middle degree records; and change. three of the five Showed a behavioral Thus, of the h? convulsive therapy subjects, h2 showed a behavioral change. significant �—6— II TABLE Ratings of Behavioral Change: Convulsive - Sdbconvulsive Therapies (Fburth-Fifth'weeks of Treatment), Moderate marked Minimal yggg i Convulsive Therapy (A?) 27 15 5 0 O 3 8 16 Subconvulsive Therapy (27) In evaluations of the degree of "improvement" 51% of the convulsive therapy group were rated as "recovered," and evaluated as sustaining the "improved," and only however, but 70% 11% III). as "improved" (Table 32% 7% were rated same weeks after treatment, "much improved" On discharge, degrees of improvement, while were ”unimproved." in the tWo first two were “unimproved," two weeks or 51% were h2% were 0f the subconvulsive group, categories, 19% after treatment. As in the "improved," these were re- ferred for a second course of therapy, hosPital discharge evaluations do not reflect the effects of subconvulsive therapy. TABLE III Ratings of Improvement: CoHVulsive-Subconvulsive Therapies (TWO Weeks After Last Treatment) Recovered Much Improved Improved Unimproved, worse Convulsive Therapy (h?) 9 15 15 8 Sdbconvulsive Therapy (27) 2 l 5 19 �Convulsive therapy induced and more favorable evaluations The significantly greater behavioral change of improvement than did subconvulsive therapy. clinical observations thus parallel the electroencephalographic data. Also, patients who showed.neither an convulsive therapy, EEG Showed both EEG and or a behavioral response to behavioral changes when Sub- placed on convulsive therapy. 3. Role of Type of Convulsive Therapy: In view of the variety of electroshock techniques employed, the relationship between EEG delta activity and the behavioral response, an analysis of the effect of type of electroshock on EEG delta activity undertaken. The results are graphically presented in Figures first figure relates and 1 and was 2. The the treatment type to the percentage of records demon- strating high degrees of EEG delta activity in each treatment group during the second, third and fburth weeks of treatment. In each period, treatnent with alternating current at suprathreshold strength gave the highest percentage of high degree delta records. Treatment with unidirectional current and with alternating current at threshold strength was less effective than the supra- threshold alternating current technique in each period; the unidirectional current treatment being method only more effective than the threShold alternating current early in the course'of therapy.* Subconvulsive techniques yielded no high degree delta activity records. The second figure demonstrates the same relationship by measuring the per cent of each treatment group showing no delta activity or only low degrees * The differences between suprathreshold and threShold treatment methods are significant at .05 by chi square in the h-é and 7-9 treatment periods, but not in 10-12 period. Parathreshold treatment methods are not significantly different free the other two methods during any treatment_period. �-8of such activity. Here, the subconvulsive group is 100% for each treatment period. Suprathreshold alternating current techniques the least number of such records in eaoh period, with threShold show and parathreshold techniques in between. h. Freguenqy of Treatment: Another factor is the frequency in the rate of development of delta activity of treatment. While three times a week, a number activity were treated were given more who all patients and In nine such patients, treatments in each instance middle or high degrees of delta activity were induced. Similar previously demonstrated by Pacella 5. Factor of In the initially treated failed to develop high degrees of delta intensively. daily or twice daily, were at 31. (9), correlates were EEG and Callaway (10). V Age: initial series of'patients, it was noted that younger patients, under hS years of age, developed greater degrees of delta activity during the first and second weeks of treatment; while older subjects developed such activity to a significant degree during the third week. By the fourth week of treatment, age no longer between the groups. Combining the data from supports this observation. all differentiated convulsive therapies During the Second week, h3% of records are in patients under the age of no; but only 30% in patients from h0-60, and 18% in patients 61 and over. In the third measured high degree delta and fourth weeks, the differences are no longer present and approximately 2/3rds of the subjects have high degree delta records times per week. when treated 3 �.9TABLE Variation in Per IV Cent High Degree Delta EEG Records with Age * 9 Treatment Period Second week Third week Fourth'week in. is. 2:2 nee ho years (28) 15% 61% 69% ’41-50 Years (28) 29% h0% 56% 51-60 years (28) 32% 56% 55% Over 61 years (18) 18% 50% 80% es To ' 6. Pre-Treatnent Record Characteristics: Previous reports, summarized by Chusid and Pacella (3), noted a significant relationship between pre-treatmnt reca» rd character- istics and the degree of induced "abnonnality." Predominant alpha rhythm, “abnormal" (3) or “borderline abnormal" (11) records were more develop alterations in the EEG liable to than those with predominantly low voltage fast activity patterns. In these series of patients, subjects whose pre-treatment'record demonstrated diffuse slow wave activity, spike or spike wave activity were not included in the statistical analyses. Eight such subjects were «- difference in incidence of hig1 degree records is significant at .01 level of confidence between the second and fourth weeks and .05 between the second and third weeks of treatment in patients over 50 years of age; but is not significantly different for these periods in groups under 50 years. The �-10.. treated with convulsive techniques, high degrees of delta activity however; and seven of them developed earlier, and for'more sustained periods, than patients without such pre-treatment abnormality. A Specific analysis of the relation between pre-treatment alpha . and the degree of induced delta activity was undertaken. Rank order correlations of the preetreatment per cent time alpha in selected leads (anterior temporaldvertex) with the degree of delta activity during the third and fourth weeks of treatment of +.2h and +.3S reapectively. The in h3 patients demonstrated correlations relationship in the fourth week significant at the .05 level of confidence; while that in the third fails of significance, although the trend is indicated. is week �.11.. DISCUSSION: aspects of these studies warrant discussion: the significance of the convulsion in the electroshock process; and the role of serial electroTwo encephalograms in the rational management and’study of convulsive therapies. In the early studies of convulsive therapy numerous authors, including Kalinowsky 23 El. (12) and Pacella and electroencephalographic gt.§£. (9), emphasized both the clinical differences between grand mal and petit mal responses. While grand mal seizures induced clinical improvement in 60 to 80% of cases, petit mal induced changes Similarly, electroencephalograms in grand activity, while in petit mal therapy, no in less than 25% of subjects. mal therapy demonstrate delta delta activity is seen. In subsequent years, various subconvulsive, brief stimulus, unidirectional stimulating, monopolar stimulating, and focal convulsive techniques in each, in.turn,,discarded in routine therapy. Bergman §§.§l, (13), for example, in describing the electroencephalographic effects of focal seizure techniques noted that 70% of patients had normal records at 15 such "seizures;“ while 70-75% had "abnormal” records after have been described, and Ulettgt El, (1h), in a careful convulsive-subconvulsive control study,reported a significant difference in the clinical response of grand mal seizures. patients receiving convulsive therapies convulsive (33%), or controls (38%). reSponse in the He (60-80%) and those noted two groups, and emphasized the for the therapeutic effect. ReCent ﬁne discrepancy in the EEG significance of the seizure additional reports based on a variety of data further emphasize receiving sub- ﬂue by various observers, significance of the convulsion �.12.. in the therapeutic response (h, 15, 16). convulsions per g2 are, or which thus indicates that reflect, the significant physiologic events are the basis for therapeutic efficacy of convulsive therapies. If the convulsion is the essential element both in the the behavioral response, does the any The evidence EEG and in induction of the seizure play mode of role in.this reSponse?. In the studies reported here, small differences in both the degree of EEG delta activity and the rate of its development different methods of induction of grand mal seizure. Ulett gt 3;, (1h) reported an improvement rate of 57% for the alternating current cenvulsive technique, and 76% for the photo-metrazol were observed between technique. While the differences are small, the authors ascribe greater clinical efficacy to the convulsive photoametrazol technique. In a discussion of this report, Kalinowsky noted.that metrazol convulsions have impressed various workers as being more efficacious than induced convulsions. convulsant drug, PM More electrically recently, Edwalds, (17) describing a 1090, ascribed to it new clinical results slightly better than electroconvulsive techniques. further noted that the convulsions induced by various techniques have varying characteristics of latency, duration, preponderance~ we have of clonic or tonic phase, apnea, 332. All grand mal seizures are seemingly not equivalent; and a seizure is not an "all or Different seizure patterns occur and these may none" phenomenon. reflect differences in the physiologic effect of different treatment methods. Further studies of this problem are in progress (18). �-13 .- While this variability in clinical results is reported, it is clear that with repeated canvulsions, rates no matter how induced, improvenent per cent are observed. The differences between various types of treatment are small, and, for the most part, may be readily obviated by of 60 to 80 the simple expedient of increasing the frequency or number of treatments. We may conclude way that convulsive therapy is nonpspecific with regard to the the convulsion is induced. The significant element is the brain change subsequent to the convulsion, and not the agent used in bringing about this brain change. In previous reports (6, 19, 20) convulsive therapy we have noted that is also non-Specific with regard to its application in mental illness, and in its clinical effects. and behavioral The present studies, amplify , therefore, the previous conclusion of the non-Specificity of convulsive we have therapies. applied methods of quantitative, serial studies reported here. EEG analyses in the clinical estimates of behavioral While change have yielded similar data, such evaluations are more dependent on the attitudes of the observer (21), and less amenable to quantification than the EEG. Application of EEG analyses to problemsin convulsive therapies provides a rational basis for the comparison of different treatment techniques. “we have previously noted clinical management patients who that EEG analyses may be applied in the of patients receiving convulsive therapy (6). In fail to show a significant behavioral response on treatnent regimens of three times per week, an electroencephalogram may serve as a �guide for further therapy. In those subjects in.whom high degree delta activity has not been induced, increasing treatment frequency, withholding premedication, or shifting to a more effective oonvulsant method, may result in the neurophysiologic changes. If the degree of delta activity is high and sustained for a number of weeks, other factors as personality (22) or environmental (19) may be assumed to preclude a satisfactory behavioral response, even when the neurophysiologic substrate and further convulsive therapy application has been suggested EEG may well be discontinued. by Roth (5) A is assured; similar for thiopental activated records. The successful application of quantitative convulsive therapies, has led to dynamic EEG techniques to their application to other physio- therapies. Recent reports from these laboratories note a similar application for the rational psychopharmacologic agents (20). management and understanding of �.15sunnru AND CONCLUSIONS: Serial quantitative analysis of the degree of induced activity in were made 173 consecutive EEG delta electrotherapy referrals. Patients were treated by three convulsive methods: suprathreShold alternating current, threshold alternating current and parathreshold unidirectional current. Random electrotherapy patients received a course of subcdnvulsive treatment instead of grand mal, in a convulsive-subconvulsive control study. 1. An induced grand mal convulsion is essential both for the electro- encephalographic and the behavioral changes ascribed to ”shock" therapy. 2. The rate (a) two The EEG delta activity of seizure induction: suprathreshold Mode techniques induce techniques. and degree of induced EEG changes earlier and is dependent upon: alternating current to a higher degree than threshold results of unidirectional current methods fall between these techniques. (b) Frequency of treatment: increasing frequency inereases degree of EEG delta activity. (c) Age of subject: Patients under delta activity earlier than older patients, but ment, differences are insignificant. (d) Pre-treatment record hS develop by the greater degrees of fourth week of treat- characteristics: Patients with dysrhythmic records or high per-cent time alpha activity develop greater degrees of delta activityearlier than patients with low per-cent time alpha activity. 3. It is suggested that serial quantitative electroencephalography provides a rational basis for the study and the clinical management of convulsive therapies. �REFERENCES l. Weinstein, E.A., Linn, L. and Kahn, R.L.: Psychosis During Electroshock Therapy: Its Relation to the Theory of Shock Therapy, Am. J. 1.92: 22-26, 1952. Psychiat. 2. Kahn, R.L., Fink, M. and Weinstein, E.A.: Relation of Amobartital Test 3. Chusid, J.G. and Pacella, B.L.: The Electroencephalogram in the Electric Shock Therapies, J. Nerv. & Ment. Dis. 116: 95-107, 1952. h. Roth, 14.: Changes S. Roth, to Clinical Improvenent in Electroshock, AMA. Arch. Neurol. in the under Barbiturate Anaesthesia Produced by Treatment and Their Significance for the Electro-Convulsive ECT EEG Clin. Neurophysiol. 2: 261-280, 1951. Theory of Action, Kay, D.W.K., Shaw, J. and Green, J.: Prognosis and Pentethal Induced Electroencephalographic Changes in Electroconvulsive Treatment, EEG Clin. Neurophysiol. _9_: 225—237, 1957. 7:41., ’ Fink, EEG M. and Kahn, R.L.: Relation of Electroencephalographic Delta A.M.A. Arch. Activity to Behavioral Beeponse in Electroshock, Neurol. and Psychiat. Z_8_: 516-525, 1957. 7. Kalinowsky, L. and Hoch, P.: ghock Treatments, Psychosurgegy and Other Somatic Treatments in Psychiatry, Grune and Stratton, N.Y. 1992. 8. Alexander, L.: Treatment of Mental Disorder, W.B. Saunders Co., Philadelphia, 1953. 9. Pacella, B.L., Barrera, E5. and Kalinowsky, L.: Variations in the Ele ctroencephalogram Associated with Electric Shock Therapy in Patients with Mental Disorders, Arch. Neurol. & Paychiat. 367-38u, 19u2. g: 10. Callaway, E.: Slow Wave Phenomena in Intensive Electroshock, Neurophysio . a: 157-162, 1950. ll. Kennard, M. and Willner, M.D.: Significance of Changes in the Electro— encephalogram which Results from Shock Therapy, Am. J. Psychiat. 1L2: : 12. 13. Olin. uo-us, 19m. Kalinowsky, L., Barrera, Reaponse l9LL2. EEG ms. in Electric and Horowitz, W.A.: The "Petit-Mal" Shock Therapy, Am.J. Psychiat. 28;: 708-711, " P.5., Impastato, D.J., Berg, S. and Feinstein, R...‘ Electroencephalographic Changes Following Electrically Induced Focal Bergman, Seizures, Conf. Neurol. 12: 271-277, .1953. �W K. and Gleser, 6.0.: Evaluation of Convulsive and Subconvulsive Shock Therapies Utilizing a Control Group, A31: Jo MChiat. 112: 79S~802, 19560 Ulett, GA” Smith, 15. weinstein, E. and Kahn, R.L.: Denial of Illness, 0.0. Thomas, Springfield, 1955. 16. Fleming, “13.0.: An Inquiry into the Mechanism of Action of Electric J. Nerv. & Ment. Dis. 121;: th-hSO, 1956. Shock. Treatments, 17. Edwalds, R.M.: Intravenous Administration of PM 1090: Clinical Elmerience with a New Convulsant Dmg. Read at FLY. Divisional Meeting A.P.A. 1957. 18. Green, M.A.: Significance ‘of Individual Variability in "EEG Respome to Electroshock, J. Hillside Hosp. é: 229-210, 1957. 19. Fink, M., Kahn, R.L. and Green, “.11.: Experimental Studies of the Electroshock Process, Dis. New. 835 . (in press). 20. Fink, M.: 21. Fink, A Unified Theory of the Action of Physiodynamic Therapies, J. Hillside M. and Kahn, 9: 197-206, 1957. R.L.: Behavioral Patterns in Induced States of Hosp. Altered Brain Function. 1957. 22. Read at N.Y. Divisional Meeting A.P.A. Personality Factors in Behavioral Response to Electroshock Therapy, Coni‘. Neurol. (in press). Kahn, R.L. and Fink, 14.: �ELECTROENCEPHALOGRAPHIC CORRELATES OF THE ELECTROSHOCK PROCESS MAX FINK, M.D., and MARTIN A. GREEN, M.D. From the Department of Experimental Psychi: atry, Hillside Hospital, Glen Oaks, .N. Y. Pro blem : In the course of an evaluation of the role of altered brain function in the electroshock process, the relation between electroencephalographic change and behavioral response has been re-assessed. Subjects and Method: Eighty consecutive electroshock patients have been studied. All patients received electroencephalograms before treatment; on a day after a treatment at weekly intervals during, and following the course of therapy until the records had achieved their pre-treatment characteristics. Treatment procedures varial, including unidirectional and alternating current electroshock, and subconvulsive technics with Pentothal premedication. Treatment was usually instituted at three times per week for 12-20 treatments. Patients who failed to develop a clinical response, or EEG changes of signiﬁcant degree, were subsequently treated at 5-10 times per week. The EEG records were classiﬁed for degree of delta activity into “high," “middle” and “low" degree delta records using the following indices: the percent-time delta; highest percent-time delta in any lead; slowest wave in the record; highest amplitude of delta; and duration of burst activity. (Arch. Neurol. & Psychiat., 78: 516-525, 1957.) Evaluations of change in behavior were made by the supervising psychiatrist at the height of the electroshock effect; and ratings of improvement were made two to three weeks following the termination of therapy. _ Results .' ~ .4]; 3, 54 I ._ 1) The appearance of a high degree EEG delta activity during the second and third weeks of treatment was signiﬁcantly correlated with change in behavior and ratings of improvement. 3) High EEG delta activity was induced in patients receiving convulsive electroshock only, and was not observed in subCOnvulsive therapy. 3) Alternating current instruments induced high degree EEG delta activity earlier than unidirectional but by the 4th week of treatment, the di' erences were eliminated. '4) There was a direct relation between the degree of EEG delta activity and the frequency of treatment; and an inverse relationship to age. ”ﬁruments, ‘ Conclusion: 1) There is a relationship between the degree of EEG delta activity in the EEG and clinical change in behavior. . 2) The time of the appearance of EEG delta activity and its persistence is related to: a) induction of grand mal seizures; b) type of current employed; 0) frequency of treatment; and d) age of the patient 3) Early. and sustained high degree electroencephalographic delta activity is a necessary,, though not sufﬁcient, pre-requisite for improvement in the electroshock process. ’4 ; Avf" �TRQIW m Subuuowluve Conoubwc \\ d, AC. and u“ .. ﬁYc-‘Hol‘b _ Paiszélﬁftfl’l _ A “ \t W: 0 2a 3! 4¢v 93¢ {I to 057:0 7‘ �. t‘, “i. I 3 “fatig- ‘ ﬂcrld;é J 1’ 3547.79 5‘ ”WW 55/ (7.?” Mfl m- a; V Ear ﬂ<.a..ma'" 7”,... 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WM¢L7A WWMZZ/é ffffww/CL/MJZ’LWM'ZW 421W yzzofs‘vwéz OWW/éﬂéuWWay /%WMMM/&aw Mu>4/L-a\ WW 4% )O/M/Mé’ Mr IQM Muwr‘ ﬂay, $4]de Wit/WC! fww ﬁWM My“ wag/WM?" MAW WM M WM WM MWM‘. jWL/éjfm/ﬁfou/W 4»! sd/zw ,e/Ze‘e/MW. ﬂaw-‘7 ��*2 31”ka only; and m wrehnws 1;) obaomd in mbcmvulsive or petﬁ» m1 curmt We! high degree mm. shaman? mam-um). max—mat, but by ﬂu hth ml: of tmtmnt, the 3) Alﬁemﬂng mar than tbs not. me. mm m a. instruments EEG were ' mum mm a» dance at m aimmty and direct relationshiptom. thatmqueneyoftmtmntxmdm L ’ ‘ Gmlusgm'i ‘ 2mm 2.qu mmmmummamgammm‘ 1) mm in a 2-, mm of mm mmw he ‘ m m or the Mes-tint: a! damn abnormliw is rented. to a) the induction of mm m mm. l 2) 10% type or electrical and us Mama mm meme I a) 1m frequency or tnatmt I 6) ago of the 3) ﬁodmmtim patiant 1n olectmahmk therapy as m mamahouk, manuals-1m alwmszmk, ammatmmm therapy .- wnm do not dmlep delta abnonmlity in than Wt, fail M whim tha therapeutic msulta at mud m1 exmam. this plaeabo affect. The limited a arrimy or mass pmduru is probably due to �Electmaephalagnphio many ' ﬂax 1* From ﬂak, 11.9., comma at the Prone“ Robert L. the Department at Experimental M3. 3“ IMO; i Electmhook m and H. Green, 3.9. mummy, Hillside Hospital, 613:: ��.3 I “,— “A May .— - ,. Mu may or ﬂu mam-m M's-3., Mn A. «ma. 3.»... m mm. 2., an. an». hm mammmwuuauuudumbmm mama hm Wumm mm meta-W MM mam; many bun W- mu 411 m; tmmt «www.mtmmmmwmmwm mm m We! pun-Wt Wam- mum www.mmmmwnmmmzw mum-m Was um mama-1 Mum Me for In many mum-ca it Wm as g dry their 33m- mock, ma M W“ 1240 mm“. atmum‘mwwmaamm.umwu mam-m.mnmmmmmammmma mmmmWWtwmamuwwm WHWW'WWNMWMWIWMW: nut-m tho pm mu; mam-*4... mu I“ awn“, amt V‘ IMWWdWhmw.mm-WM,M m'mM§ msmumWMWqu-y,mzomm “mm; M 3-95 1997;: 2 ‘s g 1 1 -§ 5 ��Electroencephalographic Correlates of the Electroshock H Max Fink, 14.13., W Process MW 1. . *- 14‘1” P: Green, H.D./ 1/ 4.. W. * From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, New York. =,\ �Problem: In the course of an evaluation of the role of altered brain function in the electroshock process, the relation between electroencephalographic change and behavioral reSponse has been re-assessed. Subjects and Method: Eighty consecutive electroshock patients have been studied. All patients received electroencephalogram before on a day after a treatment” mg card» oﬁuntime intervals during, and following IKE/MA retheir pie-treatment characteristics. treatment at weekly . cords had achieved ‘ .“ -~ 7 1-..9- ~. WW . ~~~~~ . mm ' ~ ' ~ . ”will. . Treatment was stituted at three times per week for 12—20 treatments. West-of atients who failed to develop a clinical response, or EEG changes of significant de- WM m gree, were At ated The EEG 9"“ M" /{“" records were classified for degree of delta abnomality ﬁih records/gang the following indices: “high" "middle" and "low" the percent-time delta; highest percent-time delta :1 wave in the record; highest amplitude ivity. ng * 5"“ Results: M 1) A W‘ -Ax/1 74 ' gs «Ede:94‘»!wa by the supervising M M fxwvm/ positive correlation was slowest delta; and duration of burst act- Kiwi” W W WM i/fal law/Mm a: fin oi‘ .0 lead; any M psychiatrist 3f 1‘41. W dan— Mﬂmdgmmzé “ﬁmmmal? A}. established between the development of ram I’lZunfgy ��In)" l- .J, nmmwmmuwuuunmbmm ammmwmmwammmm 7mm mmwmmgmawmaw ummmvmrmmwmummumw mmmmnmmmm; Wt”.- W mum‘mmammmwmmru-mmm mommimmmﬁwmummum mmmumwuamm.umwu mummmmmam ' ”T” . «mﬁwwwumm,mwmm I EMA : I/r/rp ��(“7 ,. ' 9/“ ;\\ KM 4/ 44(ég/7’M4 4% 4%”‘49444.44.44 /4u44.. ﬁod—n—«a— A: 44.4.44. 14 m @ 4 4 4 L?! («I , I er!) ,1 rd 449-64 -wmm.mm.mnu4— Md ‘chZJ‘M- if éw/AMM -4444 (24 [44/2444] 444 743444.444. ~ 4444424444; (4472442444,) 44 444444 4245/44“ maﬁa-,4 ﬁwjj/WJZM 444444 W \WW’W ‘ 44.4 I 44444444444444 44- £441,148 ‘43 44.474444744- 44.4444/‘ WU) Ker-44444.4. 447444.544” MMW //-/v -n $4244 77 rte—“4.44.4 1/ 44444 45/4 4 ’4 (I) @)(3) 4045': ...44. 4..."... ..... ~ £44444 {Que/7 5:7 82444444 44,444 4 K M444 4244 5447 47,424,, 4244444 ,. �1: 2/1/58 EEG Correlates of Electroshock Process During the past few years, incnasing attention has been given to the ic relation between changes in the electroencephalogram and the behavioral change induced by electroshock. The initial application of EEG techniques to the electr0310ck problem in the period l9hO-l950, was summarized in an excellent review of treatments in 1952, that the who noted rather than the degree of induced neurophysiologic (reflected in the peutic by Chusid and Pacella outcome. EEG) These was the primary number change factor related to favorable thera- studies, largely based on descriptive analyses of pre and post-treatment records, were followed by serial quantitative analyses. In 1951 and 1952, Roth analyzed the in patients during a course of was related to the process ECT and of recovery. In 1953, in the laboratories EEG activated by this- He concluded that thiopental delta noted that induced detal activity at Hillside Hospital, we analysis of neurophysiologic bases of electroshock, based " undertook an on a hypothesis expressed by Weinstein and his coaworkere in which they related improvement in electroshock to persistent states of altered cerebral function. Our �-2... first did studies utilized the amobarbital test show a provement. relationShip and these, parenthetically, between changes in language and Our second index was the ratings of delta index of the electroencephalogram. In our original review of patients, recently reported, significant relationship between the degree delta activity It is and im— and we noted a duration of the induced clinical evaluation of behavioral change and "improvement." our purpose tonight to review these findings; to describe subsequent studies in which various aSpects of the treatment process were the degree of EEG delta activity; and to conclude with a related to summary of the present neurophysiologic adaptive view of convulsive therapy. One hundred and have been studied. a day forty-eight consecutive patien electroshock referrals Electroencephalograms were taken before treatment, on after a treatment at weekly intervals during, course of therapy, istics. until the record had achieved and following the its pre-treatment character- Various treatment procedures have been used, including alternating current threshold and suprathreshold electrodhock; parathreshold unidirectional current electroshock; and subconvulsive techniques with pentothal premedication. �-3- alternating current suprathreshold The K ) and unidirectional parathreshold (Reiter) teChniques are well described in the threshold alternating current patients, without prior sedation, received a methods, for 0.1 second, which was usually sufficient for a petit 20 second second. intervals, voltage increased by 10 volts 90 until a grand mal absence. At up to mal convulsion was induced. just necessary to induce a grand 1&0 volts, 0.1 mal was the threshold voltage and The value. In subconvulsive techniques, patients were given pentothal intravenously asleep, volts Voltage was then reduced to 100 volts x 0.2 second, and increased by 10 volt steps time was current, low and then either low voltage . current of or alternating unidirectional current for ”a 80 nvolts x until 60 seconds; . . 0.1 second were administered for one to three applications. All treatments were given three times a week treatments. Patients who failed to develop clinical reSponse, or EEG changes of treated 5-10 times per All EEG a initially, for 12-00 significant behavioral or significant degree, were subsequently week. records were quantitatively measured for the degree of delta activity. This index was determined by measuring the per cent time delta �.uin 180 seconds of each of three lead combinations, and both the average _and the highest index in any one lead were used; the slowest frequency and highest amplitude delta; Records in the and the initial series duration of the longest burst were placed those with the greatest changes in slow Degree Delta Activity." Delta Activity" and "Low Degree week of The specific limits of ratings of Low degree treatment. 3) Evaluations of changes in behavior were and "High were "Moderate Degree following three slides demonstrate a High-Middle and psychiatrist upper third - earlier report. (Figs. 1, 2, weeks thirds Delta Activity." record obtained during the fourth The The activity - were called wave The middle and lower each range are described in the The into sequence. . made by the supervising resident therapist at the height of the treatment effect. "improvement" were made by these physicians two to after treatment was terminated, and were based on the three four fold "much improved," "Improved" and "unimproved classification of "re00vered," or‘worse." In our initial reports ( , ) we noted that patients who developed �-5high degree delta sustained, activity early, and in whom such delta activity was were evaluated as "much improved" or "recovered" with a greater incidence than those patients who failed to demonstrate significantly delta such activity. These observations are portrayed in slide h. (Slide h; These patients had been treated with a unidirectional convulsive therapy. In a subsequent series of 5b ~ in Graph EST #1) which the degree of patients, a predictive study was undertaken delta activity induced during the second weeks of treatment was determined. 0f the subjects in whom and high degrees of delta activity were induced during both weeks, 67% were eventually much improved; while of those either week, only 30% who did rated as not have a high degree record in were so evaluated. treated with a unidiructional current; third and Of these patients, half were half with a suprathreshold alternating current technique. Slide 5 - (Table I, Exp. Studies) Results: 1. Role of Convulsion§:in Therapy. In the most recent series of patients, randomly selected subjects �-5received subconvulsive therapies instead of grand mal; and both alternating current Of and unidirectional current techniques were used. the subjects who received convulsive therapy, ______had high degree delta records in both second, third and fourth weeks of treatment; .____ during periods. two of the three weeks, and ____ during only one of the Only _____ subjects failed to show a single high record test on con- vulsive therapy. Of 27 the/subjects who received subconvulsive therapy, however, none demonstrated middle or high degree delta of treatment. Low activity records during any week degrees of delta activity were noted in three subjects during both the second and third weeks of treatment, and in 8 subjects during the fourth week. Concurrent analyses of the behavioral ratings showed _____ of the con- vulsive group rated as showing marked behavioral change; while of the suboonvulsive group, 25 showed no behavioral changes. were referred for a second course of therapy. In 1h of electroshock induced high degree delta activity and behavioral change. activity Of the five who all Of these, nineteen these, grand mal showed a significant failed to demonstrate high degree delta on convulsive electroshock, all-showed middle degree records; �-7and two of the five 2. Factor of Type showed a behavioral change. of Therapy: In view of the variety of electroshock techniques employed, and the relationship between EEG delta activity and the behavioral response, an analysis of the effect of type of electroshock in EEG delta activity was undertaken. The results are graphically presented in Figures 7. The first related the percentage of records in each treatment group during the second, third and fourth weeks of treatment high degrees of EEG current techniques The gave a lower percentage of high degree unidirectional technique was also degree delta delta records. less effective'than the supra- all these periods. Although effective than threshold alternating current course of therapy. who demonstrated delta activity. In each period,threshold alternating threshold alternating current technique, in more 6 and methods early in the Note, that subconvulsive techniques yield no high activity records. In the next figure, the converse is demonstrated. The relationship between type of treatment, treatment period and percentage of treatment group showing no delta activity or only low degrees of such activity. �-3Here, the subconvulsive group is for each treatment period. Supra- 100% threshold alternating current techniques show the least number of Such records in each period. 3. Frequency of Treatment: Another factor on the rate of development of delta frequency treatment. While convulsive therapies were treated given daily or twice daily. activity were initially treated three failed to develop high degrees of delta activity times a week, a number who on all patients activity is the In all more sudh intensively. Treatments were instances high degrees of delta were induced. u. Factors of In the Age and Diagnosis: initial series of patients, it was noted that younger patients, under #5 years of age, developedlgreater degrees of delta the first such activity during and second weeks of treatment; while older subjects developed activity to a significant degree during the third week. week of treatment, age was no longer a By the fourth differentiating aSpect between the groups. With increasing series of patients, utilizing various treatment techniques, the differences between successive groups is largely a matter of treatment technique rather than age. �.9Similarly, conventional discharge diagnoses bear to the rate or degree of delta activity induced. in young schizophrenics, no The relation either delta activity induced older depressed, older schizophrenic paranoid, younger reactive depressed subjects are similar in indidence of high, middle and low degrees not, of itself, a at different stages of therapy. The diagnosis is significant neurophysiologic factor in electroshock. and �combining the data from all convulsive therapies supports this observa— tion. During the second week,h3% of records are high degree delta in patients ho; but only 30% in patients from uo-so, and 18% 61 and over. In the third and fourth weeks, the differences are no longer present and approximately 2/3 of the subjects have high degree when treated 3 delta records times per week. TABLE Variation in % High Degree Delta EEG Records with Age Treatment Pe riod To ho years hl-SO (28) (25) h3% 61% 69% 29% h0% 56% 51-60 (28) 32% 56% 55% 61+ (18) 18% 50% 80% S. Pre-Treatment Record Characteristibs: Previous reports, summarized by Chusid and Pacella; a ( ) rated significant relationship between pre-treatment records characteristics the degree of induced "abnormality? Escords with predominant alpha rhythm or "abnormal" (Chusid and Pacella) or "borderline abnonnal" and �.10- liable to developé alterations in the (Bagchi §£.El) records were more EEG than those with predominantly low voltage fast activity patterns. Rank order correlations of the pre-treahent per cent time alpha in selected leads (anterior temporal - vertex) with the degree of delta activity during the third and fourth patients demonstrated correlations of +.2h The weeks of treatment in h3 and +.35 reSpectively rehationship in the fourth week is significant at the .05 level of confidence; while that in the third week the trend fails of significance, although is apparently indicated. Discussion: Two aspects of these studies warrant discussion; the significance of the convulsion in the electroshock process; and ﬁne role of electro- encephalography in the rational management and study of convulsive therapies. (1) Significance of Convulsions: In the initial studies of convulsive therapy numerous authors, Kalinowsky including Kalmaasky at al,(l9h2), and Pacella gt_§l:(l9h2) emphasized both the clinical and electroencephalographic differences and petit-mal responses. provement in 60 to 80% While grand mal between the grand-mal seizures induced clinical im- of cases, petit mal induced changes in less than �.1125% of subjects. Similarly, the electroencephalographic reSponse to grand mal is one of delta activity, and to petit mal, is delta activity. no In subsequent years, various subconvulsive, brief stimulus, unidirectional stimulating, monopolar stimulating, focal convulsive techniques have been described, and each, in turn, discarded in routine therapy. Bergman gt_§l”( ) for example, in describing the electroencquh- eIographic effects of focal seizure techniques noted that patients had normal records "abnormal" records after after 15 such l0% "seizures;" while grand mal seizures. Ulett gt §l° 20 of the - 75% had ), in a ( careful control convulsive-subconvulsive amdy, reported the significant differences in the clinical changes between the convulsive therapies (60-80%) and subconvulsive (33%), and noted the discrepancy response in the two groups, and emphasized the in EEQ significance of the seizure for the therapeutic effect. These studies emphasize the significance of the grand mal convulsion, both for the clinical therapeutic effect and the electroencephalographic reaponse. Recent reports by various observers, and based on a variety of data, support this conclusion. If the convulsion is the essential element in the EEG and �-12behavioral reSponse in electrotherapy, does convulsion is the induced?. In the studies reported here, small differences in both the degree of were observed. it matter in what way EEG delta activity and the rate of the development Clinical evaluation demonstrated concomitant greater degrees of clinical efficacy for the suprathreshold alternating current method to the two other convulsive techniques. 'Other studies have also for various convulsive techniques. shown differences in clinical results Ulett gt_§l. ( ) noted similar differences in clinical results in a study of patients receiving alternating current5'and photic-metrazole convulsive and subconvulsive techniques. He reported improvement rate of Sl%,'76% and concluded, 33% respectively; that the convulsive photoshock technique clinical efficacy. Epstein and Wender (1955) compared unidirectional current techniques, and reported no results but that unidirectional techniques required more had the than alternating current methods. More a new convulsant drug,.Hﬂ 1090, ascribed to greater than electroconvulsive techniques. and greatest alternating and difference in clinical one to two treatments recently, Edwalds, describing it a clinical efficacy slightly �-13while some variability in clinical results is reported, is clear that with repeated convulsions, provement rates of 60 and for the most part, treatment. regard to have noted we may its 80% are induced; may be no matter how induced, imThe differences are small, obviated by increasing the frequency of conclude that convulsive therapy mode of tat - it is non-specific with induction. In previous reports convulsive therapy (EEG is non-specific with Theory) we regard to their application in mental illness, nor is their clinical or behavioral effects. The present studies amplify, therefore, the previous conclusion that convulsive therapies are non-Specific. 2. Role of Electroencephalography in Convulsive Therapy: we have applied methods of quantitative, serial in the studies reported here. change may give similar data, such evaluations are the attitudes of the observer of EEG ( analyses clinical estimates of behavioral While on EEG ) than the EEG. more closely dependent Further application Analyses to other problems in convulsive therapies may provide a rational basis for comparison of different treatment techniques. �We have previously noted in the clinical management of that EEG analyses may be applied patients receiving convulsive therapy. of In our experience, the early and sustained induction of high degreaydelta _ activity provides the physiologic basis for behavioral vulsive therapy. a An electroencephalogram in patients significant behavioral response per week may subjects in change who in fail on treatment regimens of high delta to show three times serve as a rational basis for clinical management. whom con— In those activity has not been induced, increasing treatment frequency, withholding premedication, or shifting to a thera- peutically more effective convulsant If the physiologic changes. be maintained may ( ) for a or environmental ( havioral response, even and degree of delta number of weeks, other ) may be assumed to when further convulsive therapy records. result in the neuro- activity is high; and it factors, as personality preclude s satisfactory be- the neurophysiologic substrate is assured; application has been suggested EEG method, may may welllae discontinued. by Roth ( ) A similar for thiopental activated �.1 5.. lhe successful application of quantitative EEG techniques to convulsive therapies, has led to their application to other physiodynamic therapies. Recent reports from these application for the rational management pharmacologic agents Summary and ( Conclusions: ). laboratories note a similar and understanding of psycho- �to“ Win the Natalya”. Watmﬁmmbun gim nation bum inﬂamed by It: omwgek. _ than olectmnuplaham In 1953. in the and behavioral mum at. dung" mud. Hospital, We“ of ashram-1019a: upon“ at olmtrouhook m mm. swim: ( champs in )1n were band on which may a. Win mm by Romain and his muted imprmmt 1n 01.6mm to tho a» mom” Mom: of paraiamat sum at altered mmbml function. mmmmmmw< Luminanctwnmtmuump how the damn am mum a: ﬁn 1mm den-a activity and mum «alum of huh-mm damp and “W.“ this report to "view than ﬁnding” to describe mum nmrophyuiolom to nuggut aspect: of u. Almanac-1m or maps-oat. of minimum: 3%! On. W bun swans. 3nd It 1. at W at mt Media in mini: m mun-at woo.” In. ”mud; MWmm in mud!“ and and sum). mom“. {Wﬁt acne-anti" «hammock Marni: a". um um baton taunts-ant, and an ammrttmtatmmquadummfmmw-mm �4-2. of therapy meal the noon: Md «mum. 45* M‘ Pntimts- mﬁpn-matnnt or significant . bum its pwtmhmt m dual-tramw- 31w m a; mum activity, mm are «eluded from tho curios. Fm tmww madman «playing 611nm 1) umg/aumam W at. “mm: 3) MW“ mm mpnthnuhold It) mbommlsiva tonhmqwu‘ with pantothnl Wt 813de m tall dumrlhod. 5%: ( 9 ma pmdicttion. Tm ( gunman; ) hummus damning current. method patients, Mind 1w “mats, mu sufficient tor a phi: 3:1 mm”. and, (Maugham); ummmm lawman! In the thrown!!! ﬁtment prior «mum. ~ W of “dam he.“ M915 smug a) nun-mung «mm at. 3* mm“; (90 Volt. M 20 for 0.1 sound), mad Manila, may, it mam-,7, duration: in” 1mm mm a and m]. whim m mama. mmmomd timmcuurytojutincmma gmdmlmtho, thruhold value. In subconvulaiu m, m.( mu )3 and um mu” u {may maimﬁann mt. for co ornamtingmté mungvoltnxOJWurn “31.31th far on. 15mm. mam, puma“ mm 31m mm warmly to three Appnoatim, for a. total. of 21: to 36 ”ﬁt m1 �A11 tmtmubn an arm: thm tints a wok initially, for trauma“. Pantom- Ibo clinkai n‘spenn, or EEG tail“: to duolop a changes of 12-20 macaw behavioral or' signiﬁcant 4.3190, are subsequently mam 5-10 than m wok. m EEG Mord: were quntiutivoly manna for the dogma or délm mm: in. «data: at to mmr ﬂu: Man-mud ”M,“ activity. The "Manta“ or "lav“ 63M er delta activity, mowing to criteria pu- ‘ ‘ awn matched ( The ). mums; three slides (immune a high, maﬁa and 101! «n: Mord: duung tho fourth-ml: at twat-cut; W l (Figs. 1, 2, 3) Ivan-um or W m hamm- an and. by the mmmm Wm“ m6 random. therapist It. the Mia“. of tho treatment at ”mama-Int" Weaken: run and. by then physician:- two tn m tominatod, and were hand on ma “mound," “men In our initial “tact. tbs-0e four tam W,” M “W or mm." Wu ( g ) no The rating: mks utter dasﬁfiéum a! wind that patients me wanna �4‘" 1:131 damn 601%: activity . My, and in when m «1%: activity 1.! wow. wr- mlulud a “lunch Wmm or “uncured" with a grater muaow than than patient: activity. Thu. chomum who such delta m pawn-wed 1n and. h. (811* In Gnﬁ 511* s In the ta damn-tutu “mutant.” '1' M ”J (km. 1, nut wont. «run or puma“. ms Studio.) mm «new plum“ w tame m nmsmmmy mind .mmmvo thmpiu mm or mad Id; Ind both atom-$1M . W WW“ mt Man. RN and mod. at tho 1:? mm at: who mm mm ”mm haunt" than”. 9 hid high dome in both «ems, mm and fourth mks at truth-at] 1.2 wring hearth-thrum, mummly'motthlmtpoﬂm. thin-In “their? lubdwtlnuodto Muuuglchiwaogrudﬂumm convulnu thunpy. at tho 2? aubjootu who mum Wain mum, Wt, m �.5. dam-mud new or high down 4.11.: nativity mom or mutant. in! now of during both ﬂu my and: mu activity m not“ in than “hm new and third min at imam. and during the fourth elm-1n; in 8 ”Mo-ct: not. Conoumnbmlymatmbmmﬂungu mmwotthch'? a the mini” map rum u showing mud behavioral champ; or no bah":m1. of ”320mm" group, 25 at the 2? ma 101:1 mm. at the 1m» amp, 19 m Mum m- a mad um want.- m than ' “than”. Inlhotthou. activity and :11 kind mmmwkmmmmmmu mm a “Mimi Wharton]. W. in damn-at. 01' tho tin Ibo m dom- dolu nativity an convulsive deutmmwk, mam-a M61. diam records; and hoof this ﬂ“ mandahwiml W. mu, «multiv- thanpy Wad simian-um mam:- antics-:1 change! macaw mini-ll with 3m Moral mango, and W with” in km or mum placat- moving than-aw, 11de both it: MYI mm mud 8E0 «an inﬁnity. mum". «1m nativity, wan. auboomuluvo EEO ma rum“ to «mum mum-:3. «hang: m plan“ an mum �In via or ﬂu mow of unwock Mama» .uployod, And the mun-uni}: ham we «1%: activity mum at +4.2. «has a: typo a: 010%ka an max-nun. Th. gun“ The Won}. "upon”, and the mammal mmw m at gummy pmmtéd in man- 5 ma 6. first agar. ulna: in tub mutant this Walnut typo in 8W dating the unsung. EEG an. activity. mutant um: daunting «mat It mmknshald high.” mom: In each period, otnncth and with numung mt at thmshou oft-cu" thin tho lupnﬁhnlhad alumnus mnem- m tho ‘ ' the tau-angst; m 1m mm, in out mar-cum; curl-mt. tmtamt being not: «mm than the tux-«hold 11th Suboomumn #:00QO yield no high dam «in: activity neural. cum-at. uthod only curly 1n the Mum WWW“: treatment the am come of mumpwmng pox-«near wh/mpwoungno «Inactivity such trut- ”may of my: (low mu mom. What with Winch 1m). nun-mt ported; of the «new. third and fourth molt: of mt Whiting mm dam of » a: nativity. Kin, tho «boom!» in map is WW- than ' «01:1:de 1005‘ for «ch tram �.7. ponod. “puma-«hold uunbor of man alumina current handgun chow th- but. rcmd: in «a: period, nth tun-had ma mmm “chum. in how. f Tm 3. ts Author factor on the truancy at tmtmont. tins a cock, u mater on convulsive nu of mama: of delta activity in tho While :11 who patents wore initially treated thm fund to therapnn vor- dculop mu! demo- or :1qu nativity tmud' non mun-may. In aim Inch uncut-,- an 3110:: an); or win any, and in «eh instant» ﬁddle or my: damn of 601%: activity an mm. 8mm- ma comm won prenatally dumtntod by mu. ﬁg... ( ). m1 cumu( mnmuta k. W' In tho )_. mun unit. or patina“, 1%. was mind that. younger patients, Mr 16 your! at ago, dmlepod grater dam of delta nativity during thnrst. and poems! activity to of & tnatnnt, m at “about; 111111. older subjects. donlopod inch signiﬁcant dogma during the third weak. 3: the fourth not m was no 10:15:01- : dittounuatiug ”poet bottom the groups. �~8— Gcnhdnmg “I. data from an. During tho undo:- mom convulsiv- m. h)! a! mm m raw demo dam in mutant: the as. of hot but only patina“ 61 and. thonpuu supports this obumum. mm no longer present. and 305 in ptﬁmto rm 1:040, In the third and fourth ”aka, the and 183 in antenna» an “mantel: 2/3 of the lubjlctl but high degree «It: «and: uhon trotted 3 tin” par wok. mu Yunnan 1n 1 8131. Dog“ mu ma mm with La * m m mm we no M 51+ 0 m be as) has (as) m (as) (13) W 1:2 as M 691 he: saw 32: 5a 95:: 18: 50: M no durum in 1mm of high dome mom 1: significant u .013 andhurthtruaunnd .OSShomthoummtndthird mic: or tun-em in patient: «or 50 your: at nan) but is not uwimny manna“ 61:1on for the“ put-1m in groups and» 50 yum. �.9. mum "pom, mm by Gama and mu“ )mm . IWmt mktimhip batman pmmst. aunt heard Mauritian and m m W “nbmlity.” new nu: mm: at or 'abnoml' (Ohmic! and alpha mm M113) or “bomﬂino ulnar-t3! (Hum 91 9;.) Wanmmummnunmummmmmum may In than 1w may tut activity ”than. «an or imam“, abduct: who“ pm-vbrnmcnt domain-1m um um «hazy apn- or space an activity nah mam.» Eight A manic mimic or the mush pro-Manta“ ﬁnality. talcum ,mﬁk order tin am in «new land: m pro-smut“ ”mutton: of an} mutton. alpha and pu-mamnt (anterior Mignon). worm) with the 601m activity during the third and tour «the cf gaunt: dalmatﬂm man of than and «It: antivity «run, and for more mm «It: activity an mandala-n dam. of or are not nausea in an gunman. Won. that in puma“ without par aunt mm... er mama-ac «any. m tmtod with emu”. taotmiquu dmlopod high amoe- at palm of a more! or +31; and «35 tmﬁmt mpoctinlm in h3 �.10. m mumumrmmmuummtn the 4351.701“ Widen“; thl while that in. tho third ‘at dwiam. although W6 a mum. W: M «poet- at” than the not an. that”... mt dimuon; tho Winn“ of, whim 1n the 01.6%!“th pm“; and the r910 at «an nontra- W! mopbnlomph (1) 1n the In the including mama: and may or convulsive therapies. mud and“: of cumulus." therapy lawman whim-c. hum-kw the clinical Ind «Mom: ‘ ﬁg. (19%), and Plum 5;. (193:2) aphasia! bah 01¢“ch diatom bum the grim n.1, mpoutm “WM mammmm-Wamm 1mm"mntinwtomofmu. ptﬁtnlindwod Weamhlstmaﬁof mycu. mm. ﬂu chem-pulmyhle mm. to m a! mu ”Univ, and {no pout m1, 1: In subsequent. you-I, various no delta grand an in mum. W131“, has! CW, mﬂmtiml “hunting, mopohr unwitting. foul contain" techniquu have been �.11. thd in mum. than”. Barman 33 3;. mum, and nah, in turn, ) tar example, in mung an cloutWaganc «not: or ( focal "inure manna-u Mad that art-r a), 15 inch "maumr' m1- "isms. Matt 93 g. study, repel-Md a halving ( of patients had - 753 had “abnormal" ), in a ammo-at autumn mm mom _ max-d: utter grand «ram comm). «muywmbeomhin 1n «mm-:1 roman "a! panam- amid" that-apt“ (W) ma theta minus abnormal-1v. (331). or control: (381). no tho two 70 70% mp3, and new tho war-may 1n the 3m noon-- in mum the signification at ﬂu loam for tho thanpuutic strict. Mint additional upon-h 17 various ohsarvm, band an a «ﬂaw of (Rain-“1n and an, alpha“ th- awinmaa at tho ”amnion. m, Roth, mung). rpm, the mm. mnem- um minim par a, an a:- mu tho signiﬁcant physiologic mu mm m the has for thirty-nut: If an. convulsion «fancy or 'oamluva than-qua." I both it tho mud chant/1n mu m and in tho behavioral "903380, does m node of inﬂation at the role in um “spam-7. In the chads." ”ported ham. uny “mama Min-mm in both the dam- ot‘ “ism play any Oman Em hut-.2 sun-u- mu activity �.12. the and at» of 11:»: “mu m abut-"d bum Miami mod: of imitation or grind u). m. m an m. pmidu but: far the mama Mm't tint .mpnthxuhold m @0an album-ting current “chum m mt “tutu. m We cmuloiva than”. “the: India ban the sham moms cumulus.“ “Wu”. exam in clinical results for 813% g 51.. ( ) mud 31:11.11- mum. ms; in mm:- mdiu or Mum waiving atom-um mt mmlpin and mumml mvulnm m! mbmvukin tech.- 1i: amen niquu. no "ported Wat. m. at $73. 763 ad 331 yumﬁuln mam ﬂat the Wain Manhunt: Wm bud tho amt.“ clinical «tinny. non may, W, doom-thing n m «walnut: and drug, a: 1090, named to it a clinical mam; unghuy gmur um dawns." wanna“. w studios an have mm mm m «Wm mam-d by Mom Wm» hm! um manna” of latency, duration, prom-mac In of claim: or tonic ammt phi“, am, two. um; not :11 mind In}, From that. Sundial, it has Mm him: at. minimum; and that : �:31)’ W; m mm a not an an or w“ cum and than my unset dim-mt. taut-mt aimed. Dunn-mo mum panama dutannm in Mahala «rout. of tho Mar mm" 01' this probhn an 11: 9'08“”- thn this "unmey in clinical 1:3qu in ”period, it in clear ma, ups-mt. raw or - in chum-d. m dﬂhmu human var-1m W or mutant m 3.311, and, for ma most part, be mm w increasing the 1:qu ﬂnt with rap-wad comma”. no author he! 60 305 may com!” may: in nonwith mum to ﬁlm W tho minim in Mad. The simiﬂmt or amber at mutants. it. any Mic «mm that amt u the bran W Mum. ta the uranium, and not an mat mamas-1mm mama“... Inwim mm (3m, Theory) in we: noted that commits.” map? 1: l1” 1%. application in with mam maul, m: in its clinical and with Wticity of convulsive. ﬂan-pin. to I bender-1 «facts. no pron-at studs.» «3mm winters, the pram» at the ”and comm �U. have appliad ”mode or quantitative, serial me the m1: studies} mporud here. We in clinical estimates at behainnl change ‘ may give of tho xinihr data, obumr ( ' ) than an m. Us lava dependent an tho m a prawn/mum]. buns for Miami tmtmnt technique“ pmionlly noted that mm mm: my be applied in the clinical magnum. or patients receiving oonmlsivo therapy tin I um tad» Wr applicttion at m analyse: to other pmhlm in convulsive thumps.” compariaon of am such evaluations am @mnua ”ported here, the curly and ( )- In sustained induction at high dam,» a! do“: activity provides the phyaiolagic bait for behavioral in cumulative mmpy. «mango fail to thm char 3 mu. increasing a electroencephalogram in patients uwﬂmt Wen]. times per week aunt. In An w when mutant. tummy, Mummiaogic more big: delta activity has withholding effective «walnut. If changes. it my be 31an for tmtmt ”31mm of norm as a rational basis for clinical manage» mbaem in thonpeutiany aspen”. on who o. tho dome of nmbor of not. been induced, pmdimtien, 0r shifting to mum, my resuli in the mm activl ty is 11139 mks, nth» future, and a punctuality �~15— ( ) or mama}. ( behavioral response, and ) my be can when the «me! to panama. a utiatactory Wide-go mbctrato is assured; further eomhivo therapy my will tion has bum suggested by an Ruth ( moons-tn]. application of convulsive therapies, ) be discontinue. m gaunt: similar applica- for buoyant-.1 activated 330 record» quantum." ‘m tachniquu to bu led to their application to nth“ hemp-us. accent reports from than laboratories not. for A as MW“ similar applicatim mum-1 moment and man-Italians of paychephameolom ( ). �416~ gagglnnianus 1.‘ In aerial qynntitativn analysis of aetitity in degroe of induced EEG delta anhjocta receiving variant convnlaivo therapies, a poaitdvu relationship betuoon the digrea o! indueod delta activity and bath tbs dagroe oi'bohavioral ehnngo and ratings of impruvamsnt 2. and induced grand mﬂl convulaian An is reported. 1: elscntinl for both the EEG behlviaral change. 3. Th3 rate a. and dogrcc‘of induced Hbdo dalta activity is dependent upon: at soiturc inductian b. Fruqunncy at treatment a. Ag. 0! lnb3oct d. Pre¢treatmsnt h. It is pmuvidoa a recommended EEG record characteristics that aerial quantitative electroencephalography rational basis both for the study and clinical managenant or variaus paychodynlmie therapies. �II: 2-5-58. 0131/11.!" Correlates of the Electroshock Pincess EEG During the past feW'years, renewed attention has been given to the relation between changes in the electroencephalogram and behavioral changes induced by electroshock. In 1953, an analysis of neurophysiologic aspects of electroshock studies ( in the laboratories at Hillside Hospital, ) in was undertaken. were based on a hypothesis expressed by Weinstein and which they related improvement The his co-workers in.electro$hock to the development of persistent states of altered cerebral function. In thii initial EEG study ( ), we noted a significant relationship between the degree and duration of the induced delta activity evaluations of tIhI=HIIEIEIIEZl=E=IIi§"improvement." It is and clinical the purpose of this report to review these findings; to describe recent studies in which various neurophysiologic aSpects of the treatment process were assessed; and to suggest the application of electroencephalography in.studies and rational management of physiodynamic One hundred and been studied. a day therapies. forty-eight consecutive electroshock referrals have Electroencephalograms were taken before treatment, and on after a treatment at weekly intervals during and following the course �-2- until the record of therapy ﬂag»! Patientsbﬂwyhgug‘pre-treatment IN EEG - . eggpktfd’ef’d .,,.,;‘""ﬂWh . activity, an...“ M"M ﬁignificant asymmetry were MW’O‘Mmmws-‘W pre-treatment characteristics. demonstrated slogwgave or spike . WW its had achieved series. from the { ‘ {V .up-w‘ . Four treatmentt procedures employing g different types of stimuli have ' i V . 1) been used; /alternating current at-threshold strength; 2) alternating current at suprathreshold strength; unidirectional current (parathreshold); 3)- h) subconvulsive techniques with pentothal premedication. The alternating current suprathreshold are well described. ( ) and unidirectional parathreshold ( ) techniques In the threshold alternating current method patients, without prior sedation, received low currents, (90 volts for 0.1 second), usually Sufficient for a and, if petit mal response. At 20 second intervals, voltage ,_ thewmwmm necessary, duration! were increased until a grand mal convulsion was induced. In subconvulsive techniques, patients were given pentothal intravenously until asleep, and then either voltage unidirectional current for ); or alternating current of seconds ( administered treatments . low l 80 (30 to 120 volts x 0.1 second were for one to three applications, for a total of 2).; to 36 petit mal �All treatments were given three'times a week Patients treatments. clinical response, who initially, for 12-20 failed to develop a significant behavioral or or‘EEG changes of significant degree, were subsequently treated 5-10 times per week. All records were quantitatively measured for the degree of delta EEG Ml WM! We! MM‘AWW activity Masada—WW ‘ delta activity, "moderate" or "low" degreet . l‘ . . I i 5 3 . The 30W week of (Figs. 1, treatment. 2,3) Evaluations of changes in behavior were made by the supervising psychiatrist resident therapist at the heigat of the treatment effect. The of "improvement" were made by these physicians tw0 to three weeks treatment "high, " following three slides demonstrate a high, middle and low degree delta record: during the fourth and M was In our after terminated, and were based on the four fold classification of _ "recovered," ratings ”va ”much improved,"nand "unimproved initial reports (' , ') we noted or worse." that patients who developed �high degree delta activity early, and in sustained, were evaluated as whom such "much improved" or greater incidence than those patients who delta activity was "recovered" with a significantly failed to demonstrate delta such activity. These observations are portrayed in slide h. (Slide u: Est #1) Graph Ecsults: The “W etweeni“! relation neurophysiologic 5" . . and behaVioral response W111 be assessed according to five aspects: 1) 0 2) Type of Convulsive Therapy 3) Frequency of Treatment h) Factor of 5) Pre-treatment Record Characteristics ’Of Age the uz’subgacts’WHo”retaived‘ccnvuISive‘tnerapy, 7 nan nigh delta records in both second, third two of the three weeks, of the u? subjects and fourth weeks of treatment; and 13 during only one of the failed to show a UEgIEE" 12 during test periods. Thirteen single high degree delta record on convulsive therapy. Of the 27 subjects who received subconvulsive therapy, however, none �high degree delta activity early, and in sustained, were evaluated as whom such "much improved" or greater incidence than those patients who delta activity was "recovered" with a significantly failed to demonstrate delta sudh activity. These observations are portrayed in slide h. (Slide u: Graph Est #1) WWW Results: 1. convulsive vs Subconvulsive Techniques: In the most recent series eizpahaaaih randomly selected patients re— ferred for electrotherapy received subconvulsive therapies instead of grand mal; and both alternating current and unidirectional current techniques were used. or the h? subjects who received convulsive therapy, delta records in both second, third two of the three weeks, and show a had high degree fourth weeks of treatment; and 13 during only one of the of the h? subjects failed to 9 12 during test periods. Thirteen single high degree delta record on convulsive therapy. Of the 27 subjects who received subconvulsive therapy, however, none �.5demonstrated middle or high degree delta Y3...” of treatment.§ x Low ( / activity records during any week degrees of delta activity were notedhiﬁwthree subjects during both tgexsecond and third weeks of treatment, and I“ .,.,_,_.,.-‘ ”mud,” Y , “W", v V .V,. inAB subjects ,, ’dmﬁgthefourth Week alli'lll=l==I-I behavioral ratings Concurrent subjects in the convulsive group rated as shining showed hZ of the h? marked behavioral change; hat ‘ while of the subconvulsive group, , ioral changes. of therapy. the Of latter 25 of the minimal or no behav- 27 group, 19 were referred for a second course In 1h of these, grand mal electroshock induced high degree delta n...» . 4,7,.“ .;...-....‘..,r,, 9...“; .. n .mm ., 3., ,. .~-wms...mu m-.. _,. ”a”. .. activity "Walnut... all showed a V.-.~...,..,..~..,.u.ma..~m.—.~..._..Mn...._,.m.. m failed all 4 f. ./ ..,,,.A. . .- significant behavioral change.#fgf the five t. ' to demgnstrate high degreewdeita “if I/VFI' My" : ’ activity a” , Thus, convulsive therapy induced showing on five . Mm)“.- . showed a behaVioral ”n,mmwm .,wmlumwﬂun. significantly greater behavioral changes neither an EEG EEG delta activity. Furthermore, or behavioral response to subconvulsive therapy, showed both the-EEG and behavioral changes therapy. convulsive”2lectroshock, delta activity, while subconvulsive therapy induced minimal behavioral change, and minimal patients 51/ Who~~ I” “(my We“ EEG ,4 .2 shdwed middle degreeprecords; and two of the associated with """ ------—--- 5"“ , /,/r ,//'change.; a r and when placed on convulsive r. e r. a 7.“, �-b2. Role of Type of Convulsive Therapy: In view of the variety of electrOShock techniques employed, and the relationship between EEG delta activity and the behavioral response, an analysis of the effect of type of electroshock undertaken. The first The delta activity on EEG results are graphically presented in Figures 5 was and 6. figure relates the treatment type to the percentage of records in each treatment group during the second, third and fourth weeks of treat- delta activity. In each period, ment demonstrating high degrees of EEG treatment with alternating current at suprathreshbld strength gave the highest percentage of high degree delta records. ieeetment'uéth-unidirect- ional current and*lith alternating current at threshold strength was less effective than the suprathreshold alternating current technique, in each period; a the udtﬁiEgﬁgie;;%reurrent treatment being more effective than the threshold alternating current method only early in the course of therapy. Subconvulsive techniques yield no high degree delta The next figure demonstrates the same activity records. relationship by measuring the treatment per cent of each/group showing no delta activity or only low degrees of such activity. Here, the subconvulsive group is 100% for each treatment �-7period. Suprathreshold alternating current techniques number of such records in each period, with threshold show the least and parathreshold techniques in between. 3. Frequency of Treatment: factor Another dn the rate of development of delta activity is the frequency of treatment. While times aweek, a number who on convulsive therapies all patients were initially treated three failed to develop high degrees of delta activity were treated more In nine such patients, intensively. treatments were given daily or_twice daily, and in each instance middle or high degrees of delta activity were induced. previouSly demonstrated by Pacella gt El. h. Factor of In the ( Similar EEG ), and Callaway ( ). Age: initial series of patients, it was noted that younger patients, under hS years of age, developed greater degrees of delta first correlates were and second weeks cf activity during the treatnent; while older subjects developed such activity to a significant degree during of treatment, age was no longer a ﬁne third week. By the fourth week differentiating asPect between the groups. . �-8data from all convulsive therapies supports this observation. Combining the During the second week, under'the age of ho; h=t===:;.30% ' patients "www-W” 9,.0. .. 1M 1‘ . at . on.» . , of records are high degree h3% M 61 and over. In the n.-“5.”. m1”- A, “W third in patients from delta in patients WW WM M ‘4 treated 3 ~ ‘ , W. W"; A .W‘ andﬁdpproXimately 2/;xtf the subjects n:/}pﬁger present M” when cue-yaw and fourth weeks, the differences arep ~ «idelta records in hO-CO, and 18% timéé per W99§° ,ffﬂ have wwww‘t4m HM\“ " ”a“ “by" ‘ high degree W“”w" ‘f" Mama.W ”Q h/‘ WWW, Wn.ﬁ,,,,.,-r..m TABLE Variation in % High Degree Delta EEG Records with Age * Treatment Pariod 5g: ' in is. 2:2 are 61% 69% (28) m ul-so (28) 29% m 56% 51-60 (28) 432% 56% 55% 61+ (18) 18% 50% 80% To no years * The difference in incidence of high degree records is significant at .Ol% between the second and fourth weeks and .05% between the second and third weeks of treatment in patients over 50 years of age; but is not significantly different for these periods in groups under 50 years. �S. \ Pre-Treatment Record Characteristics: In earlier studies, a relationship between pre-treatment record characteristics, notably degree of abnormality or predominant alpha, the degree of induced "abnormality" was noted ( , ). and g In these series of patients, subjects whose pre-treatment record demonstrated slow wave Spike or Spike wave activity of a diffuse, or dysrhythmic variety, or activity were not included in the statistical analyses. W, Eight such subjects were treated with convulsive techniques and seven of them developed high degrees of delta activity earlier, and for more sustained periods than in patients without such pre-treatment abnormality. A Specific analysis of the relation delta activity was undertakenjémk order between pre-treatment alpha and correlations of the pre-treatment per cent time alpha ée—Ge-lMed-ﬁeds—éea-teWﬂ—aemﬁ-with the degree of delta 4. patients demonstrated correlation‘ of . 95’ M activity during the third-and four weeks of treatment in M/Wima . 4'“ M +.35’ if ' I43 f5” 4d” �-95. Pie-Treatment Record Characteristics: Previous reports, summarized by Chusid and Pacella,( ) noted a significant relationship between pre-treat ment record characteristics and the degree of induced "abnormality." Records with predominant alpha rhythn or "abnormal" (Chusid and Pacella) or "borderline abnormal" (Bagchi 33 13;.) records were more liable to develop alterations in the EEG than those with fast activity patterns. predominantly low voltage ,1 In these series of patients, subjects whose pre-treatment record~ demonstrated slow wave Spike or Spike wave activity of a diffuse, or dysrhythmic variety, or activity were not included in the statistical analyses. W, Eight such subjects were treated with convulsive techniquesﬂand seven of them developed high degrees of delta activity earlier, and for more sustained periods than in patients without such pre-treatment abnormality. A Specific analysis of the relation delta activity was undertaken'éxk. per cent time alpha degree of delta order activity during the third—and patients demonstrated correlation( of 05’ correlations of the pre-treatment WWWWith a, , between pre-treatment alpha and M/W/mu . M the four weeks of treatment in 4'“ W +35) [a ' 1.13 ”(tyne/l @4’” �gr.“ 3 r% \ -1¢¥“""‘MI‘CWEHi ‘ — n—fJ‘r‘mWﬁ“ is” w? \\\\- r" ”y, wwﬂ:;¢"‘”w {awr rth geeﬁ'is Significant at the IQ§hlével of . the relatidﬁship in The , .10- ,_ PMW’MW v . . . > I? if“? f e . . iﬁcénfidence; while thatﬂin the . ”His" ”419"“ M third . a"? "’1’ if.” . ﬁx ,q/J’WNW lynx-"”61 (”fl ”M" . . ' . the trend rewindicated. ’71" a/«am “Mmmmmwmm“minim“..m“, Discussion: aspects of these studies warrant discussion; the significance of Two the convulsion in the electroshock process; and the role of serial electroencephalogragh in the rational management and study of convulsive therapies. (1) Significance of Convulsions:’ In the initial studies of convulsive therapy numerous authors, including Kalinowsky gt_gl. (19h2), and Pacella gt ﬁl‘ (19h2) emphasized both clinical the and electroencephalographic ‘3' petit and , .. “7:4!“{ "5 “vﬁﬂu.. “2. ‘ ., r , mal responses. ',>~'(:.w ’ i differences idwmaewa‘huwmmmm. I'“.ﬁ:W’"amhma-~vmmm~a While Sa-‘iukw‘ﬂ-‘Ih-m‘yow'wwmmmww“ ‘ anthem," between the grand mal. k» " qut‘w' cal 'mal seizures inducedngﬂmd c 12 prove- gﬁetrﬁ‘w afﬁx), ‘ ducedﬁphaﬁges MW“ in less than 25% 0 4745“ M M one of delta activity:‘and to petit mal, is no delta activity. . WW 7 mm M In subsequent years, various subconvulsive, brief stimulus, unidirectional stimulating, monopolar stimulating, focal convulsive techniques have been �.11described, and each, in turn, discarded in routine therapy. ( gt al. for example, in describing the electroencephalographic effects of ) focal seizure techniques noted that 70% I after mal Bergman 15 such of patients had normal records 4 "seizures;" while seizures. Ulett 23 El. 70 - 75% after had "abnormal" records grand ), in a careful control convulsive-subconvulsive ( study, reported a significant difference in clinical reSponse of patients receiving convulsive therapies (60-80%) and those receiving subconvulsive w” as; 6L. (33%).{es—eontrele-438%92J He noted the discrepancy in the . . EEG response in the two groups, and emphasized the significance of the seizure for the therapeutic effect. Recent additidnal reports on a by various observers, based variety of data,&emphasize the significance of the convulsion. (Weinstein and Kahn, Roth, Fleming). Thus, the evidence indicates that convulsions per se, are’or reflectlgthe significant physiologic events which are 0 the bases for therapeutic efficacy of "convulsive therapies." . both If the convulsion is the essential element/in the . . behavioral reponse, does the mode EEG and in the of induction of the seizure play role in this reSponse?. In the studies reported here, small but cally significant differences in both the degree of EEG any dLr statisti- delta activity �-12— and the rate of its ' development were observed between different methods of induction of grand mal seizure. Ulett gt al, ( ) reported an improvement rate of current convulsive technidue, but and concluded 76% 57% for alternating for the photic metrazol technique, that the convulsive photo-metrazol technique had a greater clinical efficacy. convulsant drug, PM More recently, Edwalds, describing a 1090, ascribed to it a new clinical efficacy slightly greater than electroconvulsive techniques. "we have further noted that the convulsions induced by various techniques have varying characteristics of latency, duration, preponderance of clonic or tonic phase, apnea, seemingly not equivalent; and a etc. All grand mal seizures are �‘ .13seizure is not an "all or occur and these may none" phenomenon. Different; seizure patterns reflect the differences in physiologic effect of the different treatment method: Further studies of this problem are in progress. While that with repeated convulsions, of 60 - 80% are obServed. The or number of treatments. We Specific with regard to the differences is the brain may way is clear no matter how induced, improvement are small, and, for the most part, element it this variability in clinical results is reported, may be between various types of treatment obviated by increasing the frequency conclude‘that convulsive therapy the convulsion is induced. change subsequent rates to the convulsion, The and is non- significant not the agent ‘ \ . 92;}, \‘> �-1u- 2. Role of Electroencephalography in Convulsive Therapy: have applied methods of quantitative, We serial EEG analyses in the studies reported here. While clinical estimates of behavioral change may give similar data, such evaluations are more dependent on the attitudes Wé‘v M30 Further application of Wt. of the observer ( 3 than the EEG.‘ EEG analyses to a (5M basis rer'ZZ‘ other problems in convulsive therapies'mey providﬁérational \ MM41$;r’.11.~:a"3"‘“é-e?fof we have clinical different treatment techniques. previously noted that management of EEG analyses may be applied patients receiving convulsive therapy ( in the ). In the experiences reported here, the early and sustained induction of high degrees of delta activity provides the physiologic basis for behavioral change fail to in convulsive therapy. show a three times per ment. An electroencephalogram in patients significant behavioral response week may who on treatment regimens of serve as a rational basis for clinical manage- In those subjects in whom high delta activity has not been induced, increasing treatment frequency, withholding premedication, or shifting to a therapeutically more effective convulsant method, neurophysiologic changes. If the it may number of weeks, be maintained for a degree of delta may result in the activity is high; and other factors, as personality �-15( ) or environmental ( behavioral response, even and ) may when further convulsive therapy tion has been suggested by , _. *MM‘ ,nm4.~~-> ....~,..~v~m be assumed to preclude a satisfactory the neurophsyiologic substrate is assured; may well be discontinued. Roth ( ‘) A similar applica- for thiopental activated «AW‘~ EEG records. V . The successful application of quantitative EEG techniques to convulsive therapies, has led to their application to other physiodynamic therapies. Recent reports from these laboratories note a similar application for the rational agents.( ). management and understanding of psychopharmacologic ..,. awuwlw'uuw... �-16Conclusions: 1. In serial quantitative analysis of degree of induced EEG delta activity in subjects receiving various convulsive therapies, a positive relationship between the degree of induced delta activity degree of behavioral change and ratings of improvement 2. An induced grand mal convulsion and both the is reported. is essential for both the EEG and behavioral change. 3. rate The a. and degree of induced Mode of delta activity is dependent upon: seizure induction b. Eiequency of treatment _ c. . 'h. It is Age of subject d. Pre-treatment recommended EEG record characteristics that serial quantitative electroencephalography provides a rational basis both for the study and clinical management of S various pix-Lodynamic therapies. �EASTERN PSYCHIATRIC RESEARCH ASSOCIATIQNHINC. OFFICERS 1957-1958 DR. DAVID J. IMPASTATO. SEC'Y-TREAS. 40 FIFTH AVENU’ETNEW YORK 11. N.Y. DR. LEO ALEXANDER. PRES. ‘33 DR. LAWRENCE H GAHAGAN, ASST. SEC'Y-TREAS. 164 EAST 74TH STREET NEW YORK 21. NHY " MARLBOROUGH ST.. BOSTON. MASS. i DR. THEODORE R. ROBIE. PRES. ELECT 676 PARK AVENUE. EAST ORANGE. N.J. DR. DR. DR . DR. DR. DR DR. WILLIAM L. HOLT. JR. ‘IST VICE‘PRES. ALBANY HOSPITAL. ALBANY. N. Y. DR. CHARLES BUCKMAN. 2ND VICEsPRES. KINGS PARK STATE HQSPITAL.KINGS PARK. N. Y. 0 0.0 COUNCIL JOSEPH EPSTEIN EMERICH FRIEDMAN WILLIAM FURST' "' PASQUALE LgorE‘sA'rA NICHOLAS Locngeio '* EVELYN‘IV'EY ' w O .0 TWELFTH SCIENTIFIC MEETING; THURSDAY, FEBRUARY 6, 1958, 8:00 P. M. SgHARP NEW YORK UNIVERSITY MEDICAL SCHOOL ALUMNIHALL-‘HALLH AII 30TH STREET AND FIRST AVE.. (ENTRANCE ON 30TH STREET) (Parking on Grounds) o '0. “O o 0‘ PROGRAM I. Electroencephalographic Correlates in EST. Max Fink, M. D. Martin Green, M. D. 2. A Drawing Completion Test (An Incisive Interpretation of the Unconscious) Ferruccio (Ii Cori, M. D. Discussant: Dr. David Wechsler 3. Apparatus and Method for the Study of Conditional Reflexes in Man. Leo AIexander, M. D. 4. Free for All Questions (if time aIIows) How much detail do you use in your examination of patients and the recording of your findings? ��EASTERN PSYCHIATRIC RESEARCH ASSOCIATION. INC. OFFICERS 1957-1958 DR. LEO ALEXANDER. PRES. 433 MARLBOROUGH 5.," BOSTON. _ MAss. DR. DAVID J. IMPASTATO. SEC Y-TREAs. 40 FIFTH AVENUE NEw YORK N. Y .f'W‘" 1“" AssT I-I SEC‘-Y TREAs. DR. LAWRENCE GAHAGAN 154 EAST 74TH STREET NEw YORK 21. N. v. II COUNCIL DR. THEODORE R. ROBIE, PRES. ELECT 676 PARK AVENUE. EAST ORANGE. N.J. DR. JOSEPH EPSTEIN DR.’ EMERICH FRIEDMAN DR. WILLIAM FURST DR. PASQUALE LOTESTA DR. NICHOLAS LOCA'SCIo DR . EVELYN IVEY DR. WILLIAM L. HOLT. JR. IST VICE-PRES. ALBANY HOSPITAL. ALBANY. N. Y. DR. CHARLES BUCKMAN. 2ND VICE-PRES. KINGS PARK STATE HQSPITAL.KINGS PARK. N. V. , 0 0.0 .0. I ' ‘ L I O 0.0 TWELFTH SCIENTIFIC MEETIN‘C THURSDAY, FEBRUARY 6, 1958, 8:00 P. M. SHARP NEW YORK UNIVERSITY MEDICAI_,,SCI:IQOL ALUMNI HALL— HALL "A" 30TH STREET AND FIRST AVE.. (ENTRANCE ON 30TH STREET) (Parking on Grounds) O 0.. M 9 0.. PROGRAM I. Electroencephalographic Correlates in EST. Max Fink, M. D. Martin Green, M. D. 2. A Drawing CompIetion Test (An Incisive Interpretation of the Unconscious) F erruccio di Cori, M. D. Discussant: 3. Dr. David WechsIer Apparatus and Method for the Study of Conditional Reflexes in Man. Leo AIexander, M. D. 4. Free for All Questions (if time aIIows) How much detaiI do you use in your examination of patients and the recording of your ﬁndings? �”mm: W A! W R433. mm, W 8mm. an. «mm W Main ~me7 WMMaotmm mm, mm mw mum at can a, m. mi» mm mm. 3.1. mum-«math-Wwwmnmaumﬂum, Wéym. ��to to m m (as) 29: ms (as) m m am (at) mm M «a (13) W «pork, m M m sea: M W mmwmama mm. ma: (.3) wanton-«arm “Manna mmmmmtm, “W“ (3) or “box-during my (11) mm: m not: 1m 1w to «:1an aluminum in tum than than with mew voltme- M nativity mtma 9”»th rum m nmm mt. «Wm mun WWW mmmmdmtho gamma. mum: mam-m Wﬂthmmutnmmmawoftmmmwm at Mt: «ﬂier, for “W pom, m mama In than not-1» at Fatima, subjects nativity, activity mad mm vim m Wham; Witty. m 01m awe may“. at mam anm mmmwmmmuwtmtymmm. mm A 4!- this a: my: damn words Miami. It mm awmmehonmdmdfmmam .WMMQMW Tha diffemm in 19 mathmmdmamthmmmmrﬁemufmymu mmmwmrmntmrthmmmmmmmm. ��‘ mm Ammqmuutmmmemmwuwm mm ”tamer mm mm W WW. momma 5.» tommmetthaméfwmafmuﬂumm.m 1. mwmmmuummmmm ,3" mtnuwdwatmwmu ”£2,“qu memumm. mm: WWW“ wwamm M Huh b. a. 1300th m1. um Mam” mum“. W:- & both for the. candy and mm Wm at ��Electroencephhlographic Correlates of the Electroshock Process MB): Fink MOD. and Martin A. Green PM). From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, in part, by grant M-927, National Institutes of Mental Health, National Institutes of Health, [1.8. Public Health Service. Aided, at the meeting of the Eastern Psychiatric Research Association, February 6, 1958. Read E: 2- 15- :2 New York, N .Y. �EEG Correlates of the Electroshock Process During the past few years, renewed attention has been given b relation between changes in the electroencephalogram and behavioral changes induced by electroshock ( l-h ). Based on a hypothesis expressed ﬂie by weinstein and his coaworkers (5% in which they related improvement in electroshock to the development of persistent states of altered cerebral function, analysis of the neurophysiologic aSpects of electroshock an was undertaken in the laboratories at the Hillside Hospital in 1953. In fig initial EEG study,” a significant relationship between the degree and duration of the induced delta activity and clinical evaluations of behavioral change and "improvement" was reportedayeThis study was based on convulsions induced by a unidirectional current instrument '(Reiter). Subsequent eXperiences with alternating current techniques demonstrated differences in the rate and degree of development of delta activity. Age of subject and frequency of treatment were also factors in the EEG reSponse to convulsions. It is the purpose of this report to assess the role of treatment method, age of subject, frequency of treatment and pre-treatment EEG record Characteristics in the EEG and clinical re- sponse to convulsive therapy. Method: : hundred and £e££f3i=irt consecutive electroshock One been a day studied. Electroencephalograms after of therapy Patients wave ﬂ a treatment were taken before treatment, and on at weekly intervals during until the record referrals have had achieved its and following the course pre-treatment characteristics. in.whom the pre-treatment electroencephalogram demonstrated slow AsymmeM/ or Spike activity, or significant aaaynetcy; were excluded from the series. �M Wﬂnﬁ rig/L Wm MW W Jam ”WWW- ﬁght/M4 W M WWW W (W) Jam MM WMWWW/ WWWW2AW W; Jaww W ,asJ—u—m 4/— .49 «3'44» :L WWWWW.%II: WWWWWMMW W ﬂéﬁw‘jﬂ. W’ W .WM MAJJA MM Wag/d �-2employing different eatments proceo Four ‘ van-us of stimuli alte .‘. ‘. current at t-- old strengthf" al - ‘ a current at suprathreshold ‘directio: current ngth; 4 w (parathreshold); t) s unvulsive techniques with -ntothal premedication. have been used' , ~. _ _ nat' The ‘ - ‘ alternating current suprathreshold (7) km W ﬁatients, unidirectional parathreshold and MW b‘ currenté’ ., without prior sedation, received for? second), usually sufficient for a petit mal response. odes second 3", (90 volts At 20 W intewals‘voltage, and; if necessary, duration! ale-re increased . . , until a grand to "Nu“ In the threshold alternating current (8) techniQues aae‘ well described. method ‘ mal convulsion was induced. mwmnl- The “voltage and induce a grand mal was the threshold value. be necessary In subconvulsive techniques, patients were given pentothal intravenously gor (>0 until asleep, either seconds (8); or alternating were administered petit and then for one to three low voltage, currentoi' 80 unidirectional current to l20 voltsﬁrézsecond applications, for a total of 2b to 3.6 mal All treatments were given three times a treatments. Patients week initially, for 12-20 failed to develop a significant behavioral or m m 55;, Mew $3 :13; gm W, were subsequently who clinical reSponse, or Jo treats (1% times per week. All activity. EEG ‘ b records were quantitatively measured for the degree of delta The "records were evaluated as to whether they demonstrated "high," "moderate" or "low" degrees of delta activity, according; to criteria pre- viously published (6). Evaluations of changes in behavior were psychiatrist and made by the supervising resident therapist at the height of the treatment effect) �, WWW WM/Jéw A?%MWW%4 /¢(WWW’MW” JKWWM HQWWWi ' ‘ �-3... and were scored as "marked," "moderate,"'hdndmal" or "none.” "improvement" were made by these physicians two ratings of The to three weeks after treatment was terminated, and were based on the four fold classifica— tion of "recovered,” "much improved," and "unimproved or worse.“ (6) Results: 1. Convulsive vs Subconvulsive Techniques: W MW, ' WW therapgrfglhad the h? subjectstwho received convulsive high degree Of delta records in-both second, third two of the three weeks, and of the )4? 13 subjects failed to the 27 subjects who and during Show a convulsive therapy. Of 6";gr one “a Low weeks of treatment; 12 during of the test periods. Thirteen high degree delta record on received subconvulsive therapy, however, none demonstrated middle or high degree delta of treatment. fourth activity records during any week degrees of delta activity were noted in three subjects during both the second and third weeks of treatment, and in 8 subjects during the fourth week. neahJ-l’ 21‘ ln concurrent behavioral ratings, hirof the.ﬁﬂ subjects in the ‘ convulsive group showed marked behavioral change; while of the subcdn- vulsive group, (Table I). therapy. *» Y‘aab éacbndldb ham, ‘ ﬂ Of 2h of the the or 27 showed minimal latter group, 19 were no behavioral changes. referred for a second course of In lb of these, grand mal electroshock induced high degree delta .RE niekagd: uan W‘LWM ,_ AAAAaaeut "W wthwﬁ W ynxuduvuax “Gunrﬂ nta. waT‘5~/::L¢Gﬁe , . I �.uactivity and all showed a significant behavioral change. Of the five who failed to demonstrate high degree delta activity on convulsive electroshock, all WW m Showed middle degree behaﬂoral change. m. L *3 3 hawk»: records; and two of the five 47 I TABIE Showed a W! 4‘ 9““..44 b ' Ratings of Behavioral Change; Convulsive—Subconvulsive Therapies (Tourth-Fifth'weeks of Treatment) Degree of Change Moderate Minimal 27 15 S O O 3 8 16 Marked ConvulSive Therapy (h?) Subconvulsive Therapy (27) None In evaluations two weeks after-treatment of the degree of "improveof the convulsive therapy grongj::ted as "much improved" or "recovered," and 32% as "improved."qag% discharge, 51% were evaluatedileZS ment," 51% sustaining the and only were were 7% same degrees of improvement, while were "unimproved." rated in the first Of "unimproved;"ﬁgﬁgeiggége§:§§:$§%§:red do were "improved," the subconvulsive group, however, two categorie51’19% hOSpital discharge evaluations h2% in the "improved,“ but for a 11% 70% second course of therapy, not reflect the effects of subconvulsive therapy. II TABLE Ratings of Improvement: Convulsive-Subconvulsive Therapies (Two'ﬂeeks After Last Treatment) Recovered Much Improved Improved Unimproved Worse Convulsive Therapy (h?) 9 15 15 8 Subconvulsive Therapy (27) 2 l S 19 �W. .r -5... din=;.€onvulsive therapyinduced signiiicantly greater behavioral MM“ whichchange and eva uations of improvement thangsubconvulsive therapy We The parallel the electroencephalogr . Also, patients -EEG clinical I observations“ ”A“! who showed neither showed both or a behavioral response to subconvulsive therapy, and behavioral changes when placed on convulsive an EEG therapy. 2.- Role of Type of Convulsive Therapy; In view of the variety of electroshock techniques employed, and the relationship between EEG delta activity and the behavioral response, an analgrsis of the was undertaken. 2. The effect The oi‘ type of electroshock on EEG delta actvity results are graphically presented in Figures first figure relates 1 and the treatment type to the percentage of weeks record ‘n each treatment group during the second, third and fourth tre:Egentgggégggggating:high degrees of EEG delta actigggi) In each of period, treatment with alternating current at suprathreshold strength gave the highest percentage of high degree delta records. Treatment with unicurrent and with alternating current at threshold strength was directional less efi'ective than the suprathreshold alternating current techniquef.in each period; the unidirectional current treatment being more effective than the threshold alternating current method only early in the course of therapy.* Vsubconvulsive techniques yielded no high degree delta activity records. The second figure demonstrates the same the per cent of each treatment group showing 7“: relationship no by measuring delta activity or only low ncés ..-»_. :v-n suprathe a‘, ent perins, tre Eur, .l-i-o . an. etho’.'5 - thre o'd reatv t si " Can at .05 by chi 7—9 “-3 ou- in} vDi7”e~' ces b tw-z para --12 0-" 0d“; no ignifican ' dWL- ‘ j . hold met‘ods, and for each method �at Mt“ M74 @WWAEW �-6Here, the subconvulsive group degrees of such activity. is lOO%_for each treatment period. Suprathreshold alternating current techniques show the least number of such records in each period, with threshold and parathreshold techniques in between. 3. Frequengy of Treatment: Another factor in the rate of development of delta activity is the frequency of treatment. While all patients were initially treated three ltimes a week, a number who failed to develop high degrees cf delta activity on convulsive therapies were treated more intensively. In nine daily or twice daily, and in each instance middle or high degrees of delta activity were induced. Similar such patients, treatments were given correlates were previously demonstrated Callaway (10). EEG h. Factor of In the by Pacella gt'gl. (9), Age: initial series of patients, it was noted that younger patients, under hS years of age, developed greater degrees of delta the first such and second weeks of activity during treatment; while older subjects developed activity to a significant degree during the third week. fourth week of treatment, the groups. Combining observation. and By the differentiating aSpect between the data from.all convulsive therapies supports this age was no longer a IMring the second week, h3% of records are high degree delta in patients under the age of no; but only 30% in patients from uo—oo, and 18% in patients 61 and over. In the third and fourth weeks, the differences are no longer present and approximately 2/3rds of the subjects degree delta records when treated 3 times per week. have high �-7TABLE Variation in % High Degree Delta Suwd To DO years (28) Records With Age M ﬁlm k2 29% ' W % Treatment Period $9.213 69% 61% h3% (28) Lil-50 EEG lit-.9. £211 £59. III W W ‘ 31-66 (28) 32% 56% 55% (18) 18% 50% 80% ‘ 61+ 5. Pre-Treatment Record Characteristics: * Previous reports, summarized by Chusid and Pacella, ($3 noted a significant relationship between pre—treatment record characteristics and the degree of induced "abnormality." Predominant alpha rhythm, "abnormal" (3» or "borderline abnormal" (11) records were more liable to develop alterations in the EEG than those with predominantly low voltage fast activity patterns. In these series of patients, subjects whose pre-treatment record demonstrated diffuse slow wave were not included activity, spike or spike wave activity in the statistical analyses. Eight such subjects were saven of them developed high degrees ”treated with convulsive technique? and of delta activity earlier, and for'more sustained periods, than patients without such pre-treatment abnormality. A Specific analysis of the relation between pre—treatment alpha and the degree of induced delta activity was undertaken, Rank order * The difference in incidence of high degree records is significant at .0 between the second and fourth weeks and .051 between the second and third weeks of treatment in patients over 50 years of age; but is not significantly different for these periods in groups under 50 years. WW WM *7 �-8correlations of the pre-treatment per cent time alpha in selected leads (anterior temporalavertex) with the degree of delta activity during the third and fourth weeks of treatment in _tions of +.2u and +.35 reSpectively. week is significant at third'week N£L0 Two h3 The patients demonstrated correlarelationship in the fourth the .05 level of confidence; while fails of significance, although the trend that in the is indicated. aspects of these studies warrant discussion; the significance of the convulsion in the electroshock process; and the role of serial electroencephalograms in the rational management and study of convulsive therapies. (1) Significance of Convulsions: In the éﬁéggél studies of convulsive therapy numerous authors, including Kalinowsky 2:". g. (12), and Pacella §_t_ (9)7 emphasized 3;]: both the clinical and electroenCephalographic'differences between grand mal and petit mal responses. While grand mal seizures induced clinical improvement in 60 to 80% of cases, petit mal induced changes subjects. Similarly, electroencephalograms in grand delta activity, while in petit mal therapy, no in less than 25% of mal therapy demonstate delta activity is seen. In subsequent years, various subconvulsive, brief stimulus, unidirectional stimulating, monopolar stimulating, been described, and and focal convulsive tedhniques have in each, in turn, discarded in routine therapy. Bergman §t_al, (13b for example, in describing the electroencephalographic effects of focal seizure techniques noted that 70% of patients had normal records 70-75% had "abnormal" records after grand after 15 such "seizures;”'while J �-9mal seizures. Ulett gt a;. (1h), in a careful control convulsive-sub- convulsive study, reported a significant difference in the clinical response of patients receiving convulsive therapies (60-80%) and those receiving subconvulsive (33%), or controls (38%). EEG He noted the discrepancy in the response in the two groups, and emphasized the significance of the seizure for the therapeutic effect. W Recent additional reports by various observers, based on a variety of data further emphasize the significance, of the convulsion in the therapeutiC'responSe (1, l5, 16).fﬁeinstein—end thus indicates that convulsions per; are, or reflect, the significant physiologic events which are the basis The evidence se_ fortherapeutic efficacy of convulsive therapies. If the convulsion is the essential the behavioral reSponse, does the any role in this reSponse?. in both the degree of EEG mode element both in the EEG and in of induction of the seizure play In the studies reported here, small differences delta activity and the rate of its development were observed between differentxnethods of induction of grand mal seizure.jh/§ Ulett gt a}: (11;) reportedan improvement rate of 57% for the alternating current convulsive technique, and 70% for the phodio-metrazol technique. While the differences are small, the authors ascribe greater clinical efficacy to the convulSive photo-metrazol technique. this repert, Kalinowsky noted 'various workers as being vulsions. Eh More more that metrazol convulsions have impressed efficacious than electrically induced con- recently, Edualds, (l7) describing a 1090, ascribed to it In a discussion of new convulsant drug, a clinical results slightly better than electro- convulsive techniques. 'We have further noted that the convulsions induced by various tech- niques have varying characteristics of latency, duration, preponderance �.10of clonic or tonic phase, apnea, not equivalent; and etc. "All grand mal seizures are seemingly a seizure is not an "all or none" phenomenon. Different reflect the differences inhphysiologic effect of the different treatment methodfp Further studies of this problem seizure patterns occur and these ‘are in progress. While this variability in clinical results is reported, that with repeated convulsions, 'of 00 may - 80% are observed. The differences element is the brain may way rates between various types of treatment benobv1ated byzincreagang the frequency we may conclude specific with regard to the is clear no matter how induced, improvement are small, and, for the most part, or number of treatments. it that convulsive therapy is the convulsion is induced. The DOD? significant change subsequent to the convulsion, and not the agent in bringing about this brain change. In previous reports (6, 18, 19) we have noted that convulsive therapy is also non-specific with regard to its application in mental illness, and in its clinical and behavioral effects.used The present studies amplify, therefore, the previous conclusion of the non- Specificity of convulsive therapies. 2. Role of Electroencephalography in Oonvulsive Therapy: applied methods of quantitative, serial EEG analyses in the studies reported here. While clinical estimates of behavioral change have we have yielded similar data, such evaluations are more dependent on the attitudes of the observer (20), and less amenable to quantification than the EEG. Further application of EEG-analyses to other problems in convulsive therapies provide a rational basis for the comparison of different treatment techniques. we have clinical previously noted that management of EEG analysis may be applied in the patients receiving convulsive therapy (6). In patients �.11Who fail to significant behavioral response show a on treatment regimens of three times per week, an electroencephalogram may serve as a guide for further therapy. In thise subjects in whom high degree delta activity has not been induced, increasing treatment frequency, withholding pre- medication, or shifting to a more effective convulsant method, may result in the neurophysiologic changes. If the degree of delta‘activity is high and sustained for a or environment#(18) number of weeks, other may be assumed factora',as personality (21) to preclude a satisfactory behavioral reSponse, even when the neurophysiologic substrate convulsive therapy is assured; and further well be discontinued. A similar application has been suggested by Roth (3) for thiopental activated EEG records. The may successful application of quantitative EEG techniques to convulsive therapies, has led to their application to other physiodynamic therapies. Recent reports from these laboratories note a similar application for the rational management and understanding of psychopharmacologic agents (19). ��3;; Zn, ~ 6w WMMWL, _ ~ 4; �(«My REFERENCES 1. Roth, 1.: Changes in the EEG Under Barbiturate Anaesthesia Produced by W.Q Electro-Convulsive Treatment and Their Significance for the . Theory of ECT Action, 3: 251-280, 1951. 33. £5 Clin. Neurophysiol. Roth, M., Kay, D. W.K., Shaw, J. and Green, J.: Prognosis and Pentothal Induced Electroencephalographic Changes in Electroconvulsive Treatment, EEG “a..- Clin. Neurophy61ol. :2, Chusid, J. G. and Pacella, B. L.: Shock Therapies, h. Ulett, G. and ,1 MM Johnson, _ J. Nerv. m M. W.: 225-237, 1957. 2_: The Electroencephalogram in the Electric:;> &:Ment. Dis. 116: 95-107, 1952. m" "' any...MA... mm:-W M and Scopolamine Upon Efiect of Atropine Electroencephalographic Changes Induced w”,// 1. By Electroconvulsive . Therapy, EEG.,Clin. Neurophysiol. 2: 217-22h, 1957. S. ‘Weinstein, E.A., Linn, L. and Kahn, R.L.: Psychosis During Electroshock Its Relation to the Therapy: Psychiat. 6. Fink, M. of Shock Therapy, and Kahn, R.L.: Relation of Electroencephalographic Delta Neurol. & EBSponse in Electroshock, A.M.A. Arch. Psychiat. Z§: 51o5525, 1957. Kalinowsky, L. and Hoch, P.: Shock Treatments, Psychosurgery And Oﬂier Somatic Treatments in_Psyohiatry, Grune 8. éﬂ:_i; 192: 22-26, 1952. Activity to Behavioral 7. Theory & Stratton, N.Y., 1952. Alexander L.: Treatment of Mental Disorder, W.B. Saunders Co. fhiladelphia, 1953. 9. Pacella, B.L., Barrera, E.S. and Kalinowsky, L.: Variations in the Electro- encephalogram Associated with Electric Shock Therapy in Patients with Mental Disorders, Arch. Neurol. & Psychiat. g1: 307-38u, 19h2. �10° 11 . Callaway, 3.: Slow wave Phenomena in Intensive E1ectroshock,«Elootpa. tag; ennaphalggrﬁk'Clin. Neurophysiol. a: 157-162, 1950. t K)~u~uu¢,nk‘04+&.LUéQQNUM’ antm 3‘ v~n£.aax+ueB ox BK 33,; swam: n 3,. H AW“ um “3' W i?! p 12. Kelinowsky, L., Barrera E.S. and Horowitz, WA“ in Electric Shock Therapy, Am. The J. Psychiat. .y. i'c I 4"?“ use... "Petit-Mal" Response 2Q: 708-711, l9h2. 13. Bergman, P.S., Impastato, D.J., Berg, S. and Feinstein, R.: Electroencephalographic Changes Following Electrically Induced Fbcal Seizures, Conf. Neurol. 11: 271-277, 1953. 1h. Ulett, G.A., Smith, K. and Gleser, 0.0.: Evaluation of ConvulSive and Subconvulsive Shock Therapies Utilizing a Control Group, gm;_g, szchiat. 113: 795-802, 1956. 15. Wéinstein, E. and Kahn, R.L.: Denial of Illness, C.C. Thomas, Springfield, i 1955. 16. Fleming, T.C.: An Treatments l7. Edwalds, Inquiry into the Mechanism of Action of Electric Shock 'Jidbnuav'nﬁuatJWor ,WO-ASO , 1950 . K.M.: Intravenous Administration of with a New Convulsant Drug. Read at PM 1090: Clinical Experience N.Y. Divisional Meeting A.P.A. 1957. 18. Fink, M., Kahn, R.L. and Green, M.A.: Experimental Studies of the ElectroShock Process, Dis. Nerv. Sys. 19. Fink, M.: A Unified Theory of the ACtion of Physiod namic Therapies, J. Hillside 20. Fink, M. and Hosp .__(_3_§ 19 7-200, 1957 . Kahn, R.L.: Behavioral Patterns Brain Function. 21. (in press). Read Kahn, R.L. and Fink, M.: at in Induced States of Altered N.Y. Divisional Meeting A.P.A., 1957. Personality Factors in Behavioral Electroshock Therapy, Conf. Neurol. (in press). Response to �mmﬁmu mumm. in M minions: W manta, mm mm am mm mu, 3.1. a: mm mm, mam mm mum mm M Mia mu: m“. &, M. at mutmmmummmmwmumamrmxm. VIM ��m W a: moo nativity «many to: tho uwmmthomw Migration“ (Miamimdmthouoomw the «Mo Wvomwmmuﬁml) Withomotmm room: Woo with Moment, Magenﬂ MWm«on ntod u “MAW of data. muty. yW WW 1 4- .. 11111 . . mammumuwumamuwmw 25mm W» W t mm ”mm Wt? 'W 28 12“ 21 8'! a 66." h“ 35 13 16“ 3 2 a M K 60 t wowmammmmgmmmw stumpWM Wommmmmmmlﬁm at m woman” mind Wm t1»npy*1n this M. m: who 34? 9 .3, ommamae monmmmmmmmmywamm 19 ”loom mu, plat tofu-rod for t «W W“ of thong, ' Win . ﬂ UWJOOM ��m Mm Mm am m 1%- M 61 M 1:: (28) W (38) M M W (28) 311‘ 565 (18) W 30% , thmum mwmmammﬂva thmm Wsmﬂmt Wampum “W" (ﬂw‘W W“ (n)mmmmmw mmnwpum. mmmerpmmmwmmm~mam ‘- _'mmunwmmu%%wapm§uwmw mmmwmmamummwa. thmmm �“Nuthmmw Mgr: than m 3mm of A. ma W,mm,W. mama“mmWWW pom, mu nativity without. such M for mm wan-«mam» Mutiny. WM maym at the man hum put-mm awn mmarwu1ummuymmm. mum mumaunpmmmmmmamnmmm (wwwm)uwmmdmummwmm m gm was « tantalum w a: mum. mm mum m at Nﬂbwhﬁmmunlyo mmumpmm comma mm“ mw3mmsmmmmm Wmum am at mum, among: an m u Mam. . ��Reprinted from Diseases of the Nervous System, Vol. XIX, No. 5, May 1958. Electroencephalographic Correlates of the Electroshock Process and MARTIN A. GREEN, M.D. In the course of an evaluation of the role of a1tered brain function in the electroshock process, the relation between electroencephalographic change and behavioral response has been re—assessed. MAX FINK, M.D., Subjects and Method: Eighty consecutive electroshock patients have been studied. All patients received electroencephalograms before treatment, on a day after a treatment at weekly intervals during, and following the course of therapy until the records had achieved their pre-treatment characteristics. Treatment procedures varied, including unidirectional and alter— nating current electroshock, and subconvulsive technics with Pentothal premedication. Treatment was usually instituted at three times per week for 12 to 20 treatments. Patients who failed to develop a clinical response, or EEG changes of signiﬁcant degree, Were subsequently treated at 5 to 10 times per week. The EEG records were classiﬁed for degree of delta activity into “high,” “middle” and “low” degree delta records using the following indices: the percent-time delta; highest percent-time delta in any lead; slowest wave in the record; highest ampli— tude of delta; and duration of burst activity. (Arch. Neurol. & Psychiat., 78: 516-525, 1957.) Evaluations of change in behavior were made by the supervising psychiatrist at the height of the Read at the meeting of Eastern Psychiatric Research Association, Inc., held Feb. 6, 1958. electroshock effect; and ratings of improvement were made two to three weeks following the termination of therapy. Results: 1) The appearance of a high degree EEG delta activity during the second and third weeks of treatment was signiﬁcantly correlated with change in behavior and ratings of improvement. 3) High EEG delta activity was induced in patients receiving convulsive electroshock only, and was not observed in subconvulsive therapy. 3) Alternating current instruments induced high degree EEG delta activity earlier than unidirectional instruments, but by the 4th week of treatment, the differences were eliminated. 4) There was a direct relation between the degree of EEG delta activity and the frequency of treatment; and an inverse relationship to age. Conclusion: 1) There is a relationship between the degree of EEG delta activity in the EEG and clinical change in behavior. 2) The time of the appearance of EEG delta activity and its persistence is related to: a) induction of grand mal seizures; b) type of current employed; 0) frequency of treatment; and d) age of the patient. 3) Early and sustained high degree electroencephalographic delta activity is a necessary, though not sufﬁcient, pre-requisite for improvement in the electroshock process. - �mmmmm Garnish” at the mammoak Mam Hawaii‘s WWW at Moan rawhiam, 35.11.3169 363331981, men Oaks, m... mamas a: mm mm mums. w grunt 16-927: 33.131th um, in wt, M. ”03¢ M116 English From the Mﬂtﬁﬂﬂ Band at 131-13 Halal, mm at the Eastern mum autumn ”Manama, ﬁat York, Pcbmary 6,. 1953. Whip-$8 Saran. 3.1. �WWMMW.WMMMMﬁmhm Wmmmmmmammmwmmmm WWW.1IW (1.1).. Wﬂﬂmhwma mmmwmamtaﬂ) unmuwmwmamMMIMm. mmmw Want Mummy m an m a mum 1mm muw um mlmum may in this laboratory, a 65 «mu um! at Wﬁ'mmw). mammmmuuam mmmmatmmwmmtmmutmmm, W a: W, mot mbmwm-mms mm mm“. Itismmwadmmwtﬁomummuuondﬂauum MwmumammmwMommmamw WWWduﬂﬂahquowhﬂnuﬁmlm mm am of mm" mm. and ��in mm Wm: GW‘WWW' The wide variability-1n the mm of mm mums»newt-w in the initial 2h gamma» (‘6) is aanfimw in them string a: mmulaiva mmyy ”towns ( table I) . While the number of law v-meamu $.12, mm We Ward: mama“ with treatmenb, 7m in the third min; and 3.8% in than fourth max, urn mu rut-ma a “1M ﬂames at am». nativity. We of EEG Dalia Activity with convulsive Therapy (Emmi; M .122 ,. High MW h - M) 2mmt Pogod ‘ L 1:2 28 1:6 66 2% Mamie Dame 1?. 21 27 32 W 99W 63 W 25 18 16 3 2 a m 2mm mmw Tim behavioral signﬁimm mama was of the amused in emmion $110? m a 1n the: EEG ma muwmbwmlsiva ﬂaw. m the h? mhjaictu" the maniac! taminva therapy in mi: “My; «It m mlmﬁm mu, incluéod 28 summit»: the pins 19 .» . cm“ of therapy. 9 had grand m1 therapy can a rmdm mimd ~ m3aota Mama for a “mound in ��of me netiv-ity. Kara. the mbcomuleive group in for each 100% treatment per-lee. Sumthrenheld alternating current techniques the least member mmmeld enact of such remade in each period, with thmmeld me teehniqma in between. it. leather teeter in the rate is the Mme? at treatment. three time a week, a while number whe a Miami. of delta aeﬂvity all patients were initially treated failed develop high degrees of “be delta activity were treated were intoneively. In em! mh peanuts, mama were given daily or twine daily, and in each instance new» or high degrees? 91’ delta activity were induced.- Similar wimely 5. F- by ' ter of In the ' Mem'gg g. EEG (9),. and con-slates were enemy (3.0). a initial «new of ptiente, it we noted that yemger patients, under 15 yum of age, Malay-ad greater $339“ ex acne nativity during the fix-at. and heme! weeks of treatment; while clear mbjeete developed such nativity he a eigﬁﬂmt degree during the mix-d week. By the fourth ml: at treatment, age no longer differentiated batman the gmups. supports Cambining the this observance. date free all convulsive therapies During the amend week, ha; of weaves are magma mg: eeme dam: in mean-es we.» the age at in pastimes and rm bones. and 18% in pemente mm wake, the difference: 2mm 63. and no; but mr. my 30% In the third are no longer present and 3.15mewa of the eubaeete have high degree eelta meeree when treated 3 time per week. �3353;;an mmgwmwmlaa 5% Ta ha W50 Over has ascoraanaaaﬁw rm‘ Huh ma SE)... 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(1153de. similar applicatim has hm suggest“: m (5) far thiamm ”bland we} mrahar ha A by am mm. m ammm'vl maintain ma uwmqma ta mmhive W121“, but led to their diminution in amt Win-- Me alumina. W mec npplioatim 13$ Mt. “ports firm the” laboratories min a W mum amt! (26) ,; applieatien tar WM aid warming at ��11;. maids, 15‘; 310 3135 . W, 30. Gamay, An 1935.- ,1: am oxidation at mews 1956. a nu. 3m.: um Wan-awn at m 1090. mama. Inquiry into the sex-«mm, 3.3.: ' a: W. mm,Mariammm»: with a m ﬂew 9mg. am at 21:2. minim Hating LﬁPi‘J HA. I 19570 Signifimaa or mmm vmbili‘g in m magma Experimental stud-1W My Edi-m and am; 31*.“ My My; (in mm). 33m. 8 mun-9mm}: Rowan, W ‘ . 6f “13 o the Action or Physiodsmmia Therapies, m, 14,: 1 Unwed Thom a:197%.;195?‘ , 21. LG»: Shook m, 19a K; and “W,springtiad,m Rd“! W a! 16. 1?. 6:13.: Evaluatim at ma Mr, (3th 00mm}. ﬁr. gamma“ m1: Wraps.“ Winning a £34., Smith, 52* 3.1m Bahamian]. mum in Induced sung or M; n. ma Kuhn. Brain mum. Rand at NJ. Biﬁaioml mung MPJ. Ligand 3‘9 7‘. ‘ 22. Kuhn, 3.1:. and Fiat, 14.: ; A,“ Mummy Futon in Behavioral Mama to Mammw}: “therapy, Gama m:1. (in press). ��“x 1%! mmmmmmwwmmmwmsw wuwmmﬁ ‘xmméugunrwar mum's, far w mum,mwmmwormmumum mmwwmwmmmmmwmu muuwmmuumnwhs. WMWmW rwmmmmmmummcymmmm mmmmm. mum-Mt m m ”##1##“, We“ m Mmaummwnmwmmywm,mm want? mam, MW W wmmmummmmmthmm mm mu to, at lama huh activity, me! for my: Wﬁm a! an mmt ma pu- mum. alpha was the We. cream mtﬂtymmmmwmormmmmema ‘tgﬁﬁmafwma “ ' ‘ ' mm u¢mwmm4munmmmwrmw ’ WW. W! z.-m:auumnwmummuuuuwumt mm: man-mm durum m mammmmtmmmmwgmmm (a) W a: am mm. m mm uMmmmmm. 31* mamam am am am �mm: mm; 1W m W mum m mmar-W: Mrwmwmm at (M ‘ we. at Mm“ (a) at «inactivity «mm hf {mm—m. (a) m m mums. warm as inmate-at. but, my the What W «Woman: “new: rm m with vammﬁmdwmuwm W‘ mm- M whim: WW W mu up» mama. WIta» W maﬁa ~1me m Mmammmmmmammm a: (3) «1' 1. Wu W. nativity that aw: 1w WWt ‘ � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Electroencephalographic correlates of the electroshock process. Dis. Nerv.Syst., 19: 227, 1958. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-32-009 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Green, Martin A. Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 12 items. 1: [preprint]. 2: Edit page. 3: Hand drawn graphs. 4: Handwritten notes. 5: Drafts. 6: Program for Eastern Psychiatric Research Association, Inc. Twelfth Scientific Meeting, February 6, 1958 (handwritten notes on back). 7: [preprint]. 8: Final copies. 9: Reprint from Diseases of the Nervous System, Vol. XIX, No. 5, May 1958 (one page). 10: [preprint]. 11: Discussion - NY Neurological Society 3-11-58. 12: [preprint]. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/ac5e73da19470d46979be1d3e57b7963.pdf 289f176e87e6c22e9a18830dea076106 PDF Text Text Reprinted from JOURNAL OF THE HILLSIDE HOSPITAL Volume V April, 1956 Number 2 �EVALUATION OF HIGH-DOSE RESERPINE THERAPY FOR RELIEF OF ANXIETY1 MORTON WACHSPRESS, M.D.,2 ARNOLD G. BLUMBERG, M.D.,3 MAX FINK, M.D.,4 and JOSEPH S. A. MILLER, M.D.5 ‘ During the past few years increasing interest has been shown in the role of drugs in psychiatric practice. Previous studies on the usefulness of extracts of Rauwolﬁa Serpentina at this hospital demonstrated minimal value for this drug in alleviating anxiety symptoms (4). In the light of these studies which contrasted with more recent enthusiastic reports, an investigation of the effectiveness of large doses of reserpine in relieving anxiety symptoms and altering behavior was undertaken. Numerous reports have appeared in the past two years describing the effectiveness of reserpine in reducing aggressive and assaultive behavior (2, 5); alleviating manic states (14); and reducing the need for electroshock therapy (10). The reports of its potency in reducing anxiety, affecting neurotic symptoms or altering depressive symptoms (6, 12) have been less laudatory. In addition, reserpine-induced depressions have been noted in the course of treatment for hypertension (9, 11). No evidence has been forthcoming that reserpine has altered the course of a psychiatric illness, although many reports emphasize the quieting effects of the drug or its usefulness as an “adjuvant to psychotherapy” (7). This investigation was undertaken to determine the usefulness of reserpine in a voluntary psychiatric hospital population treated in an open ward setting. A double-blind placebo controlled study with 1 From the Research Service and Medical Department of the Hillside Hospital, Glen Oaks, N. Y. ZSenior Resident Psychiatrist, Hillside Hospital, Glen Oaks, N. Y. 3 Associate Visiting Physician, Hillside Hospital, Glen Oaks, N. Y. 4 Director of Research, Hillside Hospital, Glen Oaks, N. Y. 5 Medical Director, Hillside Hospital, Glen Oaks, N. Y. 67 �68 WACHSPRESS—BLUMBERG—FINK—MILLER large ﬁxed doses of drug was selected as a technic of evaluation for this study. The evaluation of improvement in a psychiatric patient under therapy presents problems which are all too familiar to careful investigators in the ﬁeld. In a hospital environment where the total therapeutic regime combines to produce improvement, the evaluation of the effect of a drug must be carefully controlled. Certain criteria must be established to differentiate between improvement consistent with the course of the disease, and improvement greater than what may be expected from the normal course of hospitalization. To properly attribute improvement to a drug the following criteria should be satisﬁed: the patient should improve while receiving medication; this improvement should be greater than at the time when the medication is replaced by suitable placebo medication; and improvement should be reproducible at a later date with a similar drug dosage. The use of a double-blind placebo controlled study provides a method for such an evaluation and it is doubtful if deﬁnitive conclusions are justiﬁed in the absence of such studies (3). To further minimize the subjective factor in the clinical evaluation, rating scales have been employed, despite their well-known limitations. In this study, the revised rating scale of Malamud and Sands (8) was utilized to provide further experience for the observers in standardizing their reports and to permit a constant frame of reference for changes in symptoms and behavior during therapy. METHOD The patients in this study were those who presented, both subjectively and objectively, severe anxiety and agitation. They were selected from the patients recommended by the resident psychiatrists for electroshock or drug therapy. The ﬁnal decision as to which patients should receive reserpine was made by the two psychiatrists working on the study, who based their selection on the presence of severe anxiety and tension symptoms. Of the original group of seventeen, ﬁfteen patients completed the study. Two male patients, one diagnosed as schizophrenia and one as psychoneurosis, discontinued the treatment because of increasing tension, agitation and nausea while on the drug regimens. Of the seventeen patients, eleven were diagnosed as schizophrenia, ﬁve as psychotic depression and- one as mixed psychoneurosis. There were eight males and nine females. The age range was 19 to 52 with a median age of thirty-three. �EVALUATION OF HIGH-DOSE RESERPINE 69 Each patient was observed for a period of twelve weeks. Every patient received an intramuscular injection of 2cc. of reserpine6 and ﬁve tablets daily throughout the twelve-week period. Depending on which regimen was selected, placebo tablets and injections were substituted for the drug. The four regimens were: reserpine, 10 mg. daily—5 mg. orally and 5 mg. intramuscular; (2) reserpine, 5 mg. daily—orally; (3) reserpine, 5 mg. daily—intramuscular; and (4) placebo only. (1) Regimens were selected in random order by the internist, and the regimen was unknown to the patient, therapist, evaluating psychiatrist or nursing personnel. Weekly psychiatric evaluations were done on each patient by an evaluating psychiatrist. A modiﬁed Malamud scale was employed as well as the subjective reports of the patient and the impressions of the observer. The patients were concurrently studied by the internist at regular intervals. Blood pressures and pulse rates were measured in a sitting position on casual examination at irregular intervals. Only two patients could be classiﬁed as hypertensive before treatment. Each patient was weighed weekly. A radioactive iodine determination was performed before starting treatment and repeated no sooner than three weeks after instituting treatment with an effective dose of reserpine. Routine blood counts, urinalyses and other laboratory tests were conducted as indicated. RESULTS Psychiatric Observations Of the ﬁfteen patients, seven showed a signiﬁcant alteration in behavior which could be related to drug dosage. Of these, three showed a relief of anxiety and tension, and four, an increase in depression, tension and agitation. The remaining eight patients manifested no change in behavior. In addition, the two patients who discontinued the drug regimens did so because of an increase in tension and anxiety accompanied by nausea and vomiting. We are indebted to the Ciba Pharmaceutical Company for the reserpine (Serpasil) and placebo medication used in this study. 6 �WACHSPRESS—BLUMBERG—FINK—MILLER 72 total scores, an item analysis of the individual behavior items was undertaken. Those representative items were selected which clinical experience suggested might reveal changes due to drug action. The items chosen were: feeling, mood, motor activity, and thought processes. An analysis of these scores failed to indicate any consistent difference in these characteristics in the patients as a group. Regarding the differences in the drug regimens, it was the clinical impression of the evaluating psychiatrists and resident therapists that more moderate doses of reserpine were preferable, giving fewer objectionable symptoms. Six of the ﬁfteen patients were subjectively worse on the daily dose of 10 mg. These six included A. 8., one of the patients who improved on drug regimen, and two of the four patients whose condition became worse. Toxic Symptoms Of seventeen patients who started on the study, two stopped because of side effects. These patients manifested increased tension and anxiety, in which nausea and vomiting became prominent symptoms. Numerous other side elfects were observed, and the incidence of each is noted in Table II. Drowsiness and dizziness were seen in most of the patients, but caused serious difﬁculty in none. Six TABLE I BEHAVIORAL RATINGS—TOTAL SCORE H.C. G.W. ES. M.C. R.S. R.D. A.S. F.G. S.G. LE. M.D. S.K. P.M. A.L. M.B. Sex Age F F M F F M F F F M F F M M M 24 52 45 19 19 20 46 28 37 50 42 37 22 37 22 Diagnosis Schiz. No Medica tion Placebo 27 Invol. Mel. Schiz. Schiz. Schiz. Schiz. Invol. Mel. Schiz. M.D.D. M.D.D. Invol. Mel. Schiz. Schiz. Schiz. Schiz. 23-36 20 35,36 30,35 37-46 29-35 34,30 12-19 20 27 36-45 16-22 27,25 27-38 6-9 23-43 16-30 18-29 18,9 19-33 26-28 53 46—57 51,64 57,66 Oral Intramus- Combined cular 15 17 28-34 50,53 23,25 27,26 38 29-39 2542 18 20-31 26 40 15,3 45,31 22,15 47,31 25,28 28 27 34 16-28 20-26 23,27 28-36 12,15 29-40 20 29 27 18—26 16—30 53 44,61 53 32-51 51-56 27 825 12,13 37,39 29—38 19 25-38 63—55 �EVALUATION OF HIGH-DOSE RESERPINE 73 patients developed a Parkinsonian muscular rigidity, which disappeared within a few days after the drug was discontinued. Four patients had one or more episodes of generalized ﬂushing lasting up to twenty-four hours. This occurred in patients on placebo as well as on drug, and was interpreted as an allergic reaction to impurities in the intramuscular solution. TABLE II TOXIC EFFECTS Incidence ................................. ................................. ...................... Nausea .................................... Parkinsonism ............................... Painful legs ................................ Hot ﬂashes ................................. Restlessness ................................. Swollen feet ................................ Drowsiness Stuffy nose Dizziness and Weakness l4 13 10 7* 6 4 4 3 l In 2 patients nausea was accompanied by vomiting and was a factor in discontinuing treatment. * Depression The enhancement of existing depressive symptoms was noted in three patients, and in another, depressive symptoms appeared where none had been evident before reserpine therapy. In each instance, electroshock therapy was recommended and improvement resulted. Electroshock therapy induced a remission of the anxiety and tension components of the illness, as well as the depressive. Of the eight patients who manifested no change with reserpine, two were eventually treated with electroshock, without clinical improvement. Physiologic Observations The systolic blood pressure was reduced in ﬁfteen of the sixteen patients observed over an extended period of time. The magnitude of this lowering was between 10 and 20 mm. Systolic blood pressures between 90 and 100 mm. were not unusual while on treatment and were not accompanied by adverse symptoms. Table III represents average ﬁgures for the highest and lowest blood pressure and pulse rate recorded during each regimen. There �74 WACHSPRESS—BLUMBERG—FINK—MILLER drop in both systolic and diastolic blood pressure and in pulse rate with reserpine therapy. There is no difference in the hypotensive or bradycardiac effect of intramuscular or oral administration of 5 mg. reserpine; nor is there any indication that a dosage of 10 mg. produces a greater effect on blood pressure or pulse rate than 5 mg. These observations are consistent with previous reports of the ﬂat dose response curve for reserpine (1). is a signiﬁcant TABLE III Medication Range Systolic Range Diastolic Pressure Pressure Range Pulse Rate Placebo 135-117 5 mg. p.o. 5 mg. i.m. 10 mg. combined 116—108 118-106 119-109 84-69 70-64 71-63 68-61 98-7 8 74-67 74-68 78-68 Most patients on reserpine reported an increase in appetite, and there was a tendency for these patients to gain weight. In seven patients, such gains varied from 3 to 20 pounds on the entire treatment program. Three patients lost weight and four showed no change. There was no consistent change in the radioactive iodine (1-131) uptake following the administration of reserpine. Nor could a correlation between weight change and this index be found. Thus, only two of the patients who gained weight had a decrease in the iodine uptake. One patient who lost weight had a rise in iodine uptake. It was concluded that the weight gain and increased appetite were not related to alteration in thyroid function. DISCUSSION High-dose reserpine therapy did not affect the symptoms of anxiety or tension in these patients. For the most part, patients were made uncomfortable by the high doses used in this study. Of the three instances where a relationship between changes in anxiety and tension could be related to drug dosage, two were noted in severely ill patients in whom overactivity and agitation were ﬁrst controlled. The relief of anxiety was secondary to the decrease in motor excitement. The previous study at this hospital demonstrated the limited usefulness of low-dosage reserpine therapy for the relief of anxiety. Considering this, and the results of the present study of �EVALUATION OF HIGH-DOSE RESERPINE 75 high-dosage reserpine, it may be concluded that reserpine therapy, either in low or high doses, has limited use for its relief of anxiety symptoms in this hospital’s population. Its use is further limited by the exacerbation in depression which was observed. Our observations, however, tend to support the reported usefulness of this medication as a sedative in the control of destructive and overactive behavior. This is seen in our two cases (R. S., M. B.) and in a series of other overactive patients at the hospital who were noted to respond to the sedative action of reserpine when this was introduced in lieu of restraints and massive sedation. The doses of reserpine in this study were generally too high. Patients were unable to tolerate 10 mg. without uncomfortable side effects. In no instance were the side effects severe or disabling, however, and in each instance the symptoms responded to a decrease in drug dosage. The symptom of depression, however, has assumed special signiﬁcance in these patients. Reserpine exaggerated this symptom and, in one instance, elicited a depression with suicidal trends. The reports of increased depression (9, 11) are thus conﬁrmed; and the usefulness of electroshock therapy in relieving these depressions can be re-emphasized. In this regard, the earlier enthusiastic reports of the usefulness of reserpine as a substitute for electroshock therapy (10) need reassessment. Reserpine is no substitute for electroshock therapy in the treatment of depressive states. It may substitute, however, for the use of electroshock as a sedative in the management of overactive and assaultive behavior. This study exempliﬁes the advantages and disadvantages of a drug evaluation study by the double-blind placebo method. With a limited number of subjects, it is possible to obtain a meaningful evaluation of the primary effects and complications of a medication. The drug effects may also be separated from the natural course of the illness, and from the investment of the therapist in the conclusions. Such a technic has the following limitations: rigidity of dosage; inability of the therapist to separate drug-induced effects from alterations in the disease process during the study period; and the necessity of the selection of patients who are tractable and can tolerate discomfort for extended periods. Furthermore, such a study may rob the therapist of his faith in the drug as a therapeutic vehicle, and thereby limit the patient’s response to the physiologic effects alone. It also limits the therapist’s control over the care of his patient, and thereby arouses feelings of helplessness and apprehension in the therapist. In such instances, the cooperation of a mature �76 WACHSPRESS—BLUMBERG—FINK—MILLER therapist is essential because there is considerable opportunity for the manipulating, demanding, and paranoid patient to arouse the therapist’s anxiety and hostility to the experimental program. This study also provided an opportunity to assess the usefulness of rating scales. In assessing the changes seen during treatment the rating scales failed to provide any information not available in the descriptive statements. They did provide, however, a frame of reference for the many items of the psychiatric interview that needed rating, and provided a base for the comparison of observations made by different observers. ' SUMMARY AND CONCLUSIONS In a double-blind placebo evaluation of 5 mg. and 10 mg. doses of oral and intramuscular reserpine, ﬁfteen voluntary hospitalized psychiatric patients with severe, overt symptoms of anxiety were studied. Three patients manifested relief of anxiety related to drug dosage. In twelve patients no relief was noted, and of these, four exhibited severe depressive reactions which eventually responded to electroshock therapy. Cardiovascular effects of high doses of reserpine were not signiﬁcantly different than previously reported effects of low dosage. There was no evidence that reserpine altered thyroid function, although weight gain frequently occurred. The usefulness of high-dose reserpine therapy in the relief of anxiety symptoms is limited. The dangers of induced depressions, as well as the rationale of placebo studies and psychiatric rating scales are discussed. REFERENCES (l) A. M. A. Report of Council On Pharmacy and Chemistry, J. A. M. A., 159: 1206, 1955. (2) Barsa, J. A. and Kline, N. 8.: Treatment of Two Hundred Disturbed Psychotics with Reserpine. J. A. M. A., 158:110, 1955. (3) Beecher, H. K.: The Powerful Placebo. J. A. M. A., 159:1602, 1955. (4) Blumberg, A. G., Cohen, L., and Miller, J. S. A.: The Effect of Rauwolﬁa Serpentina on Anxiety States. This Journal, 3:140-146, 1954. (5) Cowden, R. C., Zax, M., and Sproles, J. A.: Reserpine—Alone and as an Adjunct to Psychotherapy in the Treatment of Schizophrenia. A. M. A. Arch. Neurol. c9" Psychiat, 74:518-522, 1955. (6) Drake, F. R. and Ebaugh, R. G.: The Use of Reserpine in Ofﬁce Psychiatry: Preliminary Report. Ann. N. Y. Acad. Sci., 61:198. 1955. (7) Hoffman, J. L. and Konchegul, L.: Clinical and Psychological Observations on Psychiatric Patients Treated with Reserpine: A Preliminary Report. Ann. N. Y. Acad. Sci., 61:144, 1955. �EVALUATION OF HIGH-DOSE RESERPINE 77 Malamud, W. and Sands, S. L.: A Revision of the Psychiatric Rating Scale. Am. ]. Psychiat., 1042231, 1947. (9) Muller, J. C., Pryor, W. W., Gibbons, J. E., and Orgain, E. 8.: Depression and Anxiety Occurring During Rauwolﬁa Therapy. J. A. M. A., 159:836, (8) 1955. (10) Noce, H., Williams, B., and Rapaport, W.: Reserpine (Serpasil) in the Man- agement of the Mentally Ill. 1. A. M. A., 158:11, 1955. (ll) Schroeder, H. A. and Perry, H. M.: Psychoses Apparently Produced by Reserpine. ]. A. M. A., 1592839, 1955. (12) Smith, S. K.: The Use of Reserpine in Private Psychiatric Practice. Arm. N. Y. Acad. Sci., 61:206, 1955. (13) Wilcoxon, F.: Some Rapid Approximate Statistical Procedures. New York: Am. Cyanamid Co., 1949. (14) Zeller, W. W., Graffagnino, P. N., Cullen, C. F. and Rietman, H. J.: Use of Chlorpromazine and Reserpine in the Treatment of Emotional Disorders. 1. A. M. 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MWMWthyummmdnm mamaamumm. mwmmtm-I mammmtmwmmmmmmmmmm www.mha‘Mdnhrm-twmm imammmnummMMnm-mmmnmmrm cumin-um». ”mummmmwwmmm ‘ �htW,M'W£5mmmn.Mdonl WWII: Wt: mm W ammgmﬁWd-mtymm Mupmmm «a mtmcnlnr mm, mm nmpamummm mammumw; MmamummmmWWnWMmW WhWW. Wmuudmmammmmummw ‘ ~ 7 mmmum wommmmmmamm mt. mummy mama. wand mun, awwwu w.» mm aw mmdmmmwnmmam magnum mmawmiamJummm mammmmmnmnmmmmm ��70 WACHSPRESS—BLUMBERG—FINK—MILLER In the improved patients, an alleviation of anxiety was apparent and related to drug administration. M. B., a 22-year-old male, diagnosed as paranoid schizophrenia, was anxious, depressed, withdrawn, blocked, delusional and hallucinating. He had been hospitalized for three of the previous ﬁve years, and had received courses of insulin coma and electroshock therapy with only transient periods of improvement. After ﬁve months of hospitalization at Hillside Hospital he showed no improvement. During the drug regimens, there was a diminution in his anxiety, depression, agitation and preoccupation with delusions. These symptoms recurred when on placebo medication. Introduction of the drug regimen again resulted in the alleviation of these symptoms, with the progressive amelioration of his depressive feelings. With the reduction of his drug dosage to mg. oral, he again manifested a recurrence of symptoms, only to have them relieved by the combined (10 mg.) regimen. The patient was maintained on this treatment and discharged, improved, six months after the treatment was instituted. A. S., a 46-year-old hypertensive woman, manifested severe tension, anxiety, depression, tremulousness and insomnia, which had ﬂuctuated over a two-year period. Her diagnosis was involutional melancholia. While on 5 mg. drug regimens, there was considerable relief of anxiety with a decrease in tremulousness. Insomnia became less, but her depression was unaffected. Placebo regimen resulted in a recrudescence of her symptoms. The combined (10 mg.) drug regimen increased the feelings of depression, induced somatic complaints and failed to abate the anxiety. A lowering of her medication to 5 mg. resulted in a repetition of the period of relief of anxiety and tremulousness. The patient was discharged, improved, on this dose of oral reserpine. R. S., a 19-year-old girl with hebephrenic schizophrenia, was overactive, anxious, tense, fearful, and manifested both ideas of reference and auditory hallucinations. Electroshock and insulin coma therapy afforded her only transient relief. While on 5 mg. drug regimens, she became less active, less anxious but more depressed. Her dress became bizarre. When placebo medication was introduced, her hallucinations ceased, her anxiety was more manifest but the depressive features were less. On combined drug regimen, she became calmer, more controlled in her behavior, but the bizarre appearance and ideational disturbances persisted. In these three cases, a relationship between drug regimens and the relief of anxiety symptoms could be demonstrated. In both M. B. 5 �EVALUATION OF HIGH-DOSE RESERPINE 71 and R. S., the overt manifestations of severe schizophrenia were sufﬁciently modiﬁed to permit participation by the patient in milieu and psychotherapeutic programs. In the other twelve cases, no such relationship could be demonstrated. Of the four cases in whom the drug regimen induced increased symptoms, each manifested severe depressive feelings, crying spells, and one, suicidal preoccupations. The following case exempliﬁes the group. G. W., a 52-year-old single woman, was admitted with a sevenyear history of depression and hypochondriasis. A previous course of electroshock therapy was not completed because of injuries sustained in a fall. She was tense, anxious, tremulous and depressed. While on drug regimens she became more depressed and retarded. Her anxiety and agitation increased. With placebo medication there was some amelioration of these symptoms. Electroshock therapy was instituted. She received ﬁfteen treatments, with a rapid relief of her tension, anxiety and depression. She was discharged one month later, much improved. There were eight patients in whom the drug regimen or placebo periods were indistinguishable. There was neither a relief nor an exaggeration of symptoms. The following case history illustrates the group. F. G., a 28-year-old woman, had a two-year history of severe anxiety, tension, feelings of depersonalization and obsessive ruminations which followed the birth of her ﬁrst child. She had previously been treated with insulin coma and three courses of electroshock therapy, with only transient relief. During the periods of reserpine study, she showed no change in her symptoms while on drug or placebo regimens. The changes in behavior determined by psychiatric interviews and rated according to the Malamud scale are represented in Table I. In these tables, the ﬁgures represent the total scores for each observation period. The higher scores indicate deviation from more “normal” behavior. The “control period” is a period of observation without any drug medication. While the table lists the different regimens in a deﬁnite sequence, the actual sequence varied from patient to patient, in a random fashion. A statistical study, using Wilcoxon’s method of paired replicates, (13) demonstrates no signiﬁcant difference in the group between any of the drug or no-drug periods. Because no signiﬁcant change was demonstrated in the study of � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Evaluation of high dose reserpine therapy for the relief of anxiety. Journal of the Hillside Hospital, 5:67-77, 1956. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-001-18-022 Date A point or period of time associated with an event in the lifecycle of the resource 1956 Creator An entity primarily responsible for making the resource Wachspress, Morton; Blumberg, Arnold G.; <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Miller, Joseph S. A. Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [Preprint] and reprint. Reprint from JOURNAL OF THE HILLSIDE HOSPITAL Volume V April, 1956 Number 2 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/159923c8867e9781f49e8300e7f3e2d3.pdf 560d0723c8cbc5298ad5e04e592ff291 PDF Text Text 0 Reprinted from the A. M. A. Archives of Neurology and Psychiatry October 1952, Vol. 68, pp. 481-490 Copyright, 1952, by American Medical Association EXOSOMESTHESIA OR DISPLACEMENT OF CUTANEOUS SENSATION INTO EXTRAPERSONAL SPACE MORTIMER F. SHAPIRO, M.D. MAX FINK, MD. AND MORRIS B. BENDER, M.D. NEW YORK MONG phenomena that may be apparent during examination of patients with disease of the sensory pathways is mislocalization of a sensory stimulus. It has long been known that a person with a sensory defect, as seen in the common varieties of cerebral hemiplegia, may inaccurately localize stimuli applied on the paretic side. Such point mislocalizations are apparent in examinations using a single stimulus and have been described in detail by Head} These mislocalizations can be accentu— ated by the use of double simultaneous stimulation techniques.2 In addition, when these techniques of examination are employed, other varieties of mislocalization, such as displacement,3 become apparent. Displacement is the patterned mislocali— zation of one of two stimuli simultaneously applied to different body areas. The direction of displacement is in a deﬁnite pattern, which is dependent upon the parts of the body stimulated. Characteristic of mislocalization so far reported has been the fact that their extent was within the limits of the patient’s body. In the course of studies of cutaneous perception, we observed a new form of displacement in which the patient consistently and in a predictable fashion mislocalized stimuli into extrapersonal space. This type of displacement we have termed “exosomesthesia.” 4 Exosomesthesia is not a commonly observed phenomenon. More than 400 patients with brain disease were examined at Psychiatric Pavilion of Bellevue Aided by a Fellowship from the National Foundation for Infantile Paralysis (Dr. Fink). This investigation was supported in part by research grant #MH-139 from the United States Public Health Service, National Institutes of Health. From the Department of Neurology and Psychiatry, New York University College of Medicine, and the Neurological Service of the Mount Sinai Hospital and Bellevue Hospital Center. 1. Head, H.: Studies in Neurology, London, Oxford University Press, 1920, Vol. 2. 2. Bender, M. B.; Shapiro, M. F., and Schappell, A. W.: Extinction Phenomenon in Hemiplegia, Arch. Neurol. & Psychiat. 62:717-724 (Dec) 1949. Bender, M. B.; The Advantages of the Method of Simultaneous Stimulation in the Neurological Examination, M. Clin. North America 32:755-758 (May) 1948. 3. Bender, M. B.; The Phenomenon of Sensory Displacement, A. M. A. Arch. Neurol. & Psychiat. 65:607-621 (May) 1951. 4. The term was derived by Dr. Judah A. Joffe (Hinsie, L. E., and Shatzky, J.: Psychiatric Dictionary, New York, Oxford University Press, 1940) from the Greek 55w, out of; will“, body, and 41709710”, perception by the senses. �2 7 Hospital Center by routine and specialized sensory tests. Exosomesthesia was observed in only 15 cases, an incidence of about 3%.5 The following case reports illustrate the phenomenon and demonstrate some of the conditions under which it was observed. CASE REPORTS CASE 1.—H. M., a man aged 64, was admitted to the Psychiatric Pavilion of Bellevue Hospital with a history of progressive mental changes of six years’ duration. The ﬁrst four years of illness were marked by slowly progressive impairment of memory, concentration, and other intellectual functions and by increasing apathy to his' environment. In the last two years there was rapid exacerbation of this condition, resulting in the loss of his job as a store manager. During this period his speech became increasingly garbled and stammering. He vacillated between irritability and complete apathy. He was occasionally incontinent, ceased bathing, had difﬁculty in dressing, and was sometimes so forgetful and confused as to wander into the street without his trousers. Routine Neurologic Examination—In walking, the trunk was tilted to the right, and there was a tendency to drag the right lower extremity. However, there was no signiﬁcant motor weakness, reﬂex change, or tonus abnormality. Coordination tests were well performed. The cranial nerve functions were intact. Vibration sense was correctly perceived only in the clavicles and the head, while position sense was lost in the ﬁngers, wrists, toes, and ankles bilaterally. Temperature differences were poorly perceived except in the face area. His responses to touch and pinprick stimulation will be described later. A mild degree of “mixed aphasia” was present. This speech difﬁculty was evident only by special testing or when the patient was fatigued by prolonged examination. There was a ﬂuctuating dyspraxia of moderate severity. Occasionally he had difﬁculty in dressing, being unable to handle buttons and sleeves. However, he could perform such functions as feeding himself, combing his hair, and other routine daily tasks. He was usually unable to mimic the more complicated patterns of the hand-praxis tests. An electroencephalogram showed bilateral diffuse abnormality, with decrease in amplitude and intermittent suppression of activity over the parietal regions. A pneumoencephalogram disclosed bilaterally dilated ventricles and moderate “cortical atrophy,” particularly in the left temporal lobe. Psychiatric Status—Although the patient was oriented for place and situation, he made errors as to date and time of day. There were defects in recent memory, concentration, calculation, and ability to assume the abstract attitude. He usually sat placidly staring into space or wandered aimlessly about the ward. He did not mix with other patients. When approached by members of the staff, he was friendly and passively cooperative. Testing procedures were approached with cheerful indifference. When, however, he was pushed into test situations greater than his capacity, he reacted with increasing irritability and tension, eventually culminating in a “catastrophic reaction.” At such times he would become red in the face, shout that he knew the answers but did not want to continue, and suddenly begin to weep. Body Schema—He was able to distinguish the right side of his body from the left, but was unable to make this distinction on the examiner’s body. He had no difﬁculty either in locating midline structures of his body, such as the nose, mouth, chin, umbilicus, and penis, or in pointing to his eyes. With eyes open he readily found both ears; but when his eyes were closed he groped about his face for several seconds before locating them. He could point to his thighs, knees, ankles, and toes but could not point to any speciﬁc toe other than the big toe. He frequently had diﬂiculty in locating portions of his upper extremities. If asked to point to his shoulders, he correctly located one shoulder but then groped behind his neck looking for the other. This defect was even more noticeable in trying to ﬁnd the “other” elbow and wrist, and greatest in trying to ﬁnd the “other” hand. His search for the “other” hand or wrist was bizarre. He would look under the pillow or rummage under the mattress, becoming tense and Fink, M.; Green, M., and Bender, M. B.: The Face-Hand Test as a Diagnostic Sign of Organic Mental Syndrome, Neurology 2:46-58 (Jan-Feb.) 1952. 5. �3 insisting it was lost. It should be emphasized that, despite the great difﬁculty in locating parts of his body, the patient was able to name the body parts, except the ﬁngers and toes. This was true whether the part pointed to was on the patient’s or on the examiner’s body. Sensory Status—(w) Single Stimulation: He had difﬁculty in differentiating between the sharp and the dull end of a pin. This defect was present throughout the body, although he made signiﬁcantly fewer errors in the face and hands. Touch stimulation was poorly perceived. Usually he could not state whether or not he had been t0uched. Again, there seemed to be relatively better preservation of this modality in the hands and face. Except under special conditions of examination of the hands, to be described later, the patient was able to locate the site of a pinprick by pointing. However, if the pin was repetitively and rapidly applied to one region, or if the prick was steadily maintained at that one place, he could not locate the point of stimulation. He would make frantic, random searching movements over his body, and not infrequently around the bedclothes, grimacing as though in pain and exclaiming that he was trying to remove the pin. If asked where he was being pricked, he dis— regarded the question and continued to try to remove the stimulus. This phenomenon occurred on stimulation of any portion of the body but was most apparent when the hand was tested. (b) Double Simultaneous Stimulation: The phenomena of extinction and displacement were frequently observed in tests of different body areas by simultaneous tactile stimulation. On stimulation of the face and hand, stimuli to the hand were not perceived or were mislocalized to the cheek. In tests of homologous body areas (as hand-hand) extinction of one percept was common. The side on which the stimulus was not perceived ﬂuctuated, so that at one moment only a. right—sided stimulus was perceived and a few moments later only a left-sided stimulus was perceived. Exosomesthesia—Whenever his palm was in contact with a portion of his body or any other object, and the dorsum of that hand was pricked with a pin, the patient consistently mislocalized the stimulus. This mislocalization was to whatever object the palmar surface of the hand was touching. For example, if the patient’s hand was resting on his thigh and the dorsum of the hand was pricked, he insisted that the thigh had been touched, and not the hand. This mislocalization —exosomesthesia—occurred to the thigh, abdomen, leg, or face and was present with stimuli to either hand. It was observed even when the patient was urged to look at the hand during the application of the pin. Exosomesthesia could not be elicited, however, by stimulation of the palm or palmar surface of the ﬁngers when the dorsum of the hand was resting on a portion of the body. Furthermore, localization of stimuli to the dorsum of the hand was correct if the hand was held in space. Mislocalization also occurred to objects external to his body. If his palm was resting on a table or on his bed, and the dorsum of the hand was pricked with a pin, he would point to these objects and state that the pin had been applied “there.” When questioned, he stated that the hand had been touched but continued to point to the bed or table. Frequently, however, he insisted that it was the bed or table that had been touched, and not his hand. If asked how he could feel the bed being pricked with a pin, he would become tense, avoid the question, and insist, “You touched the bed, not me.” Displacement into extrapersonal space was not eliminated by simultaneous stimulation, even when extinction of one of the percepts occurred. For example, if pins were simultaneously applied to the dorsa of the hands while the palms were resting on a table, he would report feeling only one pinprick, that on the left (or right, as dominance ﬂuctuated) and point to the place where the left hand had been resting, saying. “You touched the bed there.” This phenomenon of displacement into extrapersonal space occurred daily during a period of more than two months. C 0mment.——~In this patient a requisite to displacement into space was that the palm of the hand be in contact with an external object. In other words, there were two cutaneous stimuli simultaneously in operation, namely, the pinprick on the dorsum of the hand and the pressure of the object in contact with the palm or ﬁngers. A single stimulus, such as pricking the dorsum of a hand held in space, did not elicit the displacement. �4 Exosomesthesia was elicited only on stimulating the hands. This occurred even though single pinprick was perceived more sharply in the hands than in any other area except the face. Although this patient showed inability to locate correctly parts of his own and the examiner’s body, it does not necessarily mean that exosomesthesia is determined by this particular type of disorder in body scheme. The following case illustrates the phenomenon of exosomesthesia in the presence of the patient’s ability to locate body parts. 2.—E. K., a woman aged 52, was admitted to the neurologic service of the Mount Sinai Hospital in August, 1950, with a history of grand mal seizures. She had been in good health until 1947, when there appeared sporadic, momentary sensations of “blacking out.” About two years before admission she began to suffer monthly grand mal seizures. There was no aura. Routine examination on admission showed that her status was within normal limits except for anosmia in the right nostril. There was no organic mental syndrome. X-ray studies revealed evidence of a subfrontal neoplasm. On August 12 a craniotomy was done, and after amputation of a portion of the right frontal lobe, a large bilateral subfrontal meningioma was excised. Her postoperative course was stormy. For two weeks she was semistuporous. She responded only to massive, painful stimulation, and these responses were limited to vague, ineffective attempts to push away the stimulus. In this period she lapsed several times into coma and showed Cheyne-Stokes respiration. The Babinski response was obtained bilaterally. Her pupils did not react to light. From about Aug. 23, 1950, the patient improved slowly and steadily. She began to respond verbally, and contact could be maintained for short periods. Vision, which had apparently been absent, began to return, although right homonymous hemianopsia remained for some time. A marked organic mental syndrome characterized by confusion, disorientation, and anosognosia, was present. Routine Neurologic Examination.——Neurologic examination in September, 1950, disclosed right homonymous hemianopsia, severe impairment of visual acuity with bilateral secondary optic nerve atrophy, nystagmus in all directions of gaze, a bilateral Babinski sign, and a mild degree of aphasia. Position sense, vibration sense, and temperature perception were unimpaired. There were difficulties in perception of touch and pinprick stimuli, as described below. Psychiatric S'tattusr—The patient was usually friendly and cooperative. However, she was frequently irritable and would not permit examination. She was disoriented as to time and occasionally to situation, but not to place. There were defects in retention and recall, covered by confabulation. She was euphoric and displayed little self-restraint or concern in social situations. Usually she would lie with her body fully exposed. Not infrequently she soiled herself or wet the bed. Anosovgnosia was prominent. Body Schema—On command, the patient was able to identify and locate correctly parts of her own and the examiner’s body, such as the ears, eyes, feet, and parts of the upper extremities. She exhibited some confusion about the right and the left side of the body. Sensory Status.—(a) Single Stimulation: The patient perceived single pinprick stimuli well, although she made occasional nonpatterned errors in localization. These errors were more frequent on the left side. (b) Double Simultaneous Stimulation: On simultaneous application of pinprick to the two sides of the body, except the hands, extinction on the left or displacement on the left toward the level of the right—sided stimulus was the usual response. Homolateral simultaneous stimulation on the right side of the body showed no extinction, but stimulation on the left side elicited frequent extinction and displacement. CASE Exosomesthesia.—Displacement into extrapersonal space occurred when the left hand was pricked at the same time that either the right hand or the right cheek was stimulated. The phenomenon could also be elicited when the left hand and any other area of the left side of the body were simultaneously stimulated. Under these conditions the patient mislocalized the stimulus to the left hand into space near that hand, or to the object on which the hand was lying. For example, if pinpricks were �5 . simultaneously applied to the right cheek and the left hand, the patient indicated she had been pricked on the right cheek and the arm of the chair on which her left hand had been resting. As a rule she answered by pointing. If asked to verbalize, she would say, “The right cheek and about here,” (pointing to the chair arm or into space near her left hand). If asked directly. “Was your hand touched?” she would avoid the question, responding only, “Here,” pointing at the same time to the left chair arm or into space. It is to be noted that, except under the special condition of simultaneous stimulation, the patient was always able to point to or to name her left hand on demand. If pricked simultaneously on the dorsa of the left and right hands, she correctly localized only the stimulus on the right, both by pointing and by stating, “My right hand.” The stimulus on the left, however, was localized only by pointing to the chair arm and saying, “Here.” If asked whether the chair arm and not her left hand, had been touched, she answered, “No, here,” pointing to the chair arm. When pinpricks were applied to the left hand and, at the same time, to another area on the left side of the body, a similar displacement into space was evident. Usually the stimulus to the left hand was mislocalized onto whatever structure the hand was resting or else 'into contiguous space. The other stimulus on the left side was usually correctly localized, though this stimulus, too, was occasionally displaced into space. When this double displacement occurred, the patient would state that she felt two stimuli and would point into space to the left of the arm, stating, “Here and here.” These mislocalizations were repeatedly observed during a period of a month and were not always limited to the left side. They were occasionally observed to occur on the right side. At these times localization on the left was always correct, as indicated by pointing and by verbalization. C omment.—Exosomesthesia was elicited in this patient only under the condition of multiple simultaneous stimulation. It could not be elicited by single—stimulation methods. Also signiﬁcant is the fact that exosomesthesia was apparent even though there was no gross disorder in body scheme on routine testing. Furthermore, it is evident that her errors in localization were not simply inability to point to or identify parts of her body by name, as ordinarily she experienced no difﬁculty in doing this. on command. Both patients mislocalized percepts to parts of the body, to objects, or into space contiguous with the area stimulated. Occasionally, we have also observed displacement of a stimulus to the person of the examiner. Usually such percepts are mislocalized to a homologous portion of the examiner’s body; e. g., a stimulus applied to the patient’s hand is reported by him as though it had been applied to the examiner’s hand. Rarely, the mislocalization is to any part of the examiner’s body. This type of displacement is illustrated in the following case. man aged 52, was admitted to the Psychiatric Pavilion of Bellevue Hospital with the complaint that he had become confused and depressed. For about a year he had been disoriented and confused as to date and his relationship to people and had wandered about the city aimlessly. He had been admitted to the Farm Colony about a half-year before and had worked as a barber until the week before his admission to the hospital. Routine N emologic Examimtion.—Neurologic examination showed normal gait and station. Coordination tests were well performed. The reﬂexes were active bilaterally, with normal plantar and abdominal responses. Cranial nerve functions were normal. The sensory status showed changes, but only with special methods of testing. A pneumoencephalogram demonstrated moderately dilated ventricles, without shift or deformity, and some dilated cerebral sulci. Psychiatric Status—A severe organic mental syndrome was evident. In the ward he sat quietly for hours by his bedside, taking little interest in his surroundings. When approached by members of the staff, he appeared perplexed but was affable. During the testing procedures he was cooperative unless confronted by a test situation in which the examiner demanded tasks CASE 3.—-R. M., a ‘ �6 ‘ beyond his ability. At such times he showed a “catastrophic” reaction, became excited, and discontinued his efforts in the examination. He was disoriented for time, place, and situation. However, he was able to ﬁnd his way about the ward, locating his bed, the nurses’ desk, the doctor’s ofﬁce, and the lavatory. Severe diﬂiculties in intellectual function were observed. He was unable to give an adequate history. He could not recall the examiner’s name or the events of several hours before but did not confabulate. Calculation and symbol—identiﬁcation tests were poorly performed. Severe aphasic difﬁculties Were evident. He was unable to name common objects, clothing, or most parts of the body. He could not comprehend written commands, nor could he write, but he was able to follow simple verbal commands. Mild dyspraxia was demonstrated in his attempts to imitate ﬁnger and mouth movements. However, he was able to dress, feed, and otherwise care for himself. Body Image.—He had difﬁculty both in naming body parts and in locating them by pointing. The defects were severest in the ﬁngers, wrists, and elbows, and occasionally the feet. There was difficulty in right-left orientation. Sensory Status—(a) Single Stimulation: Routine sensory studies of touch, pinprick, and vibration stimuli showed no consistent impairment. These stimuli were usually correctly localized and described. Occasionally a single stimulus to the hand or forearm was displaced to a contiguous object or to space about the upper extremity. (b) Double Simultaneous Stimulation: On double simultaneous [touch] stimulation the patient displayed extinction and displacement of tactile stimuli. This was most evident in trials of the face—hand test 6 but was seen in tests of other body parts as well. For example, on simultaneous stimulation of the cheek and the opposite hand, he would either report only the stimulus to the cheek (extinction of the hand stimulus) or report a stimulus to each cheek (displacement of the hand stimulus). The pattern of sensory dominance was that usually seen in diffuse cerebral disease, the face being most dominant, the hand least.5 There was no lateral dominance. Exosolm-esthesriav.—Displacement into extrapersonal space was occasionally observed on single stimulation. This displacement was from the hand, forearm, or elbow to space contiguous to the part touched. Exosomesthesia was, however, markedly exaggerated when double simul— taneous stimulation was employed. Again, the areas from which the phenomenon was most frequently observed were the hands, forearms, and elbows. For example, when stimuli were applied to the dorsa of the hands as they were lying on the patient’s lap, he pointed to space in front of his knees. If asked to state where he had been touched, he would say, “The hands,” but would continue to point to the space in front of his knees. Exosomesthesia was rarely noted when other body parts, such as the cheeks or shoulders, were simultaneously stimulated. Occasionally it was found that on tests with double simultaneous stimulation the patient mislocalized a stimulus from his body to the homologous region of the examiner’s body. For instance, when the hands were simultaneously touched, he would grasp the examiner’s hands and affirm he had been touched “there.” Despite the examiner’s insistence that the stimulus had been to the patient’s hands, the patient would persist in pointing to the examiner’s hands. When asked to name the parts touched, he would say “There, there.” The same phenomenon was occasionally observed on simultaneous stimulation of the two elbOWS or cheeks. It was signiﬁcant that this mislocalization to the examiner’s body occurred even when the patient was urged to look at the stimulations. It was observed that emotional tension, increase in the rate of testing or undue prolongation of the examination increased the incidence of exosomesthesia. For example, to initial application of pinprick to the right hand and the left cheek, the patient reported only the face percept, omitting the hand stimulus. Later, he localized the two stimuli to the cheeks. As the examination progressed and the physician speeded up the testing, the patient became tenser. He then localized the face percept correctly but insisted that the hand stimulation was into space in front of the hand. Finally, both stimuli were displaced into space or to the examiner’s body. These phenomena were observed daily over a period of 2% months. . Bender, M. B.; Fink, M., and Green, M.: Patterns in Perception on Simultaneous Tests of Face and Hand, Tr. Am. Neurol. A. 75:250-252 (June) 1950; Patterns in Perception on Simultaneous Tests of Face and Hand, A. M. A. Arch. Neurol. & Psychiat. 66:35‘5-262 6. (Sept) 1951. �7 Comment—While single stimulation occasionally produced exosomesthesia in this patient, the phenomenon was more pronounced under conditions of double simultaneous stimulation. This patient also mislocalized stimuli to the examiner’s body. Emotional tension, prolonged examination, or increase in the rate of testing exaggerated the phenomenon of exosomesthesia. GENERAL COMMENT On consideration of these cases, it is immediately apparent that exosomesthesia is associated with a severe organic mental syndrome. Therefore, it might be argued that exosomesthesia is merely a manifestation of the patient’s mental confusion; that the patient simply points into space because he is confused. However, we have examined many severely confused patients and found exosomesthesia only rarely. Moreover, exosomesthesia is a patterned phenomenon, demonstrable in each patient under deﬁned conditions, predictable as to the area from which it will occur and the extrapersonal spatial region to which the sensation will be projected. For example, in Case 1 exosomesthesia could be elicited only from the hand, and only when the dorsum was stimulated at the same time that the palm or ﬁngers were in contact with another object. Displacement under these circumstances was usually not haphazard. As a rule it occurred to the object touching the palm or ﬁngers. In Case 2 exosomesthesia could be elicited only by double simultaneous stimulation. It was seen most clearly in the hand and could be elicited only unilaterally at any one examination. Again, the displacement was not haphazard; the stimulus as a rule was localized to extrapersonal space contiguous to the area actually stimulated. In Case 3 the phenomenon was observed again under conditions of double simultaneous stimulation, and the displacements were either to space contiguous to the stimulated area or to homologous areas of the examiner’s body. It is signiﬁcant that these displacements could be elicited even when the patient was urged to look at the application of the stimuli. Moreover, even when the examiner pointed out the error in localization and emphasized the implausibility of the response, the patient characteristically insisted on the correctness of the mislocalization. Factors Inﬂnencing Exosoimesthesiax—Many factors inﬂuence the appearance of exosomesthesia. Except in children under special conditions, it has been observed exclusively in patients with severe mental changes resulting from disease of the brain. It is inﬂuenced by the type of stimulus used and the rate of stimulation, as well as by the element of simultaneity of stimuli. Moreover, the emotional state of the patient has a signiﬁcant effect on the phenomenon, as does the part of the body stimulated. In some cases exosomesthesia has been made apparent by administration of small doses of amobarbital sodium. These factors will be discussed. (a) Bilateral Cerebral Disease: The symptom background in every case of exosomesthesia is an organic mental syndrome secondary to bilateral cerebral disease. We have not been able to demonstrate exosomesthesia in an adult unless there were severe mental changes. But, as previously noted, it is a rare phenomenon, and only a few patients with severe organic mental syndrome show it. In 400 patients with organic cerebral disease, of varying severity, exosomesthesia was observed in approximately 3%.5 Even in these patients it was not manifest in every examination, and its frequency was readily altered by changes in the conditions of testing. It is therefore evident that severe bilateral cerebral disease in itself is not sufﬁcient to produce exosomesthesia. �8 That simultaneous stimulation may elicit sensory phenomena not apparent on single stimulation has previously been demonstrated.2 For example, a hemisensory syndrome in a hemiplegic patient may not be discernible except under conditions of double simultaneous stimulation. Thus, single stimulation may be well perceived and localized by the patient, but the addition of a second stimulus simultaneously applied may so affect integration that the phenomena of extinction, obscuration, and displacement become apparent. Similarly, simultaneous stimulation elicited exosomesthesia when it was absent on single-stimulus examination, or exaggerated it when it was occasionally manifest on routine stimulation. In Cases 1 and 2 simultaneous stimulation was a necessary condition for eliciting the phenomenon. It could not be demonstrated by single stimulation. In Case 3 exosomesthesia could occasionally be elicited on single stimulation, but with simultaneous stimulation the phenomenon was demonstrated with much greater frequency. (c) Type of Stimulus Most Effective: Of the various stimuli used in these examinations, such as single touch, single pinprick, repetitive touch, and repetitive pinprick, it was noted that repetitive touch stimuli were most effective in eliciting exosomesthesia. This was especially true on double simultaneous stimulation. (d) Effect of the Patient’s Emotional State: Exosomesthesia was exaggerated by alterations in the test situation which made performances more difﬁcult. Increasing the rate of stimulation or unduly prolonging the examination increased the displacements to extrapersonal space. If the examiner was deliberately critical of the patient’s errors, the phenomenon also appeared with greater frequency. These factors increased the emotional tension of the patient and if carried further produced a “catastrophic” reaction. (e) Effect of Drugs: It has previously been demonstrated that difﬁculties in perception may be exaggerated by barbiturate intoxicants.5 Amobarbital sodium was administered intravenously in doses of 3 to 7 grains (0.2 to 0.45 gm.) to patients with diffuse cerebral disease. Prior to administration of the drug, these patients manifested the phenomena of extinction and displacement of percepts on simultaneous tests, but not exosomesthesia. While under the inﬂuence of the barbiturate, three patients showed exosomesthesia, in addition to extinction and displacement. In two other patients, in whom exosomesthesia had been elicited only after a protracted testing period, the administration of amobarbital sodium elicited exosomesthesia at the onset of testing and exaggerated the phenomena of extinction (2)) Effect of Simultaneous Stimuli: and displacement. Relation of Exo'somest‘hesia to: Extinction, Obscumtioln, and Displacement—In our experience, whenever exosomesthesia has been observed, the phenomena of extinction, obscuration, and displacement are also present. Exosomesthesia, how— ever, is a rare phenomenon, whereas extinction, obscuration, and displacement are commonly observed. Moreover, whereas extinction, obscuration, and displacement are frequently seen in adult patients with mild cerebral dysfunction,5 displacement into extrapersonal space is present only in cases of severe mental changes due to disease of the brain. It may therefore be concluded that exosomesthesia in adults represents a severer type of cerebral dysfunction than other simultaneous stimulation phenomena. �9 Relation of Exosomes'th‘esia; to Body I mage.——It might be said that exosomesthesia is a pathologic extension of the body image. The normal person is continually extending the boundaries of this image. For example, Head cites the examples of the woman with a feather in her hat who “feels” when the feather is touched, and the surgeon who handles his probe as though it were an extension. of his ﬁngers.1 In the normal person, however, these extensions of the body image are ﬂuid, immediately reversible, and clearly recognized by the subject as artiﬁcial. The surgeon, for example, is able at any moment to redeﬁne correctly his body image. He “knows” that the probe is not his ﬁnger. In the group of patients described above, however, the extension of the body image seems to operate in a pathologic, rigid form. Under certain conditions these patients lose the ability to maintain a realistic deﬁnition of the limits of their body. They behave as though portions of the contiguous external world are concretely incorporated into the inner image of their body’s extent. Although we may consider exosomestheisa as a specialized body-image disturbance, it should be noted that patients who do not show difﬁculties in identiﬁcation and location of body parts still may show mislocalization into extrapersonal space. On the other hand, patients with an inability to identify or locate their body parts on command do not necessarily manifest exosomesthesia. In similar fashion, there is no necessary relationship between exosomesthesia and position-sense difﬁculties. A patient (Case 3) who manifested displacement of sensation into extrapersonal space did not make errors in routine tests of position sense in the extremities. This is consistent with observations previously made by Head1 that localization of single stimuli is not functionally related to sense of position of the extremities. Role of the Hand—Although displacement into extrapersonal space has been elicited from various areas of the body, it has been observed to occur most frequently from the hand. Moreover, in no case has it been elicited from another area and been absent from the hand. This predilection for the hand is consistent with the manner in which other dysfunctions of the nervous system are reﬂected. As a rule, when the functioning of one side of the body is impaired through cerebral disease, the disorder is most manifest in the hand. Thus, in the usual hemiplegia resulting from a capsular lesion the paresis, body-image disturbance, and sensory loss are most prominent in the hand and ﬁngers. In these patients, and in others with diffuse cerebral disease, the phenomena of extinction, obscuration, and displacement are also best elicited when the hand is tested. Furthermore, studies of the order of sensory dominance of various areas of the body demonstrate that the hand is in the lowest rank. This is true of the dominance order of patients with cerebral disease,5 and also of normal subjects, both adults and children.6 Similarly, when allesthesia is observed, it is seen most clearly in the hand. Bender and Nathanson 7 described a case in which the clinical course was reﬂected in a Bender, M. B., and Nathanson, M.: Patterns in Allesthesia and Their Relation to Disorder of Body Scheme and Other Sensory Phenomena, Arch. Neurol. & Psychiat. 64:501-515 7. (Oct) 1950. ‘ �10 waxing and waning allesthesia. As this patient improved, the areas from which the phenomenon could be elicited diminished, until ﬁnally allesthesia was demonstrable only in the hand. In autotopagnosia the hands are more profoundly affected than other regions. Finger agnosia, possibly the earliest sign of body-image disturbance, is frequently seen in the absence of other gross disturbances of the body schema. Furthermore, phantom limb, anosognosia, causalgia, and synesthesia are phenomena in which the role of the hand is especially prominent. Just as these pathologic phenomena are manifest in tests of other body parts, but are most clearly demonstrable in the hand, so, too, exosomesthesia, though occasionally demonstrable elsewhere, is most apparent in examination of the functions of the hand. Exosomesthesia in the N ormal C hild.—It has been observed that sensory phenomena which occur in patients with cerebral dysfunction may be found in the nor— mal young child.6 Similarly, exosomesthesia, which we have never found in adults except when there is severe cerebral disease, can be readily observed in children up to the age of 4 years. In examination of a large series of normal children it was noted that the initial responses of children to double simultaneous stimulation fre— quently included exosomesthesia, although the commoner responses were extinction and displacement. Exosomesthesia was rare, however, after the initial few trials. The frequency with which exosomesthesia may be seen in children up to the age of 4 years suggests that it may represent, in the child, a “normal” developmental stage in the organization of perception. Its appearance in adults with severe brain disease may possibly be, as with other pathologic phenomena, a regression in function to a previous level of sensory integration. SUMMARY , The patterned mislocalization of tactile stimuli into extrapersonal space is described and termed exosomesthesia. Exosomesthesia is observed in patients with severe organic mental syndromes. It is apparent only rarely on single tactile stimulation and is more readily elicited by the technique of double simultaneous stimulation. It is exaggerated by fatigue, rapid testing, and increased emotional tension. Barbiturate intoxication also may elicit or exaggerate the phenomenon. Exosomesthesia is most apparent in stimulation of the hand but has been observed in tests of other body parts. While it may be considered a pathologic extension of the body image, it is not dependent upon concomitant body-image disturbances. Although exosomesthesia has been observed chieﬂy in patients with severe mental changes, it is not a manifestation of confusion, but is a patterned, predictable phenomenon. It may be a regression, in patients with cerebral dysfunction, to a previously “normal” stage in sensory development, as suggested by the fact that it is readily observed in simultaneous tactile tests of young children. Printed and Published in the United States of America �EXOBOMIBTHIBIA OR DIEPLkGIIIIT 0P OBTlﬂlﬂﬂs 83N3£TIOIIINQO EantuflRSOIAL BPACE‘ EV Martino:- F. Shapiro. am. an: Fink, K.D.'* and Kerri: B. Bender, H.D. ., " "i 3”“ a"? ,y. Univcruity College or’ncdieiuc and tn. 3 enrol 651331 Service of thc Haunt ﬂinﬁi ﬁclpital Ind lollcvuo ﬁbﬂpitﬂl, I0! Yer! 0131. 'Dntdod by a ﬂullaulhip tram thy lationnl roundntion for Infantile QJ‘ V‘W‘ , g j , ‘9ar111510. ibis investigltion in. lupportod, in partin:by a rouonroh grant stutt- Public not ammo. mum or ﬁanlth. aun-139 tram tho unit.d Inltitutel ﬂ �Among phenomena bbeb new be epperenb during exe-inebion or petienbe eith dieeeee or the eeneory pebbueye is nielooelisebion It individual with e eeneory defeat, on eeen in the cannon vuriebiee or cerebrel beniplegie, any looeiioe ineoonrebely ebiuuli applied on the of e eeneory etienioo. bee long been known that on ‘ perebio bide. point nielooelieebiono ere epperenb in exelinetionl ueing e eingie ebiunlue, end have been deeoribedbin detail by Hood (1). These nationalisation: can be eooentuobed/b‘e uee or double Snob einnlbeneoue obi-ulebion techniques (2).- In eddidon, when theee technique. of exeninetion Ire enployed, other veriebiee or nielooeiieetion,-euob ee diepieoenent (3). become apparent. niepleoe-nnb ie the petberned nielooelieebion or one or two ebinnli eiunlbeneouely applied to different body areas. The direction or diepleoeuent ie in e definite pattern, which is dependent upon the parts or the body Ibilnleted. choreoterietio of nieiooelieetion on for reported bee been ‘ tho fact bhet their lxtent VII uibbin the lilibl of the patient’l body. In the oouree or obodiee or outeneoue peroeption we obeerved I new torn or diepleoenent in which the patient oonoietenbiy end in e prediobeble reebion nielooelieel obi-n11 into extra-pereonei epeoe. Thin type of diepieoenont on have teamed “exoeo-oebheeie'.¢ of the derived by Dr. Judeh A. Jotte, Editor 19%0, the tron Press. Oxford Boivereity reyobietrio biotic: none", , by ”eiotheeie”, perception body; the Greek "one", out or; 139 FI?’!53'€5§E eeneee. wee ll; Exoeoleebbeeie ie not e commonly oboerved phenomenon. more than #00 patient: with brain dieeeee were examined at Bellevue Peyobietrio Hoopibel by routine end epeoielieed eeneory beete. �2. Shoeoneetheeie wee obeerved in only 15 oeeee ~ en incidence of ebout 3! (5). who following oeee reporte illustrete the phehoaenon end deoonetrete eoee o: the oonditione ﬁnder which it wee obeerved. Case 15 H.I., e 6% year old male, wee admitted to Bellevoe Peyohietrio noepitel with e hietory or progreeeive sentel cheeses or eix years doretion. The firet tour yeere or illneee were lurked by eloely progreeeive ilpeirnent of memory, oonoentretion end other intellectual funotione. end inoreeeing epeth: to hie environnent la the leet teo ii yeere thie oondition exacerbated rapidly, reeulting the lone of hie Job ee e etore neneser. During thie period hie epeeoh bean-e inoreeeingly serbled end Ito-nerihg, Be veeoilleted oolplete epethy.i. 1*: f”;irTWT€nL. he wee oooeeionelly incontinent. mm bathing; nee dittioulty in dreeeing, end wee eoneti-ee eo forgetful end oonrueed ee to wander into the etteet eithout hie troueere. Routine georologio Ian-ioetion; In welkins the trunk wee tilted to the right end there wee e tendency to drag the right, lower extreaity. However, there wee no eignitioent motor weekneee. reflex change or tonne ebnor-elity. Coordination teete were well perromned. The oreniel nerve function: were intact. Vibretion eenee wee correctly perceived only in the oleviolee end the heed, while poeition eenee wee lost in the tinsere, eriete, toee end enklee bilaterally. Temperature difference: were poorly peroeived exoept in the teoe.eree. hie reeponeee to touch end pin prick between irritebility end nild degree or “mixed epheeie" was present. This epeeoh difficulty we: evident only epeoiel testing or then the petient wee retigued by prolonged eti-uletion will exeeinetion. be deeoribed leter. A by there one e fluctuating dyeprexie of noderete eeverity. �3. Occuionally n. ma difficulty in drawing, being unable to handle button: and alaavca. however, he could partonn Inch tunaticna aa reading hinaalr, ccwbing hia hair and cthar routine daily taaka. Ha waa naually unabla to wiwic tha aura ccwplicatad pattarna of the hand~praxia tanta. licetrcancaphalcgrwa ahcwad_bilatcral dittuao abncmnality. with dacraaaa in awplituda and interwittant auppraaaion or activity ova: tha pariatal regiona. Pnauacancaphalcgranldiaclcaod bilaterally dilated vanericlna and wodarato “cortical atrophy". particularly in an ion moral lobe. szphiatric Statua; Although tha patiant waa ariantcd for place and situation, he wada crrora an to data and than or day. Thar. war. datacta in vacant unwary, concentration, calculation and ability to aaauln the abatract attituda. no uwually aat placidly ataring intc apaca or wandered aialaaaly about tha ward. Ia did hat win with cthar pationta. whcn approachad by tag atarf he waa friendly and paaaivoly cccparativa.' Tasting proceduraa ware approachad with a chaarful indittcranca. Hhan, hcwavcr, ha was panhad into Boat aituaticna :raatar than hia capacity, ha reactad with incrwaainx itvitability and tanaicn, avantually calainating in a “cataatrcphic reaction.” it such tiwna ha would baccwa rod in tho taco, about that ha know tha ahawara but didn't want to continua and mcccniy basin to map. a. waa can. to distinguish tho right aid. or his: body tro- the 1321:; but waa unable to wake can distinction on tha miner's body. 11. had no difficulty either in locating nidlinc atruccuraa or hia body, auch aa tha uoaa, heath, chin. nabilicua and pania, or in pointing to hia cyan. With oyoa cpan ha readily fauna W ' �e. hath eere, but when hie eyee were cloned he seeped ebeut hie teee for eeverel eeeende betere leeetlns then. he eeuld'belne to hie thighs, kneee, ankles end tees but could not point to any epeclrlo toe ether thin the his teen. frequently had Alrtlculty 1n locetlns port1ene or hie upper extrenltlee. It eeked to point to hle ehouldere. be correctly located one ehoulder, but then grayed behind his neck locking for the other. This defect was even more noticeable in trying tn find the ”other" elbow and wriet, and creeteet in trying to find the "other" hind. ﬁle eeereh for the ”other" hand or wrist Be bizarre. He would parts of hie body, the look under the pillow, or rummage under the nettreee becnnlng tenee and ineietius it we. lost. It should be eupheeieed that despite the great difficulty in lecetlns was petlent was able to name the body parts. except the tinseve end toee. This was true whether the pert pointed to nee on the petient'e or on the examiner'e body. 33939;; Stetueg (e) ééﬁﬁl? Btlnhletlon: He had difficulty in differentleeins between the sheep end dull end of e pin. This defeat wee preach: throughout the body, elthoush he made eignitieently fewer erreee 1n the reee end hende. Touch atlauletian was poorly perceived. Heuelly he coulé not state whether or not he had been tauched. Again, there �5. «m to be relatively better preoorvotion or this modality in ' the hand: and face. Except under opooiol oonditiono or examinotion of tho hands, to he described liter, the patient who ohle to locate the eite of it the pin on. repetitively and or it the priok woo steadily maintained a pin prick by pointing. however, rapidly applied to one rosion, at that one place, he could not looeto the point of otinmlotion. tendon scorching lav-neat: over hio body and not infrequently around the bed olotheo. srinaoing on thouah in pain and exoloinins that he one trying to renove the pin. If ookod He would make frantic, where he one being priokod, ho diorozorded the question and con» mm on tinued to try to move the stimulus. "m. phmmnon stimulation or any portion or the body, but who most apparent when the hand no tested. (h) Double SiuultOneouo ethnolotigg; Tho phone-en: or oxtinotion end dioplooo-ont were frequently ohoerved in tests or different body area- by oilultoneouo tactile otiuuli. 0n etinnletins tho race and hand. otinuli to the hand we». not perceived, or nioloooliaod to the cheek. In touting honolosoue bod: stone (on hondvhond) extinction of one poroept III col-on. The side on which the stimulus III not pcrooivod fluctuated, no that at one uooont only a right-sided stimulus one perceived and o for momentleter, only a lott~oided etinnloo not perceived. Exooonootheoio; Whenever his pal: who in oontoot with a portion or his body or any other ohJeot, and the dorouh of that hand In: prioked with o pin, the patient oonoiotently nioloohliaod the �6. ottuulun. this nialooaiisation who to whatever object the phi-tr tartan! of the hand was touching. For txlhplc, 1f the pntioht'l hand was routing on his thigh and the doroun of tho hand VII priokod, he insisted that tho thigh had boon touched, and not the hand. Th1: ninlootlisntion ~ oxooonoothooio - occurrod to the thigh, obdonnn, 105 or (too, had who present with stimuli to oithor hind. It Ill observed even when the patient who urged to look 1t tho hlhdt durtng the application or the pin. nah-anesthesia could not be elicited, however, by otinulhtion of tho pnln or polmar curtuoes of tho ringer! uhnn the aorta: of tho hhné ill rooting on a portion or the My, runner-more. ionization or dorul hand amnion um correct 1! the hind III hold in space. Iloloooltsntion also ooourrod to abduct: external to hit body. It h1o pal: ill rooting on I tabla or on his bad. and the doroun of tho hand It; prioknd with I pin, ho would point to those ohjooto and 091th thlt tho pin had been $991106 "thmru." Whoa quantionod. ho hinted thlt tho hand had huen touched, but continued to point to tho bid or table. Proquontly. however. ho'inntotod thht it on. tho bod or tohlo that hon boon touohnd thdhnntphhohhnnd. Ir alkod how he could too;_tho bod being priokod with a pin he would booonn ton... avoid the queut1on and inliot ”you touohod the bed, not In". III not ell-inatod by Itlhltanooun stimulution, oven whnn extinction of one of tho parocpto occurred. for 03:391., 1! pins hero oinulthnoouoly applied to the aorta of both hands Ihllo tho pal-n wore resting on o table, he would report fetish; only on. p1n prick, that on tho loft (or right, a: dominance fluctuhtod) and point to thn plloo whore the loft hind huh boon rooting. saying ”you touohod the bed thoro.” Displheonont into outrouporoonnl than. �this phone-enon or dilplucancnt into cxtra~peroonal tpnoe occurrcd daily during e period or over two nonthn. Commont: In this paticnt a rccuicitc to dimplecenmnt into space was that the pmlm or the hand be in contact with an external object. In other words. then. were two cutaneooo stimuli limnltcnecully in operation, nemoly the pin prick on the doreun or the hand and tho pro-lure or the object in contact with the palm or ringcro. A single nti-nluc. eooh II pricking the dornun or e hand held in upeoe. did not elicit the dicplnccmnnt. luoeomeutholih III elicited only on otimullting the hands. mu oocumd am though Ilmle pin print as: perceived me cum: in the hand: than in any other areo. excepting the thee. Although thin potient showed In lnability to oorroctly locate phrte or his own and tho esnminor's body, it doc: not necoecnrily amen that exolcnelthscic in dutenmined by thie particular type of disorder in body ache-n. the following case illustrate. the phenomenon or exoocmeetheaiu in the preeonce or to. patient'n some: to locate body pam. can. 23 l.l., a 52 your old woman, III edmitted to the. Neurolosio Service of the ﬂaunt Sinai hoeoitdl in August 1950 with I history of grand hnl eelxuroo. She had been in good honlth until 1937 uhcn there appeared sporadio, noncntnry ecnuutione of "blacking out." About two year: before hdniehion she began to suffer Ionthly ' Ill leisurel. There was no euro. Routino exeminntion on admiulion III within normal limits, oxoept for dnolmia in tho right nontril. there one no organio honthl cyndromo. apocinl x~rcy studiel reveoled evidonoo or a oohfronthl grand necplcen. an August 19th a oreniotoly mm: done and following amputation of e portion or the right frontal lobe, a large bilateral �8. ‘tub-troattl III umniaginnn was axcitcd. nor pout~opcrutive courts an; stormy. For tut lacks an. saui~stup¢rann.r 3h. raupondod anly ta lassive, painful stimu— than: renpanuaa ﬂirt limited to vague ineffective nttenpta ta.punh Quay tat stimulun. In this pcriod the lnpuod uovcral tin»: latian, irate and om um: "sputum um chem-Magma did not Bar rttpannoa rare pruatnt. pupil: mutem ublmkl retot to light. tn. pltiint inproved slowly and steadily. an. hogan to rtlpond vcrbtlly and contact could be maintained far short poriodn. Vinita, union and apparently been absent, begin Frau about Augunt 23, 1950 to rcturn, tlthough a right unnonyloul halinntpuia tiltinoﬁ for Dunn tino. A Iarkod orgtnic nanttl syndrtlo characterised by confusion. disorientation and nuouognusin was prcnant. Routine laurolggic xxnlinntion: laurtlosit exnuination in aoptonbor 1950 diteltuoa a right honcnynnun honiunopnil, asthma impairment of vilual Inuit: with bilatorul nocondnry Optic atraphy, urttaslnl in all directions or ante, bilaterally patitiv. nabintki night. and a nild dogree or uphatin. Position nan... vibration and tonporntur. porcuptian wire unimpairtd. Thor. were difficulties in perceptien or touch Ind pin prick stimuli at anacribod belwu. Puzehiutric Status: The patient was usually friendly and cooperative. Bouvver, the III frequtntly irritable 1nd unuld not pomnit culmination. an: an. dilaritnt-d II to tins and notational: to situation, but not to placa. Thar: var. defeat: in retention Ind maul covered by contabulatian. am am euphoric and 41:91:,“ littlc self restraint er aoneern in social oituatiana. Usatlly uh: would lie with her body fully oxpoaod. not intrtqunntly she toiled �bereelt or wet the bed. Anaeognoein In: prominent. Bod: Scheme: 0n contend the petient we: able to identity lbette correctly parts of her can and the examiner's body, such In ears, eyee, feet and parts of the upper extremities. She exhibited name oenfueion about the right and left eidee a! the bady. end Season; statues] (a) siggie atiuulntian: The patient perceived single pin prick cumin mi, eitheugh m undo 0003:1011“ nompntterned em» in localisation. Theta errors were more frequent on the left side. (b) Double ginniteheaue stimuletion: 0n sinulteneouu epplicetion of pin prick: ta both tides or the body (excluding the hands) extinction on the left, or dieplaceaent on the left toward the level at the right-aided stimulus were the usual reepaneee. amneleterll linulteneaus etimuletion on the right side or the body shaved no extinction, but ntinuiatian on the left side elicited frequent extinetian and displacement. Runneleetheeieg Dieplaeenent lute extra—portend! space either occur-m than the lettihahdawn pridked at the me time the right hand or right cheek were stimulated. The phenamenon could u ' ulna be elieited then the left hand and day other are: or the left side or the body were simultAneeualy etimnleted. Under theee conditions the patient nislocelixed the stimulus to the left bend.inte evade near that hand, or to the object on whieh the mind was lying. For example. it pin pricku were e’imltehemu applied to m right cheek and the 1m; tune, the patient indicated she had been pricked on the right cheek and the are or the chair on Ihich her left bend had been renting; As 1 rule ehe answered by pointing. I: neked to verbelise the ebuld any, “the right cheek end about here,“ (painting to the their emu er into space near be: lett �10. hand). 1! ssksd dirsotiy, “was year hsnd touched,” sh. sauld avoid the gunmen mymzug can; "use," pointing st m um em to tbs 10ft oasis sun at ta spans. It is to be netsd that oxespt undsr the spssisl condition at sinultsnsaus stimulation tbs patient was always sbls to point tu as to ash. hsr‘istt hand on dsssnd. 1r prieksd silnltsnsuusiy an tho dorss or was isrt sud right hands. shs carrots}: localissd only tbs stimulus an tbs right, been by painting sad ststins. “I: right hand.” 2h! stilnlus an the new-y». m 190311104me by painting to m chair s:- and saying, “asrs.* 'It ssksd lasthsr the «hair sun. sud not but 10!: hand use issn toushsd, shs snsssrsd. ”as. hs:s’ pointing to tbs chair an, sun. Inna pin prints ssrs spplisd to tho lsrt hand. sad It the suns «ins, to snethsr sass on the 1st: sids or any baay,s 51-11.: dispisosssus into spsos III status. Ususlly tbs stisulus to tbs lift hand was sislosslissd onto Instsvsr structurs the hsnd sss rusting at else t9 contiguous spsos. tbs uthsr‘stﬂsuius an tbs 10ft sids was ususiiy oarssotly locslissd, though this stimulus too It: onessionsiiy displaced into spans. when this doubis displsosssnt oocurrsd, tho psiisnt.soula stats sh. rsit eve stimuli and staid paint inte space to tbs lots sf tbs ans. stating "bars and have”. !hsss saslosslisstiens ssrs rspsstsdiy ohssrvsa during s period or s.smnth, sad wars not sissys limited to tbs 1st: lids. tbs: ssrs ecossionslly obssrssd to scan: on sh. right sins. At an... c1... localisation on tho lots its slings aorrsot ss indiestsd by pointing and vsrbslisstion. . siioitsd in this pstisnu only the oenditian or Imitiplo smsuitsnsaus sci-ulstian. It scald can-snsz Ixososssthssis was ' under not be sliaitsd by .1331. summon isthmus. mo signifiosnt :- �11. that oxooonoothooid Ill appoxont ovoa though thoro In. no gross diuordor in body ooh... on routine touting. rurthonuoro, it is evident that bar errors in localisation not» not oi-ply on inabiiiiy to point to or identity park: or her body by nine. ll ordinarily the exporidaood no difficulty in doing this on oonldad. In hoth onto. paranoia word nioiooolinod to part. or the body, to abstain. or into npnoe contiguous with tho tron stinulotod. ooouoiondliy. we have nine observed dilpldodnant or a stimulus to the pardon or the can-inor; Usually ouch percent: art nioloodlilcd to o homologous portion of tho cal-inor'o body, 0.3., a otilniud appliod to tho potiont'u hand in reportod by hin.oo if it had been oppiiod to tho tau-inor'o hand. 'narolr, tho nioioodlizntion ll to any part? of the oxaniner'o body.‘ this §ypo or dioplaoonont is illuotmttod in the following on... also 3; 1.1., o 52 your old male, to: aduittod to Boliovuo Payohiltrio Hoopitll with the oonplnint that ha pad hood-o oontuoed and doprooood. for about a yetr ho had boon disoriented, oootnsod on to date dud rolutionohipo of pooyIi, and had uialdred ubout the 01¢: dill-nix. a. and been to um um colony about a mu “ you: beforo, and had uorkod no d harbor until tho rook before his mum“ to the hupiui. mum ' Slowing shouod non-o1 tomnod. lm;gio ﬁxation! leurologiool examination gait and Itation. coordination Scots our. '01: per- lagrrotioxoo wore doiive bilaterally with normal plantar and undo-inol.rolponnoo. Cranial norvo runoiiono ward now-n1. otltuo thouud Ohtnxil, but only by opooidi nothodo or testing. A pnou-oonoophalogrnu dononotrutod nodordtoly dilated ventrioloo "ith°“t '31" 0’ def°flitia Ind ton. dilated cerebral ouloi. 098.1110 mu} Indra. Status I donoory Militia 3 m “. �12. evident. 0n the word he eet quietly for boure by hie bedside taking little interest in hie surroundinge. 'Ihen opproeched by the eterr he eppeered perplexed but one erreble. During the teeting procedures be one cooperative unleee confronted by e teet eitoetion in which the emeniner demanded teeke beyond hie ebility. At theee ti-ee he showed e ”ceteetrophic' reeotion, bece-e excited end diecontinued the exeeinetion. Re wee dieoriented for time. place, end eituetion. However, he nee eble to find hie Hey about the nerd, looeting hie bed, the nnreee deek, the dootore office end the lavatory. severe ditticultiee in intellectual function were obeerved. He nee oneble to give en edeqnete bietcry. ﬁe could not recell the examiner's none nor the evente or several houre before, but did not contehulete. Celculetion end eyebol identification teete were poorly performed. severe epheeic difficultiee were evident. Re nee uneble to none cannon objecte, clothing or moat body perte. He could not colorehend written collende nor could he write, but he wee able to einple verbal cannon. lilo dreorexie nee demonstreted in hie ettenpte to imitate ringer end mouth novenente. nouever, he lee able to drone, feed, end otherwise cere for hinoelt. Bod: gaggeg He bed difficulty both in neling body perte, end in locating the: by pointing. the defect: were Imet eevere in the fingers, wriete end elbows, and ooceeionlly feet. There nee difficulty mm ‘ ' in right-10ft orientetlan. age-or: Statue; (e) giggle Stinuletionx Routine eon-cry etudiee or touch, pin prick and vibration eboeed no ooneietent inpeinlent. Theee �13. correctly looalieed and deaoribed. Oooaaiohally a eihgle stimulue to the hand or toreahn wee dieplaoed to a contiguous object, or to apaee about the upper extremity. (h) Double Simultaneoae stimulation: 0n double aiaultaneoua touch atinolation the patient dieplayed extinction and dieplaoaleht atianli or were ueually tactile etinali. lhie he would trials or the teoemhand teete or other body parte as well. to: on ai-nltaneouely etindlating the cheek end the oppoeite hand either report only the etioulue to the cheek (extinction of text (6), hot example, nae moat evident on nae eeen in the hand etianlua) or would report e etmlulue to eeoh oheek (displacement or the hand stimulus). The pattern or seneory doainanoe wee that oeoally eeen in ditruae cerebral dieeaee, the race being aoet dominant. the hand leaet (5). There nae no lateral doaihanoe. Rho-oaeetheeia; Dieplaoeeent into extra-pereonal apece eaa oceaaionelly ohaerved on single etiaulation. This displaoeaent vae fro- the hand, forearm. or the elbow to apaoe oontiguoue to the part touched. lxoaoaeetheeia was however aarkedly exaggerated when double einultaneoua atuuuuon was employed. Again the am. from which the phenomenon was noet frequently dheerved were the hands. toreeraa and elbovl. tor ext-pie, when etieuli were applied to the dorae or both hande ae they were lying on the patieht'e lap he pointed to epeoe in front of his kneea. It aaked to etate where he had been touched he uould say. "the hande" but would continue to point to the epaoe in front or hie knees. laoeo-eetheeie nae rarely noted when other body parta. euoh ae oheeke or ehouldere were simultaneoualy stimulated. Occasionally it one found that on teete with double allula taneoue atinulation the patient nielooeliued a etihnlue tron hie body to the hoaologoue region or the exeeiner'e body. For inetanoe, when both hand: were oinultaheoualy touched he would grasp the exauiner'e �1%. binds and strin- ho had boon touched “there.” Dsopito tho sxosinor's insiotsnoo thst tho stinnlu: hsd boon to tho outiont'o hoods, tho pstiont would persist in pointing to tho oxouinsr's hands. When asked to noon the ports touched, he would on: 'thsro. thorc." The ﬁll. phonononon Isl occasionally observed on liltltsnoons sti-nlotions or both elbows or ohooko. It was signirioont that this nislooslisotion to tho oxosinor's body occurred oven thou tho potiont urgod to look ot tho otinnlotiono. It III observed that onotionsl tension, inoresoing tho rot. or touting or unduly prolonging the oxasinotion, inorossod tho inoidonoo of oxosolosthosis. ror ext-910, to initisl sppliostion was of pin priok to the right hand and loft chock, tho pstiont reportsd only tho the. psrospt, quitting tho hsnd stimulus. Lstor, ho localised the two othnulino tho ohooks. As tho sxoninotion pro« groslod sad the phyoioion opsodod up the testing. tho patient boot-o sore tohss. no thin looslisod tho toos pore-pt correctly, but innistsd thst the hand otimlntion as into upon. in front at the hand. tinslly both stimuli our. displaced into spooo or to tho oxaninor's body. those phononons wort obsorvod dsily over s period of two and a half unhthl. Coulent: Hhilo single stimulation occasionally produced oxooolnlthosio in this individual, tho phenomenon Ill note pronounced under conditions of double oi-ultonoouo Iti-nlstion. this ntiont sloo lioloooliood stilnli to tho oxsninor's body. lhotionol tonoion, prolonged canninstion, or inorossing tho onto or touting exaggerated the phone-anon or ozosonosthosin. Bisousoion; In oonoidoring thou. ossoo it is illodistoly opporont thst oxooolosthosis is osoooiotod with o savor. orgsnio �sentsl syhdrose. therefore, it night he ersued thst exoscseethesis ‘is sorely e ssniteststiou of the petient's sentsl contusion; thst 15. the petient sisply points into spsce becsuse he is confused. However, we hsve eyesined sssy severely confused pstieuts end found exososesthesis only rarely. moreover, exososestheeie is e petterned phenomenon. desonetrstle in eschvpstieat under defined conditions, predicteble ss to the eree tron which it will occur end the extra» personel spetisl region to which the sensation will be projected. For exemple, in Case I, exoscsssthesie could be elicited only from the head end only when the dorsus use etisuleted st the sese tine es the psls or fingers were in contsct with smother object. Displscesent under these circusstsuoes use ususlly not hephsssrd. sis s rule it occurred to the object touchins.the palm or fingers. In exososesthesis could be elicited only by double silulteneous stteulstion. It see seen most clearly in the head end could be elicited only unileterslly st say one exesinetion. Again the Case 2, displace-eat use not hspheesrd; the stimulus es s rule use locslised to extre-pereonsl speoe contiguous to the eree sctuelly stilulsted. In Cece 3 the phenosenon use observed sgsin under conditions or double sinnltsneous stimulation. end the displsceseuts were either to spece contiguous to the stisnlsted eree, or to honologous srees of the exsliner'e body. It is signifiosnt thst these displscesente could be elicited even when the or the stimuli. pstients to look st the epplicstion the ensuiner pointed out the error were urged noreover, even when in looelisstion end esphssised the i-plsusebility or their response. the pstiente chsrecteristioelly insisted on the correctness of the nislooslistion. rectors Influencing lxososesthesisa There ere esny rectors which influence the sppesrsnce of exoeosesthesis. Except under specisl conditions in children, it �16. has been obeerved exclueively in patiente uith severe mental chensee reeulting true dieeeee or the brein. It ie influenaed by the type of etianlue need. the rate or etiluletion. ee veil an by the elelent of einnlteneity or eti-mli. loreover, the e-otianel etete at the petient nee e eignificent effect the phenuuenon ee doee the pert or the body etinnleted. In ease oeeee exoeaneetheeie nee been nude epperent by edeinietretion at eeell doeee or enoberbitei eodiun. :heee feature will be diecueeed. (e) Bilateral Cerebrel Dieeeee; the emlptae beekground in every eeee or exoealnetheeie ie en arsenic uentel eyndraee eeoondery to bilateral ceretrel dieeeee. we have not been eble to denonetrute exeealeetheeie in en adult unleee there «ere eevere neutel thengee. But,ee previouely noted,it ie e rare phenonenou end only few or the individuele vith eevere arseniereentel eyndruee show it. In boo patiente with arsenic brain dieeeee at verging eeverity, exoeaneetheeie ee- obeerved in ephroxintely as or the one: (5 ). Even in then patiente, it wee not leniteet in every exeeinetion. end it: frequency vee reedily eltered by «bungee in the oonditione of teeting. It ie therefore evident that eevere bileterel oerebrel dieeeee, in iteelr, ie not sufficient to produce exoeoleetheeie. (b) Irrect or Binnlteneaue atiunli: whet einnlteneoue eti-uletion nay elicit eeneory phenaleue not epperent on eingle eti-nletion nee been previouely denonetreted (2). tor exllple, e henieeneorw eyndrtne in e heeiplegia petient he: not be diecernihle except under eonditione or double ei-nlteneuue etinuletion. Tune. single etilnietion may be well perceived end latelieed by the petient. but the eddition at e eecond etinulue einulteneouely applied .1: no effect integration thet the phenomene of extination, obecuretion end diepleaeeent become epperent. on �17. ‘ m ‘sullarly, “alumnus “mutton elicited “comma 1: an aunt an angle annulus umlnulon. or magnum 11: when 'oun 1 n In Manama: mun: and 2. man. stimulation. In ulmltmem «mung» am a menu»: “mum on for aligning the phonon-anon. It could not be amount-um by tingle uttunlatlan. In am 3, ant-tumult could “nationally onum on .112ng stimulation. but annulment “mutton dmmtum ﬂu. inhuman run much water frequency. b0 (a) :12! a! gtggglu! Inst lrtbotgvug or tub vurioua Uzi-”11 and in that Manama. mix as ﬁnal. when. :5.le pin prick, ripotltlvc tauch and rlpctltlvc pin prick. it It: noted that mutt" tmh "man mm was: «1'00th 1!: allowing cucum- thuu. m. m «mull: two on double almlum Itimlltion. (a) gram o: t! "time's an»! momentum-la anal um amt-mud hr 31%.!!qu in th- m: “mum which and» mum“. not. difﬁcult. lama tbs n“ of “hunting, artho unduly prolonging mn~m~ml Imo. tantalum 1mm“ Alta, 11‘ the the Multan-nt- to twin" was deliberately critical or the mtlmt'o 0mm, tho phonmmm appomd with 5mm futon mam-d an. action“ switch at tho Imam”. patient, and 1t amt-d mun-r. prom.“ I "ututmphlo" mctlan. m man of m: It In» boon pmlmly dmtnm that arugula» in pomcpucm my be magnum by mum-ac. (0) nous-mu: team an administered lutnvmmly la 400.30! or 3 to 7 srllnl tn pltlonta Ilth altrus. ctrohwll distant. Prior to am “nutrition. thou patent! mnltum the phone-on. at «amulet: and dllplumt at pump” on ““1”me tutu, but lntuloanta not. (5) . alumnus“. m1 lo under the lntlmmc or the Whitman �18. three pationta ahovad oxoaoneatheaia. in addition to extinction and displacement. In two other patienta. in whoa axoooaootheaia has boon alioited only after a protraoted taating period. the administration or anoharbital aodiua elicited exoaoaeatheaia at the onset or teating and exaggerated the phone-one of extinction and displace-ant. Relation of lxoaoleotheaie to Extinction, Ottonretion and Diaplaoalent: In our experience. whenever exoooaeatheaia haa been observed. phonon-nu of extinction, obeouration and displacement are alao preaent. lxoaoaoathaeia, hou‘var. ia a rare phone-anon, whereae extinction, ohaouration and diaplaoolent are eon-only ohaerved. loreover. ahareaa extinction, otaouration end diaplaoaaont ere treouontly aeon in coult patient: with lilo cerebral dyoronotion (5). diapleoelent into extranperooael opeoe 1a only preaont in oaaaa or severe aental ohangea due to diaeaae ot-the brain. It may therefore he oonoluded that exoeolootheaia in adult: repreaenta a aora severe type or oarebrel dratunotion than other oiaultenaoua m otiaulation phone-one. nalation of Ixoaoleatheaia to gag: logger It night he aeid that exoaoaaatheaia ia a pathologio extenaion or the body image. The normal individual is continually extending the boundariea or thia image. For example, need oitae the eta-plea of tho lolan with a teeter in her hat who “real!" when the feather ie tonohod, and the aurgeon who handlea hia probe as though it were an axtanaion or hia tingera (1). In the normal individual, holever, theae extension. of the body 1-130 art fluid, illediately raveruibla and clearly recognised by the individual aa artificial. the surgeon for example, ia able at any'nolent to redefine correctly hia body Liege. no “known" that the prob. it not his finger. In the group or petionta ’ �19. described above. hosover. the extension of tho body isage scans to operate in a pathologio, rigid tons. under certain conditions these patients lose the ability to ssintain a realistic definition of tho lisits of their body. The: behave as though portions or the contiguous external world are concrsteix incorporated into tho inner image of their body's extent. Although say oonsider exosoaesthesis- a spooiaiiaed body ilage disturbance it should ho noted that patients who do not show we diftionlties in identifioation location of body parts still us: show aisiocaiisstion into estrsapersonsl space. Convorsely, patients with so atolhility to identity or locate their body parts on oosssnd. do not neoessariiy sanirest eaosoassthesis. In similar fashion, thers is no necessary relationship between ascsoaoothsais and position sense difficulties. A patient (Case 3) who manifested displacessnt of sensation into extrs~personai space, did not asks errors in routine tests a: position sense in” tho extresitiee. this it oonsistent sith observations previously ssdc by Head that localiation of single stilnli is not functionally roleted to senss of position or the extrusities (1). non or the land: Although displsoelont into extrs~persona1 space has been elioited tron various areas or the body, it has been observed to ooouh lost frocoentiy tron the hand. loreover. in no ossc hoe it been elicited from another area and been absent tron and 1 the hand. this oredileotion tor the hand is consistent with the ssnncr in shioh other dysfunctions of the nervous system are reflected. As a role when tho functioning of one side of tho body is impaired through cerebral disease the pathology is soot saniast in the hand. �20. lhne 1n the annex heuiplegit reeultina tram e capeulur leeion the pereeie, body image diuturhenoe end eeneory late ere use: pruexnene 1n the hind Ind (insert. In the-e petaente end in other. eleh dzrruee cerebral dieelee the phennlenl a: extinction. eheourltion end diepleoenent Ire elee beet e11¢18ed when the head in teeeed. lurthenlore. etuﬂiee at eh. order at eeneory dullnenee or verioau ereee or the had: Genoa-trite the hand in the lowest hunk. thie in true in the eminence order or petunia with cox-em), dieeue (5). and mm nor-e1 eubjeete, both edulte and children (6). stallerly, then elleetheaie 1: oheerved, 1% 1e eeen she: olenrlr 1n khe head. Bender tad lethnneon (it) deeovihed e «nee 1n ehioh'the clinical courae III reflected in e waxing end unnans alleetheexe. Ae than petient inpraved, the trees from ehseh the phenunmaen oould be elicited amniniehed. ale delohetreble only in the hand. until finally alleethneie In entotopegneeie the hands hre ante proraundly effected thin other regiane. ringer Isnneie. paneibly the enrlieet etsn or body image dieturbenee, 1- trequentlr eeen 1n the eheenae or other groee dieeurbanaee or the bed: eehnne. Furthemeore, phantom 11gb, tnoeosnoeia. cluellsxn and eyneetheeie Ire phenalnne in which the role a: the hand 1e eepectclly praninent. Just an en». ”811010310 puma-em uniteet in tests or other body parte. but 3:. that aleerly delonetrehle 1n the hand. so the. exoealeetheete, though nonunionnlly delanetrnhle eleevhere, layman: apparent in exnlihntion of the function! at an. hand. 14: It hne been observed that luaealeytheele 1n the ham-e1 eeneory pheno-mne which aoeur 1n pettente with cerebral dylrunction m �.1 {{{{{ 21. h any bu fauna in tho annual young child (6). Similarly. have unvor fauna in adult: nxecpt than QSOOGIOIthlltl, thick I. that. in lirkod cornbrnl Ginsu... nun b0 roadily obnorvod in childrcu up to in. ago or tour. In urn-ining a 13:30 302103 of norm. chiidm it u. now that the initial mpm or ohildron to iambic ninnitunooal Itinuiation fruqunatly incinnnd' axoianucthnuia. nithough tho nor. can-an rosponnos In». «xtinctian and dispinou-ont. lionenusthonia was IIrO. havuvor. utter tho initili til trinis. In» truqunaa: with union uaonalusthnain.nnw he noon in children up to tho as. or tour insanity that it an: roprouont. in thy child, 3 ”annual" dovelopnuntai Itsse in on: ergnnisation of perception. It: uppourunan in uduits with novor. brain €110.30 any possibly ha. I. with aunt: pathologio phauulcnu, a rungIIion in function to a pruvioul iovvi at ntnnory integration. aBIIiII; lillooIIilation of tnotil. Itﬂluli into axtrn~poruuna1 space is dcnarihad tad tar-pd alone-cathonii. Bantu-nathnlil 1' aha-trod in pationta with saver. organic unntal lynarunon. It in apnaront only very rural: on tingle tactilu Itilnintion and in not. readily elicitdd by tho t'ahnituo of Gambia lilnltnnsoul atiunlntian. It is exaggcrntod by fatigue, rigid touting ﬁnd incrOIlld unotional tonlian. lurhitnrttc intaxiention also may elicit or uxnggorlto the phauuncnon. Eh. pattoraod linsannathnuin in swat apparnnt in Itinniutian of the hand, but his bOCn obsorVCd in tiatl of othnr body part0. ﬂail. it an: be canaidorod t pathologio axttntian of an. bad: image, it is act dopondcnt upan othcr ¢on¢anitunt body inns. disturbanotl. �nelmthOllt Mu bola observed chltfly 1n gamma nth nun natal chanson, u 1: not a manna» or contusion, but a patterned pnucun- phonmnm. It may be a "mum,“ patient: win: Mum}, animation. to I 93110th “new” was. in smear «alumna, u mated by the rut Although that 1t 1. «mum. "Ian: abut-"d in cinnamon- men. tut: 91‘ mg �1. 2. 1mm, 3.: Studies London, 1920. (a) £3. &1mm in lourolcgy, Vol. II, Oxford Univ. Prom, ammo, Id. lad wanna, Mm: Extinction mu, inILL, humans“. mu.xm1.unzuhut., g2; 717-725 phenomenon member, 19%. m, m. as: Itnuutien (b) r advantage. or the method at unannounthe neurological omimtion. monument: Anal-1c... 11.3.: 12.; 755-458. 1n V was. mm: he pheamnm or union unplacuo‘nt. mm, Awhmmelwr .. u. 9 607-621, lay, 1951. (I) MIR, LB... SWIM), IJ‘. lad gutuiugggo: the body team. W Arcth m ﬂ.gm1.uq¢nug., a 1 m 3.1“: - ind anaemia §£L tea-am. Jeannine” ‘ (b) LB. and “We! 11.: Pattern: in alumni: their unﬁt»: to disorder of ﬁnd: when and other unto” phone-m. 5. vm, I... ﬁlm, I. Ind g5; 501615, October, m and 1950. tun-mm tut mm, Maximum sign or untrue heatnmiymejnmlm, 3!. £6.58, 1952. 6. (I) and mm, In Datum 1n perception I... rm,atII.no. on IMltlmm 0! Ind land. I I 250-»252, June, 1950. aura“) LBJ m, (2:) an , 809mb“, 1951. 0. . . 111.8. mm, I. and 11.: mm, mm, {out or and hand. “autumn no. §§: 355-362. £8 Patterns 11: . ”nation mammobgguglg8%.. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Exosomesthesia; the displacement of cutaneous sensation into extra-personal space. Trans Am Neurol Assoc. 1952; 56 (77th Meeting): 260-2. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-001-6a-008 Date A point or period of time associated with an event in the lifecycle of the resource 1952 Creator An entity primarily responsible for making the resource Shapiro, Mortimer F.; <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Bender, Morris B Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [Preprint] and reprint. Reprint from the A.M.A. Archives of Neurology and Psychiatry, October 1952, Vol. 68, pp. 481-490 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/9cd1485c72c87cfe41a9b822584a53cf.pdf 399d53acd860a7f8f327c824ea2685e0 PDF Text Text Reprinted from the A. M. A. Archives of Neurology and Psychiatry October 1952, Vol. 68, pp. 481-490 Copyright, 1952, by American Medical Association EXOSOMESTHESIA OR DISPLACEMENT OF CUTANEOUS SENSATION INTO EXTRAPERSONAL SPACE MORTIMER F. SHAPIRO, M.D. MAX FINK, MD. AND MORRIS B. BENDER, M.D. NEW YORK phenomena that may be apparent during examination of patients with AMONG disease of the sensory pathways is mislocalization of a sensory stimulus. 'It has long been known that a person with a sensory defect, as seen in the common varieties of cerebral hemiplegia, may inaccurately localize stimuli applied on the paretic side. Such point mislocalizations are apparent in examinations using a single stimulus and have been described in detail by Head.1 These mislocalizations can be accentu— ated by the use of double simultaneous stimulation techniques.2 In addition, when these techniques of examination are employed, other varieties of mislocalization, such as displacement,3 become apparent. Displacement is the patterned mislocalization of one of two stimuli simultaneously applied to diﬁ’erent body areas. The direction of displacement is in a deﬁnite pattern, which is dependent upon the parts of the body stimulated. Characteristic of mislocalization so far reported has been the fact that their extent was within the limits of the patient’s body. In the course of studies. of cutaneous perception, we observed a new form of displacement in which the patient consistently and in a predictable fashion mislocalized stimuli into extrapersonal space. This type of displacement we have termed “exosomesthesia.” 4 Exosomesthesia is not a commonly observed phenomenon. More than 400 patients with brain disease were examined at Psychiatric Pavilion of Bellevue Aided by a Fellowship from the National Foundation for Infantile Paralysis (Dr. Fink). This investigation was supported in part by research grant #MH-139 from the United States Public Health Service, National Institutes of Health. From the Department of Neurology and Psychiatry, New York University College of Medicine, and the Neurological Service of the Mount Sinai Hospital and Bellevue Hospital Center. 1. Head, H.: Studies in Neurology, London, Oxford University Press, 1920, Vol. 2. 2. Bender, M. B.; Shapiro, M. F., and Schappell, A. W.: Extinction Phenomenon in Hemiplegia, Arch. Neurol. & Psychiat. 62:717-724 (Dec.) 1949. Bender, M. B.: The Advantages of the Method of Simultaneous Stimulation in the Neurological Examination, M. Clin. North America 32:755—758 (May) 1948. 3. Bender, M. B.: The Phenomenon of Sensory Displacement, A. M. A. Arch. Neurol. & Psychiat. 65:607—621 (May) 1951. 4. The term was derived by Dr. Judah A. Joﬁe (Hinsie, L. E., and Shatzky, J.: Psychiatric Dictionary, New York, Oxford University Press, 1940) from the Greek 3w, out of ; mind, body, and al’dﬁww, perception by the senses. �2 Hospital Center by routine and specialized sensory tests. Exosomesthesia was observed in only 15 cases, an incidence of about 3%.5 The following case reports illustrate the phenomenon and demonstrate some of the conditions under which it was observed. CASE REPORTS CASE 1.—H. M., a man aged 64, was admitted to the Psychiatric Pavilion of Bellevue Hospital with a history of progressive mental changes of six years’ duration. The ﬁrst four years of illness were marked by slowly progressive impairment of memory, concentration, and other intellectual functions and by increasing apathy to his environment. In the last two years there was rapid exacerbation of this condition, resulting in the loss of his job as a store manager. During this period his speech became increasingly garbled and stammering. He vacillated between irritability and complete apathy. He was occasionally incontinent, ceased bathing, had difficulty in dressing, and was sometimes so forgetful and confused as to wander into the street without his trousers. Routine Neurologic Examination—In walking, the trunk was tilted to the right, and there was a tendency to drag the right lower extremity. However, there was no signiﬁcant motor weakness, reﬂex change, or tonus abnormality. Coordination tests were well performed. The cranial nerve functions were intact. Vibration sense was correctly perceived only in the clavicles and the head, while position sense was lost in the ﬁngers, wrists, toes, and ankles bilaterally. Temperature differences were poorly perceived except in the face area. His responses to touch and pinprick stimulation will be described later. A mild degree of “mixed aphasia” was present. This speech difficulty was evident only by special testing or when the patient was fatigued by prolonged examination. There was a ﬂuctuating dyspraxia of moderate severity. Occasionally he had difficulty in dressing, being unable to handle buttons and sleeves. However, he could perform such functions as feeding himself, combing his hair, and other routine daily tasks. He was usually unable to mimic the more complicated patterns of the hand—praxis tests. An electroencephalogram showed bilateral diffuse abnormality, with decrease in amplitude and intermittent suppression of activity over the parietal regions. A pneumoencephalogram dis— closed bilaterally dilated ventricles and moderate “cortical atrophy,” particularly in the left temporal lobe. PsychiatricStatus—Although the patient was oriented for place and situation, he made errors as to date and time of day. There were defects in recent memory, concentration, calculation, and ability to assume the abstract attitude. He usually sat placidly staring into space or wandered aimlessly about the ward. He did not mix with other patients. When approached by members of the staff, he was friendly and passively cooperative. Testing procedures were approached with cheerful indifference. When, however, he was pushed into test situations greater than his capacity, he reacted with increasing irritability and tension, eventually culminating in a “catastrophic reaction.” At such times he would become red in the face, shout that he knew the answers but did not want to continue, and suddenly begin to weep. Body Schema—He was able to distinguish the right side of his body from the left, but was unable to make this distinction on the examiner’s body. He had no difficulty either in locating midline structures of his body, such as the nose, mouth, chin, umbilicus, and penis, or in pointing to his eyes. With eyes open he readily found both ears; but when his eyes were closed he groped about his face for several seconds before locating them. He could point to his thighs, knees, ankles, and toes but could not point to any speciﬁc toe other than the big toe. He frequently had difﬁculty in locating portions of his upper extremities. If asked to point to his shoulders, he correctly located one shoulder but then groped behind his neck looking for the other. This defect was even more noticeable in trying to ﬁnd the “other” elbow and wrist, and greatest in trying to ﬁnd the “other” hand. His search for the “other” hand or wrist was bizarre. He would look under the pillow or rummage under the mattress, becoming tense and ' Fink, M.; Green, M., and Bender, M. B.: The Face-Hand Test as a Diagnostic Sign of Organic Mental Syndrome, Neurology 2:46—58 (Jan-Feb.) 1952. 5. �3 insisting it was lost. It should be emphasized that, despite the great difﬁculty in locating parts of his body, the patient was able to name the body parts, except the ﬁngers and toes. This was true whether the part pointed to was on the patient’s or on the examiner’s body. Sensory Stanton—(w) Single Stimulation: He had difﬁculty in differentiating between the sharp and the dull end of a pin. This defect was present throughout the body, although he made signiﬁcantly fewer errors in the face and hands. Touch stimulation was poorly perceived. Usually he could not state whether or not he had been touched. Again, there seemed to be relatively better preservation of this modality in the hands and face. Except under special conditions of examination of the hands, to be described later, the patient was able to locate the site of a pinprick by pointing. However, if the pin was repetitively and rapidly applied to one region, or if the prick was steadily maintained at that one place, he could not locate the point of stimulation. He would make frantic, random searching movements over his body, and not infrequently around the bedclothes, grimacing as though in pain and exclaiming that he was trying to- remove the pin. If asked where he was being pricked, he disregarded the question and continued to try to remove the stimulus. This phenomenon occurred on stimulation of any portion of the body but was most apparent when the hand was tested. (17) Double Simultaneous Stimulation: The phenomena of extinction and displacement were frequently observed in tests of different body areas by simultaneous tactile stimulation. On stimulation of the face and hand, stimuli to the hand were not perceived or were mislocalized to the cheek. In tests of homologous body areas (as hand-hand) extinction of one percept was common. The side on which the stimulus was not perceived ﬂuctuated, so that at one moment only a right—sided stimulus was perceived and a few moments later only a left-sided stimulus was perceived. Exosomesthesia.——Whenever his palm was in contact with a portion of his body or any other object, and the dorsum of that hand was pricked with a pin, the patient consistently mislocalized the stimulus. This mislocalization was to whatever object the palmar surface of the hand was touching. For example, if the patient’s hand was resting on his thigh and the dorsum of the hand was pricked, he insisted that the thigh had been touched, and not the hand. This mislocalization —exosomesthesia—occurred to the thigh, abdomen, leg, or face and was present with stimuli to either hand. It was observed even when the patient was urged to look at the hand during the application of the pin. Exosomesthesia could not be elicited, however, by stimulation of the palm or palmar surface of the ﬁngers when the dorsum of the hand was resting on a portion of the body. Furthermore, localization of stimuli to the dorsum of the hand was correct if the hand was held in space. Mislocalization also occurred to objects external to his body. If his palm was resting on a table or on his bed, and the dorsum of the hand was pricked with a pin, he would point to these objects and state that the pin had been applied “there.” When questioned, he stated that the hand had been touched but continued to point to the bed or table. Frequently, however, he insisted that it was the bed or table that had been touched, and not his hand. If asked how he could feel the bed being pricked with a pin, he would become tense, avoid the question, and insist, “You touched the bed, not me.” Displacement into extrapersonal space was not eliminated by simultaneous stimulation, even when extinction of one of the percepts occurred. For example, if pins were simultaneously applied to the dorsa of the hands while the palms were resting on a table, he would report feeling only one pinprick, that on the left (or right, as dominance ﬂuctuated) and point to the place where the left hand had been resting, saying. “You touched the bed there.” This phenomenon of displacement into extrapersonal space occurred daily during a period of more than two months. Comment—In this patient a requisite to displacement into space was that the palm of the hand be in contact with an external object. In other words, there were two cutaneous stimuli simultaneously in operation, namely, the pinprick on the dorsum of the hand and the pressure of the object in contact with the palm or ﬁngers. A single stimulus, such as pricking the dorsum of a hand held in space, did not elicit the displacement. �4 Exosomesthesia was elicited only on stimulating the hands. This occurred even though single pinprick was perceived more sharply in the hands than in any other area except the face. Although this patient showed inability to locate correctly parts of his own and the examiner’s body, it does not necessarily mean that exosomesthesia is determined by this particular type of disorder in body scheme. The following case illustrates the phenomenon of exosomesthesia in the presence of the patient’s ability to locate body parts. CASE 2.-—E. K., a woman aged 52, was admitted to the neurologic service of the Mount Sinai Hospital in August, 1950, with a history of grand mal seizures. She had been in good health until 1947, when there appeared sporadic, momentary sensations of “blacking out.” About two years before admission she began to suffer monthly grand mal seizures. There was no aura. Routine examination on admission showed that her status was within normal limits except for anosmia in the right nostril. There was no organic mental syndrome. X—ray studies revealed evidence of a subfrontal neoplasm. On August 12 a craniotomy was done, and after amputation of a portion of the right frontal lobe, a large bilateral subfrontal meningioma was excised. Her postoperative course was stormy. For two weeks she was semistuporous. She responded only to massive, painful stimulation, and these responses were limited to vague, ineffective attempts to push away the stimulus. In this period she lapsed several times into coma and showed Cheyne—Stokes respiration. The Babinski response was obtained bilaterally. Her pupils did not react to light. From about Aug. 23, 1950, the patient improved slowly and steadily. She began to respond verbally, and contact could be maintained for short periods. Vision, which had apparently been absent, began to return, although right homonymous hemianopsia remained for some time. A marked organic mental syndrome characterized by confusion, disorientation, and anosognosia, was present. Routine Neurologic Examination—Neurologic examination in September, 1950, disclosed right homonymous hemianopsia, severe impairment of visual acuity with bilateral secondary optic nerve atrophy, nystagmus in all directions of gaze, a bilateral Babinski sign, and a mild degree of aphasia. Position sense, vibration sense, and temperature perception were unimpaired. There were diﬂiculties in perception of touch and pinprick stimuli, as described below. Psychiatric Statue—The patient was usually friendly and cooperative. However, she was frequently irritable and would not permit examination. She was disoriented as to time and occasionally to situation, but not to place. There were defects in retention and recall, covered by confabulation. She was euphoric and displayed little self-restraint or concern in social situations. Usually she would lie with her body fully exposed. Not infrequently she ,soiled herself or wet the bed. Anosognosia was prominent. Body Schema—On command, the patient was able to identify and locate correctly parts of her own and the examiner’s body, such as the ears, eyes, feet, and parts of the upper extremities. She exhibited some confusion about the right and the left side of the body. Sensory Status.—(a) Single Stimulation: The patient perceived single pinprick stimuli well, although she made occasional nonpatterned errors in localization. These errors were more frequent on the left side. (b) Double Simultaneous Stimulation: On simultaneous application of pinprick to the two sides of the body, except the hands, extinction on the left or displacement on the left toward the level of the right-sided stimulus was the usual response. Homolateral simultaneous stimulation on the right side of the-body showed no extinction, but stimulation on the left side elicited frequent extinction and displacement. Exosomesthesia.——Displacement into extrapersonal space occurred when the left hand was pricked at the same time that either the right hand or the right cheek was stimulated. The phenomenon could also be elicited when the left hand and any other area of the left side of the body were simultaneously stimulated. Under these conditions the patient mislocalized the stimulus to the left hand into space near that hand, or to the object on which the hand was lying. For example, if pinpricks were �5 simultaneously applied to the right cheek and the left hand, the patient indicated she had been pricked on the right cheek and the arm of the chair on which her left hand had been resting. As a rule she answered by pointing. If asked to verbalize, she would say, “The right cheek and about here,” (pointing to the chair arm or into space near her left hand). If asked directly. “Was your hand touched?” she would avoid the question, responding only, “Here,” pointing at the same time to the left chair arm or into space. It is to be noted that, except under the special condition of simultaneous stimulation, the patient was always able to point to or to name her left hand on demand. If pricked simultaneously on the dorsa of the left and right hands, she correctly localized only the stimulus on the right, both by pointing and by stating, “My right hand.” The stimulus on the left, however, was localized only by pointing to the chair arm and saying, “Here.” If asked whether the chair arm and not her left hand, had been touched, she answered, “No, here,” pointing to the chair arm. When pinpricks were applied to the left hand and, at the same time, to another area on the left side of the body, a similar displacement into space was evident. Usually the stimulus to the left hand was mislocalized onto whatever structure the hand was resting or else into contiguous space. The other stimulus on the left side was usually correctly localized, though this stimulus, too, was occasionally displaced into space. When this double displacement occurred, the patient would state that she felt two stimuli and would point into space to the left of the arm, stating, “Here and here.” These mislocalizations were repeatedly observed during a period of a month and were not always limited to the left side. They were occasionally observed to occur on the right side. At these times localization on the left was always correct, as indicated by pointing and by verbalization. C 0mment.——Exosomesthesia was elicited in this patient only under the condition of multiple simultaneous stimulation. It could not be elicited by single—stimulation methods. Also signiﬁcant is the fact that exosomesthesia was apparent even though there was no gross disorder in body scheme on routine testing. Furthermore, it is evident that her errors in localization were not simply inability to point to or identify parts of her body by name, as ordinarily she experienced no difﬁculty in doing this on command. Both patients mislocalized percepts to parts of the body, to objects, or into space contiguous with the area stimulated. Occasionally, we have also observed displacement of a stimulus to the person of the examiner. Usually such percepts are mislocalized to a homologous portion of the examiner’s body; e. g., a stimulus applied to the patient’s hand is reported by him as though it had been applied to the examiner’s hand. Rarely, the mislocalization is to any part of the examiner’s body. This type of displacement is illustrated in the following case. CASE 3.—R. M., a man aged 52, was admitted to the Psychiatric Pavilion of Bellevue Hospital with the complaint that he had become confused and depressed. For about a year he had been disoriented and confused as to date and his relationship to people and had wandered about the city aimlessly. He had been admitted to the Farm Colony about a half-year before and had worked as a barber until the week before his admission to the hospital. Routine N euro'logic Examination—Neurologic examination showed normal gait and station. Coordination tests were well performed. The reﬂexes were active bilaterally, with normal plantar and abdominal responses. Cranial nerve functions were normal. The sensory status showed changes, but only with special methods of testing. A pneumoencephalogram demonstrated moderately dilated ventricles, without shift or deformity, and some dilated cerebral sulci. Psychiatric StaWs.——-A severe organic mental syndrome was evident. In the ward he sat quietly for hours by his bedside, taking little interest in his surroundings. When approached by members of the staff, he appeared perplexed but was affable. During the testing procedures he was cooperative unless confronted by a test situation in which the examiner demanded tasks �6 , beyond his ability. At such times he showed a “catastrophic” reaction, became excited, and discontinued his efforts in the examination. He was disoriented for time, place, and situation. However, he was able to ﬁnd his‘way about the ward, locating his bed, the nurses’ desk, the doctor’s ofﬁce, and the lavatory. Severe difﬁculties in intellectual function were observed. He was unable to give an adequate history. He could not recall the examiner’s name or the events of several hours before but did not confabulate. Calculation and symbol-identiﬁcation tests were poorly performed. Severe aphasic difﬁculties were evident. He was unable to name common objects, clothing, or most parts of the body. He could not comprehend written commands, nor could he write, but he was able 'to follow simple verbal commands. Mild dyspraxia was demonstrated in his attempts to imitate ﬁnger and mouth movements. However, he was able to dress, feed, and otherwise care for himself. Body Image.——He had difﬁculty both in naming body parts and in locating them by pointing. The defects were severest in the ﬁngers, wrists, and elbows, and occasionally the feet. There was difﬁculty in right-left orientation. Sensory Statute—(a) Single Stimulation: Routine sensory studies of touch, pinprick, and vibration stimuli showed no consistent impairment. These stimuli were usually correctly localized and described. Occasionally a single stimulus to the hand or forearm was displaced to a contiguous object or to space about the upper extremity. (b) Double Simultaneous Stimulation: On double simultaneous [touch] stimulation the patient displayed extinction and displacement of tactile stimuli. This was most evident in trials of the face-hand test 6 but was seen in tests of other body parts as well. For example, on simultaneous stimulation of the cheek and the opposite hand, he would either report only the stimulus to the cheek (extinction of the hand stimulus) or report a stimulus to each cheek (displacement of the hand stimulus). The pattern of sensory dominance was that usually seen in diffuse cerebral disease, the face being most dominant, the hand least.5 There was no lateral dominance. ,Exosoimestheyiat—Displacement into extrapersonal space was occasionally observed on single stimulation. This displacement was from the hand, forearm, or elbow to space contiguous to the part touched. Exosomesthesia was, however, markedly exaggerated when double simultaneous stimulation was employed. Again, the areas from which the phenomenon was most frequently'observed were the hands, forearms, and elbows. For example, when stimuli were applied to the dorsa of the hands as they were lying on the patient’s lap, he pointed to space in front of his knees. If asked to state where he had been touched, he would say, “The hands,” but would continue to point to the space in front of his knees. Exosomesthesia was rarely noted when other body parts, such as the cheeks or shoulders, were simultaneously stimulated. Occasionally it was found that on tests with double simultaneous stimulation the patient mislocalized a stimulus from his body to the homologous region of the examiner’s body. For instance, when the hands were simultaneously touched, he would grasp the examiner’s hands and affirm he had been touched “there.” Despite the examiner’s insistence that the stimulus had been to the patient’s hands, the patient would persist in pointing to the examiner’s hands. When asked to name the parts touched, he would say “There, there.” The same phenomenon was occasionally observed on simultaneous stimulation of the two elbows or cheeks. It was signiﬁcant that this mislocalization to the examiner’s body occurred even when the patient was urged to look at the stimulations. It was observed that emotional tension, increase in the rate of testing or undue prolongation of the examination increased the incidence of exosomesthesia. For example, to initial application of pinprick to the right hand and the left cheek, the patient reported only the face percept, omitting the hand stimulus. Later, he localized the two stimuli to the cheeks. As the examination progressed and the physician speeded up the testing, the patient became tenser. He then localized the face percept correctly but insisted that the hand stimulation was into space in front of the hand. Finally, both stimuli were displaced into space or to the examiner’s body. These phenomena were observed daily over a period of 2% months. Bender, M. B.; Fink, M., and Green, M.: Patterns in Perception on Simultaneous Tests of Face and Hand, Tr. Am. Neurol. A. 75:250-252 (June) 1950; Patterns in Perception On Simultaneous Tests of Face and Hand, A. M. A. Arch. Neurol. & Psychiat. 66:35-5-262 6. (Sept) 1951. ' - - �7 Comment—While single stimulation occasionally produced exosomesthesia in this patient, the phenomenon was more pronounced under conditions of double simultaneous stimulation. This patient also mislocalized stimuli to the examiner’s body. Emotional tension, prolonged examination, or increase in the rate of testing. exaggerated the phenomenon of exosomesthesia. GENERAL COM MENT On consideration of these cases, it is immediately apparent that exosomesthesia is associated with a severe organic mental syndrome. Therefore, it might be argued that exosomesthesia is merely a manifestation of the patient’s mental confusion; that the patient simply points into space because he is confused. However, we have examined many severely confused patients and found exosomesthesia only rarely. Moreover, exosomesthesia is a patterned phenomenon, demonstrable in each patient under deﬁned conditions, predictable as to the area from which it will occur and the extrapersonal spatial region to which the sensation will be projected. For example, in Case 1 exosomesthesia could be elicited only from the hand, and only when the dorsum was stimulated at the same time that the palm or ﬁngers were in contact with another object. Displacement under these circumstances was usually not haphazard. As a rule it occurred to the object touching the palm or ﬁngers. In Case 2 exosomesthesia could be elicited only by double simultaneous stimulation. It was seen most clearly in the hand and could be elicited only unilaterally at any oneexamination. Again, the displacement was not haphazard; the stimulus as a rule was localized to extrapersonal space contiguous to the area actually stimulated. In Case 3 the phenomenon was observed again under conditions of double simultaneous stimulation, and the displacements were either to space contiguous to the stimulated area or to homologous areas of the examiner’s body. It is signiﬁcant that these displacements could be elicited even when the patient was urged to look at the application of the stimuli. Moreover, even when the examiner pointed out the error in localization and emphasized the implausibility of the response, the patient characteristically insisted on the correctness of the mislocalization. Factors Inﬂuencing Exosomesthesia.—Many factors inﬂuence the appearance of exosomesthesia. Except in children under special conditions, it has been observed exclusively in patients with severe mental changes resulting from disease of the brain. It is inﬂuenced by the type of stimulus used and the rate of stimulation, as well as by the element of simultaneity of stimuli. Moreover, the emotional state of the patient has a signiﬁcant effect on the phenomenon, as does the part of the body stimulated. In some cases exosomesthesia has been made apparent by administration of small doses of amobarbital sodium. These factors will be discussed. (a) Bilateral Cerebral Disease: The symptom background in everycase of exosomesthesia is an organic mental syndrome secondary to bilateral cerebral disease. We have not been able to demonstrate exosomesthesia in an adult unless there were severe mental changes. But, as previously noted, it is a rare phenomenon, and only a few patients with severe organic mental syndrome show it. In 400 patients with organic cerebral disease, of varying severity, exosomesthesia was observed in approximately 3%.5 Even in these patients it was not manifest in every examination, and its frequency was readily altered by changes in the conditions of testing. It is therefore evident that severe bilateral cerebral disease in itself is not sufﬁcient to produce exosomesthesia. �8 Effect of Simultaneous Stimuli: That simultaneous stimulation may elicit sensory phenomena not apparent on single stimulation has previously been demonstrated.2 For example, a hemisensory syndrome in a hemiplegic patient may not be discernible except under conditions of double simultaneous stimulation. Thus, single stimulation may be well perceived and localized by the patient, but the addition of a second stimulus simultaneously applied may so affect integration that the phenomena of extinction, obscuration, and displacement become apparent. Similarly, simultaneous stimulation elicited exosomesthesia when it was absent on single-stimulus examination, or exaggerated it when it was occasionally manifest on routine stimulation. In Cases 1 and 2 simultaneous stimulation was a necessary condition for eliciting the phenomenon. It could not be demonstrated by single stimulation. In Case 3 exosomesthesia could occasionally be elicited on single stimulation, but with simultaneous stimulation the phenomenon was demonstrated with much greater frequency. (6) Type of Stimulus Most Effective: Of the various stimuli used in these examinations, such as single touch, single pinprick, repetitive touch, and repetitive pinprick, it was noted that repetitive touch stimuli were most effective in eliciting nexosomesthesia. This was especially true on double simultaneous stimulation. (d) Effect of the Patient’s Emotional State: Exosomesthesia was exaggerated by alterations in the test situation which made performances more difﬁcult. Increasing the rate of stimulation or unduly prolonging the examination increased the displacements to extrapersonal space. If the examiner was deliberately critical of the patient’s errors, the phenomenon also appeared with greater frequency. These factors increased the emotional tension of the patient and if carried further produced a “catastrophic” reaction. (e) Effect of Drugs: It has previously been demonstrated that difﬁculties in perception may be exaggerated by barbiturate intoxicants.5 Amobarbital sodium was administered intravenously in doses of 3 to 7 grains (0.2 to 0.45 gm.) to patients with diffuse cerebral disease. Prior to administration of the drug, these patients manifested the phenomena of extinction and displacement of percepts on simultaneous tests, but not exosomesthesia. While under the inﬂuence of the barbiturate;'three patients showed exosomesthesia, in addition to extinction and displacement. In two other patients, in whom exosomesthesia had been elicited only after a protracted testing period, the administration of amobarbital sodium elicited exosomesthesia at the onset of testing and exaggerated the phenomena of extinction and displacement. Relation of Exosomest‘hesia to Extinction, Obscumtvian, and Displacement—In our experience, whenever exosomesthesia has been observed, the phenomena of extinction, obscuration, and displacement are also present. Exosomesthesia, however, is a rare phenomenon, whereas extinction, obscuration, and displacement are commonly observed. Moreover, whereas extinction, obscuration, and displacement are frequently seen in adult patients with mild cerebral dysfunction,5 displacement into extrapersonal space is present only in cases of severe mental changes due to disease of the brain. It may therefore be concluded that exosomesthesia in adults represents a severer type of cerebral dysfunction than other simultaneous stimulation phenomena. (13) �9 Relation of Exosomesthle'sia to- Body I wage—It might be said that exosomesthesia is a pathologic extension of the body image. The normal person is continually of cites the Head of examples For this boundaries example, the image. extending the woman with a feather in her hat who “feels” when the feather is touched, and the surgeon who handles his probe as though it were an extension of his ﬁngers.1 In the normal person, however, these extensions of the body image are ﬂuid, immediately reversible, and clearly recognized by the subject as artiﬁcial. The surgeon, for example, is able at any moment to redeﬁne correctly his body image. He “knows” that the probe is not his ﬁnger. In the group of patients described above, however, the extension of the body image seems to operate in a pathologic, rigid form. Under certain conditions these patients lose the ability to maintain a realistic deﬁnition of the limits of their body. They behave as though portions of the contiguous external world are concretely incorporated into the inner image of their body’s extent. Although we may consider exosomestheisa as a specialized body-image disturbin identiﬁcation difﬁculties show do who be not that noted should it patients ance, and location of body parts still may show mislocalization into extrapersonal space. On the other hand, patients with an inability to identify or locate their body parts on command do not necessarily manifest exosomesthesia. In similar fashion, there is no necessary relationship between exosomesthesia and of manifested who dis-placement A difﬁculties. 3) (Case patient position-sense sensation into extrapersonal space did not make errors in routine tests of position made by observations with is consistent previously This in extremities. the sense Head1 that localization of single stimuli is not functionally related to sense of position of the extremities. Role of the Hand—Although displacement into extrapersonal space has been elicited from various areas of the body, it has been observed to occur most frequently from the hand. Moreover, in no case has it been elicited from another area and been absent from the hand. This predilection for the hand is consistent with the manner in which other the when As functioning reﬂected. rule, of a the are nervous system dysfunctions of one side of the body is impaired through cerebral disease, the disorder is most manifest in the hand. Thus, in the usual hemiplegia resulting from a capsular lesion the paresis, body-image disturbance, and sensory loss are most prominent in the hand and ﬁngers. of the cerebral diffuse disease, with phenomena in others and these In patients, extinction, obscuration, and displacement are also best elicited when the hand is tested. Furthermore, studies of the order of sensory dominance of various areas of the body demonstrate that the hand is in the lowest rank. This is true of the dominance order of patients with cerebral disease,5 and also of normal subjects, both adults and children.6 Similarly, when allesthesia is observed, it is seen most clearly in the hand. Ben7 described a case in which the clinical course was reﬂected in a Nathanson and der Bender, M. B., and Nathanson, M.: Patterns in Allesthesia and Their Relation to Disorder of Body Scheme and Other Sensory Phenomena, Arch. Neurol. & Psychiat. 64:501-515 7. (Oct) 1950. �10 waxing and waning allesthesia. As this patient improved, the areas from which the phenomenon could be elicited diminished, until ﬁnally allesthesia was demonstrable only in the hand. In autotopagnosia the hands are more profoundly affected than other regions. Finger agnosia, possibly the earliest sign of body-image disturbance, is frequently seen in the absence of other gross disturbances of the body schema. Furthermore, phantom limb, anosognosia, causalgia, and synesthesia are phenomena in which the role of the hand is especially prominent. Just as these pathologic phenomena are manifest in tests of other body parts, but are most clearly demonstrable in the hand, so, too, exosomesthesia, though occasion— ally demonstrable elsewhere, is most apparent in examination of the functions of the hand. Exosomesthesia in the Normal Child.—-It has been observed that sensory phenomena which occur in patients with cerebral dysfunction may be found in the nor— mal young child.6 Similarly, exosomesthesia, which we have never found in adults except when there is severe cerebral disease, can be readily observed in children up to the age of 4 years. In examination of a large series of normal children it was noted that the initial responses of children to double simultaneous stimulation frequently included exosomesthesia, although the commoner responses were extinction and displacement. Exosomesthesia was rare, however, after the initial few trials. The frequency with which exosomesthesia may be seen in children up to the age of 4 years suggests that it may represent, in the child, a “normal” developmental stage in the organization of perception. Its appearance in adults with severe brain disease may possibly be, as with other pathologic phenomena, a regression in function to a previous level of sensory integration. SUMMARY The patterned mislocalization of tactile stimuli into extrapersonal space is described and termed exosomesthesia. Exosomesthesia is observed in patients with severe organic mental syndromes. It is apparent only rarely on single tactile stimulation and is more readily elicited by the technique of double simultaneous stimulation. It is exaggerated by fatigue, rapid testing, and increased emotional tension. Barbiturate intoxication also may elicit or exaggerate the phenomenon. Exosomesthesia is most apparent in stimulation of the hand but has been observed in tests of other body parts. While it may be considered a pathologic extension of the body image, it is not dependent upon concomitant body-image disturbances. Although exosomesthesia has been observed chieﬂy in patients with severe mental changes, it is not a manifestation of confusion, but is a patterned, predictable phenomenon. It may be a regression, in patients with cerebral dysfunction, to a previously “normal” stage in sensory development, as suggested by the fact that it is readily observed in simultaneous tactile tests of young children. , Printed and Published in the United States of America � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Exosomesthesia; the displacement of cutaneous sensation into extra-personal space. Trans Am Neurol Assoc. 1952;56 (77th Meeting):260-2. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-001-6b-009 Date A point or period of time associated with an event in the lifecycle of the resource 1952 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprinted from the A.M.A. Archives of Neurology and Psychiatry, October 1952, Vol. 68, pp. 481-490 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/2f72d717289d05cb684207e823cb7f30.pdf 566433f2c3abf4221015fe305a951903 PDF Text Text Psychopharmacology erVicc Center ulletin N IMH-Sponsored Collaborative Study of Phenothiazine Treatment of Acute Schizophrenic Psychoses, p. 1 January 1961 NIMH Grant Support for Early Clinical Drug Evaluation Units, p. 3 NIMH—PSC Outpatient Study of Drug-Set Interaction, p. 4 Research Conference on Drugs and Community Care, p. 7 Conference on Information Needs of Psychopharmacologists, p. 13 The Psychopharmacology Research Unit at the Downstate Medical Center, Brooklyn, N.Y., p. 15 Experimental Psychiatric Programs at Hillside Hospital, ' p. 18 Coca-Leaf Chewing in the Andes, p. 22 Publications, p. 25 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE - Public Health Service �Inquiries about the Psychopharmacology Service Center’s program are invited. Please write to: Dr. Jonathan 0. Cole Chief, Psychopharmacology Service Center National Institute of Mental Health Bethesda 14, Md. Correspondence regarding the Psychopharmacology Service Center Bulletin should be sent to: Dr. Lorraine Bouthilet Head, Scientiﬁc Information Unit Psychopharmacology Service Center National Institute of Mental Health Bethesda 14-, Md. The Psychopharmacology Service Center Bulletin is distributed at irregular intervals by the Psychopharmacology Service Center, National Institute of Mental Health, Bethesda l4, Md. It is issued for information purposes to investigators interested in psychopharmacology. It is requested that the Bulletin not be considered part of the scientiﬁc literature, and not be cited, abstracted, or reprinted. �NIMH-Spemered Collaborative Study of P/eemtbz'drz'ne Treatment of Acute Se/ez'gopbrem'e Pylcboyef The National Institute of Mental Health, through its Psychopharmacology Service Center, is sponsoring a collaborative study of phenothiazine treatment of acute schizophrenic psychoses. The comparative efﬁcacy of thioridazine (Mellaril) , fluphenazine (Permitil, Prolixin), and chlorpromazine (Thorazine) in the treatment of a large group of hospitalized acute schizophrenic patients will be evaluated at nine psychiatric institutions. Investigators at the collaborating hospitals applied for, and have now received, N IMH research grants which will support their participation in the study, which is expected to begin in February 1961 and to continue for 2 years. The grants were awarded to the following investigators and institutions on the basis of their interest and research experience, the availability of patients, and the geographical location and type of hospital organization: Principal Investigators Edwin M. Davidson Melvin M. Kayce Institutions Boston State Hospital Dorchester, Mass. Richard Steinbach Bernard Levy Georgetown University and D.C. General Hospital, Washington, D.C. Robert R. Knowles Edgar A. Moles Kentucky State Hospital, Danville, Ky. Kathleen Smith Washington University and Malcolm Bliss Mental Health Center, St. Louis, Mo. James H. Ewing Harold H. Morris University of Pennsylvania and Mercy-Douglass Hospital, Philadelphia, Pa. Frederic F. Flach Charles I. Celian Cornell University and Payne Whitney Clinic, New York, N.Y. Guy M. Walters Christopher F. Terrence Rochester State Hospital, Rochester, N.Y. Springﬁeld State Hospital, SykesVille, Md. George A. Ulett Martin Gross Irene L. Hitchman John Donnelly Francis J. Braceland Bernard C. Glueck, Jr. The Institute of Living, Hartford, Conn. The study is under the overall supervision of Jonathan O. Cole, Chief of the Psychopharmacology Service Center. Gerald L. Klerrnan, PSC Research Psychiatrist, *Prepared by Gerald L. Klerman, Research Psychiatrist, Psychopharmacology Service Center, National Institute of Mental Health, Bethesda l4, Md. will serve as project coordinator. Other members of the PSC staff who are involved in the study are Eva Y. Deykin, Research Social Worker, Martin M. Katz, Research Psychologist, and C. Jelleﬂ' Carr, Chief of PSC’s Pharmacology Unit. The Planning Committee, composed of the principal investigators in the collaborating hospitals and the participating members of the PSC staff, provides for the coordination and execution of the speciﬁc projects. Because of the parallels with the Veterans Administration Cooperative Studies of Chemotherapy in Psychiatry, the committee maintains close liaison with the VA Central Neuro-Psychiatric Research Laboratory at Perry Point, Md. The Committee on Clinical Psychopharmacology, a group of outside consultants appointed by the NIMH, serves as the advisory and consultative body to NIMH on this project, as Well as on other aspects of the Center’s clinical program. Members of this committee are Henry Brill (Chairman), Deputy Commissioner of the New York Department of Mental Hygiene, Albany, N .Y. ; Sol L. Garﬁeld, Professor of Medical Psychology, Nebraska Psychiatric Institute, Omaha, Nebr. ; Goldine Gleser, Associate Professor of Psychology, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio; Leo E. Hollister, Chief, Medical Service, Veterans Administration Hospital, Palo Alto, Calif.; and George D. Ulett, Associate Professor, Department of Psychiatry, Washington University Medical School, St. Louis. Mo. DEVELOPMENT AND DESIGN OF THE STUDY The Committee on Clinical Psychopharmacology and the PSC staﬂ' designed this research project during the spring of 1960. Following general approval by the National Advisory Mental Health Council of the principles of the study, the Center staff discussed it with a number of clinical investigators who had previously expressed interest in such a project. In June 1960, representatives from more than a dozen institutions met to plan and clarify the research methods and aims of the study. A number of the investigators who attended the meeting subsequently submitted applications for an NIMH research grant to support their participation in the study. Thus the ﬁnal design and methodology of the study resulted from the combined efforts of the Committee on Clinical Psychopharmacology, members of the PSC staff, 1 �In psychiatry, cooperative research has been slower to and the principal investigators. The staff of the Biometric Laboratory of George Washington University, which operates under contract to the NIMH, will provide ongoing consultation on matters of research design and statistical techniques and will analyze the data from the study. The primary aim of the project is to evaluate the effects of two new phenothiazine derivatives, thioridazine (Mellaril) and ﬂuphenazine (Permitil, Prolixin) on schizophrenic symptoms and behavior by comparing them with the effects of chlorpromazine (Thorazine). Each of the 9 hospitals will study 40 patients (10 in each of the 4 treatment groups) . Newly admitted schizophrenic if the for selected will be 16 study 40 to aged patients they present two or more of the following types of symptoms or behavior: Thinking and speech disturbances, catatonic motor behavior, paranoid ideation, hallucinations, delusional thinking, disturbed affect and emotion, and disturbances of social behavior and interpersonal relations. The patients will be on the prescribed research treatment regimen for 6 weeks. A double-blind procedure will be used throughout. Improvement during the hospitalization phase will be assessed by the Lorr Inpatient Multidimensional Psychiatric Scale, the Burdock Ward Behavior Rating Scale, the Clyde Mood Scale, and clinical judgments. In addition to the primary aim, evaluating the efﬁcacy of the drugs, the study will also allow for the followup of 2 least for of at cohort patients schizophrenic a large made will be assessments 6-month At intervals, years. of the patients’ discharge status, psychopathology, social performance and adjustment, and treatment program. Social workers will interview family members for their perceptions of the patients’ progress, home conditions, and attitudes toward treatment. COLLABORATIVE AND COOPERATIVE RESEARCH Since World War II, collaborative and cooperative research, in which a number of institutions follow a common research design, has been successful in many areas of medicine. The trials of antimalarial drugs during World War II, the extensive studies of antituberculous drugs now in their 17th year, and the British-United States research on cortisone and aspirin in acute rheumatic fever are some examples. NIH experience with cooperative research includes the current extensive cancer chemotherapy program of the National Cancer Institute and the Collaborative Study of Cerebral Palsy, Mental Retardation, and Other Neurological and Sensory Disorders of Infancy and Childhood being conducted by the National Institute of Neurological Diseases and Blindness. 2 _ in of studies extensive penicillin the although develop, CNS syphilis during the 1940’s stands out as a notable AdministraVeterans the effort. In recent early years tion has developed its Cooperative Studies of Chemodemonhave studies VA now The in Psychiatry. therapy strated the value of cooperative studies as a means of clarifying important issues in psychopharmacology. From the scientiﬁc point of view, there are two major reasons for collaborative studies of psychiatric drug therapy. First, such studies allow one to increase the generalizability of ﬁndings. If the only question being asked is whether drug X is better than placebo, then the 40 of 20 with to obtained be often pagroups answer can tients. However, much larger groups of patients are discriminareﬁned make wishes to if (a) one necessary tions between compounds which are closely related chemically and pharmacologically, such as the phenothiazines; (b) to increase knowledge of predictors of drug response; whom for of a the patients deﬁne speciﬁc types to (c) or particular drug is best suited. Multihospital studies allow for comparisons among institutions. In the mental health ﬁeld there has been much discussion of the possible differences in the effectiveness of drugs given in varying hospital and clinical settings. A multihospital study provides both the number of hospitals and the number of patients needed to clarify these complex drug-environment interactions. The pros and cons of conducting large-scale, multihospital cooperative studies of psychopharmacological its and NIMH by been have weighed carefully agents advisory groups during the 4 years of the Institute’s proPSC. the administered by in psychopharmacology, gram The NIMH ﬁrst developed a wide program of basic and clinical studies in psychopharmacology, and has until now centered its major efforts upon the stimulation and support of individual research projects. While this program has resulted in a great deal of clinical drug research, it has not met the need for large-scale evaluation of widely prescribed psychiatric drugs. The several Cooperative Studies of Chemotherapy in Psychiatry which have been developed by the Veterans Administration in recent years have provided a great deal of useful information about some of the newer psychiatric drugs. The generalizability of these ﬁndings has, however, been limited by the special characteristics of the clinical material available to the Veterans Administration. The NIMH Collaborative Study of Phenothiazine Treatment of Acute Schizophrenic Psychoses has been designed to provide information on the effectiveness of new drugs in a population which will include female patients. The patients will, in general, be more acutely ill and will be treated in a wider range of hospital milieus than could be the case within the Veterans Administration. In addition, the study is designed speciﬁcally to explore possible interactions between hospital milieu and has than in systematic manner more a drug response �been possible in the earlier studies conducted by the Veterans Administration. The success of the Collaborative Study, a complex research endeavor, will depend upon close and continuing cooperation and collaboration between the research teams in the participating hospitals, the staff of the Psychopharmacology Service Center, and the advisory bodies of the National Institute of Mental Health. As this project develops, it is hoped that the participating groups will undertake a continuing series of investigations of the treatment of acute schizophrenic psychoses. NIMH Grant Support for Early Clinical Evaluation Unity Drag In November 1960, the National Institute of Mental Health announced the establishment of special grants for early clinical investigations of psychiatric drugs. The primary purpose of the grants is to broaden the present scope of early clinical trials of promising new compounds and to make it possible to screen more new drugs for effectiveness in the treatment of psychiatric disorders. The grants will be awarded to a limited number of carefully selected clinical units to support trials of promising compounds in patients to determine the safety, appropriate dose ranges, and side effects of the drugs, preliminary studies of their clinical effectiveness in the treatment of particular symptoms or syndromes, and small controlled comparisons of new drugs with known standard drugs or placebo. Because of the need for ﬂexibility in tailoring a clinical research design to ﬁt the types of drugs and types of patients under study, an attempt will be made to achieve an adequate balance between careful observational studies and small-scale comparative and controlled studies. This particular area was chosen for expansion because NIMH considered it to be more seriously in need of further support than either of the other two major stages of new drug development; i.e., (a) preliminary screening of new drugs in animals to determine safety and pharmacological activity, which is being adequately supported by the drug industry and by National Institutes of Health grants for basic research, and (b) deﬁnitive clinical drug research (controlled clinical trials and hypothesis-oriented clinical investigations), which is amply provided for by the existing NIMH research grant program in psychopharmacology. Expansion of support for early clinical drug evaluation was therefore recommended by the Advisory Committee on Psychopharmacology and by the National Advisory Mental Health Council, and the Congress subsequently provided funds for the establishment of special grants in this area. The program will be administered by the Psychopharmacology Service Center. �NIMH-PSC Outpatient Study The National Institute of Mental Health has recently awarded research grants to Karl Rickels, of the University of Pennsylvania, Philadelphia, Pa., and E. H. Uhlenhuth, of the Johns Hopkins University, Baltimore, Md., to support their participation in a special research project initiated by the Psychopharmacology Service Center. The study is a double-blind, placebo-controlled investigation of the effects of an active psychopharmacological agent (meprobamate) and physicians’ attitudes on a carefully deﬁned sample of neurotic outpatients. It is one of the ﬁrst known attempts to control experimentally the communication of differential attitudes by physicians when administering medication. The project is to be conducted at three clinics simultaneously, the Henry Phipps Psychiatric Clinic of the Johns Hopkins University, the Functional Clinic of the Hospital of the University of Pennsylvania, and the Neuropsychiatric Clinic of the Philadelphia General Hospital. The study was designed by the staff of PSC’s Special Studies Unit in collaboration with the two principal investigators, Drs. Rickels and Uhlenhuth, and was approved by the Committee on Clinical Psychopharmacology and the Advisory Committee on Psychopharmacology, both of which are appointed groups of consultants who serve the National Institute of Mental Health in an advisory capacity. The two principal investigators subsequently applied for and received, on recommendation of the National Advisory Mental Health Council, research grants to carry out the study. Coordination of the project will be handled by the Center’s Special Studies Unit, whose members are Seymour Fisher, Seymour H. Baron, Mitchell B. Balter, and Elizabeth Hackett. Under contract with the National Institute of Mental Health, the Biometric Laboratory of George Washington University, Washington, D.C., will assist in the analysis of the data. RESEARCH DESIGN AND METHODS The Outpatient Study of Drug-Set Interaction is part of a larger special program which is concerned with the effects of psychological set and social interaction upon drug response in both patients and normal subjects. The study has three main purposes: *Prepared by Seymour Fisher, Chief, Special Studies Unit, Psychopharmacology Service Center, National Institute of Mental Health, Bethesda 14, Md. 4 of Drug-Set Interaction“ To determine whether meprobamate, administered for a 6-week period at a ﬁxed dosage, is more effective than an inert placebo in the treatment of neurotic outpatients. (See Laties and Weiss, 1958.) 2. To determine whether patients’ expectations or set (as induced by contrasting behavioral roles by the doctors participating in the project) have a signiﬁcant effect upon treatment course. Set will be varied by training one group of doctors (the “T” group) to maintain a positive, consistent, enthusiastic, “therapeutic” approach to their patients; another group (the “E” group) will be trained to manifest a more aloof, uncertain, “experimental” approach in relating to their patients. The “T” therapists will attempt to convey the belief that they are treating the patient with a known, efﬁcacious agent; the “E” therapists will attempt to convey the belief that they are evaluating the agent. 3. To determine whether a signiﬁcant drug-set interaction exists; i.e., to test the hypothesis that a “T” set will potentiate response to the active drug. Following a pilot study of 24- patients, a total of 200 patients will be treated for a 6-week period, 50 patients being assigned to each of the following 4 treatments: Meprobamate combined with “therapeutic” set; mepro— bamate combined with “experimental” set; placebo combined with “therapeutic” set; and placebo combined with “experimental” set. The basic research design is in the form of a 2 x 2 factorial analysis, with each of the two independent variables being varied in two ways. Table 1 shows the four-cell design, which permits an exact statistical test (by analysis of covariance) of the three 1. hypotheses. Patients will be seen biweekly for 6 weeks. In order to rule out the effects of the personality characteristics of the doctors in the study, a total of 12 physicians will participate, 4 psychiatric residents at each of the 3 clinics. Thus, interclinic‘ comparisons will be possible. An attempt will also be made to validate the role behaviors in the doctors. TABLE 1.—-Researc}z Design Medication (N=200 patients) Set Meprobamate ......... ........ “Therapeutic” “Experimental” 50 patients 50 patients ....... ....... Placebo 50 patients. 50 patients. �The dependent variables are ratings—patients’ selfratings as well as doctors’ ratings—on a symptom-distress checklist, on the Clyde Mood Scale, and of overall change. Dropout rate will also be considered. BACKGROUND OF THE STUDY The impetus for this study stems from the Psychopharmacology Service Center’s interest in various methodological problems involved in the clinical evaluation of psychiatric drugs, in particular the problem of attitudinal variables and their effect upon drug response. The basic thinking underlying this approach was presented in a draft paper prepared some months ago (Fisher, 1960). That paper also pointed out the kinds of speciﬁc research designs which would test for any unique interactive effects between medication and set (i.e., attitudes and expectations) . A review of the literature has revealed much clinical suspicion that patients’ expectations may interact with medication to produce differential clinical effects, but supporting evidence for such speculations is rather tenuous. Sabshin and Ramot (1956) note that: “Often the patient may interpret a change in his internal milieu in the context of being a change in the expected direction. It is thus possible for a subtle type of communication to take place . . . and this may potentiate the drug effects. Hence a relatively speciﬁc effect can be geometrically increased.” However, the investigators do not present empirical evidence. That a particular drug can have one effect under one psychological condition and a quite different effect under another psychological condition is well documented experimentally. This holds for animals (e.g., Brown, 1958; Chance, 1946; Gunn and Gurd, 1940) and for humans. In an elegantly designed experiment, Hill, Belleville, and Wikler (1957) clearly demonstrated a signiﬁcant interaction between incentive conditions and drug response in human subjects. Nowlis and Nowlis (1956) and Starkweather (1959), in studies of normals, report complex interactions between drug response and the subject’s perception of other subjects’ behavior. In the clinical setting, Feldman’s paper (1956) indicated that the physician’s attitude toward medication is reﬂected in his report of degree of improvement in psychiatric patients. However, that is not conclusive evidence for an interaction effect, since placebos were not employed for comparison, and evaluation of the patients was badly contaminated by the fact that each of the participating physicians made his own overall estimate of change The latter comment also applies to a clinical study reported by Kast and Loesch (1959), who similarly argue that the action of a psychopharrnacological agent can be made disproportionately more effective than an inactive placebo when the medication is administered within the context of a positive set (i.e., a given set can potentiate drug response). While their theoretical formulation is quite ingenious and heuristic, their experimental design does not afford a valid test of their hypothesis. A more dramatic study concerned with potentiation was published by Uhlenhuth et al. (1959). In a doubleblind, cross-over design using meprobamate, phenobarbital, and placebo, two physicians obtained signiﬁcantly different rates of drug-related improvement in their patients. One physician (who was “therapeutic” and enthusiastic) obtained signiﬁcant differences between the active drugs and placebo, while the other physician (who was more skeptical and “experimental”) found no signiﬁcant differences among the three agents. The results of this study are certainly suggestive, but they are difﬁcult to interpret since one cannot state deﬁnitively what the effective differentiating characteristic(s) between the two physicians was (i.e., in addition to “attitude,” they obviously differed in an inﬁnite number of ways), and because of the complication introduced by using a three-way cross-over of drugs. In March 1960, Irvin S. Wolf, of Denison University, and PSC’s Special Studies Unit tested the interaction‘ hypothesis on normal subjects who were given dextroamphetamine and placebo under three different attitudinal sets (consistent, uncertain, and inconsistent expectations). Analysis of covariance for a 3 x 2 factorial design on subjective and psychomotor dependent variables revealed a number of signiﬁcant or near-signiﬁcant trends (all in the anticipated direction) suggesting a drug-set interaction. The signiﬁcance of this research approach is perhaps revealed in the following considerations. When reference is made to a “place-b0 response,” it is evident that the concept is a complex one. In a placebo-controlled experiment, not only is there a general set of expectations associated with the symbolic value of receiving medication from a prestige authority, but there are also undoubtedly speciﬁc expectations about the nature, purpose, and action of the medication. These different kinds of expectations have been discussed elsewhere (Fisher, 1960), but one important implication is worth repeating here. The most frequently used model in controlled evaluations of drugs assumes that the “placebo response” (i.e., the amount of change attributed to nonpharmacological factors) is a type of “error” involved in assessing the pharmacological effects of the active drug: If one can accurately measure the degree of placebo response, that effect can be subtracted from the total effect, thus giving the pharmacological component. This assumes that the psychological (i.e., general and speciﬁc expectations) and the pharmacological components are additive in nature. As shown in ﬁgure 1, speciﬁc expectations 5 �CLINICAL IMPROVEMENT SET A FIGURE 1. SET B Hypothetical Data Illustrating Additive Model. (sets A and B) do affect the response, but essentially equally for subjects who receive the active drug and for those who receive placebo. Irrespective of the set under which the drug is evaluated, the conclusion is the same—— the drug is X units more effective than placebo. CLINICAL IMPROVEMENT PLACEBO\ SET A FIGURE 2. \\\ O SET B Hypothetical Data Illustrating Interactive Model. A quite different possible model, however, can be built on the‘ assumption that the pharmacological and psychological components are interactive. As shown in ﬁgure 2, the speciﬁc expectations in set A potentiate the drug response, and one cannot generalize the effect of the drug without taking into account the set under which it was administered. Note in ﬁgure 2 that if the drug were evaluated in an experiment in which only set B was operative, one would conclude that the drug was no more effective than placebo—a conclusion which, though 6 correct, would have to be limited to the conditions of the experiment. Figure 2 also shows, however, that under set A the drug was obviously superior to the placebo— an equally correct conclusion for the given conditions. Thus, if it were established that the interactive model is more appropriate for certain kinds of clinical evaluation, one would run the risk of rejecting as ineffective a treatment which really does have an effect (type II error) whenever the clinical trial is conducted under inappropriate conditions of set. A great deal has been written about the need for controls in clinical research. It has often been noted that new forms of therapy are enthusiastically received on the basis of early uncontrolled clinical impressions, only to be laid to rest by subsequent controlled evaluation (Cornell Conference, 1954) . Recent papers by Foulds ( 1958) and Astin and Ross (1960) show that a signiﬁcantly greater number of uncontrolled studies in psychopharmacology yield positive results than do controlled experiments. Undoubtedly, this difference can be partly attributed to such factors as lack of controls, faulty or biased measurement, faulty design, etc., in the uncontrolled studies, or to insufﬁcient dosage or duration of medication, or sampling bias, in the controlled experiments. On the other hand, it is possible that this difference is not all due to various kinds of “error.” If some genuine interaction effect should exist between physicianmilieu and drug action, that would go a long way in accounting for many of the apparent discrepancies between the ﬁndings of hardheaded researchers and those of equally hardheaded clinicians. In uncontrolled clinical trials, the patients may be exposed to a quite different “attitudinal” atmosphere: They more often see themselves as being “treated” rather than “researched,” and that might provide a quite different setting for drug action. In many controlled experiments, the patients are deﬁnitely aware that they are participating in a research project (implying “Let’s see if the drugs will help you”), and such a perception is probably reinforced whenever patients ﬁnd themselves periodically being observed, tested, and probed. The overall aim of the Outpatient Study of Drug-Set Interaction is to attempt to create experimentally these two contrasting attitudinal sets within the context of a controlled clinical evaluation. REFERENCES Astin, A. W., and Ross, S. Glutamic acid and human intelligence. Psychological Bulletin, 1960, 57, 429—434. Brown, B. Inﬂuence of inter-animal and environmental stimulation on action of central nervous system drugs. Proceedings of the Western Pharmacological Society, San Francisco, January 27—28, 1958. Chance, M. R. A. Aggregation as a factor inﬂuencing the toxicity of sympathomimetic amines in mice. Journal of Pharmacology and Experimental Therapeutics, 1946, 87, 214—219. �Cornell Conference on Therapy. How to evaluate a new drug. American Journal of Medicine, 1954-, 17, 722—727. Feldman, P. E. The personal element in psychiatric research. American Journal of Psychiatry, 1956, 113, 52—54. Fisher, S. Milieu controls in psychopharmacology. Manuscript, 1960. Foulds, G. A. Clinical research in psychiatry. Journal of Mental Science, 1958, 104-, 259—265. Gunn, J. A., and Gurd, M. R. The action of some amines related to adrenaline. Cyclohexylalkylamines. Journal of Physiology, 1940, 97, 453—470. Hill, H. E., Belleville, R. E., and Wilder, A. Motivational determinants in modiﬁcation of behavior by morphine and pentobarbital. A.M.A. Archives of Neurology and Psychiatry, 1957, 77, 28—35. Kast, E. C., and Loesch, J. A contribution to the methodology of clinical appraisal of drug action. Psychosomatic Medicine, 1959, 21, 228—234. Laties, V. G., and Weiss, B. A critical review of the efﬁcacy of meprobamate (Miltown, Equanil) in the treatment of anxiety. Journal of Chronic Diseases, 1958, 7, 500—519. Nowlis, V., and Nowlis, Helen H. The description and analysis of mood. Annals of the New York Academy of Sciences, 1956, 65, 345—355. Sabshin, M., and Ramot, J. Pharrnacotherapeutic evaluation and the psychiatric setting. A.M.A. Archives of Neurology and Psychiatry, 1956, 75, 362—370. Uhlenhuth, E. H., Canter, A., Neustadt, J. 0., and Payson, H. E. The symptomatic relief of anxiety with meprobamate, phenobarbital and placebo. American Journal of Psychiatry, 1959, 115, 905-910. Research Conference on Drugs and Community Care“ In September, the Psychopharmacology Service Center sponsored a “Research Conference on Drugs and Community Care” to bring a number of investigators together to discuss problems of research on the use of drug therapy in the care of psychiatric patients living in the community. The conference, held in Washington, D.C., dealt with studies of both acute and chronic patients, evaluations of home-treatment or day-hospital care, maintenance therapy, treatment speciﬁcally designed to prevent relapse in previously hospitalized patients or to treat relapsed patients in the community, and followup studies. The primary objectives of the conference were (a) to permit investigators whose research in this area is supported by NIMH to discuss problems and to exchange ideas and experiences related to solutions to problems; (b) to provide the Center, its consultants, and the participating research investigators with an overview of the nature of the research now being supported; (c) to determine what has been learned from these studies about the role of drugs in the community care of psychotics; and (d) to assess progress in dealing with the technical aspects of these kinds of research; e.g., the establishment of criteria and the development of methods for classifying patients and for evaluating change and adjustment. In addition to NIMH grantees conducting research on drug therapy in the community, the participants included investigators whose interests and experience were compatible with the aims of the conference and several who are just entering research related to this general ﬁeld. The conference was organized by Martin M. Katz, PSC research psychologist. The formal participants *Prepared by Martin M. Katz, Research Psychologist, Psychopharmacology Service Center, National Institute of Mental Health, Bethesda l4, Md. were Dean J. Clyde, Washington, D.C.; Jonathan 0. Cole, PSC; Joel J. Elkes, Bethesda, Md.; David M. Engelhardt, Brooklyn, N.Y.; Leon Epstein, Sacramento, Calif; Seymour Fisher, Houston, Tex.; Norbert F reedman, Brooklyn, N.Y.; Sol L. Garﬁeld, Omaha, Nebr.; Goldine Gleser, Cincinnati, Ohio; Bernard Glueck, Hartford, Conn.; Milton Greenblatt, Boston, Mass.; Martin Gross, Sykesville, Md.; Leo E. Hollister, Palo Alto, Calif. ; Martin M. Katz, PSC; Else B. Kris, New York, N .Y.; Jordan Lawrence, Sykesville, Md.; Mark Lefton, Columbus, Ohio; Samuel B. Lyerly, Washington, D.C.; David Mann, Brooklyn, N.Y.; Richard D. Morgan, Sacramento, Calif.; Benjamin Pasamanick, Columbus, Ohio; Leonard Pearlin, Bethesda, Md.; Seymour Perlin, New York, N.Y. ; George A. Ulett, St. Louis, Mo. ; and Joseph Zubin, New York, N.Y. The ﬁrst half of the program was devoted to reports on six research projects, each of which was related to some aspect of drugs and community care. The papers reporting the projects emphasized aims and general research design, methodological and operational problems, and plans for future work. The second half of the conference was devoted to theoretical and practical problems of methodology. In many cases, new methods and methodological problems mentioned brieﬂy in the research reports were presented in greater detail and discussed more fully during the second half of the meeting. Some of the points made in each paper are summarized in the following paragraphs. These summaries do not, of course, cover all of the points covered by the speakers, but it is hoped that they will provide at least enough information to convey some impression of the overall content of the meeting and of the major issues which were considered. �SIX RESEARCH PROJECTS Home Versus Hospital Care for Schizophrenics. Presented by Benjamin Pasamanick, Department of Psychiatry, Ohio State University Medical School, Columbus, Ohio. This study is designed to test the hypothesis that acute schizophrenic patients can be treated at home when proper public health care is combined with appropriate drug therapy. All ﬁrst-admission schizophrenic patients referred to the Columbus Psychiatric Institute are to be considered for the study. Those who are suicidal, homicidal, or so violently disturbed that it would be impossible to keep them in the home will be dropped from further consideration. The remaining patients will then be randomly assigned to one of the following three treatment groups: (a) A group treated at home with drugs plus frequent visits by a public health nurse; ( b) a group treated at home with placebo plus frequent visits by a public health nurse; and (c) a hospitalized group treated with the usual methods of the hospital. The three groups are to be evaluated before treatment, after 1 year, and after 2 years by psychiatric and psychological examinations, and by reports and ratings from nurses and social workers (including interview data from patients and their families). Quality of housing and general home environment of all three groups will also be rated. A public health nurse, working in consultation with the psychiatrist and social worker, will frequently visit each home-care patient to give nursing guidance and counsel to the patient and his family. Patients in the home-care groups will be hospitalized when that is recommended, on the basis of previously established criteria, by a diagnostic council from the Institute. The hospitalized group and the home-treatment groups are to be compared for total length of hospitalization, psychiatric condition, and family reaction and receptivity. The two home-care groups—one on placebo, one on drug—will be compared for rate of hospital admission. Discussion of this study was devoted to such matters as control of medication in the home-care groups, degree of comparability of the hospitalized and home-treatment groups, and problems related to hospitalization of patients assigned to home treatment. Later in the conference, Lefton, also from the Columbus Psychiatric Institute, presented a detailed discussion of the interview schedules which will be used in the study. A Study of Ataractics in Outpatient Schizophrenia. Presented by David M. Englehardt and Norbert Freedman, State University of New York, Downstate Medical Center, Brooklyn, NY. This project was described as a longitudinal study of the effects of tranquilizers on the community adaptation of schizophrenic outpatients. Questions of interest in the study are whether continuation of medication after an initial gain will prevent relapse, whether further improvement is noted when med8 ication is continued, and, when there has been no initial gain, whether improvement will occur after prolonged administration of drug. Changes in symptomatology and in social behavior associated with drug therapy will be assessed after a brief time and after sustained administration of drug. The following criteria of outpatient adaptation are being used: Maintenance of outpatient status (i.e., avoidance of hospitalization), reduction in psychopathology, freedom from functional decrement, reduction in social dysfunctioning, concordance between social adaptation and psychopathological changes, and stability of clinic course during a prolonged period (up to 24 months) of continuous treatment with drug or placebo. Baseline psychiatric and psychological data are obtained during the ﬁrst week. The patient is then placed on promazine, chlorpromazine, or placebo. Dosage levels are ﬂexible and medication is administered doubleblind. Supportive psychotherapy is given, but the emphasis is on medication. Patients are seen in the clinic at frequent intervals. Detailed re-evaluations are conducted after 3 months and at the end of 1 year. Preliminary ﬁndings reported by Engelhardt show that the rehospitalization rate is signiﬁcantly lower in the drug groups than in the placebo group. Also, the number of patients showing clinical improvement at 6 months is much higher in. the drug groups than in patients on placebo, as is the rate of improvement of a group of patients who demonstrate severe thought disturbance on initial evaluation. Further, the amount of social dysfunctioning as reported by the relative has been found to be greater in the placebo group than in the patients on chlorpromazine. A detailed report on the accumulation and analysis of the data on social behavior was presented later in the meeting by Mann and Freedman, participating investigators in the study. Freedman also discussed the problem of dropout, which has been one of the major difﬁculties thus far. Attempts to distinguish clear-cut differences in personality or psychopathological features in the patients who drop out have not been successful, though the speculation is that there may be a complex interaction between the patient’s expectation concerning treatment and what he actually experiences in the clinic. Discussion of this project centered around the speciﬁc kinds of information obtained from the patient’s relatives, the handling of such data, problems of following up patients who drop out of the study, possible reasons for dropping out, side effects (which have not been a problem), the ethics of using placebos, and the possible relation between degree of social dysfunction and level of drug dosage. Drug Therapy in a Daycare Facility for Relapse Control. Presented by Else B. Kris, Manhattan Aftercare Clinic, New York, NY. The aims of this project are to evaluate �day hospital care plus drug therapy as a means of controlling relapse and preventing rehospitalization of formerly hospitalized psychotics, primarily schizophrenics. Acutely disturbed (relapsed) patients who would ordinarily be rehospitalized are randomly assigned to one of two treatments: (a) Rehospitalization and usual hospital care, or (b) drug therapy in a special day hospital afﬁliated with the Research Unit of the Manhattan Aftercare Clinic. At the time of assignment to a treatment group, the psychotic condition of each patient is determined by use of the Wittenborn Psychiatric Rating Scales. Patients assigned to the day hospital are immediately started on intensive pharmacotherapy, with drug dosage individualized according to patients’ needs. Length of time between onset of relapse and subsequent remission in the two treatment groups, and community adaptation following remission, are being compared. After patients are released from either the hospital or the day hospital, the investigators will study the patients further to determine whether remission achieved in the day hospital is temporary or lasting. Community adaptation is being measured by a set of scales developed by Katz, who described them more fully later in the conference. Kris reported that the most remarkable ﬁnding thus far has been the rapid achievement of remission in the day hospital patients, who return to their jobs far sooner than patients who were rehospitalized. She also noted that treatment in the day hospital seems to promote better community adjustment and that patients seen in the day hospital seem to have learned that they can discuss recurrence of symptoms without fear of being rehospitalized. Questions about the details of handling patients at the day hospital were discussed, along with comments about the liaison betwen the day hospital and employment agencies or vocational rehabilitation centers, possibilities of using the center as a training facility for physicians and psychiatrists in private practice, criteria for admission to the study, and the stafﬁng and physical layout of the day hospital. Termination of Treatment With Ataractic Drugs. Presented by Martin Gross, Springﬁeld State Hospital, Sykcsville, Md. This project, begun in 1958, investigated the importance of continuing chronic psychotic patients on medication after their release from the hospital. All patients in the study were ﬁrst stabilized on one of six drugs and then randomly assigned to either (a) a control group which was continued on active medication, or (b) an experimental group which was gradually transferred from drug to placebo under double-blind conditions. Patients who relapsed were removed from the study and placed on medication if they had been receiving placebo or were rehospitalized. The criterion for relapse was the clinical judgment of the treating psychiatrist. A rating scale developed to permit objective determination of the ' psychiatric condition and social adjustment of the patients was described by Lawrence during the second half of the conference. During the preliminary phase of the study, and at intervals thereafter, patients were evaluated by psychological tests, and their families or the people with whom they were living were interviewed by the social workers. Frequency of relapse while on active medication was compared with that which occurred while patients were on placebo. Summarizing some of the ﬁndings from the study, Gross reported that relapse occurred signiﬁcantly more frequently during the withdrawal or placebo period, the relapse rate being approximately three times as high during the placebo period as during the period on medication. He also noted that three-fourths of the patients who relapsed while on placebo did not require rehospitalization but were able to regain stability after medication was resumed. Among the problems of methodology and design which Gross enumerated were the difficulties experienced in dealing with six different drugs rather than with a single drug. He noted also that the generalizability of the ﬁndings was limited in that patients in the project—— chronic psychotics who were free from alcoholism and organic brain damage and who were able to attend the clinic regularly—could not be considered representative of the general outpatient clinic population. In reply to a question, Gross stated that he felt the low incidence of dropout was due to the personal contact between the patients and the social worker and physician. Other points discussed were the difficulties of maintaining double-blind conditions and of objectively determining the point of relapse, procedures for determining whether the patients took their medication, and techniques for switching patients from drug to placebo. Drugs and Social Therapy in Chronic Schizophrenia. Presented by Milton Greenblatt, Massachusetts Mental Health Center, Boston, Mass. This study was initiated to determine (a) how much of drug effectiveness is due to the drug per se and how much to other causes, and (b) whether there are signiﬁcant social and environmental differences between hospitals which may account for the differences between drug effects in one setting and another. Sixty chronic schizophrenics were transferred from a State hospital to an intensive treatment center (the Massachusetts Mental Health Center), where 33 received drug in addition to other therapy and 27 were not given drug. Comparison groups were composed of 55 patients remaining at the State hospital, of whom 25 were assigned to drug treatment and 20 were not. In neither setting were the patients assigned to “research wards.” The criteria on which patients in the four groups were compared were clinical improvement and discharge rate. �Findings reported by Greenblatt showed only slight differences between the State hospital groups and the MMHC groups after 6 months. At 18 months, however, there were differences which suggested the possibility of a beneﬁcial carryover of milieu effects in patients who had originally been transferred to the MMHC. In commenting on discharge rate, Greenblatt indicated that the State hospital criteria for discharge are much more stringent than those of the MMHC. He also noted that discharge rate was affected by the availability of a family or a transitional facility to which the patients could be released. Among other special problems which he discussed were the difﬁculties of incorporating chronic schizophrenic patients into MMHC treatment routines without changing the environment of the Center, the reasons for having decided not to attempt double-blind administration of drugs, and the possible signiﬁcance of any effects of “transfer trauma” in patients moved from one setting to another. The Eﬂeet of Ataractie Drugs on Hospital Release Rates. Presented by Richard D. Morgan and Leon Epstein, California State Department of Mental Hygiene, Sacramento, Calif. This project is one aspect of a much broader study of population movement in the California State mental hospitals. Morgan’s paper was devoted to the overall study, and Epstein’s to the parts of it which are speciﬁcally concerned with drug therapy. Morgan ﬁrst brieﬂy explained the system of cohort followup analysis which is being used, noting that it is essentially the application of individual followup analysis techniques to a group of patients who have one or more characteristics in common—cg, age, year of admission, sex, diagnosis, etc. Having set July 1948 as the beginning point for the collection of data, the California State Department of Mental Hygiene is now systematically coding and punching onto IBM cards detailed information on all ﬁrst-admission patients in the State’s 11hospital system. The records are not restricted to the period of ﬁrst admission, but cover residence during subsequent readmissions in the same hospital or in a different one within the State system. A wealth of information is collected for each patient: Vital statistics, diagnosis and details of treatment, and data covering current hospital entry, previous hospitalizations, leaves, etc. Thus, a patient’s complete record of hospitalization can be examined in great detail at any point during the followup period, and cohorts can be constructed on the basis of any combination of a large number of descriptive characteristics. Morgan observed that this technique permits analysis of the frequency or the likelihood of occurrence of changes in status during any speciﬁed interval in the followup. The status of a given cohort of patients can be examined for any period of time. Data being collected in this study are proving valuable in studies of current administrative policies and investigations of the 10 effectiveness of new or expanded programs. This system is also valuable in providing retrospective control data which may be used in lieu of a control group in evaluations of speciﬁc programs. Following Morgan’s report, Epstein discussed a particular set of analyses of these data in which the aim is to evaluate the role of tranquilizing drugs in the recent decline in State mental hospital populations, a decline which has occurred in California as well as in other States. For the period from July 1, 1955, through December 31, 1957, additional information (i.e., additional to that routinely obtained for all patients) on details of drug therapy was recorded for each patient in the State system who had received treatment with drugs. Name of the drug, total amount of drug administered, number of days on drug, and the reason for stopping drug treatment were among the additional data recorded. By looking at signiﬁcant subgroups—for example, ﬁrst-admission male schizophrenics between the ages of 25 and 4-4—the investigators hope to be able to draw certain conclusions about shortened periods of hospitalization and their association with drug therapy. Data concerning drug usage during the period of the study are now being analyzed. Epstein stated that investigators participating in this study are “painfully aware” that the data involve a variety of physicians, drugs, settings, and timings of drug treatment in relation to admission, as well as a variety of discharge policies among the 11 different hospitals. Despite such problems, the data do provide some reﬂection of what may be associated with drugs as they are used in a total system. A number of the conference participants were particularly interested in certain speciﬁc applications of data being recorded in the California studies or of cohort analysis techniques generally. Others expressed concern about the use of release rates as a criterion in studies such as these, questioned the comparability of present-day schizophrenics with those of a few decades ago, or asked whether the current “decline” in certain hospital populations might not be in part a reﬂection of the decline in birth rate which occurred during the depression. RESEARCH METHODS The section of the conference which dealt speciﬁcally with methods was devoted to technical and theoretical problems which arise in carrying out research on drugs and community care. In accord with evidence that drugs in combination with other psychiatric treatments are contributing signiﬁcantly toward. maintaining formerly hospitalized patients in the community, investigations have been initiated which are aimed at specifying the nature of these treatments and their effects. For purposes of the conference, the question of speciﬁcity was seen as having two major parts. The ﬁrst was concerned with the problems of specifying the kinds of �patients who are helped by a given treatment, identifying the clinical, personal, and social characteristics of patients which are associated with response to treatment, and identifying the “types” of patients who are most likely to respond to a given treatment. In addition to the question of types of variables which merit study with regard to this problem, the technical problems which arise here, such as coding and the application of multivariate analysis procedures, were also considered in separate papers. The second part of the section on methods was concerned with the problems of specifying the effects of a given treatment, of measuring clinical change and the various aspects of adjustment. Several approaches to these problems were described. Population Speciﬁcation Three papers were concerned with the search for signiﬁcant variables in clinical history, sociological characteristics, or personality of the patients. Clinical history was discussed by Bernard Glueck, of the Institute of Living, Hartford, Conn. Although several clinical and social variables have demonstrated some general predictive value in studies of response to treatment, Glueck observed that the search for speciﬁc prognostic factors in these areas has not been very successful. He reviewed some of the clinical history variables which have been linked to response to insulin therapy, electroshock, and lobotomy, and commented to the scarcity of such information in relation to treatment with drugs. His major criticism was aimed at the continuing lack of a common language to describe psychiatric conditions. Following a description of Q-sort techniques which he and his associates are applying to this problem, Glueck suggested that Q-sort methods provide a means of standardizing language and making comparable the ﬁndings from different clinics or hospitals. Sociological variables were covered by Leonard Pearlin, of the National Institute of Mental Health, Bethesda, Md. Arguing for greater speciﬁcity in this area, Pearlin observed that generic variables such as social class, age, and sex role are too global to be of much value in understanding the relations among variables. The need, he maintained, is for greater emphasis on description of the social context—i.e., the family, the community—and a descriptive system in which the “social characteristic in context” is the unit of analysis. The role of personality in the prediction of response to treatment was the topic of the paper by Seymour Fisher, of Baylor Medical School, Houston, Tex. His review of previous work in the personality area and his own experience led him to the opinion that the more simple personality variables have not been very helpful in the past as predictors and are not likely to be too helpful in the 580375—61—2 future. Increased emphasis should, he felt, be placed on theoretically derived conﬁgural measures of personality. Several possible conceptual dimensions were described. He acknowledeged, however, that the linking of personality variables to response to treatment is subject to a number of pitfalls, some of which he enumerated. The discussion which followed focused upon the issue of the single variable versus the conﬁgural approaches in attempts to relate personality and treatment response, and resulted in some clariﬁcation of the roles of each. The issue, however, was not resolved. Methods for dealing with population variables were discussed by Samuel B. Lyerly, of the Society for Investigation of Human Ecology, Washington, D.C., and Dean J. Clyde, of the Biometric Laboratory of George Washington University, Washington, DC. Lyerly, in a paper entitled “Interview Data: Coding, Scaling, and Selection of Potentially Useful Variables,” emphasized the differences in hospital and community situations which affect the collection and analysis of data, the characteristics of information which are essential to statistical analysis of data, and the importance of insuring that information collected is comparable from subject to subject. With regard to coding, he discussed different types of data and classiﬁcation systems, the role of the pilot study, ways of handling of “free responses,” and the application of simple mathematical procedures to patterning problems. Problems of weighting, suggestions for dealing with “does not apply” responses, and the application of different types of validity models were also considered. Clyde’s paper, “Multivariate Problems: Clustering Variables and Classifying Patients into Types,” focused on the role of multivariate models in drug research. He described the following three approaches and presented examples of the application of each: (a) Analysis of covariance, whose use was exempliﬁed in a study in which control of the pretreatment level of severity of illness was required; (b) factor analysis, which was used, in the example presented, to reduce a large number of items in a rating scale to two independent dimensions and thus served to clarify the composition and meaning of the instrument; and (c) discriminant function, which was applied to a problem of separating out groups of patients on the basis of their differential response to drug treatment. The relevance of the latter procedure to the problem of etiology was also considered. In discussing these papers, Goldine Gleser, of the University of Cincinnati, Cincinnati, Ohio, elaborated upon several approaches to separating subjects into meaningful groups. Three statistical models for accomplishing this kind of separation were described. She stressed that the state of knowledge in the ﬁeld is not sufﬁciently advanced to permit the prediction beforehand of the best way of separating groups, but pointed out that study 11 �of the outcome of such empirical separation can yield hypotheses which can then be cross-validated in other studies. Methods for Measuring Improvement Papers presented in this section of the conference described methods which are being used or developed to evaluate the adjustment of the patient and to specify ways in which improvement is manifested. Norbert Freedman and David Mann, of the State University of New York, Downstate Medical Center, Brooklyn, N.Y., described the manner in which they are attempting to measure psychopathology and social behavior. Emphasis within the clinic is on the psychiatric rating scale approach, and in their community studies emphasis is on a “naturalistic” approach. They have, through preliminary analysis of their psychopathology ratings, identiﬁed factors which improve with drug treatment and which predict drug response to treatment. In the area of social behavior, development of an extensive interview schedule covering such areas as family history, work history, and social pathology was described by Mann. He also discussed in some detail their coding procedures, the progress of their approach to studying the “typical day in the patient’s life,” and the dimensions of classiﬁcation which have been derived from the social data and which will contribute toward deﬁning “social remission.” It was pointed out that the deﬁnition of social remission is one of the central aims of the project. The details of a rating scale for measuring the improvement of outpatient psychotics treated with drug and placebo were discussed by Jordan Lawrence, formerly of Springﬁeld State Hospital, Sykesville, Md. The scale, which is completed by a psychiatrist or psychologist and a social worker following an interview with the patient, has three sections, one covering major psychopathology, one describing neurotic symptoms, and one concerned with social adjustment. Lawrence reported that the more reliable items in the scale have been factored and have yielded tentative dimensions of “schizophrenia” and “depression.” He also indicated that the three subscores and the total score have been found to discriminate well between pre-relapse and relapse conditions, but noted that further, better controlled validational studies need to be carried out. Progress on the development of a set of inventories designed to assess clinical and social adjustment was reported by Martin M. Katz, of the Psychopharmacology Service Center. He noted that the instruments are based on the need to integrate two points of view, the patient’s and the relative’s, in assessing the adjustment and per- 12 of the patient. The inventories represent atobtain objective estimates of (a) the amount of home and free-time activity in which the involved, and (b) the patient’s and the relative’s level of satisfaction with the patient’s functioning in the clinical, work, social behavior, and free-timeactivity areas. A validity study was described in which relatives were shown to be in very high agreement with psychiatric assessment (based on intensive clinical study of the patient) with regard to the level of psychopathology present and the extent of home, social, and free-time activities of the patient. Several trends in the data were noted: The relative is capable of providing accurate, objective information in certain areas; the sheer quantity of activity as reported by patient and relative reﬂects the level of adjustment; and the relative’s level of expectations at the time of assessment correlate highly with adjustment. More detailed study of the composition of the instruments and their general applicability is in progress. Mark Lefton, of Ohio State University, Columbus, Ohio, described his implementation of the interviewschedule approach, which had some similarity to others with regard to the areas of functioning sampled. Separate schedules were designed for the patient and the relative. The variables of prime interest in Lefton’s assessment of community adjustment are social participation, work performance, psychological functioning as measured by a relative’s ratings on a list of psychopathological indices, performance as a homemaker, and meas» ures of the relative’s expectations and tolerance of deviation. He reported that several measures have been found to discriminate between patients who were returned to the hospital within 6 months and those who remained in the community, as well as between patients who function well and those who function poorly in the community. During the discussion of these papers, one participant commented on the salutary effect that commitment to a particular approach has in this area, but he cautioned against inﬂexibility at this early stage in the development of the ﬁeld. The use of clinical judgment as a criterion‘has its advantages, but it was noted that areas of disagreement among raters can be just as important for understanding the nature of the problem. formance tempts to and kind patient is In an area that has seen only scattered attention in the past, the conference participants agreed that the diversity and extent of efforts now being directed toward assessing the clinical and social effects of various psychiatric treatments are very promising developments. �Conference on Information Needo A conference on scientists’ need for information, sponsored by the Psychopharmacology Service Center under contract wtih the Matrix Corp., of Arlington, Va., was held on November 25 and 26 in Washington, DC. It was a small, invitational conference of scientists active in research in psychopharmacology, documentalists, and other information storage and retrieval specialists. The aims of the conference were several: To learn whether the conference method of face-to-face interchange would reveal more relevant data about scientists’ needs in the ﬁeld of information and. communication than has hitherto been revealed in questionnaire and interview studies; to learn whether bringing the generators and users of information into direct contact with the experts in documentation would yield information of value to both; to obtain speciﬁc information about needs of scientists working in psychopharmacology; and, as a byproduct, to help the PSC’s Scientiﬁc Information Unit plan its future activities. The meeting was very informal. There was no prearranged agenda, nor was any attempt made to arrive at speciﬁc recommendations. Under the chairmanship of Roger W. Russell, of Indiana University, Bloomington, Ind., three speakers presented papers as starting points for the discussion. Robert J. Hayes, of the Electrada Corp., Los Angeles, Calif., reviewed the whole ﬁeld of information storage and retrieval, emphasing new methods and machines. He brought out that there are now machines that can be applied to almost any problem or situation in the ﬁeld of information storage and retrieval. Emphasizing the team approach to the problem, the cooperative efforts of users, operators, and machine experts, he observed that the application of machine methods to information problems is successful only when the machine specialists and documentalists have a clear understanding of the users’ requirements. Daniel X. Freedman, of Yale University, New Haven, Conn., discussed the use of information in his own research, reviewed the development of his research program and the role of information in the program, and mentioned ways in which information could be more useful. Murray E. Jarvik, of Yeshiva University, New York, N.Y., also reviewed the sources of information that he employs, including journals, monographs, books, reprints, review articles, conferences, the public press, science writers, drug company literature, textbooks, and other materials. In addition to these three speakers, several other participants described their uses of information, covering of Pyye/oop/onrmneologz'rtx kinds of information used, how it is used, and ways in which they would like to have it improved. Interspersed among the papers was lively and varied discussion from most of the participants. The following summary attempts to convey some of the ideas presented in the discussions, but it does not cover all the points that were made. Throughout the meeting one recurring theme was concern about the quality of scientiﬁc information. Commenting on the many problems of so-called scientiﬁc writing, one participant observed that much scientiﬁc writing occludes more than it illuminates. Most participants felt that many experiments were poor to begin with and should never have been published. They pointed to the need for editors of scientiﬁc journals to evaluate work more carefully and more critically before accepting it for publication. On the other side of the question were emphatic comments that strong efforts in this direction could lead to stultifying and untenable orthodoxy in science. One of the participants maintained that the problem was too much information, and that steps should be taken to cut it off at the source; i.e., to induce the scientist himself to be more selective in reporting his work. Another took the opposite point of view, saying that, as with farm surpluses, the real problem is not that of having too much information but of distributing and using information more effectively. A frequently recurring generalization was that scientists do not make maximal, or even good use of the many sources of information available to them. As each participant mentioned kinds of information he used, others remarked that they did not know of those sources. Similarly, when speciﬁc needs were mentioned, other participants often retorted that such needs were now being satisﬁed and the scientist had only to take advantage of available services. One of the questions raised was whether centralized, or even decentralized, information services could ever serve all the needs of scientists. One participant suggested that much of the seeming dissatisfaction with present information and communication is due to the unrealistic expectations of scientists, who often want answers to research questions that they themselves should submit to research. Information at the forefront of knowledge must be obtained by the scientist; readymade answers do not exist. A related comment was that information needs differ from one stage of research to another. A point that could be generalized from the discussion was that scientists perhaps do not know what they want 13 �in the way of information, and that it is, therefore, the duty of specialists in the information area to provide scientists with a wide variety of information presented in many different forms. If that were done, the scientists could then select what they need from what is offered to them. The usefulness of critical reviews of the literature was discussed in some detail. Although all agreed that critical reviews are valuable, they noted that ﬁnding really eminent scientists to write the reviews constitutes a major problem. Handbooks and other compilations of factual information that would be of particular value to the applied scientist were also felt to be of great importance. Many participants cited reprints, rather than journals, as one of the most useful forms of information, and felt that much could be done to make distribution of individual articles more feasible and more effective. In discussions of systems of handling information, it was noted that a scientiﬁc discipline is itself an informational system, and that some disciplines are, at different times, much more tightly organized systems than others. Physics and chemistry, for example, are at present rela- 14 tively more “organized” than the biological sciences and, therefore, in a sense, present fewer information and communication problems. This discussion, which occasionally bordered on excursions into the philosophy of science, brought out the paradoxical observation that as a body of knowledge or science develops and overthrows old concepts and formulations, it is in a continuous cycle of creating chaos out of order and then creating order out of chaos. In general, the conference participants agreed that the most important and effective means of disseminating and exchanging new information are by personal contacts at scientiﬁc meetings, by the “ﬁrst” type of scientiﬁc communication—the letter—and by visits with other scientists. In discussing the value of this kind of direct, personal interchange, it was suggested that tape recorders, which are now available in most laboratories and university departments, might be used to simplify and speed up the informal exchange of information. The practical value of directories of scientists and of indexed compilations of ﬁlms and other audiovisual aids was also stressed. �The Pylebep/aarmacolegy Rerearcb Umt State Unevem'ty of New Yer/e Dowmtate Medical Center" The Psychopharmacology Research and Treatment Unit of the Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, N.Y., was established in October 1957. From its inception, the Unit has been concerned with the study of the effects of long-term psychopharmacological treatment on the community adaptation of schizophrenic outpatients. In the selection of ambulatory schizophrenic patients as our study population we were guided by the wide use to which psychopharmacological treatment is put with such patients. By setting community adaptation as the criterion of treatment outcome we hope to emphasize that change in these patients must be deﬁned in terms of performance at home, at work, and in the community, as well as in terms of the usual criteria of psychological and psy— chiatric functioning. By assessing the effects of longterm, sustained drug action (1 to 5 years of continuous drug administration) we expect to determine to what extent such treatment may prevent relapse or lead to further improvement after an initial stabilization has been attained. The Unit thus focuses on the behavioral (i.e., psychological as well as social behavioral) correlates of drug treatment and tries to apply the method of controlled investigation to the clinical setting. Considerable effort is also being extended to the methodology of outpatient drug assessment and to the basic research task of developing objective assessment techniques which will allow for the tracing of changes in the qualities of community adaptation. These overall research objectives are discriminated into the seven speciﬁc studies outlined below. The overall project is in part supported by Public Health Service grant MY—1983. In addition to these long-term studies of chronic schizophrenic outpatients, a section of the Research Unit is speciﬁcally concerned with the testing of new drugs. In the course of the short-term studies we have an opportunity to test the validity of some of the assessment techniques developed in the longterrn studies. Finally, the staff of the Research Unit also engages in teaching psychopharmacology to undergraduate medical students and psychiatric residents. A *Prepared on request by David M. Engelhardt and Norbert Freedman, Psychopharmacology Research Unit, State University of New York, Downstate Medical Center, Brooklyn, N .Y. research fellowship program is carried out by the Research Unit with second- and third-year medical students who are expected to conduct their own experiments in psychopharmacology. The present staff of the Unit includes David M. Englehardt, Director, Norbert Freedman, Associate Director, Leon D. Hankoff, Research Psychiatrist and Director of the Treatment Unit, David Mann, Research Social Psychologist, and Reuben Margolis, Research Clinical Psychologist. The research design of the principal (long-term) project has the following essential features: (a) A free-clinic population of chronic schizophrenic patients is studied. Some patients come with a history of prolonged hospitalization, some with a history of brief recurrent hospitalization, some without previous hospitalization. The population is ethnically heterogeneous, evenly divided between males and females, and draws upon the lower socioeconomic groups. (b) Patients are given one of three commonly used agents, chlorpromazine, promazine, and placebo, and are seen in a setting which emphasizes a supportive doctor-patient relationship. The drugs are given under double-blind conditions, and drug assignment is made randomly. (6) Assessment of treatment effects is made by psychiatric ratings and psychological tests, as well as by detailed social behavior interviews administered to key relatives of the patient according to a predetermined schedule. Psychopathology and social behavior are thus independently evaluated, the former in the clinic by a psychiatrist and psychologist and the latter by the report of a relative. It is planned to assemble a cohort of 500 patients who have completed 3 months of treatment and a smaller number of patients who have completed 1 to 2 years of treatment under these relatively standard conditions. Study 1: The Role of Ataractio Treatment in the Maintenance of Community Status Treatment may affect both incidence of hospitalization and clinic dropout. Preliminary ﬁndings show that drug treatment (chlorpromazine) is associated with lower incidence of hospitalization. Our next goal is to determine the role of drug treatment in preventing hospitalization by separately studying certain criterion groups. 15 �Thus, we hope to deﬁne incidence of hospitalization on the basis of diagnosis, socioeconomic status, the relative’s tolerance for the patient, and previous hospitalizations, and to ascertain the probability of hospitalization for each of these criterion groups separately, for drug andplacebo conditions. Clinic attrition for reasons other than hospitalization is also being studied systematically. Analysis of dropout patients relative to patients remaining represents an important methodological task because of the potential bias that early attrition may introduce in the interpretation of results of change. Drug treatment does not appear to affect dropout rate. Instead, dropout appears to be affected by factors in the patient’s motivation toward treatment and certain factors in the treatment situation. Social (group membership) determinants also appear to be implicated. Study 2: The Measurement of Social Behavior and Social Behavior Change Emphasis is placed on the development of quantitative and qualitative indices of community adaptation. The instrument used is a detailed focused interview. This interview elicits from a relative a reportorial description of the patient’s activities at home and at work, covering a speciﬁed timespan. These detailed reportorial accounts by the relatives provide measures predictive of change as well as measures denoting changes per se over the course of drug treatment. Preliminary data have shown that the effects of drug treatment can be discriminated by a relative reporting on the patient’s behavior. This preliminary study has involved the use of a simple checklist of social dysfunctioning ﬁlled out by the relative. Patients on drug showed greater reductions in dysfunctional social behavior than did the patients receiving a placebo. Relatives having no awareness of the speciﬁc treatment the patient was receiving were able to make this discrimination. The meaning of these differential changes must await the detailed coding of qualitative behavioral descriptions. Study 3: Changes in Psychopathology and their Concordance with Social Behavior Changes Changes in psychopathology are evaluated by the coding of the doctors’ clinical judgments (progress notes), a detailed psychiatric rating scale, and certain psychological test performances. Psychological tests are used primarily to elucidate the meaning of changes observed on psychiatric and social behavior indices. A cluster analysis of psychiatric ratings suggests that psychiatric changes may be described in terms of two relatively independent dimensions of change, a cluster called thought disorder and a cluster called change in anxiety and treatment contact. There is a trend for patients on chlor16 promazine to show greater reduction of thought disorder than for patients on placebo. Once the social behavior indices of change are sufficiently developed, we expect to determine the degree to which psychiatric judgment and relatives’ observations concur or diverge. Speciﬁcally, we expect to inquire whether relatives and psychiatrists concur on speciﬁc aspects of the patient’s behavior (i.e., belligerence) or whether both concur that change has taken place but are in fact referring to different areas of change. Preliminary data so far indicate greater concordance of change on certain speciﬁc variables for patients on drug than for patients on placebo. Basically, this study seeks to attack the question of generality of the treatment effect. Is the treatment effect limited to change observed in the doctor’s office, or does it extend to the patient’s functioning in the community as this is perceived by a representative of the community? Implicitly, we are studying variations in the conceptions of mental health and illness as these are held by different observers. Study 4: Freedom from Functional Decrement The possibility that sustained treatment with psychopharmacological agents may bring about a decrement in the effectiveness of the patient’s functioning is especially important for outpatients, on whom the demands for effective performance in a community are greater than for inpatients. Psychiatric ratings and relatives’ reports on such variables as sluggishness, apathy, inertia, etc., are especially relevant here. Equally cogent in determining functional decrement are psychological test performances on measures of inertia and perseveration* and the Porteus Maze Test. Data on about 100 patients treated with drug or placebo for a 3-month period have been analyzed for changes in maze performance; so far we have not been able to substantiate Porteus’ general ﬁndings of a decrement with chlorpromazine treatment, but we have observed a decrement in one speciﬁc subgroup. The subgroup was characterized by a “more complex” level of cognitive organization. (See the following description of study 5.) Study 5: Prediction of Clinical Course Underlying our studies of the community adaptation of a heterogeneous group of schizophrenic patients being treated with drugs is the assumption that outcome is modiﬁed by factors within the patient and within his social mileu. Preliminary data suggest that several parameters other than drug must be considered in predicting clinical outcome: (a) The patient’s motivation toward treatment, (b) his cognitive organization, and (c) the attitude of the family toward the patient’s illness. The patient’s cognitive organization as gleaned from *See Cattell, R. B. On the measurement of perseveration. British Journal of Educational Psychology, 1935, 5, 76-92. �Rorschach responses (based on a scoring derived from Werner’s concepts) has been especially helpful in elucidating a “pattern of drug effects”: the direction of change in response to a given medication depended upon the patient’s cognitive organization. Study 6: Incidental (Nondrug) Treatment Factors In addition to the prognostic indices just enumerated, the role of several nondrug factors within the treatment situation has been observed. We have explored the signiﬁcance of the initial response to placebo and the doctorpatient relationship as they may affect the patient’s clinic attendance (dropout or hospitalization), as well as qualitative changes observed by the psychiatrist. Scoring procedures for the assessment of both doctor-patient relationship during the initial interview and response to placebo have been devised. These studies have emphasized the importance of nonverbal communication in the psychopharmacological treatment of schizophrenic outpatients. They have also delineated the contributions of the active agents to the treatment effect in some patients, but have suggested that in other patient groups the nondrug factor was prepotent. Study 7: Long-Term Drug Action Patients remaining in treatment for 12 to 24- months under drug and placebo conditions are observed at monthly intervals and their progress is then graphically charted. Our approach to long-term studies has been to select one of the more reliable change indices (psychoticism) and trace the patient’s status at successive intervals. In analyzing the time trends we have found it useful to distinguish two baselines, one at intake and a second after approximately 3 months of treatment. This second baseline permits the comparison of any further improvement or worsening in the patient’s adaptation after allowance for the initial drug effect has been made. It must be emphasized, however, that this study is always limited to patients willing and able to remain in treatment for such a long period of time. We are continually assessing differences between remainers and dropouts, so as to be in a position to detect bias introduced by the selective attrition of the sample. These long-term studies will also be corroborated by intensive case studies. Study 8: New Drug Testing The major efforts of the Unit are devoted to the study of long-term drug responses of chronic schizophrenic outpatients. Three relatively commonly used agents are employed. However, one section of the Unit is concerned with exploring the suitability of newer psycho— pharrnacological agents, speciﬁcally as they may be applicable to outpatients. Assessment methods which have proved to be useful in the larger study are also employed with the relatively brief trials of new drugs for outpatient use. With the study of new drugs we also hope to extend our information about the behavioral changes among outpatients in different diagnostic groups such as depressed patients. Studies of the following compounds have been completed or are in progress: fluphenazine (Prolixin), isocarboxazid (Marplan), imipramine (Tofranil) , and pyrbenzindole (IN—461, or 4-(1-benzyl-3-indolylethyl) pyridine hydrochloride) . In the course of conducting these studies we are accumulating a body of information about the methodology of outpatient drug testing; i.e., we are beginning to delineate the relative advantages and limitations of double-blind procedures in long-term assessment, the merits of simultaneous appraisal of an agent by the multiple clinic-community-member criteria, the utility of at least two baselines in the study of long-term trends, and the advantages of a drug spectrum of chemically similar agents which vary in presumed clinical intensity. Future Plans The ﬁndings so far support the view that the hospitalization rate tends to be lower for schizophrenic patients on active medication than for those on placebo; that psychotic symptomatology among these patients tends to be reduced by the drug; and that the adequacy of social behavior as judged by the relative appears improved, although we are not able to specify the quality of behavioral changes implicated here. Preliminary data on such variables as “psychotic thinking” also suggest that with prolonged administration of medication there tends to be less relapse with drug than with placebo. F urthermore, the data suggest that signiﬁcant variations in the effectiveness of drugs depend on the patient’s cognitive organization and his motivation toward treatment. In certain criterion groups, incidence of remission tends to be high regardless of drug treatment. In other criterion groups whose improvement is lower, the remission rate for patients on active drug exceeds the expectancy of improvement attributable to nondrug factors. Our next step in the project is to place these ﬁndings on a more solid foundation: We expect to study a sample of 5-00 patients who have received 3 months of treatment; we expect to cross-validate some of the speciﬁc predictions drawn from the initial sample; we expect to specify the meaning of the qualities of treatment outcome, particularly in the area of community behavior, through qualitative coding of behavioral descriptions by the relative; we expect to conduct certain control studies on the source of dropout, the patient’s condition after separation from the clinic, and changes in a sample of “isolated” schizophrenic patients, i.e., those not living with relatives. Finally, we hope to describe changes in subjective experiences among those patients judged by 17 �psychiatrists and relatives to be in remission. Thus, we hope to describe improvement from three vantage points, the community’s, the psychiatrist’s, and the patient’s. In most general terms, it is hoped that our Unit can contribute to the knowledge of the effectiveness of psy— chopharmacological treatment of schizophrenic outpatients by developing and delineating criteria of treatment outcome, by specifying expectancies of clinical change for speciﬁc patient groups, by indicating the role of the drug and nondrug factors in outcome, and by tracing the long-term consequences of treatment. Once this information has been derived from a large heterogeneous group of schizophrenic patients under relatively standard treatment conditions, it is hoped that newer agents can be tested more effectively; i.e., that the larger sample can be used as a reference group and that inferences can be drawn from smaller patient groups seen over briefer periods of observation. Finally, we hope that the accumulated data will increase our knowledge of the schizophrenic outpatient. Experimental Pay/chiatric Program: at Hillside Hospital, located in Glen Oaks, Long Island, N.Y., is a nonproﬁt, philanthropically supported psychiatric institution to which patients are admitted voluntarily for extensive psychotherapeutic treatment. Patients are from a predominantly middle-class, urban population, and most have high educational attainment. The programs of the Department of Experimental Psychiatry are a cluster of interrelated studies focused on common population samples. Other research laboratories in biochemistry and in medicine are active, and laboratories in psychodynamic psychiatry are being developed. The programs of the Department of Experimental Psychiatry have developed over 6 years, and are devoted to understanding of the mode of action of psychiatric therapies through studies of brain function. The principal techniques have been adapted from descriptive psychiatry, neuropsychology, electroencephalography, linguistics, pharmacology, and sociology. Members of the staff, representing various disciplines, are Max Fink, Director, Karl Anderrnann, Ira Belmont, Martin A. Green, Abraham A. Kaplan, Eric Karp, Donald F. Klein, George Krauthamer, Joseph Jaffe, John C. Kramer, Max Pollack, and Nathaniel Siegel. Former associates who contributed to these programs are Harold Esecover, Robert L. Kahn, Hyman Korin, and Henry J. Lefkowits. In initial studies of convulsive therapy, changes in brain function were found to relate both to evaluations of improvement and to pretreatment psychological variables. As our understanding of convulsive therapy developed, a general neurophysiological-adaptive view of somatic therapies emerged. In this view, psychiatric treatments are therapeutically effective to the degree that brain function is measurably altered. While change in brain function is necessary for behavioral change, the type of adaptation varies, depending upon pretreatment psychological and sociological characteristics of the subject. Thus, the mode of action is not seen as either “organic” or “psychological,” but rather as the inter18 Hz'ZZJz'de HarpiMF action of diffuse neurophysiological changes and adaptive mechanisms. Further, while behavioral change is related to changes in brain function, and the adaptive characteristics, psychological to pretreatment pattern evaluations of “improvement”—being special types of evaluation of change—are derivative judgments based on staff and family expectations and tolerances. This hypothesis was developed and sustained in a series of studies of convulsive therapy. Concurrent studies of insulin coma indicated that behavioral change here, too, was related to the onset and degree of prolonged coma or repeated seizures, these being the prin— cipal manifestations of prolonged neurophysiological change in this therapy. The mode of action of the new psychotropic agents was also expressed within this hypothesis. It was suggested that these agents would be effective to the degree that they induced persistent changes in brain function, and that the type of behavioral response would be related to the type of brain change and to prernorbid psychological (personality) patterns. The present programs in the Department are designed to study these relationships in detail. Convulsive Therapy Process Of various measures of brain function, the amount of slow wave activity in the electroencephalogram and confabulatory and denial language patterns after amobarbital were the most sensitive indices in convulsive therapy subjects. In one experiment, improvement ratings were correlated with the appearance of high degrees of change in these indices. These observations were tested in a double-blind study in which patients referred for electroshock were randomly assigned to courses of either convulsive or sub' *Prepared on request by Max Fink, Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, Long Island, N.Y. �»n-s,ww.- . . E convulsive therapy under thiopental (Pentothal) premedication. High degrees of neurophysiological change were observed only in the convulsive group; improvement rates were signiﬁcantly higher in this group; and when subconvulsive subjects were re-treated by convulsive applications, the improvement rate was similar to the original convulsive group. In the subjects given subconvulsive treatment considerable amounts of electric current passed between the bitemporal electrodes. It appeared that the therapeutic agent was not the total electrical current per se, but an all-or—none quality manifested by the grand mal seizure. The signiﬁcance of the grand mal seizure was examined in studies of the inhalant convulsant hexaﬂuorodiethylether (Indoklon). Similar degrees of electrographic change, improvement rates, types of behavioral change, and changes in neuropsychological task behavior were observed in the Indoklon group and in the electrically treated group.- It was soon apparent that not all subjects manifesting high degrees of physiological change were rated as “improved.” In a descriptive typological study, ﬁve patterns were described, empirically termed “euphoric,” “hypomanic,” “somatization,” “paranoid-withdrawal,” and “panic.” While the ﬁrst two of these adaptive modes were rated as “much improved,” the latter two were seen as “unimproved” or “worse.” In studies of psychological variables, it was reported that patients rated as much improved and recovered frequently manifested personality patterns similar to that described by Weinstein and Kahn as the “explicit verbal denial personality.” In language patterns, patients expressed the “language of denial” when diffuse brain change was induced, exhibiting such aspects as explicit denial, minimization, displacement, cliches, etc., more frequently than unimproved subjects. Other indices related to favorable outcome were high scores on the California F Scale, and Rorschach determinants of pure color, absent movement, and absent form-color. In this population, also, favorable outcome was associated with low educational achievement and foreign birth. Anticholinergic Compounds and Convulsive Therapy Seeking a way to augment the degree of postconvulsive EEG slow wave activitiy, an anticholinergic compound, diethazine, was given intravenously at various stages of the convulsive therapy process. Contrary to expectations, diethazine caused an immediate and sustained decrease in EEG slowing. Patients with denial language patterns relinquished them. Instead of feeling euphoric and experiencing a sense of well-being, the subjects became irritable, anxious, and showed symptoms expressive of pretreatment patterns. Prior to convulsive or drug therapy, diethazine induced excitement, tension, anxiety, and illusory sensations. Subsequent studies with other central anticholinergic compounds—WIN—2299 (2-diethylaminoethyl-a-cyclo- pentyl-a-(Z-thienyl)-glycolate HCl), JB—318 ( l-ethyl3-piperidy1 benzilate HCl), JB—336 (N-methyl-3-piperidyl benzilate) , and benactyzine—showed behavioral and electrographic patterns similar to those of diethazine. Similar desynchronization of postconvulsive EEG slowing was also noted with central sympathomimetic hallucinogens (amphetamine, mescaline, LSD—25), and has been reported for antihistamines (diphenylhydramine). These observations led to the suggestion that an increase in central cholinergic activity was a biochemical basis for the convulsive therapy process. Psychopharmacological Agents and EEG During this period, the mode of action of newer psychopharmacological agents aroused interest. Following the concepts derived from convulsive therapy, the neurophysiological changes induced by drugs were tested within the same acute experimental framework of the EEG setting. It was observed that phenothiazines (chlorpromazine, promazine, triﬂupromazine) induced EEG synchronization and a shifting of the spectrum to the slow frequencies; meprobamate and barbiturates induced an increased synchronization and a shift of spectrum to fast frequencies; reserpine induced an increased slowing with synchronization at low dosages and desynchronization at higher levels ; and imipramine induced desynchronization with a shift of frequencies to the slow bands. Other experimental compounds tested included BLM188 (which is 4-dimethylamino-3,4,5-trimethoxybenzanilide) and phenyltoloxamine, deanol and its various congeners, WY—214-9 (which is tropin-4-chlorbenzhydryl ether HCl), and azacyclonol. No consistent electrographic pattern was recorded for any of these compounds. It was suggested that psychopharmacological agents provide a means for eliciting a variety of neurophysiological patterns in contrast to the single pattern of induced convulsions. Furthermore, the type of neurophysiological alteration, as reﬂected in EEG synchrony and frequency patterns, was related to speciﬁed types of behavioral adaptation. Increasing EEG synchrony and a shift to slow frequencies were associated with tranquilization, sedation, and decreasing agitation, while desynchronization and a shift to fast frequencies were associated with excitement, illusions, and delusional ideation. These observations are consistent with hypotheses of Wikler. The advantages of EEG techniques for the assay of new psychiatric drugs have already been reported.* Psychopharmacology Evaluation Program The present psychopharmacology program, instituted in October 1959, was based on the studies described in the *See Fink, M. EEG and behavioral effects of psychopharmacological agents. In P. B. Bradley, P. Deniker, and C. RadoucoThomas (Eds), Neuro-psychopharmacology. New York: Elsevier Publishing Co., 1959. Pp. 441—446. 19 �preceding paragraphs. It is designed to answer the following questions: Is there a relation between measurable alteration in brain function and behavioral change with psychotropic drugs on chronic administration? Are there pretreatment clusters of psychiatric physiological and psychological variables related to the type of behavioral adaptation? And, are such clusters related to the type and degree of physiological change? Method. As an initial approximation, a double-blind drug study was undertaken in which subjects were randomly assigned to a ﬁxed-dosage schedule. On the basis of our clinical experiences with various psychotropic compounds from 1954 to 1959, we selected three classes of drugs according to their patterns of EEG response. The agents selected were those with either predominant desynchronizing patterns, synchronizing and slowing, or minimal or no effect. After medical examination and after all other medications have been discontinued, patients referred for drug therapy are randomly assigned to treatment with a compound in one of these three classes. Convulsive and drug therapies are prescribed by staff psychiatrists on referral to the Department of Experimental Psychiatry. All treatment is administered by the Department staff, so that the experimental variables of drug dosage, route of administration, assignment to groups, etc., are readily controlled. All patients in the hospital are available for study. The mean duration of stay for patients is 7 months. After a testing period, all patients receive 40 cc. of liquid medication daily from individually labeled bottles. Dosages are increased in ﬁxed weekly steps until a maximum dosage is achieved at 4‘ weeks. After 2 weeks on maximum dosage, retesting occurs. To date, 140 subjects have been referred, and 110 have completed the study period. Preliminary analyses of the data are now in progress. Behavioral Change. In a survey of the behavioral adaptations of patients receiving various agents during 1958— 59 a number of clusters of behaviors were developed. The typologies were based on the treatment response and on pretreatment psychiatric proﬁles. In the present study, the typologies are being tested and various measures of behavioral change are being studied. These include therapist referral questionnaires and 6-week evaluations; therapist’s ratings of patients on the Clyde Mood Scale; the Multidimensional Scale for Rating Psychiatric Patients, used for evaluations in interview by two research psychiatrists; the Lorr Psychiatric Behavior Rating Scales for ward behavior (AAMI: Level of Anxiety, Level of Activity, Mental Disorganization and Interpersonal Relationships); and patients’ self-ratings on the Johns Hopkins symptom checklist, the Chicago Attitude 20 Scales (self-perceptual scales devised to elicit attitudes of dependency, ﬁght, ﬂight, and pairing), and the Clyde Mood Scale. Neuropsychology. Psychological tasks have been viewed both as change variables and predictive variables. In convulsive therapy, changes in memory tasks, tactile perception, Wechsler—Bellevue, critical ﬂicker frequency, ﬁgure-ground tasks, and tachistoscopic recognition of ﬁgures were related to the degree of induced neurophysiological change. For each task, the degree of decrement in task performance was found to be positiVely correlated with the amount of EEG slowing. Following treatment completion, with the return of physiological indices to pretreatment levels, performance on these psychological tasks also returned to pretreatment levels or higher, a betterment of performance ascribed to practice effect. Denial scores on interview, Rorschach determinants, F scale scores, language patterns after amobarbital, auditory feedback, and perception of the visual upright have been viewed as predictive indices of the behavioral changes following ECT. Psychopharmacological agents are now being used to assess these various tasks, their capacity to change with various agents, or their capacity to predict change. Electroencephalography. In the studies of convulsive therapy, the degree of EEG slowing was measured by counting the consecutive waves in selected samples. When the more subtle changes of drug effects are studied, it is necessary to apply less tedious techniques. Electronic frequency analysis was introduced in August 1959. By measuring the pen deﬂection for various frequencies from 3 to 33 c.p.s. in 10-second epochs, rapid measurement of apparently small changes in total activity and frequency spectra are now obtained and applied. Other physiological variables studied in this program include the response of EEG to intravenous chlorpromazine, blood-pressure response to Mecholyl, the EKG, radioactive iodine uptake, and analyses of various blood and urine elements. Psycholinguistics Another series of studies in the Department has been devoted to formal language patterns. Following the studies of syntactic language patterns in convulsive therapy, other aspects of language were studied as indices of change in interpersonal behavior. Jaffe, after considerable exploration with various linguistic measures, suggested that type-token-ratios (TTR) of consecutive samples of dyadic speech might be a useful index. While TTR had previously been applied to written texts or to the language samples of individuals, Jaffee indicated that the two-person communication (dyad) was a more signiﬁcant index of the state of the �interaction than were analyses of separate samples from the participants. Applying this technique to patients receiving convulsive therapy, changes in TTR mean and standard deviations were related both to the degree of induced EEG slow wave activity and to syntactic language patterns obtained in independent structured interviews. Speech became more repetitive (lowered mean TTR) and more variable in consecutive samples (increased standard deviation). In interviews before and after the intravenous administration of centrally active agents, similar changes were observed. Agents with a predominant synchronization pattern on the EEG exhibited a decrease in mean TTR and an increase in standard deviation of scores, while desynchronizing compounds elicited greater variability in speech patterns (increase in TTR mean) and a decrease in variability of consecutive scores (decrease in standard deviation). Other language measures studied included distressrelief quotients, self-reference, and alteration in tense and person. It was suggested that these psycholinguistic measures are potent techniques for the operational analyses of physiological and psychological effects of psychopharmacological agents. Sociological Studies In the course of these psychiatric programs, considerable interest was engendered in the family organization to which patients were returning. Also, the general problem of the relation of social factors to choice and results of psychiatric treatment, and the speciﬁc problem of the relation of these factors to the referral patterns, led to a series of population studies. In one study, education, age, place of birth, and score on the California F scale were signiﬁcantly related to the type of therapy received and the utilization of adjunctive hospital services. Thus, patients who were older, poorly educated, had higher F scores, and were foreign born, particularly those born in Eastern Europe, were most likely to be referred for electroshock. These relationships were independent of diagnosis. Within the group of electroshock patients, the time of referral for ECT was also related to these factors. In a second study, duration of hospitalization, discharge evaluation, and diagnosis were related to the same social factors. For example, patients hospitalized for the shortest period were oldest, had the least education, were most likely to have been foreign born, and had the higher F scale scores. Younger, native-born, better educated patients who had lower F scale scores were hospitalized the longest. These relationships held true within treatment type and within diagnostic class. On discharge, older patients had the most favorable ratings. In ECT, patients rated as recovered or much improved had the highest F scores, least education, and were most likely to be foreign born. In another study of patient refusal of ECT, similar relationships were observed. These relationships are now under study in the Outpatient Department and in a trihospital comparative study. This study is assessing the populations of three hospitals, each of which has a prevailing patient population which differs from that of the other two. In each of the three hospitals, all therapies are equally available to all patients. The participating hospitals are the Menninger Foundation Hospital, whose population is primarily upper class and Protestant; the Massachusetts Mental Health Center, whose population is primarily lower class and Catholic; and the Hillside Hospital, whose population is predominantly middle class and Jewish. It has been postulated that the relationships mentioned in the preceding paragraphs reﬂect the inﬂuence of social background on psychological processes, such as habitual patterns of communication and modes of expression. The contribution of these factors to the pattern of mental illness and to the patient-therapist interaction are being investigated. Plans for Future Work Further growth and the direction of ensuing studies will depend upon the results of the investigations described here, as well as upon the growing institutional awareness that research is as much an integral part of the hospital’s operation and budgets as are patient treatment and staff training. 21 �Angler" the in Com-Leaf Chewing For many centuries, at least as far back as 1000 B.C., the inhabitants of the highlands in the Andean region have been habituated to the consumption of the leaves of Erythroxilon coca, a shrub growing in the Andean mountainsides at an altitude between 1,500 and 6,000 feet above sea level. At present, the production of coca leaves in Peru is estimated at 10 million kg. per year; approximately 40,000 acres of cultivated land are used, empIOying 25,000 workers (approximately 2 percent of the population devoted to agricultural tasks). The leaves of this shrub may be cropped on the second or third life-year, and the plant continues to produce for 20 years, yielding from three to six crops per year. The leaves are dried in the sun for several hours and then kept in cool, shadowed places until sold for human consumption. Marketing is essentially free, being only under the necessary controls for proper taxation and to avoid illegal exportation. Coca leaves are sold all over Peru, in any requested amount, from a few grams to several th0usand kilograms. Human consumption of the leaves, as such, is unrestricted. Industrial processing for the production of cocaine is forbidden by law, although frequent disclosure of illegal factories and cocaine rings calls for improved. methods of ﬁscal control. Coca leaves contain 0.60 to 1.80 percent of cocaine and 0.03 to 0.90 percent of ecgonine, according to calculations from different laboratories and varying also with the region and method of cultivation. Mention is also frequently made of the fact that coca leaves contain vitamin B1 (6 to 8 mg. per kg), riboflavin (10 mg. per kg.) and vitamin C (150 to 200 mg. per kg.). The high content of cocaine in the coca leaves becomes more meaningful if one realizes that the Peruvian people consume an estimated 9 million kg. of coca leaves per year, representing an average of 90,000 kg. of cocaine per year. The legally approved medical requirements of all the rest of the world amount only to 2,500 to 3,000 kg. per year. (This does not include the legally approved consumption in the United States. According to ofﬁcial information from Peruvian sources, the Coca-Cola Co. imports from Peru 140,000 kg. of coca leaves per year. These coca leaves are decocainized and the decocainized product is used in the manufacture of the Coca-Cola bevis turned obtained cocaine The as subproduct a erage. over to the proper authorities for legally approved consumption, the surplus being incinerated. The United States, thus, does not import or export cocaine.) The 90,000 kg. of cocaine contained in the 9 million kg. of coca leaves are consumed by approximately 2 million of the total 10 million inhabitants of Peru. These 22 million people represent 90 percent of all adult males in the highlands, 20 percent of all adult women in the highlands, and a large, but undetermined, percentage of male children over 12 years of age in the highlands. Consumption of coca leaves at lower altitudes is exceptional. The amount of coca leaf taken daily per individual varies from 10 to 100 gm. The average adult man takes approximately 30 gm. daily, but there are exceptional chewers who will take as much as 200 to 300 gm. every day. Although one speaks usually of “coca chewing,” the act of consumption may not properly be called chewing, at least in its complete process. The habitual chewer usually takes a handful of coca leaves and carefully cleans it from dirt, debris, and the main nerves of the leaf. He puts the clean leaves into his mouth and chews on them for 3 or 4 minutes until a bolus is well formed. Then he takes the bolus in his ﬁngers and pricks it deeply and repeatedly with a pointed stick which carries an alkaline powder, to be described below. The bolus is thereafter put back in the mouth and kept there, under the cheek, without chewing, for about 1 or 2 hours, during which the “chewer” sucks on it while he goes about his business. Finally, the bolus is either discarded or 2 swallowed. Usually, this process is repeated with 10 gm. of leaves every 3 to 4 hours, with interruption of current activities for about 45 minutes in order to prepare the bolus, in what might be called a “coca break.” It is exceptional to ﬁnd “chain chewing,” which brings up daily consumption to about 300 gm. per person. The addition of an alkaline substance to the bolus is a rather intriguing subject. The composition of this powder varies from region to region, ranging from plain quicklime to ground seashells or ashes of different plants. In exceptional cases, chewers do not use the alkaline subshow that evidence is to there but archeological stance, in one way or another it has been used for as long as coca has been known to man. One might speculate that this procedure increases the yield of alkaloid in the mouth, but there is conﬂicting evidence that this is a real fact. Gutierrez Noriega, one of the authorities on this subject, claims that the yield is increased by only 4 percent. Other explanations have been offered—improvement of taste, breaking up of the cellular membrane, etc.—but there is an obvious need for further research in this direction. *Prepared by Fernando Cabieses, Professor of Neurosurgery, San Marcos University, Lima, Peru. Mailing address: Talara 655, Lima, Peru. �It is generally accepted that cocaine is liberated in the mouth, being extracted from the bolus. Actually, that should not be a very difficult point to settle, but nonetheless different observers have reported very conflicting data. The actual yield, which should result from subtracting the amount of cocaine in the discarded bolus from the content of a similar amount of leaves, is difficult to obtain because of the rather frequent spitting, the swallowing of part or all of the bolus, and the different methods of titration. Published results vary from a 10- to a 90-percent yield. Also, whether the saliva contains free or bound alkaloid is not well known. At any rate, some form of cocaine is swallowed and, again, not much is known about its fate on reaching the stomach and intestine. How much of it is destroyed or further activated by the digestive juices is also in question. F urthermore, we have no information about how much is absorbed into the bloodstream or about the behavior of the gastric and intestinal mucosa exposed to bound or free cocaine. Cocaine absorbed into the bloodstream reaches the liver through the portal system, but no one really knows much about its metabolism at this level. There is some evidence that liver tissue will detoxify cocaine in vitro, and this has led to the thought that only a minimal amount of the ingested alkaloid actually reaches the general circulation. Here, again, careful evaluation is needed, since it seems that blood itself will partly destroy cocaine added to it in vitro. And, to complicate matters further, the results of determinations of cocaine blood levels in coca-leaf chewers are riddled with very difficult problems of interpretation, mainly because of the lack of appropriate methods of titration. Even if this information were available, absolute ﬁgures on cocaine blood levels would have but little meaning, owing to the lack of information on the level of neural toxicity of this substance. How high a blood level of cocaine can be tolerated without nervous effects in a normal individual, in a cocaine addict, and in a coca-leaf chewer is thus unknown. In spite of all these important questions, it is quite evident that some cocaine, or a cocainelike substance, reaches the nervous system of the coca-leaf chewers. This is easily concluded from clinical observation. Cocaine is perhaps the best antifatigue substance known to man. And it is a well proved fact that coca-leaf chewing is an excellent means of combating fatigue, both in industrial work and under experimental conditions. The possible differences between the effects of parenterally or orally administered cocaine and those obtained by chewing coca leaves, in normal as well as in habituated persons, and the action of cocaine and coca leaves on different types of fatigue remain to be experimentally evaluated. Cocaine decreases hunger sensation, admittedly through its central action. And this is also a very well known effect of chewing coca leaves, brought about either through a similar mechanism or, as commonly assumed, through local anesthetic action on the digestive tract. Whatever the mechanism is, coca-leaf chewing kills hunger. And this effect has an obvious social implication. It is said, on the one hand, that because of this action coca chewing leads to malnutrition. Other groups of sociologists claim the opposite; that malnutrition leads to coca chewing. And a third factor is brought into play when one is reminded that the coca leaves contain a fair amount of certain vitamins which are ordinarily lacking in other constituents of the usual diet of the dwellers of the high Andes. A pharmacological problem thus becomes a problem of socioeconomics and of social anthropology. Malnutrition, poverty, low culture, and coca chewing all go together, and at times it becomes almost impossible to disentangle one from the other. And if to this mixture we add high altitude, the problem becomes more and more intriguing and complicated. One cannot but wonder why, if the coca tree is only cultivated at altitudes lower than 6,000 feet, the habit of chewing coca leaves is found mainly above that level. Very few communities in the coastal area show the habit, which is mainly concentrated in the high altitudes. Futhermore, the habit of chewing coca leaves, a habit carried on continuously for many years, is usually abandoned when the individual is permanently transferred to lower geographical levels. And one cannot dismiss the frequent claims of travelers and of cultured dwellers of the highlands regarding the beneﬁcial effects of coca tea or coca chewing against the acute symptoms of mountain sickness. Unfortunately, no experimental evaluation has been made of these observations, which have been subject to much literary discussion in years past. It is true, of course, that high altitude is only one of the factors of a very complicated problem seen through the narrow light of an off—habit, on-habit proposition. But only a careful experimental approach will tell us what the real importance of this factor is, especially in the presence of a drug with as many unpredictable pharmacological actions as cocaine. It is commonly accepted that cocaine has a deleterious effect on the central nervous system when taken chronically. And it is only logical that this concept has been used in the interpretation of the mental functions of the coca-leaf chewers. This assumption, however, may not be entirely justiﬁed, since most of the alleged “facts” lack experimental veriﬁcation. The so-called effects of chronic consumption of coca leaves are always related to the other factors of the socioeconomic complex sur‘ rounding the coca habit; poverty, malnutrition, low culture, poor educational facilities, high altitude, etc. And although coca may be an important determining cause, the alleged low mental output of the Andean dweller should not be blamed only on this factor, as it frequently is. The appraisal of chronic coca-leaf consumption com23 �pletely separated from its socioeconomic constellation is, however, very difﬁcult to achieve. The acute action of coca-leaf chewing on mental processes also lacks sound and thorough experimental evaluation. A few experiments suggest that the effects are quite different in habituated and nonhabituated individuals, as would logically be expected. The extent and mechanism of these differences remain to be determined. There is also some indication that muscular activity during the process of coca chewing basically alters its mental effects. It is said that if the individual is resting, daydreaming and pseudohallucinations ensue, but that these mental effects can be prevented by physical activity. These observations need further experimental study, but this type of psychopharmacological study would meet with great obstacles in the markedly introvert personality of the Peruvian Indian, his resistance to participation in experimental studies of this type, the frequent language difﬁculties, and the lack of basic psychological and social anthropological studies in the Andean milieu. It is thus evident that there are many questions to be answered concerning the pharmacology of coca leaves and the socioanthropological aspects of this widespread habit. Differences between the chronic or acute effects of parenterally administered cocaine (a subject on which much remains to be settled) and the chronic or acute effects of coca-leaf chewing should be investigated. The 24 former leads to a rather well known condition: cocainism, i.e., addiction to cocaine. The latter leads to a habit, cocaism, which apparently does not follow the same psychopharmacological pattern, since a simple change in socioeconomic status or a change in geographical milieu leads to its spontaneous discontinuance; there is not a clear tendency to increase the dosage, as there is in cocainism, nor are there any evident withdrawal symptoms. Are these differences due only to the route of administration of cocaine? One certainly can provoke a clear syndrome of cocaine addiction in experimental animals (dogs, monkeys) by chronically administering cocaine by the parenteral route. But so far it has not been possible to obtain similar results by oral administration of this drug. Research Opportunities There are many stimulating areas for research on cocaleaf chewing. Facilities for research in this ﬁeld are potentially available at the Brain Research Center of the Armed Forces of Peru, of which I am director, and at the American Hospital in Lima, which has a good neurological and neurosurgical service. Investigators who wish to explore the possibility of conducting research related to coca-leaf chewing, or who wish to obtain further information, are invited to write to me at the following address: Dr. Fernando Cabieses, Talara 655, Lima, Peru. �Publications Tranquilizing and Anti-Depressant Drugs. Veterans Administration Department of Medicine and Surgery Medical Bulletin MB—6, September 12, 1960. Washington, D.C.: U.S. Government Printing Ofﬁce. This 19page bulletin is by Eugene M. Caffey, Jr., Leo E. Hollister, Alex D. Pokomy, and Jesse L. Bennett, all of whom are members of the Executive Committee of the Veterans Administration Cooperative Chemotherapy Studies in Psychiatry. It presents a general summary of current practices in the use of tranquilizers and antidepressives in psychiatry and in nonpsychiatn'c practice, and includes tabulations of generic names, trade names, and range of total daily dosage of drugs for outpatients and for hospitalized patients. The price of the publication is $0.15. Copies should be ordered from the Superintendent of Documents, U.S. Government Printing Ofﬁce, Washington 25, DC. Agressologie, an International Review of Physio-Biology and Pharmacology Applied to the Eﬁ‘ects of Agression, is a recently established journal that should be of interest to psychopharmacologists. In the preface to the ﬁrst issue, the title of the journal is explained: The commonly understood meaning of the word aggression is applied to the action of agents which harm the living organism by attacking it abruptly (from the outside or from the inside), including cold, heat, lack of air, surgery, disease, poisoning, and other causes of physiobiological disequilibrium which results in “more or less profound and lasting disturbances” in cellular metabolism. The purpose of the journal is to synthesize and integrate contributions which many basic disciplines are making to the study of the effects of “aggression” as previously deﬁned, and to the prevention and treatment of such effects. The journal is being published and edited by Henri Laborit, of the H6pital Boucicaut, 78 rue de la Convention, Paris 15, France, and P. Huguenard, of the Hopital de Vaugirard, Paris 15, France. Metabolism of, and Analytical Methods for, Phenothiazine Derivatives Used in Psychopharmacology; A Selected Annotated Reference List, compiled by the Scientiﬁc Information Unit of the Psychopharmacology Service Center. This list of approximately 65 references is made up primarily of articles concerned with analytical methods for the detection of phenothiazine derivatives used in psychopharrnacology, together with a few more general articles on the metabolism of these agents. The annotations are factual summaries of the articles, and are not evaluative or critical. The list is arranged chronologically. Copies may be obtained by writing to: Dr. Lorraine Bouthilet, Head, Scientiﬁc Information Unit, Psychopharmacology Service Center, National Institute of Mental Health, Bethesda 14, Md. 25 U. S. GOVERNMENT PRINTING OFFICE: 1961 0- 580375 �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Experimental Psychiatric Programs at Hillside Hospital, Psychopharmacology Service Center Bulletin, January 1961 (U.S. Department of Health, Education, and Welfare) Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-001-0-009 Date A point or period of time associated with an event in the lifecycle of the resource 1961 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Article based on Hillside Hospital annual report. One of nine articles in the Psychopharmacology Service Center Bulletin: NIMH-sponsored collborative study of phenothiazine treatment of acute schizophrenic psychoses; NIMH grant support for early clinincal drug evaluation units; Research conference on drugs and community care; Confernce on informaiton needs of psychopharmacologists; The psychopharmacology research unit at the Downstate Medical Center, Brooklyn N.Y.; Experimental psychiatric programs at Hillside Hospital; Coca-leaf chewing in the Andes; Publications. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/07a3d1b2eec1cf62891da3ff4c4049c8.pdf f5bf70eb575371f639319602e2837d97 PDF Text Text EXPERIMENTAL PSYCHIATRIC RESEARCH AT HILLSIDE Review and Prospect MAX FINK, M.D. Reprinted from JOURNAL OF THE HILLSIDE HOSPITAL Volume X ° Nos. 3-4 ° July-Oct. 1961 �EXPERIMENTAL PSYCHIATRIC RESEARCH AT HILLSIDE Review and Prospect MAX FINK, MD. The dedication of Hillside Hospital as a Research Institute has been a dream of many of its students—a dream that may achieve realization in this decade. Dr. Tarachow was an early proponent of this view; and both in his sponsorship of the Journal, and in his encouragement of research studies, he presaged this development. He was also the inadvertent sire of the research studies in experimental psychiatry. While I was a resident in psychiatry in 1952, we collaborated in a study of the relation of the early separation of child from a parent to the adult choice of neurosis. Reviewing the hospital records of ﬁve previous years we concluded that there was, indeed, a relation—— neurotic patients with obsessional neuroses had a signiﬁcantly, greater incidence of separation than patients with hysterical neuroses (2). This report was the beginning of the patient population studies described here. Since 1954 the various programs in experimental psychiatry have been devoted to an understanding of the mode of action of the psy- chiatric therapies of the hospital. The techniques have been adapted from descriptive and dynamic psychiatry, neuropsychology, electroencephalography, linguistics, pharmacology, and sociology. This report reviews these studies and presents support for the creation of a Research Institute at Hillside. PAST STUDIES In our early studies of convulsive therapy, instituted with the 1 From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, N. Y. The studies reported here have been aided by the Board of Directors Research Fund; the National Institute of Mental Health (Grants M-927; MY-2092,-27l5, -4798; MF-12,033); Foundations Fund for Research in Psychiatry (FFRP 56-151); Kaufmann, and Dazian Foundations; and numerous pharmaceutical concerns including Geigy, Bristol, Wyeth and Smith, Kline 8c French Laboratories. 159 �160 MAX FINK aid of a grant award of the National Institute of Mental Health, evaluations of patient improvement were shown to be dependent both on changes in brain function and on psychological factors. As our understanding of convulsive therapy developed, a general neurophysiologic-adaptive view of somatic therapies emerged (6). A change in brain function was seen as a necessary condition for behavioral change, with the type of change varying, depending upon psychological and sociological characteristics of the subject (22, 25). Thus, the mode of action was not seen as either “organic” or “psychological” but rather as the interaction of neurophysiological changes and individual patterns of response and behavior. This hypothesis was sustained in studies of convulsive and in sulin coma therapies (21, 22); and the mode of action of the new psychotropic agents was expressed within this hypothesis. It was suggested that psychotropic drugs would be effective to the extent that persistent changes in brain function were induced; and that the type of behavioral response would be related to the type of brain change, and to individual premorbid psychologic (personality) patterns (6, 28, 40). Convulsive Therapy Process: Seeking a measure of altered neurophysiological change that was sensitive and suitable for repeated retests, various measures were studied including changes in the face-hand test (1, 10, 13, 35), memory tests (17, 35), amount of slow-wave activity in the EEG (16, 23) and confabulatory and denial language patterns after amobarbital (3, 15). The latter two, EEG and amobarbital tests, were the most sensitive indices of change in convulsive therapy subjects. In one experiment, clinical ratings of improvement were correlated with high degrees of change in these indices (15, 16). These observations were tested in a double-blind study in which patients referred for electroshock were randomly assigned to either convulsive or subconvulsive therapy. High degrees of electrographic slow-wave activity and positive amobarbital tests were observed only in the convulsive group; improvement rates were signiﬁcantly higher in this group, and when subconvulsive subjects were retreated by convulsive applications, the improvement rate was similar to the convulsive group (22). In subconvulsive applications, considerable electric current passes between the electrodes. It was postulated that the therapeutic agent was not the total electrical current per se, but the “all or none” quality manifested by the grand-ma] seizure (9, 23, 42). The signiﬁ1. �EXPERIMENTAL PSYCHIATRIC RESEARCH 16] cance of the grand-mal seizure was examined in a comparative study of the inhalant convulsant, hexaﬂuorodiethylether (Indoklon), and electrically induced seizures. Similar degrees of electrographic change, improvement rates, types of behavioral adaptations, and changes in neuropsychological task behavior were observed in both the inhalant and in the electrically treated groups (49). However, not all subjects manifesting high degrees of physiological change were evaluated as “improved.” In a descriptive typologic study, ﬁve adaptive modes were described, empirically termed “eu— phoric,” “hypomanic,” “somatization,” “paranoid-withdrawal," and “panic.” While the ﬁrst two patterns were rated as “much improved,” the latter two were seen as “unimproved" or “worse” (50). In studies of psychological variables, it was reported that patients rated “much improved” and “recovered” frequently manifested personality patterns akin to the explicit verbal denial personality type (37). These patients expressed the “language of denial” more frequently than unimproved subjects, exhibiting such aspects as explicit. denial, minimization, displacement and clichés (27). Other psychological indices also related to favorable outcome included high F Scale score (42), Rorschach determinants of color, absent movement and absent form-color (30, 45), and low educational achievement and foreign birth (31). 2. Anticholinergz'c Compounds and Convulsive Therapy: Seek-ing a way to augment the degree of postconvulsive EEG slow-waveactivity, an anticholinergic compound diethazine, was given intravenously at various stages of the convulsive therapy process (20, 24).. Unexpectedly, diethazine caused an immediate and sustained de-crease in EEG slowing, which was associated with marked changes. in language and mood. In patients with denial language patterns. (27), these could no longer be elicited. Instead of euphoria and wellbeing, the subjects became irritable, anxious, and complaining. In‘ subjects prior to convulsive or drug therapy, diethazine induced, ex-citement, tension, anxiety, and illusory sensations. Subsequent studies with other central anticholinergic compounds" and sympathomimetic hallucinogens showed behavior and electrographic patterns similar to diethazine. These observations led to the suggestion that an increase in the cholinergic activity of the central nervous system was the biochemical basis for the convulsive therapy process (38). Psychotropic Drugs and EEG: Following these studies, the: neurophysiological changes induced by drugs were testedwithinan. 3. �162 MAX FINK acute experimental-EEG setting. It was observed that phenothiazines induced EEG synchronization and a shifting of the frequency spectrum to the slow frequencies; meprobamate and barbiturates, an increased synchronization and a shift of the spectrum to fast frequencies; reserpine, an increased slowing with synchronization at low dosages, and desynchronization at higher levels (18, 26, 28, 40). Imipramine induced desynchronization with a shift of frequencies to the slow bands (33, 34). Each active psychotropic compound was thus shown to have a characteristic frequency pattern. Various other experimental compounds were also tested, and for these no consistent electrographic pattern was recorded. These compounds have since been shown to have either no or very limited clinical psychotropic activity. The absence of behavioral change with these compounds lent further support to the assumption that brain change is a necessary condition for the action of psychotropic drugs. These observations suggested that psychopharmacological agents provide a means for eliciting various types of altered brain function in contrast to the single pattern following convulsive therapy. Furthermore, the type of neurophysiological alteration, as reﬂected in EEG synchrony and frequency patterns, was found to be related to speciﬁed types of behavioral adaptation. The advantage of EEG techniques for the assay of new psychotropic agents and the technical merits of electronic frequency analysis were assayed and described (47, 52). 4. Insulin Coma Therapy: In our insulin coma studies we con- ﬁrmed earlier observations that persistent alterations of brain function were related to prolonged coma and spontaneous seizures; and saw in this relationship support for a neurophysiologic-adaptive hypothesis. With the availability of the new psychotropic agent chlorpromazine, a controlled chlorpromazine-insulin coma study was undertaken in September, 1955. As patients were referred for insulin coma they were randomly assigned to courses of either oral chlorpromazine for at least three months in doses adjusted to fall short of toxicity; or insulin coma, induced by a standard technique at least ﬁfty times in each patient. While a number of minor differences were noted in comparing the two therapies, the results at time of discharge showed no statistical difference in the effectiveness of both treatments. Neither treatment seemed to affect the basic schizophrenic process, but chlorpromazine had the advantage of being safer, easier to administer, and better suited to long-term management (21). Concurrently, following the suggestion by the Creedmoor workers that �EXPERIMENTAL PSYCHIATRIC RESEARCH 163 divided insulin doses were superior to single insulin doses, Blumberg and Laderman (39) essayed this problem and demonstrated no significant merit to the multiple-dose technique. (In 1958, following the general conﬁrmation of these observations, insulin coma therapy was discontinued at Hillside). 5. Neuropsychology: Various psychophysical tests were adapted from neuropsychology, where their signiﬁcance in brain-damaged subjects had been demonstrated. The early studies assessed these tasks as indices of altered brain function (35), and measured the range of performances of psychiatric patients, who are generally assumed not to be brain-damaged. Thus, memory function was assessed on immediate recall, after various interpolated learning tasks (17, 35), as well as during convulsive therapy (17). Tactile perceptual tasks were ﬁrst examined in the clinical population (1). Later, with more sensitive electrical tactile stimuli, Korin (10) observed the range of thresholds in different body parts, the changes with altered brain function (10), and the inﬂuence of set (instruction) on performance (36). We also studied the perception of embedded geometric ﬁgures (43), tachistoscopic presentation of embedded color ﬁgures (55), perception of the visual upright (55), critical ﬂicker frequency (49), and interference in reading time by delayed auditory feedback (55). For each task, the degree of decrement in task performance was found to be positively correlated with the amount of EEG slowing. Following treatment completion, with the return of physiological indices to pretreatment levels, performance in these psychological tasks also returned to pretreatment levels, or higher—a betterment of performance ascribed to practice effect. Concurrently, assessment of various psychological measures as indices predictive of behavioral change during convulsive and drug therapies led to studies of the Rorschach determinants (30, 45), California F Scale scores (30, 42), language patterns after amobarbital (27), denial scores on interview (37), and the perception of the visual upright and auditory feedback (55). 6. Psycholinguistics: Concurrent with the syntactic language studies (27), analyses of other language patterns were undertaken, both in a search for more objective indices of behavioral change and to gain experience in the technical problems of tape analysis for psychotherapy research. An index of variability in the vocabulary of speech, the type-token ratio (TTR) of consecutive samples of dyadic speech, was extensively studied (7,41, 44, 46, 56, 57). In convulsive therapy patients, signiﬁcant changes in TTR mean �164 MAX FINK and standard deviations were related both to the degree of induced EEG slow-wave activity and to syntactic language patterns obtained in independent structured interviews. It was noted that speech became more repetitive (lowered mean TTR) and more variable in consecutive samples (41). In interviews before and after the intravenous administration of centrally active agents, similar changes were observed. Agents which produced predominant synchronization patterns on the EEG were related to a decrease in mean TTR and an increase in the standard deviation of scores, while desynchronizing compounds elicited greater variability in speech patterns and decrease in variability of consecutive scores (44). Other language measures studied included distress-relief quotients, self-reference, and alterations in tense and person. It was suggested that these psycholinguistic measures are useful techniques for the operational analyses of physiological and psychological effects of psychopharmacological agents (44, 46). 7. Brain Damage and Schizophrenia: Following his studies at Ittleson Center, Pollack reviewed the relationship between age of hospitalization, intellectual functioning and prognosis in schizophrenic children and adults. He noted that initial hospitalization in childhood and adolescence was related to I. Q. scores in the subnor— mal range, deviant performance on psychomotor tasks, and more frequent ratings of “unimproved” at hospital discharge than was initial hospitalization as an adult. The early and insidious onset of the behavioral syndrome “schizophrenia” was thus related to brain dysfunction (54). Findings suggest that different subgroups of schizophrenia may be classiﬁed on the basis of neuropsychological deviancy. 8. Sociological Studies: Considerable interest in the family organization to which discharged patients were returning, the relation of social factors to choice and results of psychiatric treatment, and the speciﬁc problem of the relation of these factors to treatment referral patterns led to a series of population studies. In one study (8), education, age, place of birth, and score on the California F Scale were signiﬁcantly related to the type of therapy received and the utilization of adjunctive hospital services. In a second study (3]), duration of hospitalization, discharge evaluation, and diagnosis were related to the same social factors, while in a study of patient refusal of ECT, similar relationships were observed (51). These observations suggested a comparative interinstitution study, and among three hospitals the relationships between social class and other demographic variables (age, sex, education) to the clinical �EXPERIMENTAL PSYCHIATRIC RESEARCH 165 variables of patient classiﬁcation (diagnosis), duration of hospitalization, selection of therapy, and discharge evaluation have been assessed. Three teaching institutions were selected in which all therapies are equally available to all patients—Menninger Foundation Hospital (upper-class, Protestant), Massachusetts Mental Health Center (lowerclass, Catholic), and Hillside Hospital (middle-class, Jewish). In such a comparison we have found the differences in designations of treatment, diagnosis, and discharge evaluation so marked as to make comparisons difﬁcult. While many relationships between social variables and clinical variables were observed in each hospital, no social variable was found related to the clinical variables in every hospital (53). In an outpatient department study, sex, age, and marital status were found to be related to the acceptance and rejection of patients and failure to complete the application process (55). These observations in population samples led to concurrent studies of staff attitudes in the selection of therapy (ll, 12). In a series of ward observation studies, Kaplan and Lefkowits indicated the signiﬁcant role of staff attitudes (especially nursing personnel) in the referral for subjects for somatic therapies, and in the transfer of patients from one ward to another. (To study the inﬂuence of staﬁ attitude on patient selection for drug therapy, we requested one ward be designated as a “no-movement” unit. This was adopted in September, 1959 and shortly thereafter by the whole hospital.) PRESENT STUDIES During the period of the convulsive therapy studies, many new psychotropic compounds were assessed clinically (5, 21), electrographically (34, 40, 48), and psychophysically (48). The present psychopharmacology evaluation program, based on these studies, was designed to answer the following questions: 1. Is there a relation between measurable alteration in brain function and behavioral change with psychotropic drugs on chronic administration? 2. Are there pretreatment clusters of psychiatric, physiological, and psychological variables which are related to the type of behavioral adaptation? 3. Are such clusters related to the type and degree of physiologi- cal change? As an initial approximation, a double-blind, ﬁxed dosage, ran- �166 MAX FINK dom assignment drug study was undertaken. Based on our clinical experiences three types of compounds were selected on the basis of their EEG patterns. In this study, 203 subjects were referred, and 149 have completed the testing program, from October, 1959 to July, 1961. l. Behavioral Change: In a survey of the behavioral adaptations of patients receiving various psychotropic compounds during 195859, a behavioral typology based on the treatment response and on pretreatment psychiatric proﬁles was developed (55). In the present study, the typologies are being tested, and various measures of behavioral change studied, including therapist ratings, self-ratings, and various ward observation scales. 2. Neuropsychology: Psychological tasks have been viewed both as indices of behavioral change and as predictive guides in convulsive therapy. Each of these tasks and a selected group of motor tasks are now being assessed for both their capacity to reveal change with various drugs and their capacity to predict change with the drugs in. this program (48). 3. Electroencephalography: In the convulsive therapy studies, the degree of EEG slowing was measured by counting the consecutive waves in selected samples (16). When the more subtle changes of drug effects are studied, it is necessary to apply less tedious techniques (48), and electronic frequency analysis was introduced in August, 1959. By measurement of the pen deflection for various frequencies from 3 to 33 cps in ten-second epochs, rapid measurement of apparently small changes in total activity and frequency spectra are obtained (52). Other physiological variables studied in this program include the response of EEG to intravenous chlorpromazine, blood pressure response to mecholyl, the EKG, radioactive iodine uptake, and analyses of various blood and urine elements. 4. Data Analysis: To analyze the data generated in this study, we have sought the aid of complex statistical methods and computational facilities. Analyses of covariance, correlation matrices, factor analyses, and discriminant function analyses are computations now in progress with these data at the NIMH Psychopharmacology Service Center’s Biometric Laboratory in Washington. THE NEXT STEPS Favored by a national research climate and a cooperative hospital staff, these studies have proceeded vigorously. The assets for research in this setting have been great—a selected, intelligent patient popula- �EXPERIMENTAL PSYCHIATRIC RESEARCH 167 tion resident from six to twelve months, without individual economic limitation of hospital stay; a sophisticated administration tolerant of controlled studies; and approval of a Board of Directors who desire “research” as an institutional function. As Dr. Lewis Robbins noted in his ﬁrst hospital report in 1959, a specialty hospital can make little impact on the mental illness problems of the community by treatment alone. The successful treatment of 350 patients a year is but little comfort to the 40,000 resident patients in the state hospitals of Long Island. Nor will the annual training of twenty or thirty physicians in the arts of psychotherapy do much to help these unfortunates or the many thousands of ambulatory mentally ill resident in the nation. No, a therapeutic goal alone is salutary but inadequate to our needs. As he proposed, the answer may lie in the dedication of a “research hospital,” as it is here that a specialty hospital can truly excel. The charter has been written in the Board’s assertion of research as a hospital goal. With the assets of an exemplary therapeutic facility, such rededication can provide the stimulus for the continuous study of the cause of mental illness and of methods of therapy. Such dedication would provide the stimulus for comparative and controlled assessments of different therapeutic techniques. Continued study is urgently required of the selection of patients for various therapies; the application and mode of action of the therapies; and the role of social and milieu factors in supporting the effects of our ther- apies. Assessments require a meaningful classiﬁcation of subjects. The behavioral variables alone, which are the basis of our present diagnostic schemata, are unsatisfactory. Study is urgently required of the applicability of social and demographic variables; psychological task performance proﬁles; typologies based on behavioral response to deﬁned stresses or drugs; and physiological reactivity measures. Such classiﬁcations are also essential for any biochemical, physiological, or evaluative study to provide homogeneous samples and comparable controls. Assessments also require meaningful indices of evaluating change. Present global “improvement” ratings and socialization measures are inadequate. Whether the intervening variable be milieu therapy, psychotherapy, drug therapy, or time, the criteria of behavioral change require deﬁnition. The applicability of rating scales, language tasks, self-ratings, psychophysical change scores, family assessments, etc., require study and evaluation. Recent studies of psychotic subjects have provided the suggestion �MAX FINK 168 that there is a neurologic factor in a group of the schizophrenias. The high incidence of electrographic and neurologic dysfunction, the lack of behavioral response to all therapies, and the relentless course of the illness suggest an “organic” involvement in this cluster. Such a substrate must be clearly sought by the application of biochemical, neurophysiological, and epidemiological techniques to various clus- ters of young psychotic subjects. These are broader views of some of the questions studied in the programs in experimental psychiatry of the past seven years. These programs, and the contemporary projects in biochemistry and in medicine, provide models of bootstrap studies undertaken with limited support. A dedication of Hillside Hospital as a Research Institute will provide the needed focus and impetus for the scientiﬁc and humanitarian forces of the community to join in a common endeavor to resolve the problems of the mentally ill. Acknowledgment: Participants in these programs include the present members of the Department of Experimental Psychiatry: Ira Belmont, Martin A. Green, Abraham Kaplan, Eric Karp, Donald F. Klein, John C. Kramer, Max Pollack, and Arthur Willner. Former associates included Karl Andermann, Joseph Jaffe, Robert L. Kahn, Hyman Korin, George Krauthamer, Nathaniel Siegel; and Research Fellows Barre Alan, Fred Coleman, Harold Esecover, Stanley Friedman, Henry J. Lefkowits, and Robert Shaw. The cooperation of Arnold G. Blumberg of the Department of Medicine in the present program is gratefully acknowledged. The reports listed here are the result of the collaboration of these workers and the professional staffs of the hospital who gave unstintingly of their time and their good-will. REFERENCES' (1) This Journal, 1:21, 1952; (2) ibid., 2:67, 1953; (3) ibid., 4:3, 1955; (4) ibid., 4:134, 1955; (5) ibid., 5:67, 1956; (6) ibid., 6:197, 1957; (7) ibid., 6:207, 1957; (8) ibid., 6:216, 1957; (9) ibid., 6:229, 1957; (10) ibid., 6:241, 1957. This Journal, 10:84, 1961; (12) ibid., 10:97, 1961; (13) Neurology, 4:211, 1954; (14) Arch. Neurol., Psychiat., 72:233, 1954; (15) ibid., 76:23, 1956; (16) ibid.‘, 78:516, 1957; (17) Conf. Neurol., 16:88, 1956; (18) EEG Clin. Neurophysiol.,9:180, 1957; (19) ibid., 10:162. 1958; (20) ibid., 10:207, 1958. (21) J. Am. Med. Assn., 166:1846, 1958; (22) Dis. Nero. Sys., 19:113, 1958; (23) ibid., 19:227, 1958; (24) Arch. Neurol., Psychiat., 80:380, 1958; (25) ibid., 80:73, 1958; (26) Neurology, 8:682, 1958; (27) Psychopathology of Commum'cation, New York: Grune 8c Stratton, 126, 1958; (28) Psychopharmacology Frontiers, New York: Little, Brown, 325, 1959; (29) Proc. XV Int. Cong. Psychol., North Holland Publ., 238, 1959; (30) J. Nerv. Ment. Dis., 1281243, (11) 1959. (31) Arch. Gen. Psychiat., 1:565, 1959; (32) EEG Clin. Neurophysiol., 11:398, �EXPERIMENTAL PSYCHIATRIC RESEARCH (41) (51) 169 1959; (33) ibid., 12:243, 1960; (34) Canad. Psychiat. Assn. 1., 4:166S, 1959; (35) Proc. Int. Cong. Neurol. Sci., Pergamon, 613, 1959; (36) Am. J. Psychol., 72:384. 1959; (37) J. Neuropsychiat., 1:45, 1959; (38) EEG Clin. Neurophysiol., 12:359, 1960; (39) Am. J. Psychiat., 116:839, 1960; (40) Neuro-Psychopharmacol., 1:441, Elsevier, 1960. J. Nerv. Ment. Dis, 130:235, 1960; (42) ibid., 130:187, 1960; (43) Arch. Neurol., 2:547, 1960; (44) Dynamics of Psychiatric Drug Therapy, Springﬁeld: Thomas, 29, 1960; (45) ]. Neuropsychiat., 1:242, 1960; (46) Am. J. Psychother., 15:46, 1961; (47) Neuro-Psychopharmacol., 2:30, Elsevier, 1961 ; (48) ibid., 2:381, 1961; (49) Arch. Gen. Psychiat., 4:259, 1961; (50) ibid., 5:30, 1961. J. New. Ment. Dis., 132:153, 1961 ; (52) Medicina Experimentalis (in press); (54) Arch. Gen. Psychiat., (53) VA Conf. Psychopharmacology (in press); 2:652, 1960; (55) Unpublished manuscript; (56) Psychiatry, 21:249, 1958; (57) Comparative Psycholinguistic Analysis of Two Psychotherapeutic Interviews. New York: Int. Univ. Press, 1961. ' Due to the length of this Bibliography, it is presented in an abbreviated form. ��IIPRIIIBIIAL PBIGIIATEIO 13831303 A! IILLBIBI noiiow and Proapoct HI: Pink, 3.9. Iron tho Dopsriuont of Export-cutnl Psychin$ry, 31113160 Hospittl, clan Oaks, L.I., 1.!. 2h. Itud1ﬁl roportod hart hi1. baa: ntdud hr tho Board Dir-ctoro Research Fund; thc lttiannl Instituto or I: Honttl nutlth (Grants l-927; I!-2092,-2715,-h7983 nr~12,033); POIndationl Fund for honoureh 1: Psychiatry (373? 56-151); xuutnan§, tad Dalian fantastical; and lustrou- pharnao ooutionl cost-rap tncIudinx 60131, Briatbl, Wrath and Snith, K1130 a Iroach Lnboratorioa. 1': 10/1/61 �Exporinontol Poyohtotrio Rooooroh ot Htlloido lovtov ood Proopoot tho dodtoottou of 3111-14. Boopttol oo o Rooooreh Inotttoto boo boon o drooo o! nony or 1to otudooto - o drool that nay oohiovo rooliootion in thin dooodo.< Dr. 3. toroohov woo on oorly propoooot of thio vtow, ood both in hto oponoorohip of tho Joorool, ond to his onooorozonont or rooooreh otldtoo, ho prooosod thio dovolopuoot. no woo oloo tho toodvortoot oiro at tho rooooroh otodtoo 1n oxporioontol poyohtotry. “halo 1 woo o rootdoot 1n poyohtotry to 1952, no oolloborotod in o otudy or tho ro~ lotion of tho oorlr ooporotsoo of child tron o ohotoo tho poroot to odolt of uoorooto. notion13¢ tho hoopttol rooordo o: ttvo proviomoyyooro no oonolodod thot thoro woo, todood, o rolotioo nourotto pottooto with otooooionol oouroooo hod oigoitxoootly xrootor tooxdoooo o: ooporotioo thou potiooto with hyotoriool oonroooo (a). rhto roport woo tho boctooinc of tho potioot popolottoo otodxoo dooorabod horo. stnoo 19Sh tho vortooo progrooo 1o exportoontol poyohiotry hooo boon dovotod to on ondorotoodtog of tho undo o: o U �.2.- antioo of tho poyehiatric thoropioo of tho hoopitol. rho tochniquoo hovo boon odoptod tron doooriptivo ood dylooio payohiotry, oouropoyoholou, olootroonoopholonophy, linguiotiuo, phoroooology, ood sociology. Ihio roport roviowo thooo otudioo ond prooooto support for tho erootion or o nooooroh lootitoto ot lilloido. PIS! SIFDIBS In our early ttudioo or oonvoloivo thoropy, inotitotod with tho oid o: o grout oword of tho Iotionol Institoto o: nontoi Roolth, ovoluotioal o: potioot iaprovonont woro ohown to to dopoodont both on choocoo in broio function ond on poyoholociool tootoro. AI our Indorotondioz of oonvoloivo thoropy dovolopod, o gonorol nooropnyoioloxio~ odoptivo viow'o: ooIotio thoropioo ooorgod (6). i cholgo in brain function woo oooo oo o noooooory condition for hohoviorol ohonuo, with tho typo or chooco, houovor, voryiu; dogoadin; upon poyoholocicol oud oooio— logiool chorooto'iotioo ox tho outjoot (22,25). thou, tho oodo o: ootioo woo not too: oo oithor “orgooie' or ”prlyoholouinl' but rotbor oo tho iotoroction or non-ophyoiologiool chooaoo nod individual pottoroo o: rooponoo oud bohovior. fhio hynothooio ' woo oootoiood in otodioo or convulsivo old insulin oono thoropioo (21,22); and tho oodo or action of tho now psychotropic oconto woo ozprooood within thin �.3. payohoiropic'drugn that It would bu urinativo to tho uxtnn‘ thu‘ pcrllutcnt ehgugon k.— ﬁypo or tho tad induncd; that brain Inuation ugro in hnvtoral reopens. would bu rolntcd to tn. iypo o: br¢1a hypothosta. wan unggun‘od chnnga, and to individual pro-norb1d psychologie (par-caulitr) vtttnrns (6,28,ho). consu1;1v3 thcrngz Draco-s: Soaking a noncaro of gltorcd nourOphgstoleglogl «hangs that w:- annuitivo 1. tnitnblo for rcpol#od rutolta, various nan-urns wort studigd inpludinx chanson in tho ts¢o~hand tout (1,10,13,35), nanory tout; (17,35), anoant .1 slow utvn activity 1» tit :30 (16,23) tld contnbulatory and duaial languago pﬁt‘Orll attur nuebarbitul (3,15). an. llttor two, EBB und unubnrbittl touts, Hit. tbs nest oonlttlvo indie.- o: chaulc 1a convulnivo thgrtpy subjects. In on. uxpcrincnt, clinical rating: a: taprcvcﬁont var. carrolatod wi‘h high 6.320.! of chungo in than. indicol (15,16). 2)... oblcrvutlon: wore touted 1n n doublo-bltnd study in which p;titntl tutorrod tor oloctroahock worn rindauly ‘3313306 to oithor convulsivo cr anhconvnlsivu and . therapy. nigh dour-on o£_oltetrogrnphic Ilcw wave :otivity and pastﬁivg nnﬁbarbttnl tout: warn obsorvod only 13 the convulaivc group3~1nprovcutnt titan were algntticuntly highQr in this group, and whnn subconvn1I1Vt aubjccto var. retransod by convulnsvo applications, (he tnprovogout rat. way 31:31.: to tho ooarulstvo ureup (22). �.3. In sibeonvuluivo applications, nousidornblo oloatric current pgaau: botwugn the cleatrudou. It wan pontulntod that tho ihcrapoustc tguut was nut tin $Otl1 olootrt¢:1 current, r so, but_thu ":11 or nonn' quali$7 llhiftl‘td by tho crana 331 Ittluro (9,23,h2). 2h. Itcniriounao o: tut [rand 3:1 .oisuro was «an-$306 in n ounparuttv. study of sh. 13ha1:nt oonvulutut, lnxaflnnrodiothylathnr (Indckloa), :nd clnotrtotlly inducad soituroa. 81:11:: dour... ct olcatrtcrnphao chango, improvuuunt rat‘s, typo. or bohnviornl ndtptntionn, Ind ohnnxcn in Inuropcychnltgiotl talk hchavior war. ohocrvod 1n bush tho inhalant And in tho alcctraa;117 tronﬁod crouy: (k9). Kuvonr, not ‘11 Iibaootl auntie-ting high dccroo: or phyttolbgiaal thugs. var. avnluttcd .3 “improved“. I: n doncrtp‘tvo typologia Iﬁndy,_£1vo .dnptivn aldol war. dusoribod, cupirxcslly torund “ouphorto', ”hypunnaic‘, "nmuuuon', 'mmnld-wtthdravnl', Vial. ‘h. strut tun pattcrnn ltttcr worn ratcd and ”pan“ . an 'uuoh inprovnd', var. loan as 'undnpruvod' or “war-0' (So). In utudloa at plynholoaicnl varinblou, it was ruportod that pationtn ratod “much inpravcd’ $36 'rocovorod' troquently nanitultnd parloatlttw pattern: :kin t. tho explicit vurbal dcntnl parnonnlity type (37). 2h... pattoutn cxproslod tho ”innauago a: 6.3151“ nor. troguontly than uninprov‘d aubjoctl, antibiting such asp-oil a: tho two �-5- explicit deeiel, einieieetiee, dieyleeeeeet eed oliehee (27). Other perchelexieel indieee else releted te fevereble eeteeee included high I ﬂeele eeere (ha). nereeheeh deternieente ex eeler, ebeent eeveeeet eed ebeeet rereneier (30,h5), eed lee edueetieael eehieveeent eed rereice birth (31). 2. Aetiohelieer ie cenmeuede end Geeveleive There seeking e we: te enceeet the degree at peet-eeevuleive EEG e10? were eetivity, en eetiehelieergie deepened dietheeine, wee given intreveueeely e. verioue etegee or the ceavuleive therepy preeeee (20,2h)Q Unexpectedly, dietheeiee eeeeed en ieeediete end eeeteined deareeee in EEG elewiec, ehieh wee eeeeeieted with eerked cheagee in lengeeae end need. In petieete with deeiel leeteege petterne (21), theee oeuid no longer be elicited. Ineteed e! eupherie eed well 'heing, the subjects beoeee'irriteble, enxieus end coepleiuinn. In eebjeote prior to convulsive or drug therepy, dietheeine induced exeiteeent, teeeiee, eexidty end illeeery eeeeetieee. Subeeqeeet-etediee with ether centrel entiehelinergie cenpeeede end eyepethenieetie helleeieegeee ehewed behevier end electregrephic petteree eieiler to dietheeiee. the-e ebeervetieee led te the eeaxeetien thet ee ieereeee ie the ehelieergic eetivity at the eentrel eerveee eyetee wee the bieoheeieel beeie to: the eenveleive therepy preceee (38). �-6Iad‘ﬁlat Fallowing thtli Itudiou, tn. neurophyliolosic‘l august: induond by drugwar! touted within a. acito oxporiadnt.1 EEG Iotttng. It run obitrvod Butt phnuothinuianu induced BIG synchronxuuticn and a Ihittlnc at tun Iroqunncy spectrum to tbs slew Iroqunuotons taprobannﬁc and barbituratoa, tn agar-1:04 lynchruatagsgon ;nd a ahttt of thy spectrum to tact troquaauiau; rosorptnu, an iuaruatod slowing with uynohrcn3. ?a tutttoa at chair: is ,r law dontgua, gnd doqynohronitasion IIVOII (18,26,28,ho). at hiahur Iazprnliao induced douynchronination with a sun .1 trauma to the now bud: (33,310. Each ‘otivu psychotrnpia compound wgu #hu: about to ant. a charactnriatic trnqnoacy patturn. Vtriouo 9th.: axpcrtncaﬁsl coipounda wort also tantad and tar than.. no noaﬁistcnt ulcotrogruphic pattart was rooordod. In... ounpuinds bl?! Gino. boon nhawa to have dittor no ¢r vary limitad clinical psychotropic :ctivity. rho .bIOﬂei of bahaviurul chins. with than. coupoundo loot turthor uupport Sc tho anlunptton that 32.1: chnnco is a accosstry condition far the neﬁion of puyehntrOptc drugs. 2h... obncrvnﬁsons auccoattd thnt psychophgrnncou 10310.1 tannin provide a noun: icr niioitin; vnriou- typgs or altarod brain function in coltrnst to tho $13319 pattcrn following canvalniva tharupy. furthermora, tn. type a: luurophrliolocionl altorution, an rallcotod in EEG Iyuohrcay �.1and traqucncy patﬁorns, val round rcln‘cd to 0’0011106 a: bohnvicrul adaptation. 2h: ndvnntazu 0: £80 toohnancs to: tho ‘Icay at new psychotrOpic taunt. sad types ﬁhy toohntcnl tarts: or aloo‘rontu Iroquanoy tally-t- «or. unnarcd and dolcrihod (£7.52). h. Insulin can: fhnragz: In our inluliu can: studies we ocuttrnod anrlaor observations that porutntout alﬁorntiona or brain tunottom were taint-d to prolonsud «one and upcntanaonu nuilnrou; and tau in this rolntioanhtp suppert for n nitroplyltologtc~ndapttvo hwpothontl. With thc grailnbtlitr 01 ‘h. ncv psychotropic asant chlnrprunasinn, a ountrollod?chlorprunaltao Insult: can; atudy was undartnkon in Sop‘anbgr 1955‘ AI patiaata war. rotorrod for insulin aim: tun: get: rundonly unsignod ﬁn couraos or nithor oral chlorprcualino for at IQlIt 3 months in dosoa adJuIt-d #0 1111 short of toxicity; or'tnnultn cans, induoud by s uuhmd «chateau at last» so was 1: «ch pattont. Vh110 a uI-bur or ulnar distoroncou worn noted in comparing the two thgrnpigs, thn results at tile or dicohtrac chewed no stutilﬁtonl ditrorcnco in tho offsettVQBQnI at both traatncntl. loithnr troutunat £00.06 to affect tn. bantc nonsquhrcnto procons, but chlorpro-asino had tn. advantagot boing 3:202, tacit: to adniniator, lad hotter suited so long torn unnnzunont (21). concurrontly, following the 0“goutton by £ha Or-odnoqr worker. thtt dividod insulin �.3. doooa woro aoﬁorior to olaglo insulin doooo, Bloabor; and Ladoroao oooayod thin probloo and donorotratod no significant oorit to tho oulttplo dooo toohoiquo (19). (lo 1958. £91 ral courtroa too at hooo oboorvotiono tho a , 5. ﬂoor woro adaptod oho :' Various poychaphyoloal tooto tron oooropoyoholozy, whoro thoir signitioaooo to brain da-agod onbdocto had boon dononotratod. 1h. oarly otodioo aooooood thooo took: on lodlcoo a: altorod brain rotation (35), aod ooaaurod tho ranzo of portornaocoo or poyohtotrlc patiooto, who oro conorally aooonad not to to brolo dana‘od. Into, looory function woo aooooood on inoodiato roooll, artor vorlouo tutorpolatod loorninc tooko (11,35), aa roll ao aorta: coorulolvo thorapy (1?). rootilo porooptoal tooko voro tirot oxaninod to tho clioioal population (1). Lator, with ooro oonoitivo eloctrioal tootilo otlaoli, Karin oboorvod tho raaﬁo o1 throoholdo 1a dittoroot body parto (10), tho ohaogoo with altorod . brain function (10) and tho inflooooo or oot (inotrootloo) on porforaanoo (36). Ho also studied tho porooption o: ooboddod gooootrio figuroo (h3), toohiotoooopio prooootatloo o1 ooboddod color rigoroo (55), porooptloo of tho vzoual oprlsht (55). orltlool illokor froqaoocr (h?) and 1ntor~ toroooo 1n roadtag tioo by dolayod auditory toodbaok (55). For oooh took, tho dogroo of dooroaoat 1» took portoroaooo �-9- gastttvaly oarralatad with tha anoint at 386 aldwtas. Folluuina troatnoat couplattan, with an. rota»: at partialoatoal tadtaaa ta pre-traatlaat lavala, partaraauoa in thaaa paychalagioal tanks also rataraad to prautraataant lavala, or tight: -.a battaraanﬁ a: partoraaaoa aacribad to practiaa afract. waa found $0 be concurrautly, aaaaaanant or varioua payoholaxtcal aaaauraa an indicaa pradictiva or behavioral «hang. daring convulsive and drug tharaptaa lad to studiaa of the Rorschach datarninanta (30,h5). calitornia F Seala nonra(30;h2), languaco pattern. attar atobarbital (21), daatal acarae an antarviaw (3:) and tha paroapttan of tho visual upright and auditory taadback (55). 6. razehalég‘uiattoa: concurrant with an: syntactic studio: languaua (27), analyaaa of othar languaga pattaraa warn andartakan, boat 1: a aaarch tor aura objective xadiaaa a: bahavtaral chaaua and to gain oxparianca in the taehnioal pwablana of tapa aaalyaia tar payahatharapy research. La . inﬂux of variability in the vocabulary of apaaoh, tha typo- tokaa-ratio (if!) of eonaacuﬁavo Iaaplaa of dyadic apaaoh, wu “unholy atudiod (1,h1,hh.h6,56). In convulsiv. aharapy patxanta, aigaiftoant chanson 1n TIE naan hué standard daviationa war. ralatnd boﬁh to the dagraa or iadaaad 280 slow wave activity and to ayniactic �~10- lcnlicsc puitarnl abicincd in indcpcndcnt tircotnrcd intnrvicvn. It was cocoa that uptick bola-o norrepetitive (lav-rod not: III) an! acre varinblo in colaocntiVb cunplc: (kl). In intnrviowl infur- nnd cttor tho intravenous administration or ccntrclly active agents. ainiIcr chanson war. ohlcrvcd. input: which produced prcdo-iaact synchronisation pattorun on tho EEO ware rclctod to a docrctso in «can 1!! cad an incronno in ﬂu: smdcrd duration or ...m. while «synchronising ccapcuada clicitod groatcr variability in cpccch pcticruc and dccrocnc in variabiliﬁr at consecutivu acorn: (hh). 0thcr 1:33:53. Iltlﬂrlﬂ atndicd included diatrclc~rclict quoticntc, colt-rotoroncc, and altar:ticnc in till. cad patina. It VIC snag-ntod that than. paychcliuguictic accsuro- arc usctnl techniqnoc for thc operational caclyscl c: phyniolcgical and psychological uttcctc or psychopharnncclcgiccl cgcnta (hh,h6). 7. ling; B‘llli gud Schinaghrcgil: rollcwiug his ' Itudicl at Ittlsccn Ccntnr, PoIlnck ruvicwod th. rclcticnu chip bctwcon can 9! hospitaliscﬁicn, intollcctucl tunationils and prognosis in cchincphrcnic childron ind nttad that initiil bagpitalilltica cdclta. H: in childhood cad Idoloaccncc was rclatcd to I.Q. secret in tko cubncrncl tango, dcvicnt pcrxcrnancc on psychanctcr ttlkﬂ, and nor. �.11; troqasat ratings or 'uaiaprsvsd” ai hospital discharge than was initial haspihaliaaiioa as as adult. rho aarly sad insidious sasst st iha hahsvisral syndrsss “sohissphrsaia‘ was ihas rslatsd to brain dysfunction (5?). Findings saggsai that say ha olsssitiod on davianoy. diffsrsat suhrroaoo s: aohisophrsoia tho basis at asarspsyohslogioal in Considarahlo iotorssi Studios: aooiols‘ioal tho family organisation to vhioh disohargsd patisnhs ohoios‘ wars rotsraing, tho ralatioa a: social factors to sad rssults o: pevohiatrio irsaiaaat, and ihs spaoifio prohlaa of tho ralatioa at thasa factors to irsatasot rorsrral paiisras lad to a ssrisa of population studios. Ia oas study (8), soaoatiao, ago, plaoa at birth and soars on tho California I seals wars significantly rslaisd to tho hypo or thorapy rsasirsd ass tho utilisation of adaaaotivs hospiial ssrviosa. In a ascend study (31), darstioa or hospitalisation, dischargs avaluaiioo and diagnosis wars rslatsd to tho sans social factors, whila in a study of patisht rafuaal of BOT, sitilar relationships wars ohsarvad (51). Thass ohssrvations suggastad a_conparativs and tho three among hospitals study, min-institution batwssn othsr demographic social class and rslationahips 8. ‘ variables (ago, sax, sdooatioo) to tho clinical variablos �.12. at patanat cltulixtcttscn (ataanonal), auruttoa o: inapttuln tuttton. soloctiqn or thornpy and dtuohnrgu uvaluntion 5.1. 3.0: unlocuod. Into. touching tuntttuttolu were :11 thortptcc arc oqaa11y avatlnblo to I11 pntiontl, - nonnincor Foundation Hospital (uppor-clusc, .Protoctant), uttsaohuontta ncntnl lualth Contor (loverclnll, Cathnlic) ind £111.16. Boaptttl (niddlo-claul, Jow1ah). In hack a canytrtton w. turn round tho dittorcaoul 1n duotgnntiona of trontnnnt, diagnoliu tad dtuehargo cvnluatton so dafforbnt an to ugh. nonpartnean difficult. Vhtla III: rolttionnhtpu tatvton Iodill varinblon 1nd 91131c31 Virilbltl var. oblarvad in each heapitnl, to 1001.1 variablo was fauna rclstcd to thc clinical variablo. 1- "01-7 hospital (53?. In an Out-Pattont Departnont utndy, sex, 8‘. 3nd narttallatata: var. found to ho rc1atod to tho acceptancand roawetion at patttuts tad fuilnr. to couplcto tho upplionttuu pIOGOII (5h), that. abatrvnt1¢nl 1; population Ianploa 10d ta coa— current Itmdios or start attituia: 1: tin Iolootion at thorapy (11,12). In a aortas o: ward obnorvation studiol; Kaplun and Lotkawttn indientsd tho significant :01. or otntt attitudes (oupocta11y turning porcannol) in thc rerorrgl tor lubaostn for lunatic thtrcp1on, and in tho tranutcr at pztiontl tron out ward to unothur. It stud. Icloctod ' 1n whaen �-13. ﬁt. tn£1u ca .1 :ﬁnxt attitndo t1§n$ soloattoa for drag thorngz, w. g33u03$nd can ward be dontgagtnd an a "ago-avnusas' unit. 2):! van ndagtad in 8:233:34: 1259 and an shor‘lz ﬁhornuttqr 3: the whole hangatul.) mum 8E1“ buriug *ho parioa at the convullivc thsrupy studios, man: nun psychotropic 00:90:36: were attained clinically (5,21) alootrographzgally (3h,h0,h8) ‘ﬁd psychophrttcnllr .(aa). rho pro-ant payehophntuncology cvaluattoa progrta, b;sod on ‘hoao u§udion, was designed in gnaw-r tbs follow- ing'qunltions: I 1. ﬁber. ; rclntion botvooa COIII9I§XI &lt.rlttga in brcin function tad bahaviurnl Chtﬂﬂﬂ with psychotrOpic drug: on circuic :d-intstrntton? Ar. that. prb-troatnoat cluttcrl of plyohtatric, phy1101031ca1 and psycho- logiotl variablnl which are rolatod to ‘ho ﬂypc at bohnvtoral adaptation? Arc ouch olultcro rclntad to thy typo and dogroo or physiolextcll chango? LI an iatt1;1 upprqxin&t19n, a doubln-blznd, fixed detach, vandal aunt‘s-ant drug study was undartakcn. Blood on our c1131ca1 cxporicaenl throo tIpCI a: compound: var. �Du. oolootod on tho boots o: thotr EEO pottoroo. 1: thin otody, 293 onhjooto woro rotoirod old 1&9 hovo oonplotod tho touting progron, tron ootohor 1959 to July 1951. 1. lohoviorol Chog‘oa In o ourvoy of tho bohoviorol Adoptotioao o: potiouto roooivin; voraoao poyohotropto compounds during 1958-59, o bohoviorol typology boood on tho arootnont rooponoo one on pro-trootnont poyohiotrto protiloo dovolopod (55). In tho pro-out otndy,tho typoloatoo oro botng tootod, old various oooouroo of bohoviorol choogo otodtod, inolnd1n‘ thoropiot ratings, coll-ratingo old various word ohoorvotaoo oooloo. woo 2. ggnr o cholo : Psychological tooko hnvo boon viovod both on indiooo of bohoviorol chonuo and on prodietivo goidoo to convulntvo thoropy. Koch o: thooo tooko and o oolootod group or uotor tooko oro now bozo; oooooood for both thoir oopoaity to rovool ohongo with voriouo drug: ood thotr oopooity to prodiot ohongo with tho drugs to this -pro.ron (hB). 3. Blootrooooogholg‘goggln In tho ooovuloivo thoropy ' otodiot, tho dogroo of slowing woo loooorod by counting tho oonoooutivo wovoo in oolootod oonploo (16). whoa tho noro oubtlo ohongoo or drug ottooto are studied, 1a noooooory to opplr loot todiouo tochniquoo (ha), ond EEG it olootronio froquonoy ontlyoio woo introdocod in August, 1959. I: nooourouont of tho pon dotlootioo for voriouo �.15- ' sooosd is_ton opoois, ropid trsqssssiss tron to nosslrsnsat or oppsrsstly sssll ohsncss is total activity and trout-soy upsets: or. sttsisod.(52). ethos physiological vsristlos stadiod in this 3 33 bps yrogron include tho rooponso of 830 to istrsvsnoos chloru ~pro-suns, blood prosaoro rospouso to nooholyl, tho EKG, radioactive iodine optsko, and saslysss or various blood tad urine olsnsnta. h. hots Ansgzgisx rs onslrso tho dots goosrotsd in this otndy, as hsvs sovxtt tho aid or complex ststisti- colon-thud: and computational tsuilitios. Analyses or notorious, osaj‘rslstioo ”trio", factor analyses and disorisintst function onslrsoo ore connotations new in prouross with this dots at tho III? Psychophsrnsoology aortic. contsr's Biolstris Laboratory in Washington. Ill-l!!! STEPS Favorsd by s notional rososroh ' clissto and s ooopor- stivo hospital staff, thsso studio; hows proooodod vigorously. Rho ssssts for rososroh is.this sotting hi7. toss arsst ~— s solsctsd, intslligont pstisst popnlstiou rssinsnt from six to twolvo months, without individual economic linitstios of hospital stay; a sophistiostsd sdninistrstioa tolorsst or controlled studios; sud spprovsl o: s 30:26 or Birootors who dosirs 'rssosroh' as on institutional function. �~16- eeted 1n hie tiret heepitel repert 1a 1959, e epeetelty heepitel eee eeke little tepeet en the eeetel illeeee prehieee er the seeeehtty by treet— eent elehe. the eeeeeeetel treeteent e: 350 petteate e contort to the h0,000 reeident petteete in but little yeer 1n the etrte heepzltele a: La; Ieleed. I» will the eeeeel treieie. or twenty er thirty phveieieee in the erte e: peyehetherepy do exeh to help theee untertnnetee or the reeident 111 theeeende of in the mentally enbnletery nee: eetiee. he, e therepeetle [eel eleee 1e eelutﬁry bet teedeqeete to ear neede. he he prepeeed, the eeewer eey lie in the deeieetiee or 'reeeereh heepttel”, ee it 1e here thet e epeeielty heepttel eee truly excel. the eherter hee been written in the neerd'e eeeertlee er reeeereh ee e heepttel ceel. with the eeeete or en exeeplery therepeette teeility, each rededteetlee eee previde the etieelee tor the centieeeue ether 9! the eeeeee er mental zlheeee end at eethode e1 therepy. Seek dedicatiee ueeld provide the etteulee tor cenperetive and controlled eeeeeeeeete e: dittereet therepeette teehniquee. Centteeed etudy 1e urgently required of the eeleettee e: petseete ter verieee therepiee; the epplieeteee end eede er eetlee e: the therepiee; end the role of eeetel end ntltee :eetere in euppertte; the exteete Le Dr. Levin hehhtee & �.17- o: oar tharaptol. tubjoctl. the hohavioral Vtrtnblou OIOII, which are tin halt: a: on: proﬁont ditcznltso Ichtnstn, arc taunts-raotcry. at:dy is urgtntly requirod at tho upyltonbtlltr a! aootnl tad dulnarnphtc i:riab1¢a; paybholoutcal t:§k pcrfornancu protilun; twpologinc bnaod ca b-havxoral response to dozinnd Itroaaun or drug.; and physiologicall roactivity measures. such olaantticatioan arc also oniéntial for any biochemical, phyainlogioal or tvnlunttvo study to pravado ha-nzonous 33:91.! and campgrablo outrun. ‘ Alloa§nantu tlnd requsro moaningtul indtcoo of evaluating 05833.. Pros-at global 'tnpro.uncnt“ rating: tad loeaalitttton noctur-n arﬁ inadequate. Whathor tho 'iatorvuuing variablo bu nilihn thnrnpy, psychothnrapy, sino,‘§héleri£irii at bohhvioril chant. max... «anti-.1»; in.” 3592;131:1511”: a: rung-«1n, drug therapy 0r ' ladguaao #:028, idlt€r££1n3n,wpsyohéphyatéal"ch:n¢cVaéufca. . family CUIOIIIO§$I5I2E2- raqniru study :33 cviilatién; Roount attains of p¢y§hottc hubjoeta has proiidcdv tho succession thit thﬁrs in a notrolosic factor 1a.: group a: eh: ichisophroainn. The h1¢h tacidoneo er citatro"graphic and aauroloxie éysiunetian, the 153k or behavioral Vidnﬁculc to all thoripiol, and tut rclontlcna course a: �-18 o illncts nascent: involvontut in thin clustcr. Such a substrate aunt bo-olourly sought by tho app11egt19n of biochemical, nourophyniolegioal and opia daiiologionl toehuiquu to Vitus elation or you; pcyohutio hubgccta. 5: Eh. quontiona broador or 110:. than. arc son. Ittdiud in thc prosrtlz in cxyurimontul psychiatry ot-tho pant aovan yéura. than. programs, and the cantonporury projaots-in hiaahuniatry and in medicino, providc nod-1s It hootuatrgp studios andor;lkon with linitod uupport. ‘A dodieltion at lilllidOIHinitll as a ncaonrch Institutc I111 providc tho neodca £96“. and impetus for tha Iciontltia and hunnnitcriun forces at the oonnnntty to Join in a connea endeavor to roaclva the problems or the tantally £11. ﬁho 1n “orznn1¢* �LGRROUIOG‘OIIi‘ Participanﬁl in than. procraua inalndo thprouont ac-bcru a: ﬁh- Dopartnnnt or Expnrtnoutnl tuyohiatry: Its lalnoat, acrtln A. Orton, thrthna Iaplnu, Brio Karp, Beunld 1. £1.13, Joha 0. truncr. an: Pollack and Arthur 33113.3. turner associntad includod Kurl tuner-nun, Joseph 4:230, lobart L. Kahn, Hyman Koran, Goircu Kruathunor, ln£h3n101 81.3.1; and angry J. Lorkauats, untold Intonvur, lid ntrrc Alan. It. couporn$1on 0! Arnold a. Blunborc ot~ Bopartaont of Hodictnn in the protont program in srqtntully the ropor‘s liltod horn are the roault at tun collnboratian of this. tartar. and ﬁt. prutoastonll atQtta a: $h| h0upita1.vha an?! unnttnttnxly or tuttr tin. acknuwlodgnd. and that: nooduw111. �W J. innum- mug. 3:21, 1. was, 67, 1956; 6. 1953; 3. 3. 1955; ha 1952; 93.59201, My 1951; 10. £535.21.» aggmh, man, 53339229, 33539216. 7. 1957; 9. 1951; wgaév. 2. 1951; 1955; 5. 19575 gnu“ 12. 1961; and 35;: 33:81:, J. gag. 13. ”surﬁng, £3211, 195k; 1!... Arch. Home)... 16. 1956; 15. 195!“ 33311923, 353 3:233, 11. 91, 1961: and. ”an“. 13.516, 1951; can. gut. . 33:88, 11. human-.101. 3:180. 1957! 19. 10:207, 1958; 21. 22. 91!. 21;. Arch. and. Im. haul. 733, 19583 ' Jon. “or. M Ann. 1956; 18. no 011:. 32:162. 1953; 20.3113 }_6_§:18h6, 1958; 23. 3333.21221, 1958; 25. 1958; and £9: £33380, . cg ’E‘L‘E 26. Iowa. 33682, 1958; 21. Pazohoutholqz 323. 323113. 1958; w. at Gal-Inna», Brno & Suntan, 126, 1958; 28. PatchesGo. 1959; 325, a Iron Luna, , zbnrnuohg nation, 29. Pros. xv 139. can. Pulp»)... lath ﬁoluud Pthln 238, 1959: 30. 3921.3, 1959. 31. Arch. 00:. PI:«but. $3565, 1959; 32. Egg cm. lam-gm“ . M 531668. 1959: 35- Pros. 33:398. 1959; 33. 6256. Porch. Luna. .1. 0.3.. Install. 501., Forum, 613, 31;. Plzchn . 133381;, 19595 31. J. 1959; 300911011. 35.2w. 36. 1960.: I“. nor. J. 11155, 1959-; �38. Ila 3113. "‘£32Ez.1.13 $30359, 1969; 39. Aunt. J. Plzdhzut. ;;§t839, 19601 ho. lonro~rozghgzhurnneologzll: n(‘) kl. Jeur. Harv. Rant. 31-. $§91235, 1960; ha. ibid $293187, 1960) h}. Arch. H.353 . 3.5h7. 1960; bk. nganien or Puyuhintrio Brag rhorugl, $9, 0.8. rhonnl, 19603 £5. 3. retrogjzoh. $3252, 1960; hé. 130:. J. Pazchuthor. $3; h7. Intro-tszghaghuguncolagz‘gc30, Elsovicr, 19613 hB. than 3:381, 1961: M9. Azeh Gan. rqzuhil . 5:259, 1961; 50. thid 2130, 1961. 56, 19611 ' orv. Rant. 91.. £2gn153, 19613 52. 535:, taint Eggorinontalcs (in prosl)£ 53. '5 can :wggvahogharuneo » (1n 5h. 890111 pro-I): 2‘; Inn‘s; (in prose); SS. Bupub~ lishoa §anulcript3 56. Pszohiltrz 3;:2h9, IQSB; 5?. Arch Gen. Paychiat. 23652, 1960. 51. Jour. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Experimental psychiatric research at Hillside: review and prospect. J Hillside Hosp. 10:15969. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-57-023 Date A point or period of time associated with an event in the lifecycle of the resource 1961 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint and [preprint]. Reprint from JOURNAL OF THE HILLSIDE HOSPITAL Volume X Nos. 3-4 July-Oct. 1961 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/549693df019a0cabd2aa7cfa90ad3ced.pdf 62db1d0b502fce82996214e0276f034a PDF Text Text ’i' WM 3mm; lacunae Whammy mum. a: convulsive ma Ems in 1:33,“;ant W Mhim Fth mm m 1-. 0-. A. 3.1% of mmm mmm, m the mam. mm m, 34.1., $1”. W Hakim}. W? of the Unﬁml Wﬁm%_ a! Manta Insti‘MkaWWith, mm ﬁﬂm mm: mm 80m“. He: 33.113169 -' Aldus! 3.33.1513, 01' a Se Wolagiaal W an arm mmg, Howof1m 3mmandm- ammal Psychiatry, Kw Yam assuming mum may, of 10-613mm, ﬂu: Kerk, 13., 1953:. Promtud a mama: . » ‘ 5.. #- sky and Mb �II: 3-1148 Experiment-3. Shame at cmvuhive and 13mg momma: in Psychiatry: Maﬁa mummy mum e the vapor rule a: the We pearly Mined. adequate aw sumac therapies in This results, in part, femhﬂon of their we at aetian. increasing evidence for a frw In the the leak at an put an: yam mmﬁyaiolaﬁemptiw view of electromoek therapy has been presented by Wemtein and Kuhn, Bath, and view, the madam Wynne prawn 1n electrocheek is [319128. in thin Mex-1m to a Imminent. alteration in cerebral function mm: madden the milieu for a change in adaptatim of the aubjwt in his anvimmnt. having the past four years in the we have attuned the autism between mum and the behavioral name physiedynemic therapioa .. laboratariu of Hillside hospital, alteration in urinal: indicate of brain at psych “trite patients ta three of the emmmwk, Win one and *tmqullieere." me nemyhyaielogcudapuw view at sleet-manna has been Wind in the” studies; has been preheated. and widenae Recently, the mar “trimmers.” :5qu we for a similar View of insulin coneep’t. em has been fruitfully extended to the The» studies provide the hands for a gmmlimtim �«2* «meaning ta a! W the. mode of the experimental mum at these therapies "idem measurable éetomine whether or not the be tenight male mean I’m their ability ta inane: manned- may altemtian in aembral function; it in ear PW the" therapist. nation of and the wrelluy questing, alteration in eerebral fumtion is efficacy of these thempiea, or mether me}: a, necessary whether mﬁtien for the We: in brain aunties: m a “maimﬁan” er "11331th when" have used We View). mime indie» of brain {Manon including mar llama, m mule pomoptual mice, and uhangea in orientatian patterns at new both clinically and utter intmmua mbarbital which be generally knew me the ”m1 test." the delta index In electroencephalographic studies, ehanges in in meuutod words mm at altered brain mum. For have been “and to be a mauve latm this mica, ehangos in this W will be ctr-eased. In the initial rotomd for mmleive nudism of normative patients therapy, oleetrmcephalogram were amazed before, tmemnt at weekly intmala timing therapy. m1 therapy three time a week, fer a total of The and an a day ate: a patients rewind 312-20 applieatim. m6 �a, thte 31w were nativity. In the mun}. We Wt the 01' the heme witty tenet, m quantitatively Mum delta eetivity during by determining the per tee-t time maintenm » each we}: at eeeh mﬁﬂty, the and the duretiee amt WW, e: berets in selected team were then new we the W thin! were at treatment We. the emm ae "high," theeeeenethieeeeﬁnieﬂcﬁmdﬁmmethMuVW demure! Mite entirety. “tee tee their We: he met meets the noted in the rim. short term emu rem (he make poet Wheat) new means: peyehutuc trauma, and were “Mentally moved“ and "We” elseeed as ”wet theme,“ �.h... In the first toms of mutants, a Want relationship human the early inﬂuation of high degree: of delta nativity, and clinical rating. at ”math Wad” m crammed. may put: «at at the “cm-ids in tho 313.1: much mma group mm high dogm mu by this 14-6 Manning pemntaga my unstained at um 91‘ the unimproved first ulna mks, 90% in the third and fourth mm. and the In mtmt, pawn“ dumped 121$ dogma! data «cards in tho and only 20% of the records in the tenth-h week are to elusifiod. Baud can those mum, u wanna nudy m undertaken. mum-d: obtained during the amend ﬁnd Wad for that. 15h:- dogroe a: W w; third mic: or mutant. mm delta nativity, and it tun 0:31:1de than patients the had high degree: a! (with activity during then periods would that better ratings of ”Wat“ than puma“ in two when �~s~ such damn mm. of delta activity were not This prediction was Fig. 5 m“ ' 1mm 1mm, an occasions were 67% at the patients with high degree records ”mach improved," “minprmd” 705 were while m: ”moderately 31‘ on both patients withaut such "earth,- tamed." Further aorrabomtzlon was obtained in a canvulaivoumbeonvulaiva control ”My. Connemara m convulsive who car of. middlo waiving referrals were plum aims:- an mboonvulsiva therapy on a random remind aubaonvulaim antivity 3110 chrothampy trauma, mm min. a: Wmm slow wave or high dogma in any use): of treatment. Waive therapy, patients 27 or; 28 EEG subjects high degree records were observed in 20 rimming the second to 1‘0qu weeks of treatment. Or 23, and the 27 mboomlsive patients, at the“, 19 mm retomd for ml elactromock induood no change 3. ”cont! in behavior coma of tmtmnt. high dogmas of delta antivity in 1h in each, a significant behavioral Me was notad. in was when! at" Grand We, and In the rim panama �«a. Iii-ham; Inch ‘ delta chug», «my m ahead a m cm“ of mutant hehmiwal W183.“ thumw indium that m slaw mo nanny 1-: as: 1nd»: at tbs chums in «ma imam man are promise to the Maria“ ' aha-nae in this turn a: ﬂwpoim or their elmtmaophdogmpma 1 moaningml W. and a mum. annual manage attack, renump Luther: um dogma ma type of mam W m mmbml function and the clinical behavioral rum is observed. The Waxing agents to imam aim of central nervous system @atmtion, a motor rigidity, deputation, «summit and. MW ability of the aver m Wu Imam. - mod on ohmumm nude in mm expat-1mm am in We manual: at various ms in ms mama-r143 partisan, m have also bun notoé. than me «that: m be clusﬂiod awarding to men in the {macaw spectrum, and m at three broad Wu: " met �“1.? 1. mm new we mum II. Instance 111. high voltage Bethrmiution WWW- with that activity. with voltage and {macaw Singularity we irregular that». activity. at the drugs that induce increased slew have mtivity the phonothiaeiha enemies. pmiee and Wine m elm We. Each drug also induce; aims in mmeptim, megawatts mum in ﬁerivatim, I epilogue shadow, and induce; enamel “thin-mien naming“ pumm. ’In the enamel eat-vice at amazes Hospital, pneumonia but in all patients reaching Mammalian, 10% of and «um: have been observed in Whit: patient. ﬁthent 3 Wm history Renee-pine how induced of ”18mm else moms delta nativity, but only when gim in it high dosage levels, it the mggmm Mum: in opium, Munroe in mm», the clinical are elemet maples. Indeed We tut nativity, barbiturate “than agents differ from the phanethiuinee and "sperms in not warming «hum. and whenoeim in me. at drugs that induce immune high voltage ah merchants hm dean. Woman, or mm their anhiamlmt nativity is measurable. �.3. minimum in readily “Mum. and ”ism: hm hm charred. Varima drug: indwo EEG domabrmiaatiw with varying «ﬂaw. lamina and damning; bamamina mm W a: mama two reports either of . MW, in mt bean «baa-wad with miss: will. than eat that: drugs, user have ”isms nr parkinamiam in. than clinical «tents «gm: at phnnothimM derimtiws, ma Wad «synchroninmm with Dalia activity has and «ﬂaw. we found Ilium-azure. mama“, dimm and WWW have been that: to mam-unis. the EEG delta moral! or patient! undergoing 010W tummy. ’16-: 6x '3': 3» M the» minor 9. Winery, ahlorpmsim, parphonuim and ”amino haw been amiatontly annually reported as paymwio barman:- panama. in me frequancioa to the most. mus are also the ma. range. mini in $3ng drugs that. mmbmte, Mm momma and groan the man. 1:6an �m 01mm 1m mm. in tha than an m agents we pmdueo m man-ea mum at :m tmunwiw er doaynchwniuum. mum, an delta range is t mcmtmt at signifimt behavioral in cumulus.“ therapy, an .3 (i5) " may, 12: the m tnqumay shut in the situate. “ magma ofinmlmemthampymbcamodina 13.22113:- rwhim. During usually pal-auto for «an am, EEG delta mmuw 1: manna, mm: to a few hams-a after gauge. not. 23212222 Mmumm, . 1— V mo third of patimta waiving hospital, 131mm” aphasia or prolonged EEG change: or alarm activity am, far “the: m 2231:! relation bahmgral am mey in this am and“. an» such pomt fer elm, and 122 «mm: mu of pmlmgad mm. how 13th am, ﬁtmd brain function am! mama has: been (anew at length by various authan Him (20220121233 that. dam. He We study. sloop Woman”: is related be 22;: 1226226321921 of organia brain haw abnamd a 31:11“ relationship, and reported am «nah A 322 you old aabimphme puma“. with puma“ 13mm: �«It» Now a loft magnum eating mm: em thmpyi efmurMe fom: With the unset nmmmamwmmmmmW. paw « withdrawal cooperative attitude. the» mm pattern we Hie mum by I Mmdly We: can wemmd by delta clung“ in the We, (6) W: While in him net bad the perennial opportunity to etudy lobetw intimate from the $93.11*. of View at this awry, mmeebumere clearly dome a of delta aetivi ty are present for W in 3 1’30 relatienmih me in all subdue“ peatwpcneivoly arm periods, up to three yours. «1mm the report: at We and peniet ﬂux-them, pests-operative m a frequent ”museum, being varieealy report“ a new 26% of subjects. �D‘IESE: has, what: "Mm “Moi thumpiw point of ﬂaw of an alteration in brain node at whim. Those m We of the imam, we may in!” a. chanson in hahnvior. «he» at these madman puma a m mum aﬁmﬁm a! the mam alteratian in brain taxation. mum 115an by am in than in Miami at W the 111.1101: «hangs data range, mm is signiﬂaanaa a: that-aw; um with an W “we“. Man :0: the mucus af faction with reaultmt Ghana“ in brain . thawing m swayed rm the apoctm of 1mm in aynahrmuatien, mat. «mouths in altering Mmatin EEG mung” immunity: proud“ the mum m delta shirt has boa: alearly dwamtmtod in elmtroaonvulsin ﬁlm m be mama iron the available data for the W pmm» Wattage agents, whammy and insulin can. mat a «mummy mu. m 3mg, mg drug atfce'aa. and maarpina m Manet” mm Wed mmmauon. has am apoaificity is Thou drugs tam .. have been at paychntic mutton soon in the analyses 61‘ mm a delta shift - thc mmﬁﬁum mandamus! mom as effeetivc Miriam and 31m.» aa Potent mumminogans. �4%." ma mt‘ma a. synchronimman in 1210 have strum of ohms: in lawn beta range, as in contrast, are poor Viki“ ( aha ) . « 03.80 in has potent. Drug: a hammme, dict-hum am! ”mains, Wars: mm and illusory Momma. mamlihathat WW“: and «9:9me sedation and trwquinsaﬁm, but that man“ we avmahmnuaticm, with than; of mam mooted by manna-d and in 11191 dosage inch-1m maisty, obnmtians are clarity maniatent when awclw in him mam of marginal: and . . raga-Glen of the mm“ a: am am amum, shifts in tha pattern a: m alwtrmaephalogrm in thy dimtim of domchmiumm new in “mam um Maw, >ha11ueimtiom, fantasies, illusions or tremors, and in with mgriu, mlmtian 801: alum and Mammal of mahmniuuam ‘meﬁ pursuant clung” in mabrai imam “feat behavior mm mm»:- m with an ﬂ'heﬂtiﬁn in tbs in. 91' than we; *memd' or 'abutomtéd.‘ antral mam mm mum, thaw an upon“ a: mam:- including .mpmn, ma, arm, attitudo. mo aéaptive :11 not Rather, is an alarmist: mam-Wt. We mdar an“ conditimn in variable �.43.. fer eeeh eebJeet end is Gee-Wt mm. W puma-3.1m and the duration of the dieeueeed in behavior are “Wamhtﬂ matteetere es the type at teierenee, nether abut-term with; . ehenge 1d net "do eve-Tented by the The” rating; “may hem no value psychiatrist as 3W, mentions. a. . «2qu In this meta-e3" the Mamie men”, they men in «relented ale inpmtehent. Ahmed the Wed behavioral name, Mm temwmnw The induce a hehmveral alteratim or eerehrel Imam themem net I ‘cmlieetien' or [In *entemw «new but the chaired goal ef these fame of during the peat the therapy . Mum. u automate w the individual hehevierel new. to the degree of upon and alteration in brain renewal: have The inﬂated ehe’epe e W “mm mm mmmm and mix-Wm on harem. er the may tine-guest therapies intmchxeeé thirty rem, me eppehenﬂye has been a. epeeitie agent fer a: psycho»: (in the tense mat penieil‘lin 1e emeiﬂe Tar WW! and nieetmic mid for pellegm émntia) , but rather with greater or lesser degrees of epplieehmty behavior by altering the hombre}. when. and mm etiieaey in altering �, in m, we hm: mm the nmmsiologie upsets at, mm WW3 woman, and hm «minded am; the therapeutic pram of ammonia, insulin can, mtw and trmqnilimrs my Mutant Ilka-mum in «new in uhptaticm at ﬁn mama. mm; pmm the silica a» s. be 3.36de to tha inductian at .J‘mbsactb his 1- , a em Wt. the «ﬂaw at web mutant. mthod in mm to its mmw w W a pursuant. «hung: in! mmbml functim, of mm m «It: shift in the m 'speom with Wad mum“ may but a, amuimt W. management of Such a ' a» bu appliabﬂity in m m at those thumping to the scram of m payohophﬁmuolngia agents. and as 3 arms of mnmﬁzysioﬁmwu atom m further new of Matter and" � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Experimental studies of convulsive and drug therapies in psychiatry: theoretical implications. Arch. Neurol. Psychiat. (Chic.), 80:733-734, 1958. (abstract). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-33a-010 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Kahn, Robert L.; Green, Martin A. Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource [preprint]. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/b574305356446714449f347eaa71e515.pdf 4bf163bfe85fee82b5e7d9be3ad5c243 PDF Text Text Experimental Studies of the Electroshock Process MAX FINK, M.D., ROBERT L. KAHN, In the last seven years, increasing study by various authors“5 of the neurophysiologic alterations occurring in electroshock has resulted in a re-assessment of the mode of action of this form of therapy. The present neurophysiologic-adaptive hypothesisly2 states that an induced change in brain function provides the milieu in which behavioral changes can occur, depending upon the characterologic predisposition of the subject. This report summarizes the data of three groups of studies which have been completed in the continuing evaluation of the electroshock process in this laboratory. These include: The relation of changes in neurophysiolog‘ic indices to behavioral change; 2. Types of psychologic response expressed and factors in the evaluation of “improvement;” 1. 3. and The role of personality in the behavioral response. and Method: The studies have been carried out in groups of consecutive, unselected electroshock referrals. The subjects are voluntary patients in an open ward psychiatric hospital. All patients are treated by resident psychiatrists, who make the referral to the elec— troshock therapy unit. The duration and type of therapy, however, are determined by the supervising psychiatrists in charge of the treatment unit. Patients varied in age from 20 to 66, and have been diagnosed as suffering from depressive and schiz0phrenic I. Subjects illnesses. (a) Tests of Brain Function: Two indices of cerebral function have been stressed: Quantitative measures of the degree of induced delta activity in the electroencephalogram,6 and changes in orientation and aware— ness of illness after amobarbital sodium.7 From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, N. Y. Aided, in part, by grant M-927, National Institute of Mental Health, National Institutes of Health, U.S. Public Health Service. Read at the Twelfth Annual Convention, Society of Biological Psychiatry, Atlantic City, N. J ., June, 1957. PH.D., and MARTIN A. GREEN, M.D. 1) EEG: Electroencephalograms were done weekly prior to treatment, and on a day following a treatment. Bipolar recording was used, and selected leads were measured fOr the degree of delta activity. The average percent time delta for each of these selected leads, the highest delta index in any one lead, the highest amplitude and slowest frequency of delta, and, the longest duration of bursts were the measures utilized in the classiﬁcation of the recOrds into “high degree]? "‘mod— erate degree” and “low degree delta activity.”6 Amobarbital Test: This is a structured interview, in which the patient is asked a standard set of questions pertaining to ori— entation and awareness of illness. Amobarbital is then administered intravenously, in a concentration based upon body weight, at a rate of 1 cc to every 40 seconds, until nystagmus and slurred speech are induced. In the initial series, a 5% solution of amobarbital was administered at the rate of 1 cc per minute. Recently, to permit simultaneous estimates of the sedation threshold} the procedure was modiﬁed to allow for weight differences of subjects. The same questions are repeated, and persistent changes in orientation, denial of illness, confabulation, and reduplication are called “positive” and are indicative of states of altered cerebral function.7 Tests were carried out before electroshock, and at weekly intervals during elestroshock on the day following treatment. (b) Evaluation of Behavior: In addition to the notes of the patient’s therapist and supervising psychiatrist, all patients were seen by the research psychiatrist at weekly intervals during treatment and 2-4 weeks after the last treatment. Evaluation of changes in behavior induced by electroshock were based on these descriptions. Ratings of improvement 'Were based on the behavioral response two to three weeks after the last treatment, and reﬂect a short term clinical rating. The patients were divided into three groups: much improved, moderately improved and unimproved, based on criteria 2)_ described.2 Reprinted from Diseases of the Nervous System, Vol. XIX, No. 3, March 1958. �(0) Evaluation of Personality .' The initial method of personality assessment employed has been a structured family interview. In their original observations, Weinstein and Kahn described the characteristics of the maintenance of high degree delta activity and short term clinical ratings.6 Of the pa— tients who were rated much improved, 90% had high degree delta EEG records in the 3rd and 4th weeks of treatment, While of the unimproved patients, only 20% had such records. The relationship between delta activity and clinical ratings is seen in Figure 1. “explicit verbal denial personality.”9 To determine the signiﬁcance of this personality type for behavioral response, a structured questionnaire was developed. In interviews OO .— MUCH IMPROVED (u) with two members of the family, the patient’s usual attitudes and interests in 15 90 .-—— moo. IMPROVENG) UNIMPROVEDW) .-.— characEach speciﬁc areas were explored. 80 teristic was rated as being absent, moderately present or markedly present. Scores 7O of 0, 1 and 2, respectively, were assigned, '60 and added—the resulting score being termed 50 the “denial personality score.”1° (d) Treatment: Electroshock was admin- 4o istered on a schedule of three treatments 3. 30 12 week. A minimum of treatments was given, except in a few cases where a. severe 20 confusional state appeared earlier. The course of treatment was determined by the supervising psychiatrist in charge of the lO-lZ electroshock unit, based upon clinical criteria. Treatments were grand mal, using either a Medcraft alternating current instruobservations In these series, subsequent ment or a Reiter C-47 electrostimulator. Pain Based extended predictive were study. a tients were generally premedicated with inthe earlier it on was suggested observations, travenous Pentothal prior to the treatment. those the much that were improved patients In the past year, a subconvulsive therapy been in had whom delta high activity degree group was instituted. Randomly selected induced in and the of treatment course early electroshock referrals received 12-42 suband Records second sustained. the during convulsive treatments, under Pentothal preweeks of third treatment, therefore, were medication. These patients were subjected in 54 consecutive The results assessed. pato the same test procedures and the same bein Table Of I. the noted tients patients are therevaluations mal havioral as the grand delta who degree developed activity high makthe Neither psychiatrist apy subjects. weeks of third second the and treatduring ing the evaluation, the patient’s therapist, while much rated 67% improved, were ment, nor the patient was cognizant of which pawithout the such of 30% aconly patients tients received which form of therapy. The rated. so were tivity data for this series of patients is now being evaluated, and reference will be made only TABLE I to the general observations. Patients With High Delta Activity During II. Observations: Second, Third Weeks of Treatment RATING CLINICAL in Cerebral Role Function of Altered (a) '8 >. Behavior: i’ 75w: a: Electroencephalogram: In these studies, we have emphasized the degree of delta activity. In the initial series of patients a direct relationship was noted between the early development and a 1. .c: EEG Delta Both High (18) One High (16) None High (20) S E to. E 5 8 a 5 12 (67%) 4 (25%) 6 (30%) a; 8 ’5‘ Q sE (22%) 8 (50%) 7 (35%) 4 a D 2 4 7 (11%) (25%) (35%) . �Amobarbital Test In the initial series of 24 patients, ‘previ: ously reported,‘-’ eleven patients were rated as much improved,,andall had positive aniobarbital test reactions after 7 to 9 treatments and sustained this response. Of the unimproved patients, 15% had positive amobarbital responses in the third week and 28% in the fourth week, but these were not Sustained. A comparison of both the EEG observations and the amobarbital test data, as related to the eventual clinical rating is seen in Table II. In 77 patients tested to date, observations during the second and third weeks of treatment were examined for the presence of high degree delta activity and positive amobarbital test results. Of the much improved patients, 75% had both positive amobarbital tests and high EEG delta activity during this period. Of the unimproved patients, however, 57% had neither positive amobarbital tests nor high EEG delta activity. It is apparent that the cluster of positive amobarbital tests, high EEG delta activity and much improved clinical ratings is a signiﬁcant one; and equally signiﬁcant is the cluster of negative amobarbital tests, low and moderate EEG delta activity and clinical rating of unimproved. TABLE II EEG and Amobarbital Test Results During Second, Third Weeks of Treatmenﬁt 2. :, .c: 8 2 8 Total .................................................... 33 .01 E 3 8 E e s E Both Positive Amobarbital and High EEG Delta Activity ........................ 25 Either Positive Amobarbital or High EEG Delta Activity .......................... 8 Neither Positive Amobarbital nor High EEG Delta Activity .............. O *Significant at better than 2 2 Q E sD 10 3 12 5 3 11 25 19 level of confidence. (b) Clinical Patterns of Behavior: In these patients, we have observed varied responses to electroshock including the absence of noticeable symptoms with a return of pre-morbid behavior; hypomania, euphoria, and denial; paranoid states with ideas of reference and delusional formation; confusional states with varying degrees of memory disturbance; increased somatic com.plaints and pre-occupations, states of in— creased panic, excitement and agitation and varying degrees of withdrawal, and seclusiveness. The degree of’behavioral change is seen to be related to the degree of alter'a} tion in the neurophysiologic indices. During electroshock, with the gradual induction of states of altered brain function, and their restitution in the weeks following cessation of therapy, behavior shows characteristic patterns. The following are but a few of the gross patterns that are observed during the period of increasing and waning states of altered brain function. An early change in behavior in retarded subjects, for example, may be a change in the degree of participation in ward activities and increased neatness and interest in personal care. This is succeeded by a phase of minimizing symptoms and displacement of complaints, mild euphoria, denial of illness, and insistence upon going home. At this time, the EEG shows the greatest degree of delta activity and amobarbital tests are positive. With the cessation of treatment, the overactivity diminishes, and interest in the future becomes prominent. Premorbid patterns of behavior are in evidence, and the EEG returns to normal and the amobarbital test becomes negative. Other depressed subjects, however, become increasingly disturbed during treatment, withdraw from participation in hospital activities, and complain increasingly of memory loss, physical distress and insomnia. Amobarbital tests and electroencephalograms may show the same degree of change as in the ﬁrst group. With cessation of treatment, there is either a return to the depressed state, or a persistent emphasis on the memory loss and physical complaints of the treatment. Another pattern, seen in hostile, negativistic and withdrawn patients, is the development of hyperactive, hypomanic, and impulsive behavior. Memory loss is marked, and clinical disorientation and confusion may be noted at the height of neurophysiologic change. After treatment is ended, ideas of reference, negativism and delusional for.3 �mation become prominent, to be followed by withdrawal and mutism. (c) Eﬁect of Subconvulsive Therapy: The interdependence of these adaptive patterns with the state of altered brain function is more clearly demonstrated by obser— vations in the subconvulsive group. TWentyseven subjects received subconvulsive therapy instead of grand mal. Minimal changes in the electroencephalogram and in amobarbital tests were induced, and the changes in clinical behavior were limited. The electroencephalograms demonstrated either no delta or a minimal amount of such activity. In no patient were moderate or high degree delta activity records observed. In the amobarbital tests, only three patients had positive tests during treatment, and in each instance it occurred only once. No change in symptoms or behavior was noted in twenty—three. Nineteen were referred for a second course of treatment. Grand mal electroshock in— duced changes in brain function of high de— gree delta activity and/or repeated positive amobarbital tests in fourteen of these. All fourteen showed signiﬁcant changes in behavior; While of the ﬁve patients in whom the physiologic indices showed only minor changes, only two patients showed a deﬁnite behavioral change. (d) Role of Personality in the Adaptive Respouse: Another variable in the adaptive response of the patients is the personality—the habitual attitudes, patterns of perception and behavior and defenses of the patient. The initial study of the role of personality related the characterological disposition of patients showing denial mechanisms to the clinical result. The relatives of 47 patients were interviewed, and denial personality scores assessed. Scores ranged from 0 to 25, with a median of 11. The scores were divided into two groups: scores from 11 to 25 were classed as the “high denial group” and those from 0-10 as the “low denial group.” Of the patients with high denial personality scores (Table III), 58% were in the much improved group, and only one patient (4%) was in the unimproved group. The ratings of improvement for the patients with low denial personality scores were random—'4 about one third appearing in each rating category. TABLE III Relation of Denial Personality Scores to Clinical Response to Electroshock Personality Score 11-25 0-10 Total Much Improved 14 Moderately Unimproved Improved 7 9 9 1 7 21 18 8 Total 24 23 47 The difference in the denial scores between the much or the moderately improved patients, when compared to the unimproved patients, is statistically signiﬁcant. That the personality ratings were indeed reﬂective of the patients’ adaptive response under the conditions of altered brain function is noted in the correlation of these scores with actual changes in language patterns which had been described11 as indicative of denial responses. As in that study, changes in language in structured interviews with the patient were studied. Each patient was classiﬁed according to whether he showed three or more explicit language changes. The group of patients With high denial personality scores showed a signiﬁcantly greater number of language changes than patients with low personality scores. The coefﬁcient of correlation is +.71, which is signiﬁcant at better than the 1% level of conﬁdence. Discussion: These studies of the neurophysiologic and psychologic aspects of electroshock support and amplify the hypothesis of electroshock action initially expressed by Weinstein, Linn and Kahn,1 and again by Kahn, Fink and Weinstein,2 and the observations of Roth,3 Aird,4 and Ulett.5av Alteration in brain function is the central effect of electroshock therapy, and is a pre-requisite to behavioral change. We have emphasized delta activity in the electroencephalogram and the patterns of disorientation, confabulation, and denial of illness after amobarbital as indices of altered brain function. Other measures, applied in the same serial fashion, will, we believe, demonstrate the same relation to changes in behavior or alteration in brain function. Under the conditions of the induced 111. ‘0 �change in brain function, altered patterns of adaptation are expressed.» The type of adaptation varies, apparently dependent upon the personality organization. In these studies we have noted the relationship of an “explicit verbal denial” personality type with the development and maintenance of clinical language patterns of denial, displacement, and minimization in structured interviews.11 We have observed that patients with high denial scores are those who are more likely to be evaluated as “much improved” (Table III). The type of adaptation is varied, however, as we have described here. In this context, therefore, the conclusion is afﬁrmed that electroshock is a means of inducing change in cerebral function in which altered patterns of adaptive-interpersonal behavior can be sustained. We have emphasized “change in behavior” in this report. In previous studies, we related our observation to “improvement.” “Improvement” is a derivative evaluation of the induced behavioral change, which is dependent upon the expectations of the therapist, the family, or the administrator, in the milieu in which the behavior is observed. When a depressed patient, who had been withdrawn, crying, and had expressed suicidal thoughts, no longer is seclusive, and is jovial, friendly and euphoric, denies his prob— lems and sees his previous thoughts of suicide as “silly,” a rating of “much improved” is made. To the extent that a schizophrenic patient is perceived as less delusional, less excited, and less Withdrawn, he is rated as “improved.” When, however, the induced behavior is one of increased anxiety and fear— fulness, or persistent complaints about memory loss, pain or other physical symptoms, or excitement and delusional thoughts, a rating of “unimproved” will be made. These studies amplify the present neurophysiologic-adaptive hypothesis of electroshock action. Further studies, deﬁning the signiﬁcant aspects of personality and of the expectations of the environment on the patterns of behavior which are observed under the condition of altered brain function are suggested. Application of this hypothesis to the effect of newer tranquilizing agents is in progress. Finally, studies of individual differences in the neurophysiologic response to equivalent amounts of cerebral trauma warrants exploration. IV. Summary and Conclusions: 1. This report summarizes continuing experimental studies of the mode of action of electroshock therapy. 2. Behavioral change in electroshock is dependent upon an alteration in brain function as evidenced by serial changes in delta activity in the electroencephalogram and disorientation and confabulation with intravenous amobarbital. 3. The pattern of behavioral alteration is shown to vary markedly, depending upon the degree of induced cerebral dysfunction, the personality of the subject and the environmental situation. 4. “Improvement” ratings are seen as a special case of behavioral change dependent upon the type of adaptation elicited, the expectation of the therapist, administrator and family, and the tolerance of the milieu. 5. The extension of this neurophysiologicadaptive hypothesis of electroshock action to other forms of somatic therapies is suggested. 1. REFERENCES Weinstein, E. A., Linn, L., and Kahn, R. L.: Psychosis During Electroshock Therapy: Its Relation to the Theory of Shock Therapy. Am. J. Psychiat, 109: 22-26, 1952. 2. Kahn, R. L., Fink, M., and Weinstein, E. A.: Re- lation of Amobarbital Test to Clinical Improvement in Electroshock. Arch. Neurol. and Psychiat., 76: 23-29, 1956. 3. Roth, M.: Changes in the EEG Under Barbiturate Anesthesia Produced by Electro—Convulsive Treatment and Their Signiﬁcance for the Theory of EST Action. EEG 01m. Neurophysiol., 3: 261-280, 1951. 4. Aird, R. N., Strait, L. A., Pace, J. W., Hernoff, M. K., and Bowditch, S. C.: Neurophysiologic Effects of Electrically Induced Convulsions. Arch. Neurol. and Psychiat, 75: 371-378, 1956. 5 a. Ulett, G. A., Smith, K., and Glesser, G. C.: Evaluation of Convulsive and Subconvulsive Shock Therapies Utilizing a Control Group. Am. J. Psychiat, 112: 795-802, 1956. 5 b. Ulett, G. A., Glesser, G. C., Caldwell, B. M., and Smith, K.: The Use of Matched Groups in the Evaluation of Convulsive and Subconvulsive Photoshock. Bull. Merm. Olin, 18: 138-146, 1954. 6 a. Fink, M., and Kahn, R. L.: Quantitative Studies of Slow Wave Activity Following Electroshock. EEG Olin. Neurophysiol., 8: 158 (Abst.) 1956. �6’ b. . . Relation of EEG Delta Activity to Behavioral Response in Electroshock: Quantitative Serial Studies. Arch. Neurol. and P31chiat, 78: 516-525, 1957. Weinstein, E. A., Kahn, R. L., Sugarman, L. A., and Linn, L.: Diagnostic Use of Amobarbital Sodium (“Amytal Sodium”) in Organic Brain Disease. Am. J. Psychiat, 112: 889-894, 1953. Shagass, C.: The Sedation Threshold. A Method for Estimating Tension in Psychiatric Patients. EEG Clin. Neurophysiol., 6: 221-233, 1954. : . Weinstein, E. A., and Kahn, R. L.: Personality Factors in Denial of Illness. Arch. Neurol.» and Psychiat, 69: 355-367, 1953. . Kahn, R. L., and Fink, M.: Personality Factors in Behavioral Response to Electroshock. Therapy. Conf. Neural. (In Press.) 11. Kahn, ;R. L., "and Fink, M.: Changes in Language During Electroshock Therapy in Psycho~ pathology of Communication (Hoch, P., and Zubin, J ., Eds.). Grune and Stratton, N. Y., 1957. (In press.) 10. _ ��.thv- AyiAuu. .gypZZILu Experimental Studies of the Electrcshock Process Max Fink, 14.13., Robert L. Kahn, 31.1). and Martin A. Green, M.D. From the Department of Experimental Psychiatry, Hillside HOSpital, Glen Oaks, N.Yo of Mental Health, part, by grant M—927, National Institute Service. Health Public U.S. of Health, National Institutes Aided, in Twelfth Annual Convention, Society of Biological Psychiatry, Atlantic City, N.J., June, 1957. Read Vo at the 6‘27-S7 �-2Experimental Studies of the Electroshock Process In the last seven years, increasing study by various authors (1-5) of the neurophysiologic alterations occurring in electroshock has re- sulted in a re-assessment of the The mode of action of this fcnm of therapy. present neurophysiologic-adaptive hypothesis (1,2) states that an induced change in brain function provides the milieu in which behavioral changes can occur, depending upon the characterologic predisposition of the subject. This report summarizes the data of three groups of studies which have been completed in this laboratory. in the continuing evaluation of the electroshock process These include: relation of changes in neurophysiologic indices in behavioral change; 1) The 2) types of psychologic response expressed and evaluation of "improvement;" and 3) the role of personality factors in the in the behavioral response. �II. -3“ Subjects and Method: studies have been carried out in groups of consecutive, unselected The electroshock referrals. ward subjects are voluntary patients in an The open psychiatric hospital. All patients are treated. by resident psychiatrists, who make the referral to the electroshock therapy unit. type of therapy, however, are determined by the supervising unit. Patients varied in age from charge of the treatment have been diagnosed as sufferina from depressive (a) Tests of Brain Function: have been Two duration and The psychiatrist in 20 to 66, and and schizophrenic illnesses. indices of the cerebral function stressed: Quantitative measures of the degree of induced delta activity in the electroencephalogram,(6) and changes in orientation awareness of illness after amobarbital sodium (7). 1) Egg: Electroencephalograms were done.weekly ment, and on a day following a treatment. selected leads were measured and prior to treat- Bipolar recording was for the degree of delta activity. used, and The average percent time delta for each of these selected leads, the highest delta index in any one lead, the highest amplitude and Slowest frequency of delta, and the longest duration of bursts were the measares utilized in the class- ification of the records into "high degree," "moderate degree" and "low degree delta activity" (7). 2) Amobarbital Test: This the patient is and awareness asked a standard set of questions pertaining to orientation of illness. Amobarbital is then administered intravenously, in a concentration based seconds,% is a structured interview, in which upon body weight, until nystagmus and at a rate of 1 cc slurred speech are induced. to every ho The same 1"“.% In the initial series, a 5% solution of amobarbital was administered at the rate of 1 cc per minute. Recently, to permit simultaneous estimates of the sedation threshold (8), the procedure was modified to allow for weight differences of subjects. �~12.- questions are repeated, and persistent changes in orientation, denial of illness, confabulation, and reduplication are called "positive" and are indicative of states of altered cerebral ftnction (7). Tests were carried at weekly intervals during.electroshock out before electrodiock, and day on a after a treatment. (b) Evaluation of Behavior: In addition to the notes of the patient's therapist and supervising psychiatrist, all patients were seen by the research psychiatrist at weekly intervals during treatment and Z-h weeks after the last treatment. Evaluation of changes in behavior induced by electroshock were based on these on descriptions. Ratings of the behavioral response reflect a short term groups: much improved, described ( two to three clinical rating. weeks The improvement were based after the last treatment, patients were divided and into three moderately improved and unimproved, based on criteria ). (c) Evaluation of Personality: The initial method of personality assessnent employed has been a structured family interview. In their orig- inal observations, Weinstein and Kahn described the characteristics of the "explicit verbal denial personality" (9). To determine the significance of this personality type for behavioral reSponse, a structured questionnaire was developed. In interviews with two members of the family, the patient’s usual attitudes and interests in 15 Specific areas were explored. Each characteristic was rated as being absent, moderately present or markedly present. Scores of 0, l and 2, reapectively, were assigned, and added - the resulting score being termed the "denial personality score" (10). (d) Treatment: Electroshock was administered on a schedule of three treatments a week. A minimum of 12 treatments was given, except in a few �cases where a severe confusional state appeared ment was determined by earlier. The course of treat- the supervising psychiatrist in charge of the electro- unit, based upon clinical criteria. Treatments were grandznal, using either a Medcraft alternating current instrument or a Reiter C-h? electro- shock stimulator. Patients were generally premedicated with.intravenous pentothal prior to the treatment. In the past year, a subconvulsive therapy group was instituted. Randemxy selected electroshock referrals received 12-h2 subconvulsive treatthe ments, under pentothal premedication. These patients were subjected to same test procedures and the same behavioral evaluations as the grand mal therapy subjects. Neither the psychiatrist making the evaluation, the patient's therapist, nor the patient was cognizant of which patients received which.form of therapy. The data for this series of‘patients being evaluated, and reference will be made only is now to the general observations. �III. Observations: A. Role of Altered Cerebral Function in Behavior: 1. Electroencephalogram: In these studies, we have emphasized the degree of delta activity. In the initial series of patients a direct relationship was noted between the early development and maintenance of high degree delta activity much and short term clinical ratings (6). or the patients who were rated weeks of improved, 90$ had high degree delta EEG records in the 3rd and hth treatment, while of the unimproved patients, only relationship between delta activity and 20% had such records. The clinical ratings is seen in Figure 1. In subsequent series, these observations were extended in a predictive much study. Based on the earlier Observations, it was suggested that the improved patients were those in high degree whom delta activity had been in the course of treatment and sustained. Records during the ant third weeks of treatment, therefore, were assessed. The results induced early second in Sh consecutive patients are noted in Table 1. veloped high degree delta ment, such 67% rated were activity were activity during the second much improved, so while only EEG High Delta and who de- third weeks of treat- of the patients without I Activity During Second, Third‘weeks of Treatment. Clinical Rating Much Imgroved Delta 30% the patients rated. TABLE Patients with Of Mbderately'lrunnved Unimproved (11%) Both High (18) 12 (67%) h (22%) 2 (16) u (25%) 8 (50%) h (25% None High (20) 6 (30%) 7 (35%) 7 One High (35%) �a7; 2. AmObarbital Test: In the of 2h patients, preViouSly reported (2), initial series eleven patients were rated as testreactions after 7 to much improved, and all 9 treatments and sustained had positive amObarbital this response. 0f the positive amobarbital reaponses in the third week and 28% in the fourth week, but these were not sustained. A comparison of'both the EEG Observations and the amobarbital test data, as related to the eventual clinical rating is seen in Table II. unimproved In 77 patients, 15% had patients tested to date, observations during the second weeks of treatment were examined activity 75% and had both and third for the presence of high degree delta positive amobarbital test results. positive amobarbital tests Of the much improved and high EEG patients, delta activity during patients, however, 57% had neither positive amobarbital tests nor high EEG delta activity. It is apparent that the cluster of positive amobarbital tests, high EEG delta activity and much improved clinical ratings is a significant one; and equally significant is this period. Of the unimproved the cluster of negative amobarbital activity and tests, low and moderate EEG clinical rating of unimproved. delta �9 ..—-- m TABLE EEG II and Amobarbital Test Results During Second, Third Weeks of Treatment.* Much Mbderately Improved gnimprovsd Improved Both Pbsitive Amobarbital and High EEG Delta Activity 25 10 3 Either Positive Amcbarbital or High EEG Delta Activity 8 12 5 _£L_ L (25) Neither Positive Amdbarbital nor High EEG Delta Activity (33) (Total) B. 1.1 (19) Clinical Patterns of Behavior: In these patients, we have observed including the absence of noticeable varied responses to electroshock symptoms with a return of yrs-morbid behavior; hypomania, euphoria, and denial; paranoid states with ideas of reference and delusional formation; confusional states with varying degrees of memory disturbance; increased somatic complaints and preoccupations, states of increased panic, excitement and agitation and varying degrees of withdrawal, and seclusiveness. The degree of behavioral change is seen to alteration in the neurophysiologic indices. brain During electroshock, with the gradual induction of states of altered function, and their restitution in the weeks following cessation of therapy, be related to the degree of behavior Shows characteristic patterns. The following are but a few of the are observed during the period of increasing and waning gross patterns that states of altered brain.function. Anearly change in behavior in retarded subjects, for example, rO-‘ﬁ’lt. * Significant at hotter than .01 level of confidence. x»,-~-n---.' ~rmw-n. may it...“ �be a change in the degree of neatness and participation in interest in personal care. This ward is activities and increased succeeded by a phase of minimizing symptoms and displacement of complaints, mild euphoria, denial this time, the EEG shows the greatest degree of delta activity and amobarbital tests are positive. With the cessation of treatment, the overactivity diminishes, and interest of illness, and in the future insistence upon going home. becomes prominent. Pre-morbid evidence, and the EEG returns to normal At patterns of behavior are in and the amdbarbital test becomes negative. Other depressed subjects, however, become increasingly disturbed and during treatment, withdraw from.participation in heapital activities, Amocomplain increasingly oi memory loss, physical distress and insomnia. barbital tests and electroencephalograms may show the same degree of change as in the first group. with cessation of treatment, there is either a return to the depressed state, or a persistent emphasis physical complaints of the treatment. Another pattern, seen is the loss is on the memory loss and in hostile, negativistic and withdrawn patients, development of hyperactive, hypomanic, and impulsive behavior. Memory marked, and clinical disorientation and confusion may be noted at thelieight o£1neurophysiologic change. After treatment is ended, ideas of reference, negativism and delusional formation become prominent, to be followed by withdrawal and mutism. C. Effect of Subconvulsive Therapy: interdependence of these adaptive patterns with the state of altered brain function is more clearly demonstrated by observations in the subconvulsive group. Twenty-seven subjects received subconvulsive The �~10; electroencephalogram therapy instead of grand mal. Minimal changes in the behavior and in smobarbital tests were induced, and the changes in clinical limited. The electroencephalograms demonstrated either no delta or were a minimal amount of such activity. In patient no were moderate or high activity records observed. In the amobarbital tests, only each instance three patients had positive tests during, treatment, and in it occurred only once . No change in symptoms or behavior was noted in degree delta treatment. twenty-times. Nineteen were referred for a second course of degree Grand mal electroshock induced changes in brain function of high delta activity and/or repeated positive amobarbital tests in fourteen of while of the these. All fourteen showed significant changes in behavior; five patients in whom the physiologic indices showed only minor changes, only two patients showed a definite behavioral change. of Personalitywin the Adaptiverg‘e‘spggg: the Another variable in the adaptive response of the patient is and behavior - the habitual attitudes, patterns of perception 1). Role personalitw and defenses of the patient. The initial study of the role of personality related the characterological disposition of patients mechanisms to the clinical result. The showing denial relatives of h? patients were inter- Scores ranged from viewed, and denial, personality scores assessed. O to 25, scores were divided into two groups: scores from and those from O - 10 as 11 to 25 were classes as the "high denial group" with a median of 11. the “low denial The gar-mp." 0f the ,.latients with high denial personality scores (Table 58%; were in the much improved group, and. only one patient (1%) was III), in �911- the unimproved group. The ratings of for the patients with - about one third appearing in improvement low denial personality scores were random i each rating category. lean; Relation of Denial Personality Scores to Clinical Response to Electroshock Much Improved Moderately Improved Unimpmved Total M9&1}EI., §9ar£ 11 — 25 1h 9 1 2h 0 - 10 7 9 7 23 21 18 8 h? Total The difference in the denial scores between the improved patients, when compared to the unimproved much or the moderately patients, is statistically significant. That the personality ratings were indeed reflective of the patients' adaptive reaponse under the conditions of altered. brain function is noted. in the correlation of these scores with actual changes in language patterns which had *een described (11) as indicative of denial responses. As in that study, changes in language in structured interviews with the patient were studied. Each patient was classified according to whether or not he shone 6. three or more explicit language changes . The group of patients with high denial personality scores showed a significantly greater number of language changes than patients with low personality scores. The co- efficient of correlation is +.7l, which is significant at better than the 1% level of confidence. �IV. Discussign: These studies of the neurophysiologic and psychologic aspects of electroshock support and amplify the hypothesis of electroshock action initially expressed by Weinstein, Linn and Kahn (l) , and again by Kahn, (3), Aird (’4), and Ulett (5a, b). Alteration in brain function is the central effect of electroshock therapy, and is a pre-requisite to behavioral change. He have emphasized delta activity in the electroencephalogram and the patterns of disorientation, confabulation, and denial of illness after amobarbital Fink and 'E-i‘einstein (2), and the observations of Roth as indices of altered brain function. Other measures, applied in the serial fashion, will, we believe, demonstrate the in behavior or alteration in brain function. Under the conditions of the induced change same same relation to changes in brain function, The type of adaptation altered patterns of adaptation are expressed. these varies, apparently dependent upon the personality organization. In studies we have noted the relationship of an "explicit verbal denial" personality type with the development and maintenance of clinical language patterns of denial, displacement, and minimization in structured interviews (11) . We have observed that patients with high denial scores are those are more likely to who The type of adaptation be evaluated as is varied, "much improved" (Table III). however, as we have described here. In this context, therefore, the conclusion is affirmed that electroshock is a in cerebral function in which altered patterns of adaptive-interpersonal behavior can be sustained. means of inducing: change We have emphasized " change in behavior" vious studies, we in this report. In pre- related our observation to "improvement." "Improvement" �:13- derivitive evaluation of the induced behavioral change, which is dependend upon the expectations of the therapist, the family, or the administrator, in the milieu in which the behavior is observed. When a depressed patient, is a who had been withdrawn, is seclusive, and crying, and had expressed suicidal thoughts, no longer is jovial, frienc‘ly and euphoric, denies his problems and sees his previous thoughts of suicide as is made. To "silly," a rating of "Inuch improved" the extent that a schizophrenic patient delusional, less excited, and less however, the induced behavior one is perceived as less rated as "improved." When, of increased anxiety and fearmlness, or loss, pain or other physical symptoms, or delusional thoughts, a rating of "unimproved" will be made. persistent complaints about excitement and is t-Iithdrawn, he is memory studies amplify the present neumphysiologic-adaptive hypothesis of electroshock action. Further studies, defining the significant aspects of personality and of the expectations of the environment on the patterns of These behavior which are observed under the condition of altered brain function are suggested. Application of this hypothesis to the effect of newer tranquillizing agents is in progress. Finally, studies of individual differences in the neurophysiologic response to equivalent amounts of cerebral trauma warrants exploration. �V. gunnery and. Conclusions: 1. This report sumarizes continuing esperimental studies of the mode of action of electroshock therapy. 2. Behavioral change in electroshock is dependent upon an altera- tion in brain function as evidenced by serial changes in delta activity in the electroencephalogram and disorientation and confabulation with intravenous amobarbital. 3. The depending upon the subject 1;. pattern of behavioral alteration is shown to vary markedly, the degree of induced cerebral dysfunction, the personality of and. the environmental situation. "Improvement" ratings are seen as a Special case of behavioral the type of adantation elicited, the expectation of the therapist , adninistrator and family, and the tolerance of the milieu. change dependent upon this neurophysiologic-adaptive hypothesis of electmshocl: action to other forms of somatic therapies is suggested. S. The extension of �m REFEIUQI‘ICES l. Juno‘s—t Weinstein, E.A., Linn, L. and Kahn, R.L.: Psychosis During Electroshock Therapy: Its relation to the Theory of Shock Therapy, Am. J. Psychiat” 109: 22-26, 1952. of Amobarbital 1. and Weinstein, E.A.: RelationA.I—-I.A. Arch. Neurol. Electroshock, in Test to Clinical Improvement 1956. and Psychiat., IQ: 23-29, Roth, 1-1.: Changes in the EEG under Barbiturate Anesthesia Proclucec‘v by Electro-Convulsive Treatment and their Significance for the Theory of EST Action, EEG. Clin. Neurophysiol., _3.: 261-280, 1951. Kahn, R.L., Fink, 3. h. Pace, J.EI., Hernaff, M.K. and Bowditch, 5.0.: Neurophysiologic Effects of lectrically Induced Convulsions, A.:-I.A. Arch. Neurol. and Psychiat., 15: 371-378, 1956. Aird, Ran, Strait, L.A., . G.A., Smith, K. 5a. Ulett, Subconvulsive Shock and Gleeser, G.C.: Evaluation of Convulsive and Therapies Utilizing a Control Group, Am. J. Psychiat., 112: 795-802, 1956. 5b. Glasser, G.C., Caldtrell, B.M., and Smith, K.: The Use of I'iatched Groups in the Evaluation of Convulsive and Subcommlsive Biotoshock, Bull. Mann. 015.11., 6a. 6b. _1__8_: 138-1h6, 1951.. H. and Kahn, R.L.: Quantitative Studies of Slow Wave Followi.n:_; Electroshock, EEG Clin. Neurophysiol” _8_: 158 Fink, Activity (Abst.) 1956. EEG Delta Activity to Behavioral and ___: Relation of Response in hilactroshock: Quantitative Serial Studies, A.itI.A. Arch. Eleurol. and Psychiat. (in press). 7. E-Jeinstein, E.A., Kahn, R.L., Sugarman, L.A. and Linn, L.:Diagnostic Use of Amobarbital Sodium ("Amytal Sodium") in Organic Brain F‘lisease, Am. J. Psychiatu .133: 889-89h, 1953. 8. Shagass, C. : The Sedation Threshold. 9. Weinstein, E.A. and Kahn, R.L.: Personality Factors in Denial of illness, in Psychiatric Patients, A.1-I.A. Arch. Neurol. and EEG A Method for Estimating Tension Clin. Neurophysiol., Psychiat., _6_: 221-233, 1951;. 99;: 355-367, 1953. Parsonality Factors in Behavioral to Electroshock Therapy, Coni‘. Neurol., (in press) Response 10 . Kahn, R.L. and Fink, 14.: 11. Kahn, R.L. and Fink, 141.: Changes in languAge During Té‘lectroshock Therapy, in P cho tholo g; Comunication (Hoch, P. and Zubin, J., 13623.), Grune and tratton, N.Y., 1957. (in press). � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. 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Archives of Neurology May 1960, Vol. 2, pp. 547—551 Copyright 1960, by Aerircm Medical Association F igure-Ground Discrimination After Induced Altered Brain Function ROBERT l.. KAHN, Ph.D.; MAX POLLACK, Ph.D., and Studies of complex visual perception with altered brain function in man have not always yielded clear or consistent results. The disagreements may be due to many factors, such as differences in population studied, types of procedures employed, and difﬁculties in evaluating the degree of alteration in brain function. Electroconvulsive therapy (ECT), however, provides a unique op portunity for studying the effects of cere— bral dysfunction in that more accurate control can be maintained over the degree of induced cerebral dysfunction and its measurement. While most investigations of brain—injured populations have focused on the role of the locus of the lesion on behavior, current studies of ECT have emphasized individual differences. Marked variability has been shown for perceptual}2 behavorial,7 and physiologic 5'8 responses to ECT. Various personality 6'11 and social factors 9'10 have also been related to differences in response to treatment. In the course of an investigation of the perceptual and behavorial changes with ECT, a convulsive—subconvulsive control study was undertaken. In this report, the performance on complex visual tasks is pre— sented. Speciﬁcally, the aim was to deter— mine whether perceptual change induced by ECT is related to the degree of altered brain function and clinical behavioral ‘ Accepted for publication Jan. 18, 1960. From The Department of Experimental Psy— chiatry, Hillside Hospital. Presented at the American Psychological Association, New York, August, 1957. Aided by Grants M-927 and MY-2092 of the National Institute of Mental Health, National Institutes of Health, US. Public Health Service. MAX FINK, M.D., Glen Oaks, New York change, and Whether the pretreatment perceptual pattern is related to physiologic changes with treatment. The method used in the study was the perception of embedded geometric ﬁgures—— a technique which has been employed in recent years in studies of perceptual change in head trauma and brain tumor pa- tients.1'“"'14 Method Population—Fifty-three consecutive patients referred for ECT were studied. These included 16 men and 37 women, the ages ranging from 22 to 66 years, with a median of 49 years. The patients were divided at random into two groups. A convulsive group, of 29 patients, received grand mal electrotherapy with thiopental (Pentothal) premedication three times a week, using either a Medcraft alternating-current instrument or a. Reiter C-47 electrostimulator. A minimum of 12 treatments was given. The total number of treat— 1. ments was determined by the supervising psychia— trist in charge of the treatment unit on the basis of clinical criteria. A subconvulsive group, of 24 patients, was treated in similar fashion except that only subconvulsive stimulation was given after the thiopental. Fourteen of the subjects in the 'subconvulsive group were subsequently given a regular course of convulsive therapy. 2. Perceptual Task—In the week prior to treat— ment and on the day following the 12th treatment each patient was tested with a modiﬁcation of the Gottschaldt hidden—ﬁgure test developed by Bat— tersby et al.1 The subject is presented with a page containing two forms—a simple geometric ﬁgure, and below it a complex ﬁgure in which the simple ﬁgure is embedded (Figure). The patient is asked to trace a speciﬁc geometric ﬁgure from the background by outlining it with a colored pencil. The discriminations range in complexity from relatively simple to more complex. There are 25 such discriminations. A maximum of two minutes is allowed for each. Performance is scored in terms of total number of errors. To minimize a practice effect, two equivalent forms of the test were used. The forms were alternated with 77/547 �A.M.A. ARCHIVES OF NEUROLOGY Comparisons for Number of Errorr Before and During EC T TABLE 1.———Intragr0up Type of Treatment Subconvulsivo Convulsive Before No. 24 43 ECT During Differ— ECT once 1’ 7.7 11.8 ~2.3 +2.3 <0.02 10.0 9.5 * (0.02 Intragroup analyses in this and in subsequent tables are based on Wilcoxon’s method of paired replicates. * Results \VAVI ‘7"7V 'AL A AL‘ Figures in hidden-ﬁgures test. The preliminary sample used to acquaint the subjects with the task is shown in a; b and c are examples of test ﬁgures. In (1 the task is complicated by having the subject determine which of the two single ﬁgures can be found in the complex ﬁgure. successive patients in pretreatment testing. During treatment the patient was reexamined with the form different from that given initially. 3. Evaluation of Physiologic Change. Two measures of brain function——the electroencephalo— gram and the amobarbital test15—were given to each patient prio1 to and at weekly intervals during treatment. The electroencephalogram was evaluated as to the degree of induced slow-wave activity according to criteria previously published.5 The amobarbital test was noted as positive or negative for brain dysfunction according to standardized criteria}5 The results of these tests during the second, third, and fourth weeks of treatment furnished the criteria for physiologic change. A combined physiologic index was obtained by ascribing to each high—degree slow—wave EEG record and each positive amobarbital test a score of one. The range of physiologic altera— tion thus ranged from 0 to 6. 4. Behavior Ratings.—Each patient’s behavior was evaluated at weekly intervals. After the 12th treatment, a rating for the degree of behavioral change was made according to four classes: marked, moderate, minimal, or none. These ratings of change were not value judgments as to the quality of change but, rather, quantitative estimates of differences in behavior patterns under similar conditions of observation. Thus, such behavior patterns as euphoria, paranoia, and withdrawal might all be rated as equivalent for degree of quantitative change, although the implications of. each for the qualitative evaluation of improvement may be diﬁ'erent. 78/548 The pretreatment and treatment scores and the mean change in the number of er— rors with treatment are shown for each group in Table 1. Intragroup analysis shows that the subconvulsive group made signiﬁ— cantly fewer errors during treatment, whereas the convulsive patients made sig— niﬁcantly more. Prior to treatment, subconvulsive patients made approximately the same number of errors as those in the convulsive group, a mean difference of 0.5 error. During treatment, however, the difference between these bet— at signiﬁcant (4.1 errors) was groups ter than the 1'% level of conﬁdence. When the data are analyzed with respect to physiologic change, signiﬁcant increases in errors are found only for those patients with great— er degrees of physiologic change. This re— lationship is present in the analysis of the amobarbital test and the EEG as separate 2,—1ntragroup Comparisons for Number of Errors Before and After EC T in Relation to Degree of Physiologic Change TABLE 3 Mean Difference in No. of Errors During Treatment Physiological Index N Amobarbital Test None or one positive 13 —0.2 Two or three positive Electroencephalogram None or one high delta 28 +3.7 23 +1.7 Two or three high delta Combined Physiologic 0 t0 3 18 +3.3 21 +1.0 20 +3.9 4 to 6 1’ Not significant <0.01 Not signiﬁcant <0.05 Not signiﬁcant <0.01 V 01. 2, May, 1960 �FIGURE-GROUND DISCRIMINATION 3,—Intragronp Comparisons for Number of Errors Before and During ECT in Relation to Degree of Behavioral Change 4.—Relation of Pretreatment Errors to Eventnal Degree of Physiologic Change TABLE Degree of Behavioral Change Marked Moderate Minimal or none N Treatment 14 5 ——0.4 Physiologic Change 1’ 0 3 5 <0.01 Not signiﬁcant Not signiﬁcant indices, and when the two tests are bined (Table 2). to 2 and N 16 4 and 6 19 8 Mean N o. of Errors Pretreatment 7.9 11.2 13.3 logic change had frequent difﬁculty following instructions. They would trace the lines com— The relationship between the degree of behavioral change and the change in num— ber of errors during treatment is shown in Table 3. Those patients with minimal or moderate behavior changes did not show an appreciable difference in number of er— rors. Those with marked behavior changes, however, made signiﬁcantly more errors during treatment. Analysis of the pretreatment error scores in relation to the degree of physiologic change is shown in Table 4. A signiﬁcant relationship is shown between the pretreatment error scores and the degree of physio— logic change during treatment. Patients with minimal physiologic change during convulsive therapy had a mean pretreat— ment score of 7.9 errors, while those who developed marked physiologic effects had a mean pretreatment score of 13.2. The triserial correlation of pretreatment score and physiologic change is +0.34, signiﬁcant at the 0.05 level of conﬁdence. Qualitative Data—Alterations in size of ﬁgure or in minor aspects of form were common types of error during both testing periods. Certain qualitative patterns were frequently noted during treatment, which occurred only rarely in the pretreatment period. It was common for patients to make no attempt to trace the more complex ﬁgures. This failure was often associated with a generalized withdrawal reaction in which theipatient was unresponsive to any stimulus or procedure. Others became hos— tile and negativistic toward the testing. Patients with the greatest amount of physio— Kalm ,et al. During Treatment Mean Difference for Number of Errors During +3.6 +1.0 24 TABLE indiscriminately, without regard for the speciﬁc ﬁgure to be traced, repeat a previous ﬁgure despite changes in the test ﬁgure, draw lines where none actually existed, and attempt to trace the stimulus ﬁgure while ignoring the more complex test ﬁgure. Such patients were likely to respond quickly and impulsively, and showed little concern about making an error even when spontaneously commenting, “I know that’s not right.” Comment This study demonstrates a relationship between the degree of cerebral dysfunction and the degree of perceptual alteration as measured by errors on the embedded-ﬁgures test. Patients with subconvulsive stimulation made fewer errors on retesting. Patients receiving convulsive therapy, in whom only minimal physiologic changes were recorded, manifested slight increase or no change in errors. The convulsive patients, however, with the more marked physiologic altera— tions, showed a signiﬁcant increase in ‘ errors. This interrelationship of brain func— tion and perception may be related both to the perceptual patterns with neurologic dis— orders and t0 the mode of action of con— vulsive therapy. It is evident that perceptual responses systematically vary with the degree of dif— fuse cerebral dysfunction. In relating these patterns to concepts of localized pathology, the role of generalized, nonspeciﬁc cerebral dysfunction must be considered. For ex— ample, unilateral spatial “inattention,” fre— quently attributed to parietal lobe lesions alone?!4 has been reported with a variety 79/ 549 �AM. A. ARCHIVES OF NEUROLOGY of lesions provided there was a somato— sensory defect and an associated generalized mental impairment."""16 Teuber and Wein— stein 1“ found that performance on an em— bedded—ﬁgures test was unrelated to locus of lesion in cases with penetrating brain wounds, but that aphasic patients made signiﬁcantly more errors than a nonaphasic group. Pollack et al.,13 using a test identical with that in this study, reported no rela— tionship between errors and the location of lesion in tumor patients. They noted, instead, that the number of errors was related to the severity of general mental changes, manifested as disorientation for time and place. The present observation that perception of embedded ﬁgures is re— lated to the degree of diffuse brain dys— function is in accord with these studies of patients with head injuries and brain tu— mors. In previous investigations of the mode of action of convulsive therapy, we have shown that clinical behavioral change is related to the degree of altered brain func— tion.5'7'8 The present study reinforces this observation, the objective criterion of per— ceptual errors being used as an index of behavioral change. As a group, the patients who showed the greatest increase in errors with treatment were those who also showed the most pronounced change in clinical behavior, as assessed by conventional psychiatric evaluation. There appeared to be considerable comparability in the type, as well as the degree, of clinical behavioral change and the quali— tative aspects of performance on the em— bedded-ﬁgures test. Failure to attempt the task characteristically accompanied with— drawal or paranoid hostility. A lack of con— cern in correcting errors was associated with clinical euphoria or hypomania. From these behavioral observations, the increases in errors may be attributed to a change in attitude toward the task or examiner, as well as to a speciﬁc defect. The altered brain function modiﬁed the total pattern of interaction with the environment, of which 80/550 the performance on a complex perceptual task is just one aspect. Previous studies have shown that there is a relationship between the clinical response to convulsive therapy and aspects of personality, deﬁned as the habitual or characteristic modes of response and adaptation.“v1°'11 In this study it has been shown that the pretreatment perceptual performance is related to the physiological response during treatment. This ﬁnding suggests that the indi— vidual differences in the development of physiologic change may also be related, in part, to personality factors. Summary and Conclusion Fifty—three consecutive patients referred for electrotherapy were studied before and after treatment on their ability to perceive embedded geometric ﬁgures. An experimental group of 29 patients received a course of grand mal therapy with thiopental (Pentothal) premedication. A control group of 24 patients received submnvulsive stimu— lation with thiopental premedication only. The experimental group made signiﬁcant— ly more errors after treatment than did the controls. Within the experimental group there was considerable variability. Increase in errors was signiﬁcantly related to the degree of altered brain function and to the degree of behavioral change. Qualitative aspects of perceptual behavior mirrored the pattern of behavioral change observed clinically. Pretreatment error scores were signiﬁ— cantly related to the degree of altered brain function developed during treatment. The signiﬁcance of this observation in terms of personality factors is indicated. Department of Experimental Psychiatry, Hillside Hospital. REFERENCES l. Battersby, W. S.; Krieger, H. P.; Pollack, M., and Bender, M. B.: Figure-Ground Discrimi— nation and the Abstract Attitude in Patients with Cerebral Neoplasms, A.M.A. Arch. Neurol. & Psychiat. 76 2369, 1956. Vol. 2, May, 1960 �FIGURE-GROUND DISCRIMINA TION Battersby, W. S.; Bender, M. B.; Pollack, M., and Kahn, R. L.: Unilateral Spatial Agnosia (Inattention) in Patients with Cerebral Lesions, Brain 79:68, 1956. 3. Critchley, MacD.: The Parietal Lobes, Baltimore, Williams & Wilkins Company, 1953. 4. Cobb, S.: Amnesia for the Left Limbs De— veloping into Anosognosia, Bull. Los Angeles Neurol. Soc. 12:48, 1947. 5. Fink, M., and Kahn, R. L.: Relation of Electroencephalographic Delta Activity to Behavioral Response in Electroshock: Quantitative Serial Studies, A.M.A. Arch. Neurol. & Psychiat. 2. 78:516, 1957. Fink, M.; Kahn, R. L., and Pollack, M.: Psychological Factors Affecting Individual Differ— ences in Behavioral Response to Convulsive Therapy, J. Nerv. & Ment. Dis. 1282243, 1959. 7. Fink, M.; Kahn, R. L., and Green, M. A.: Experimental Studies of the Electroshock Process, Dis. Nerv. System 19:1, 1958. 8. Kahn, R. L.; Fink, M., and Weinstein, E. A.: Relation of Amobarbital Test to Clinical Improve— ment in Electroshock, A.M.A. Arch. Neurol. & Psychiat. 76:23, 1956. 9. Kahn, R. L.; Pollack, M., and Fink, M.: Social Factors in the Selection of Therapy in a Voluntary Mental Hospital, J. Hillside Hosp. 6: 6. 216, 1957. Kalm cl 0]. Kahn, R. L.; Pollack, M., and Fink, M.: Sociopsychologic Aspects of Psychiatric Treatment in a Voluntary Mental Hospital, A.M.A. Arch. Gen. Psychiat. 1:565, 1959. 11. Kahn, R. L., and Fink, M.: Personality Factors in Behavioral Response to Electroshock Therapy, J. Neuropsychiat. 1:45, 1959. 12. Landis, C.; Dillon, D., and Leopold, 8.: Changes in Flicker-Fusion Threshold and in Choice Reaction Time Induced by Electroconvul— sive Therapy, J. Psychol. 41:61, 1956. 13. Pollack, M.; Battersby, W. S., and Bender, M. B.: Figure—Ground Discrimination in Patients with Cerebral Tumor, read at Eastern Psychological Association, 1957. 14. Teuber, H. L., and Weinstein, 5.: Ability to Discover Hidden Figures After Cerebral Lesions, A.M.A. Arch. Neurol. & Psychiat. 76: 10. 369, 1956. Weinstein, E. A.; Kahn, R. L.; Sugarman, L. A., and Linn, L.: Diagnostic Use of Amo— barbital Sodium (“Amytal Sodium”) in Brain Disease, Am. J. Psychiat. 112 2889. 1953. 16. Weinstein, E. A.; Kahn, R. L., and Slote, W. H.: Withdrawal, Inattention, and Pain Asymbolia, A.M.A. Arch. 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Inuﬁttntoa at laulth, Intlnall Innath, laatal Iorvtao. ’rnacutod a! nastiest fartholuntaul inuuctn‘aon. l.!.. luau-S 195? ‘ Vt: 10-59 �11¢."de nun-mints.” in mt �Iaaurtocrilnd Dinertllnntiaa Attor~xu¢n¢¢d llturnd Drain Flaottlu at «unplax $111.1 yﬁvucytaau with altartd brain :buattnn.£n man have lat ulnar: yiuldad Bill! or couuautaut rsIuZtu. an. dtn‘groanautn to at. to stay Inn‘oru, than ﬁtnuxgu I! dirtbrcncoa It: 1a populutluu s‘ua1ca, $39.: a: tools :34 pranocnrna unplayud. and a1:ttou1t1.a In 01.1;‘t13: ﬁlo d:¢vao a: Iltlritltt 1g bruit minuttaa. llaitrOOOBthttvo thnrupr (ref). houuvur, prcvs$un u uaaqnt oppurﬁuuaty for 1%‘431nc it: vitamin u: ctrubrnl irntinataan in ‘htﬁ no». acouruho .oltvol tan b. untacntnoa trot tin Cairo. at tndnata corubrul drutunntaau and its gonnur'nunt. will. invautiguttann at ﬁrstnntuanrud pdpnIntitnn hnvu ttauucod 10! it. loot part on ﬁat til. at loéittal‘of logttl on ht$aviur. nurroat ltultan at an! hurt taphutitad its manna rum- .3 manna: a» «mm... mun“: ton aim-n m- unupm; (a), “man: (h). and pmwmun (2.5) vtnpauttu ‘0 not. In Iﬁdl‘iia, Virii‘l portounlity (3) and loclal luster: (6.?) ﬂat. bat: rolntud ﬁoldtttortasau 1n rtuponno $0 ‘rcntuunt. In it. «attic a: la invautttgtSOI at ‘3. yorunptnnl :36 tchavtavuz thungca with Int. n.Iauvulotvo~osboouvnlutvo unailwz .5343 cat Indurtaktg. In ‘hiu roport. sh: partorunuca an outwit: vtnunl Qtakt it praaautud. splattaually, tho .1: 83' to ﬁattrnino utnﬁhnr purcoytlnl thing. iﬂdlﬂid up new it um suntan or an behavioral «minute and uhtilnr it; pvctrttﬁlnnt yarotpinul pttiurn is roxaind ﬁt plytitltciu chance: with troatannt. “um u «m; nuns um “um: �4". m ”and uni 1a a. menu “mun “mu and; m «- a Mini: m ”In"!!! at which bu tun unity“ a mum you: 1: than 0: ”run“: WI a: um ”um «I be“: Wu:- nﬁnh (1, 0. 16). �m: 1) gagglggﬁggo rttﬁy-£hrcc coal-cuttvc putt-mt. martyred for In! rare s‘n4114. 230.0 includcd 16 no: and 37 Human. I1¢h n30: ranging tram 1! to 66 utth a Isltil at £9 rinru. A «111604 tun rauduu gronyn. I!» patttutc var. at tat. can'tzntvo grin: or I? pntlnuta too-:vud [kind In: olonﬁrnu ' thorlpy'vttb ponto‘hnl pronndsuattln ﬂhrco'ttnna a aver. tutu; utﬁhar a lcdnrttﬁ t1tarna$¢u¢ entrant tustrllnnﬁ or u A e-hv olcc‘ruotSunlntar. mitt-I: at 1! ‘tOﬂﬁlII‘l lattir IaturIAnoa nmahar so$a1 troutnoi‘n c: given. III It: rut. by it. any-twining ,lrahlutvtlt an churxo at ‘ho truntncu‘ A 01 nubcaavnlltv: owls-via. 01:110.; basis unit 9» ti. (was: a: th patients van truttcd 1: nihilnr t‘nhina, uxcapi that only unbcouvuloivc a‘tln1n§1¢u van given following $30 polbthal. rbnrtctn of thy lubaoatavtn tho InbouthI-iva grin; wort cuinnq13ntly':1vun a rcgnlnr coura- ot couvulatvn tharupy. itch prior ﬁo-‘roctutut and I) £2:ggg§3g§_§gg§u In it. it. any tullantnc ‘5. 12‘3 ﬁction vtﬁh a nultttatttaa of nu tritiuunt can) pa‘taut an: hiddun £1113! oottaohnll‘ it. to.‘ dovulopo‘ by Itt‘orlby'3§_g§,(1). III Ittjltt is prouontod with I page containing two torn. ¢ a usual. cut-n$rtnl which QIH’XQI and in holov 1‘ in. atlulc ticuro a tantru, Illlft an ouhcdnod (11;. 1). tbs passlnt :- .akod ‘0 ﬁrst. I apoottio goo-attic ttxuro tram tin inchcrcund by outlining 1t vl‘h t col-rut 903.11. It: altars-tuition: range in noupluxaty :90. —-.‘q--_ 313. 1 Cunﬁoodu �~h~ such :5 tr. diucrtuiautioun. a .311!!! at tun uluuton 1. ullnuod tor onah. Portarnnaco as :¢¢rud in turn: 0: ﬁnial lllbir a: aurora. lb i181l1‘¢ a prautttn Itruct $ro tqslvaloaﬁ lawn. a: $3. iau£ any: unod. 2h. torn: var. nltaruntut vi‘h Inactnuav. yuttcu‘n ttlnttvaly ainplt ta hart couplux. that: “prawn-u ”um. mm: What a. ”unﬁt m ”umuu an» m an autumt tun um um mum”. 3) _ . .NMV . ,Jﬂ ,7 run Inalurol at ﬁrst: Stuntiou . tun cluatrnoacaphnlogrna and st. nasbattxtil taut (11) '0'. ctvuu in itih puttnnt grist in. uni at vigil: ‘1uﬁcrvu1n airing tronﬂnnut. 13. n1..tuuunaophn1&¢run In: tvdlnntid .- to th: dsxtno ct tutucod delta activity tcgor¢1nu to ctttcrtt prcvtoully publishud (s). Thu nuabarbttal tout nogn%1vu brain utt¢¢ for or pouttivc lycttnatiuu a. It. uncaritng t. ntsudnr¢1Qid critoria (11). it. rattlta u: this. during sh. sonata. third tad rourtb itch; of ironing»: turntlhod tho critcrin tar phwutolocacal litill. A «onhiuad 'Bhrlltltxtﬁil $34.: was obtntnud by usarihtn; to oath high inure. Salt. Ila UQIOIC nut 05:! poattiv. anotnrhttal tnnﬁ a lanai a: nut. 1h. rang. at phwitaloatcnl a1&nrat1nn thuu test: ruagnd tron h) atra'io nix. la tr *1: It Bash pctaauﬁ's hchnvtor In. cvnlnatud 3‘ wtokly intarvals. Artur ‘3: 12th trcn‘uant, a rtttal for it. dugvnu a: bnhtvinral thing. It: and. ¢os.vdll¢ ta tan! clnsucut unwind, nod¢rnto. Iantunl or menu. Th... rating: at «hang. vura ant VIII. audgnnnutu ta ta tho unaatty �.5. u “than“ in“ “my «unaba- uuntu‘ in boinvtov pu‘tnrau unit: tintlar mandatsana at uhocrv.‘10u¢ than. tuch‘bolnvtur psi$urua nu «upharsa, viruautn or withdrawn: usgl‘ .11 ha astod as aqutvnlcnt to: ‘OCIOI u: an minute“ or out chum. thy qunlt£nttvu cvnluutsna a: tlprcwuuuat um; to dartornut. at than, wanna“ am» in �mu» nud-truatnoét ae¢r¢t uni tic luau :3. pretrtatuaut ¢hanzc in *5. 31:30! at or!.ra I1$h trnntutnt Ara uncut {ﬁr caah group in 1.31. X. Intrusrtur‘uaalyaas that: thus tho ,Ititotvalaiva crazy aqdn utgnitivnntly tenor ovroro aartn; tru¢tnunt, whili thc.uguvultavu pn$1¢atu nun. stun:tt¢n&t11 . '3’“! naucc&ao§~ um I vriur to tvattunat, subconvulnzvu pattout: Inn. upprcun alnﬁnlr ﬁts can. nuuhur 0: cart»: 1: than: in tho annvula:v&. autumn of «1:05. Wing trauma {my vi“ a hatunda tiott gran»: (h.1 cfrorn) «aircrunnn hosuvwr, t3. an m untrumt a «an: «m an 1:: 1m: or wanna“. Intlywod tit) racpoe‘ to phyiiclazit cunnsc, utsutrlnuut xgcrtnuoa in error. art taunt out: ta than. pittnntu ut‘h 31.3%.! diurnal at plrltuloxin ohnagt. 2&1: rwluisunuhtp anabnrbttll taat and the it pvuuta‘ tn $hc analyttt or :36 ﬁt ¢:partta latte... 331 was: tit $20 tact: urn «unbluoi ﬂﬁnu tn. data 1: it. (Quilt 1!). “.‘.‘.*..mm it: fun raltttaauhtp intact: tn. 1032*. 01 bahnv1:rnl chant. a:& chtago ta nulkor of «pants dnrtng imattuant-ta inﬂux ti: or a... an: «an m. ”man “am want. a �at?“ bchlviar changcu £1: acﬁ than an uppgoainbio difiaruaeo untied bchnwilr chanson, In author a: Qtfl?Io Shag: with Errata-It. «trans uaAc crvarn nuratcnttiolatly lavorur, > tn‘woum 143%! 111 rnlnﬁtou tin arctroa‘I'It atttr 1:11:31. at 1n 17. thunk chango ta tail! of phauanlaciuul in tin ducts. roloﬁtkunhtp hetuuuu tin prothan uttnttlaaaﬁ a result. it: 00.9.. $3 phyat;lo¢tou1 change or incrno ‘roaﬁlcut crror chanco physiological with Itatnnl Pa‘iantu during trons-ou‘. a: had prntrhﬁﬁnalﬂ intro u than convulclvu ‘hnrnyy ‘ﬁfll' anrhad uh» phyniulogtoal duvclaycd ‘30:. 1.! aurora, tail. ﬁrst-21.1 13.3. 1:. at htd acct. protr:ntuunt a nut: trtoa$u, in rhyrt01131¢nl «hang: and corral-ﬁat. at protvan‘nunt tear. *33, ttgustaoaut t$ ‘ho .05 lcvul a: canttdtnoo. ”nan-unufllﬁl I? IOOIOI and 1h» W Altamitlcnn In a1:- 01 (aggro or in unit: unpuu‘: of ha‘h sot£1n¢ partoiac taping arrow at annual typo. no». (at: ear‘atn qualiﬁn‘tvo patiorua turn troqn.ntly'nuta¢ «‘21:; inuniuaat ho-Ivnt, which oacurrtd our rarely a: to I lancer alﬁon‘ 1: tin prttrultlun‘ portcd. It vat gonna: for putataﬂu �mu. I: m»: “I rum man. m m at 1'10th sun-mun” mu» ‘ 3 auto" m: mm: :6! mum“ a 1’. 2B 19.0 .7»? *2“! .0! h) 9.5 11.8 «.3 -.ea ' my“: 1“"!er 811mm now 0: mm "plant“. in this and aubuqunt “nu band on �. Iu‘rnctunp cuuparlaonn ,1331nataauaa Iran: Aaszsthéaa!_z:£& lung or on. ,- In: lI-bav It Izrnra nut-rt I Inc: Bittbrcnoo 1- 13 06.! ,‘Ci‘l’i :8 ‘30? loan or at. high «01‘. 23 01.7 pauzttv. 9!. or thrto turn. or401%. ﬁt. high 3’ Us and 'IleI p Int tinnittaon‘ 001 lat lttuttloant , ' 10 .3.) 33 *1.o :3 ‘30, .05 lat attaittcunt . 001 �-W and having Safari o: strata cunpurtllnu tor_IIuh¢r In‘rnur1up angrvo O! lohnvacrnl ﬁlingt . litttd ”liturunconilnbﬁr a: 03.6 01.0 ~0.h Eh lb locnrato hiatus: or that R¢1u$ton I lat: x W t: at Pritv‘nﬁnunt tutor. p x... .ﬂl lot aaanlftcaat Int atctitlnant xv'utunx 20;?!0 or rhrltolscidax 72353;; agggg‘ zggggggg , W! 9 $0 2 3 '3‘ ‘ I 1‘ 70’ I, 11.1 �«a. to ink: I6 nttcnpt tn tvtau ﬁt. hora cunplcx figures. was. v.1poncc uga ottou unnaaiatud lith I gsnarnltacd r1tbdrauu1 rcdctlun in witch ‘ha paticnt was unruuponniva $0 an: attnula: u! pracodura. ethnra b.3335 hua‘tlo and uncuttviuilu touted it. tasting. ratauntu with th- groaﬁu-t tumult or phytiologtanl thing. it‘an had ditticllty I‘llivtas tantruc%a.ag. 13¢: it‘ld in... ‘IC 113.. stalwartntn.tolr I1th¢:§ rognra 1.: it. #9001113 tigurt‘ic it uttlsutd; rtpousod a pruvitun txatr‘ doapitc august. 1: ti. #0:: figurn; draw 11:». uhnro aunt uc$nully Oxiiﬁad; and aﬁtnnutcd to trlcc tbs tttunluc tinny: Ital-'1cuorlig 1h: Into couplcx toot»:1:url. patleuﬁn VOID and uhuvud it.) might 11kuly ltttlu ﬁuah it rcupaud quickly and tawlzclvuxr. o-annvu about making an arrow 0": «tan apantanoiutly dounont, '1 luau $hst'n unt rich€.' �W! .9, bdiuuon $|o d.:run ruln‘ionnhip fit: Ot'ﬁi’ibrll‘ﬁyiflllﬁtlt and $ha aggro. u! parnuptual :Itcrn31ln taut. unbuddui PI‘tcutt eh. nunpurod on figiruu an h: crrurn ‘utth aubcolvnlsxvu uttlslntton-Iika shunt aurora an rotuattua. A ultghs dgcrauss or unwahanul tn Ottawa octurrnd in that. who riogtvzaz ahnitd cuntulitvo ally'haallnl thirty: pattlatt thing‘s. in. aunvulsivu pittcatl, houivor, ut‘t pkg-Intogtcul atudr‘luunlatrlitu - & 68. unit anvkud phamaglcgtcux altsruttnn, Ihnvtd a ctxuttlnnat tn¢r0330 1n number at strewn. 1‘4: lntorrnlntaoauhAp at bruit £una££un aha porcupiiuu or caboddcd tsguvuu is in actard wi‘t atudtnn of pu$tnutu with altarud tibia rua¢ttiu an. to htad wutaatoia u (10) uppaytng fwuﬁtr tad taunt. taint: ul-ilur inuhuta 1n QISI& with pauotrattng brain unuadt, tutu alldud that ycrrurllnan Inn_uarnln&ua to lien. or lonlua but ihat uphuuic pntttnto and. nixaittcnntly'unru arvnra thtu & unaunphnnlc bruinwtnjirol group. Pollack g§_g§, (9). 1113‘ ruporﬁod Qltc SI an taxation-t1, an taut atuty. tauntttul tit httuuul attain and ‘h. laaation a: 10010: &n tutor patsoutt. ﬁts rnlutol author at that rwporﬁad. tuntnnd, in: Irrort it!) to it: stvurtty o: amok unut¢1 changes an dzuaritatntiau. 1‘ should be yuanint o‘t «hat the total prc‘roatunnt than atom. tow I11 pntlcnt- r‘larraa lav upnvulntvo thnruyy ﬁn sauna hy saunt1¢a1 10.5 n linou‘ nun». tat! ctrurn. at. and brain nxmk 21.5%: (9) an um: man tw pltluu“. an” ‘ use populations It. auuparublc 3: turn: .1 a£hnr pntnntﬁura £11or1u1u.~ xvuund In $3. and lattata figurt ceuautiwa. a: as. two �‘16“ iii! oaunct in rugurﬁud an rntlntttvc o: notnhrtl 43:9inotaou an an inalnﬁad out$£y tbairna‘od (It. ﬁt. t¢tn11my at hchavtur. hasn‘t ‘hll beta; :- 3.0Io in tin rolatloatth, your parttvuuaau tn aunt inthu any be due to it: internation a: Ina: tn:$«rn. mu 117thth um. an); an. my “on m nu.»watt nation cnrnbrcl din... uh» lit! fi'tf hit!!! an $ht- iatk than ocntrul llhltt‘l viﬁh tn§n¢t turtbrnl tunataun. In in. prbouaﬁ otudy It. rtugc at altturoacou lull: $hn pattunﬁ: prior ‘0 ‘lﬂﬂildli nun cruator than thnﬁ uhintlud cvua‘ux‘h atrium: phyasalartall chlacu. “’11. patlaut in thy nahnoavnlatva group wish I high author at prutvtnilaut «trorn at: ants a yrlattcn attics In ritcnttn; watt a ruita£1on in crrtra, hit nbnulutc arrow near: :nr still bu hixhnr tits shut it n puiinnﬁ ronutvilu tournlntvn ‘hnaunr_uh¢ had Irv protv*ainnnt erurn 0“ I:s alum: auurtaacd dattxaulsy with trociunnt. than. obnnrvatioan tuccuuﬁ thtt isttanulty 1| ptrtotvtnc cnhaadad (tutti. ta tainted to acrintu ’Oviiilltiw unpocti tn v.11 n: it ﬁrst. ttwthnstailu Galituﬁalt with talc aanulptiou. ﬂttita (1!, 13) but thiod tha‘ ﬁt. Hurlid thtividi&1 dillnrwunua in tin porttptaoa-c: haddnu tautrla nuns; 0011.10 otudoatn If. rtlnﬁci to purnounIAtr tun$oro. its rvlatlllnhip or parucpintl altnruticn to bohavtornl 1.: clearly during u: u group an than haunt ,puiauntc at. thalud Qt. cystitis snaruutu in autumn during trouﬁuant viii than. vi. .130 lhlﬂtl tun swat yruaouncod ah$a¢u m t manna. �«11¢ mucmd mm puma: cult“: team”. may“. Wt... “mum. «aunt-ta a a: to “we“ m mum m“ m mutt" on a» mom: tutu an mm tun-Int. ham to may 1n or mu. pm» «at» «um tut m um‘ WW 1» in Inﬁnity um "mum u t pm.“ at «ml mu, “ton. A or raw- to an um In! of mm in wanna: "mm at non-um claim ”its!“ c: mm“ 1:. mun“ :- «W. m «$81th with «d mu. than” m. tho ”that“! to arr an.» «aim an n m mi: num. a. a 0: 0: m uuutm 1: tutu mum. am... a can N on mum.“ u Mutt“ an omit: ﬂﬂmm tut with or a m ammt. u it. ”won “and“: u W mmum to 0 in in rim . am nun“ :0:m 3m1¢1u1031 mum. in “an.“ manual» m In at no“ c: a «an “null". that». WI1: mm an 3m um I m mm“ cm“ «mitnm a Manna.” ﬂu at ﬂu t ”can.” «alum for at Ma pron-«mat mum M3. mulch. mm man»- that m in a» mum! wanna».- mover. at of a dam. mun-«u: “an a 4mm“ ma M at much "nut ”nanny. u m an (a, 5). to ”an": �all; taxman. manna ”than ”1‘qu hr in mm. m an: What “tummy an um; A: 4“ ms: an“: man «ma mm. that... 0: gm, a 0: I! united min-um ”an“ mu mi 1. m mm: i It“ mum: Man...n-mu‘m with ”nun-a My nun” ”ulna «hum. m In: a: It pmmutm my. I. a. madman “110'“; What M ' ' in»: an an “Mina: m “I! «am... ram as manual no» mu m tﬂlﬂﬂ'ﬂth in» tun-nu "nanny. mm an imminent” mum u ‘ ' ' 3. mumuotnwmmunmumnmnu “but!“ “use. p um um: mo autumn: of bran alum m «gm tutu“ amino! mm u In run-«hunt W Mm at ”nanny («my tmhmt. I'M 1.th mint“. “ﬂute!!!“ at “It! in .1 psi-«pm W10: mu“: “than chum: «1mm». no puns-u or human: 5. m M am �mm: M. 1|"le 11133th a: hut (ulna. m 1.: In.“ ma: man ﬂu u mutt as also.“ m1. "by 9.: Wk mug-ma um m an.“ u 3. n g m an: m tn um» Hm. «I: u “I“ an at“ m was “we. W m �«1 3a References I. Inttarahy, w.s.. traccnr. x.r., reliant, n. and nundlr. 3.3.: figuruogrcmnd ¢£unr£uannt1nu and the abatrtut uttitncn 1n putatuta with narchrax neayltnna. 5,555, ‘4 xi, '_'_, gaig.~;k;w., 19; 369, 195$. 2. rink. I. and Kuhn, Into: leln‘ttn Qt ita ﬁcltl anivtty ‘a behavioral raapouao an electrouhaaks quantitnﬁivn ' sorts: utiliaa, ewe .'o 1!? a 516. 1951. J. rink. h. m. I.t. tucturc vayuhnlnnzaal l.u rlmllsh, l.. Ittecttng individual attrcrlacus In hohtvanrtl filviiii Kata. and a. «man mm. mg... m: m. 1939. m. rm, M... and arm. ma... Mora-um mm. ' 0! the alaotveuhaek prune... Egg, leggg 51p., l2! 1. 1958. 5. mm. 2.3... rm, 1:. mt manna, 1m... lemma .3 Innhtrbttaa tout to altﬁiﬁll inprrvoann‘ in cleatrclhatk, 1.mt.,‘1§I 83. 1956. 6. Kuhn, 3.3.. Pollnel, ﬂ. and tint, n.a auutul flatari 1n ‘ho taxonﬁauu at thtvlwy ta 3 valuntear ninth: hanpttal. ,. 7. .ﬁ _. , uI. go :16”. 1997. Iain, I.L., Pulltnk, and risk, 3.: atatapuylhaluuto ﬁrtntlnut an I reinstary ninth! haspt‘tl. 5.x.n. trot. ﬂan. Payer. (In preto). I. tenets, 6.. 3111‘», a. and beeper; 8.! damage: 3: little:lliinn thrtlhﬁld and in until. vtnnﬁtlu $1.! Indtotd 1956. by 61. that-pr. a: magenta ‘3 paguhtttrso “wanna“ W... �...L 1.1.23.1...LL hunt. I... ground tuna”. 10. rum, Id. I). 8.3.: W and 'nnna W M. ‘ 5.: woman. attu- {W “any hunt, mm 1;.»- m. 1m. to hunch, 3a.. uh. IJ...‘ Guam. ammo m a a man“ in“ than. 1953. 1!. mm. Wumm M, 1‘va mu“ mm: 11. ma. m4 itltrﬁntnlttui in pttllut: itth carthvll at Panama“). Amati“. m. m 1957. ‘ mm. 3.4.1. “It. in: m: 889. on «an (Inn: want) ’ . «mm». 8.5.: .1 unhaido‘ tiguruu, g, rugg.. in £23 «u a! 1, 1936. swam mm»: um Wu 3.9M. um. 1M. pot-«yam. a a: W" LA... um .1 � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Figure-ground discrimination after induced altered brain function. Arch Neurol. (Chic.) 1960 May; 2:547-51 Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-47-013 Date A point or period of time associated with an event in the lifecycle of the resource 1960 Creator An entity primarily responsible for making the resource Kahn, Robert L.; Pollack, Max; <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint and [preprint]. Reprinted from the A.M.A. Archives of Neurology May 1960, Vol. 2, pp. 547—551 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/e7dc2fcb5fc19380588fec1c1d7b8cf6.pdf e4bf0125cc9cc7fe7c750dbacfa00dd7 PDF Text Text �SOME EFFECTS OF A NEW PSYCHQTOQEN IN BEFRESSIVE STATES J. Mednna Univereity of Illinoie College of L. G. Ahood A and L. Hedioine group of 3~R~snhetitnted piperidyl beneiletee have been recently denonetreted to poseees peychotceieetic propertiee(l.2). The N-nethyl-snpiperidyl beneilete, in doeegee of 5-10 mg orally, produced distinct auditory and visual hellucinatione in every nor-e1 individual teeted. The hallucinations lasted for many bears, and were accompanied by green distortion of visual perand by e confosionel etete corresponding to delirium. ception A nnnber of subjects exhibited paranoid ideotion and ideee of grandeur, while others suffered a conplete loee of contact with the environ-eat, end frequently reacted to their hallocinetione. When the toxic symptoee disappeared, the experienced ethecte e earked physical eeekneee for 10—24 honre, after which period they regained their pro-experimental statue. It see noticed, however, that some of the normal volunteer subJects developed a change in their heeic mood and drive. This change usually appeared 24 to 48 hours after the phyeicel weakness disappeared. The newly energies modulation of need can be characterized es slightly hypenenic end of increeeed drive. This leet observation indicated that the drug night he naefnl in the treatment of peychietric states in which the ontetending eyepton ie a depressed need. In the course of exonining the structureoaotivity relationships of various congenere of the piperidyl beneiletee (3), it wee found that substitution or e cyclopentyl for one of the phenyl groups in beneilic acid considerably enhanced peychotogenie potency end greatly prolonged the duration of action. The colu pound, deeigneted JB-329', has the following structure: Q *- {’ I “2‘5 0 Ell/Q - g 361 ‘0 N-ethyl-B-piperidyl cyclopentylphenyl glycolate hydrochloride This derivative also eeened to produce considerably more hyperend central etieeletion than did its beneilate congener. ectivity The present comnunicotion concerns the nee of J8~339 on psychi- etric patients. DB, one a 60-year-old eon, e first patient, §5g3_ﬁgt_*: ormer r cklayer, who had been hospitalized for the last ten years. Exeeinetion revealed his caee to be one of eevere depres» eion iith suicidal tendencies, ceoeed apparently by the necrotic The �. 7 .., . t V... ".7“ .........4. ,g-vvwmh . ”a...“ . man. w.- ...,..r.....,....... r.” ..u._,..,,.,.—Y “any,” p,..r.._....~.w.....F—, .»... wwv.-.» an...“ ...~.,v»,., . "ﬁn y”... wr—u-nrl’nu _,., V... ..W;.,..I.:.v...._.._..r*‘ 7.. reaction of his burned~out body to the insoluble probles of his wife’s gsychotio illness. The patient eas given 12 as of 33-329, and sit in an hour showed signs of confusion, drowsiness, ataxia, and hypereflexia. A few hours later he began hallucina~ having tions, saa disoriented, extreaely restless, and beg nning to lose contact with the environaent. Autonosic syaptoas were present throughout, such as aydriasis, tachycardia, dryness of the south, and muscular weakness. At the end of 24 hours, he seeaed con~_ siderahly less depressed, sailed, laughed, and was such sore talkative, although he professed to be Just as depressed as he was before the treat-ant. Psychological re-exaaination with the Eduardo and Rorschach tests indicated a definite iaproveaent in seed and general outlook, and although the depression still existed, it seessd realistically based, and was considerably less overehelding. The patient, hosever,.rofased to go back to his psychotic wife, and was returned to a state hospital. EP, a an 33~year-eld unaarried shite aan, coaplained he, 0%.. o extreee apathy, and a chronic spastic colitis. spression, He had quit his job over a year ago because of an increasing depression, accompanied by feelings of inadequacy and lack of desire to work. Psychological tests revealed his to be iasature, with little or no effect, no signs of anxiety, and no insight into his condition. He reacted to 10 ag of JB~329 in such the seas manner as the previous patient, covering a tine-span of 18 hours. At the and of this period, he appeared very cheerful, and of the depressed, haunted features of his face had disappeared. all He gave the iapression of a nan sell on the way to after recovery a long illness. That ease day he indulged in a rather vigorous gene of baseball, nixed, and talked freely with the other patients. He adsitted feeling sore aggressive and exuberant, and expressed a desire to go back to sort as soon as he was discharged. Psychological re~exaaination showed his to be sore responsive, less inhibited, and his outlook less liaited. The patient was discharged two days after receiving the drug, and two days later be procured a position, which he still retains after three aonths. c a had lea, 47-yearweld'aarried.aan, a history §%;f_§g‘_%l 0 ntera ttent depressions since 1953. He had been unable to work during the past year because of the depression. at the ties of his admission, he showed syaptoas of restlessness and extreae agitation; he ens harassed by self-accusations and feelin of guilt. Pro-therapy tests revealed an inadequate personal ty with en extreaely passive dependence.on other people. The existent anxiety and depressive features sore overlaid upon a longostanding character disorder. The patient's response to 12 ng of JB~329 differed fro: the previous patients only insofar as the halluci» natory episodes sere far aore vivid and of longer duration. After 36 hours, the patient exhibited aarked increase in actor activity and a draaatic iaproveaent in need. Psychological reexasination revealed that he was now able to express hopeful and resolute attitudes toward the future, although he still had little confidence in his ability to achieve the goals he envisioned. �after being discharged, which he spontaneously erote a letter were taken the following statements: free For your infor~ nation, ay progress has been good. I as working about [all tine have gained-about ten pounds. ﬂy appetite is very good not. as extremely grateful to you for what you have done.‘ Two weeks ...I ...I who a 54*yearuold earried sea shite eoaan ap» gagg_§g‘_3z each older, and had been in a very severe depree~ pears very sion for the last ten years. She had phobic paranoid reactions, suicidal ideas, and hysterical attacks accoepenied by screening. excessive crying, and other indications of desire {or attention. Psychological exaninetion indicated an unsound personality strse~ tnre which scene to have been infantile even before the onset of the present illness. The effects produced by 12 a; of JB~329 were to those in the other patients. and lasted for 24 hours. eiailer The following day, she appeared more vivacious and nest of the outward signs of her illness had disappeared. 0n the succeeding day, she socialised for the first time with other patients, and participated in occupational therapy activities. She seeaed‘sur~ prisingly cheerful, enjoyed her food, and appeared outgoing. After three days, when her husband case to take her hose, she reacted violently and relapsed into her previous condition. Her' condition was apparently developing into a full—bloen psychosis. Electroshock therapy was adninistered during the next week, and although the patient showed improvement at first, she again relapsed into the previousaagiteted depressive condition. No 5: KB, a 46—year-old shite-nnaerried resale with Ca paranoia delusions. was depressed and apathetic. She was extra-sly tense and anxious. and her grasp on reality was tenuous. Her reaction to 10 a; of JB~329 see similar to that of the other except that the hallucinations and disorientation lasted patients, up to 36 hours. Two days later, she appeared definitely anieated. cheerful. and coegosed. When questioned about her past condition, she replied, "I feel such more alert and don’t toel.depressed. Strangely enough, this was one of the first things I noticed. I feel new as it before the treat-ant I had been living in a [let tee-dimensional eorld and I had sort of retreated into ayseli. and nee, after this treatment, I feel I as out in the noraal three-dioensional world. I feel such sore alive...I have lore energy and enthusiasm.“ The patient resneed her work on the day following.her discharge. She continued to shoe improve-ant during B the next few weeks, although after one south-she appears to be relapstng into her former state. She reported. however, that a symptoms, which she referred to as a ”catatonic nightnere." a condition during which sheeeeeaed to be conscious but was unable to sore and which had existed for eany years before the treat— aent, had coapletely disappeared and had not yet returned. LCCT ' DISCUSSION Five cases have been presented which serve as pilot experiaents in the application of the piperidyl bensilatee to patients manifesting psychopathology. Of the five cases, the first and �“-vv—l‘vrr‘vr‘n-I—vw—v'wvwbvu' .V ‘1"N"x'-w-*,—- meg-w,v—u—m- . mun—aw wr— . Wmuw‘aw—r _.. wenhvvrv-"v' Wham-1 rap. >mvr-.-.—_—,WVgrnww.-m.n WK‘J'W‘ wm ~ wane—v - .w u-‘nnw -4the fourth can be considered eo experieentel ouccooeee but therepeutic failures. These two particular ceeee have never reepondod‘eell to any other for: of therapy, including electron check and drugs. In three case: (Noe. 2, 3, end 3) the single application of the oxperiaentol dru; proved to he of therepeutic value. Cece: No. 2 and 3, who were unable to work for over e before the oxyear porieent, were able to do oo. Case No. 5, which is the neat interesting of our small oxporieental group, wee working prior to the experiment; but that petiont'e state-onto end our objective observation are both indicative of the therapeutic effectivonoee of the drug. Cece No. 4 proved to be a therapeutic failure with reepect to the drug. but the patient aloe failed to recover after electric convulsive trootnonte., All five canoe treated hed only one synptoa in cannon-~ooee degree of doproeeion. The other most remarkable con-on feature of cases No. 3, 3, 4, and 5 one an extreme infantile personality which could not be expected to change after a eingle treatment of whatever eort. If it were not for the fifth coco, where the loot remarkable ohengee were produced, this drug, 38-329 and ite con¢enere could be earmarked for the treatment of depreoeive otateo only. In the fifth case, however, beneath the light dopreeeion were deeper disturbances of thinking end perception eluding superficial observation. In effect, ehe eee psychotic. lhethor her perticular paranoid state ehoold be diegnoeod ae latent eohieophrenie, effeltivo paychooie, or achieophroniforio beside the point. The ieportance of this case io that it indicates some usefulness of the piperidyl benziletee in e patient eith lurked perceptual and cognitive dieturbenooo. There are a great nu-ber of questions uneneeered by thie proliainary experiment. Both the extent and duration of leproveaent have not been fully aeeoeeod. It reneino to be detereinod 1) whether repelted adainietretion of the drug in hallucinogenic doeeo would have produced a greater degree of improvement in the eueceeefei canoe and total or partial leproveaont in the unseen ooeeful fourth cone; or 2) whether the production of the poychotogonic etete ie necoeeery et oil to produce ieprovenent; or 3) if deily repeated small doses of the drug for an extended time would have produced the care but clover iiproveoent. Both the effect end proper doeege ochedule of e aeintonenco ascent of JB-329 have yet to be determined. Finally, the proper field of application of this drug in peychiatry ie in doubt. do for co the cxporieentol results on nornel and pathologic etheoto permit any conclueion, the drug would be epglicable to depree~ eive etetee. Our fifth case. however, reieee some slight hope that JB-329 or related derivetivee night be useful in treating the grove personality dieordere cocoonly diagnosed an albino. , - a phrenil. L of enticholinergic egonte in the treetaont of eohieophroeie ie not nee. Forror and eo~eorkere (4) odainieterod very large The nee '10.!"me �W “u—wmumw—HWM‘ w , y:- m ;«m« mu, 7-" v mlm“ wﬂwnm—u‘u—w“ Imam. m... .. -. . .r t i . a r n . - _ _ i n. --'—-'-v>-vv_uru'v » 'I‘uﬂv-"vWO4‘m‘ <‘AmevN’--ww z-ew11IUI'm—rl—I- .5doses (up to 200 mg) of atropine intramuscnlerly to schizophrenics seniteetinc eose degree of anxiety. [Such doses of atropine produced core; but nest of tho psychotogonic and stisuleting notions achieved with JB—329 were absent. It remains to be seen whether the besic eeoheniss ot-thooe tvo nodes of therapy is sisiler, although our findings suggest that atropine is devoid of the exceesive stimulating properties of JB~329. LSD—38,_enother hellnoinogen, has been used therapeutically in treating psychotics, lsrsely es en edJunct to psychotherapy or electroshock convul— sions (5, 6). With regard to the code of sction hardly more can be said than that the substance has definite enticholinorgic properties, but evidence thet the central ettect itself involved cholisergic blocksde is locking (1, 3). The piperidyl bensiletes in smaller doses produce facilitation of sotor neurons (Renshee cells) in the lesbsr region of the cat‘s spinal cord, while larger doses produced couplete inhibition (7). Acetylcholine is presumed to be a mediator in Renshew cells which are believed to exercise a generalized sup reesion in motor neurons innervating okeletel soocle.v Kiseich ‘8) hes demonstrated en inhibition of electricel activity in the reticular bulber forention of the rabbit with 2.5 eg/kg of JB~329. in contradictincticn to LSD, which in exci~ tetory. Such neurophysiologicel studies are merely prelisinsry end. although they say oxplsin certain effects of the drug, such es hyporrcrlexie. considerably more work of this sort releins to be done. clinical results with the drug are even more obscure, perticnlerly since the therepentic effects become apparent long after the hellucinatione and autonomic sysgtoss have disappeared. Furthersoro, otudieo on animals indicate that the drug is rcedilg hydrolyzed in the body, and is completely elisineted in 24-48 ours.. One can only conclude, therefore, that therapeutic effects are related to the drug in a secondary manner. The piperidyl beneilntos probably serve es a trigger necheniss for e long series of neuroohysiologicol effects resulting in the inprevelent in the pstient s psychopathslogicel etstns. Sub~ sequent clinioel work ie oiled at working out proper dosage schedules, on well no the indications for the use of this and other related drugs. The SUMMARY entioholinergic psychotonimetic agent, Noethyl-3~piperidyl cyclopentylphenyl glycolote (JR-329), has been used in the treat~ sent of e snail author of depreeeed patients. The drug induces e drive of eotivity eccosponied by sons sood elevation. This sceningly desirable effect tron s therapist's viewpoint occurs after e period in which there are psychopathologicel effects or s definitely psychotic nature. The post~psychotic effects which sees desirable are of a prolonged duretion (days to reeks possibly). There is st least all ht evidence in two casee or e continuing stete of isprovenent n inte3retion of the mental functioning and A new behavior. ' �. ,w... E. n‘vw-“m-w~'mwwm‘w‘m‘—Iw — ,., -—- --——- q"r.xr)r.«,"l‘w wine—uw.w m_m , .v . w-..-....w w. m—u—wnm .c up... (“mu—r . .- "le- REFERENCES l. 6., Oetfeld, N., and Biol, J. A new group of peychotceieetic egente. Proc. Soc. Exp. Biol. end ﬂed., Ahead, L. A. 97: 433, 1958. 2. Oetteld. A. l., Ahead, L. 6., end Hercne, D. A. Studies with cerulopleeein end e nee hellucinogea. A.M.A. Arch. Neurol. and Peychiet.. 79: 317, 1958. Abuod. L. 6., 03:5.1a. A. u., and 31.1, a. Structure~ activity roletionehipe of Supiperidyl heneiletee with peychotcgenic propertiee. Arch. Int. Phereecody. ct Thor. (in prose, 1958). Forrer, G. R. AtrOplne toxicity there_y in the treatment of aental dieeese. AI. J. Paychiet., 08: 107, 1951. Just, F., and Penal, ﬂ. Proepective peychietry. Inch. Mod. ﬁche-chr.. 99: 889, 1957. Sandlson, R. A., end Whitelae, J. D. A. Further etudiee in the therapeutic velue of LSD in eentel(illnees. J. » 3. 4. 5. 6. 7. 8. Heat. Sci., 103: 332, 1957. Ueki, 8., hiehi, 8., end chcteu, K. Hieeich. K. Persoael coneunicetion. Personal communication. Foorxowas ‘ Syntheeieed bf Dr. John Biel, Lekeeide Leboretoriee, Hilveukee, Wieceeein. authors ere deeply lndebteﬂ to Dr. F. J. Gerty for hie eeny invaluable suggeetione, end to Dr. Alec K. Roeeneeld for the plydhalogicel teete. Aiéed by greute free the Mental Health Fund, Stete at Illincie. end the Teegle Foundation. The �Institute of Human Nutrition, Praha, (J. Mast-k) A PSYCHOSIS CAUSED BY BENACTYZIN INTOXICATION Minis VoJ'i‘cmuovsm" The dimethylaminoethyl ester of benzylic acid is known in the literature by the following names: Benaetyzin, Suavitil, Parasan. It was synthesized in 1936 in the CIBA Laboratories in Switzerland as a spasmolytic agent, but it was not until 1955 that it first came to be used in psychiatry by Munkuad & Jacobsen, where it proved to be a useful tool for decreasing anxiety and psychic tension, without having any hypnotic side effect. During the following two years it was roughly investigated for both its clinical and pharmacological qualities and was applied to many patients in various institutions. The specific action of this drug upon the central nervous system placed it, together with the tranquilizers, on the level of the leading modern psychopharmacological agents. For its composition and central nervous action it was called an “antiphobic” agent, while its chemical structure ranged it among the diphcnylmethanes having a central nervous effect (together with e.g. Meratran. Frenquel, or Atarax). 'I‘herapeutically it is used more commonly in cases of neurosis than in psychotic cases. Its pharmacological and clinical attributes have been described thoroughly in other publications. This substance was also synthesized in Czechoslovakia, in the Laboratories of the Institute for Research in Pharmacology and Biochemistry and has been tested since May 1956 in several clinical institutions (Dr. Hanzlic‘ek, Dr. Vina‘r’, Dr. Vojté’chovsk‘y). The results of these tests have been published elsewhere. At the clinical department of the Institute of Human Nutrition we administer Benactyzin in the therapy of some gastrointestinal diseases. Thus we had an opportunity to observe the course of an acute intoxication, which we refer to in the following case history. It was the enormous size of the dose used, fifteen times greater than described in the literature (Jacobsen (1955)— 90 mg). as well as the fact that to our knowledge it is the only case where psychotic symptoms appeared, which stimulated the communication. .43, . i �A PSYCHOSIS CAUSED BY BENACTYZIN INTOXICATION MILos \’o.1'r1'«:1;11ovs1\'\" The dimethylaminocthyl ester of benzylic acid is known in the literature by the following names: Benactyzin, Suavitil, Parasan. It was synthesized in 1936 in the CIBA Laboratories in Switzerland as a spasmolytic agent, but it was not until 1955 that it first came to be used in psychiatry by Munkvad & Jacobsen, where it proved to be a useful tool for decreasing anxiety and psychic tension, without having any hypnotic side effect. During the following two years it was roughly investigated for both its clinical and pharmacological qualities and was applied to many patients in various institutions. The specific action of this drug upon the central nervous system placed it, together with the tranquilizers, on the level of the leading modern psychopharmacological agents. For its composition and central nervous action it was called an “antiphobic” agent, while its chemical structure ranged it among the diphenylmcthanes having a central nervous effect (together with e.g. Meratran, Frenquel, or Atarax). Therapeutically it is used more commonlyin cases of neurosis than1n psychotic cases. Its pharmacological and clinical attributes have been described thoroughly in other publications. This substance was also synthesized in Czechoslovakia, in the Laboratories of the Institute for Research in Pharmacology and Biochemistry and has been tested since May 1956 in several clinical institutions (Dr. Hanzlié’ek, Dr. Vina‘r’, Dr. Vojféchovsk'y). The results of these tests have been published elsewhere. At the clinical department of the Institute of Human Nutrition we administer Benactyzin in the therapy of some gastrointestinal diseases. Thus we had an opportunity to observe the course of an acute intoxication, which we refer to in the following case history. It was the enormous size of the dose used. fifteen times greater than described in the literature (Jacobsen (1955)— 90 mg), as well as the fact that to our knowledge it is the only case where psychotic symptoms appeared, which stimulated the communication. �515 CASE HISTORY L.B., a 29 year old married female, a physician by profession, with a sensitivepersonality, but without previous psychiatric symptoms, during a short period of emotional excitement following some misunderstanding with her husband, consumed almost a teaspoonful of pure Benactyzin. (During the reconstruction of the case it was ascertained by weighing approximately the same amount of the drug, that the patient had consumed about 1300—1400 mg of Benactyzin). It was used solely for its soothing effect without any intention of committing suicide. The course taken by the intoxication, as described by the patient herself and corroborated by her husband and the physician summoned to the case, was as follows: About ten to fifteen minutes after taking the drug the patient became confused, she felt as if she were looking at herself and her surroundings from a distance is; as if everything was running away from her. She expected to faint, but remained seated quietly on the sofa. After about twenty minutes she became agitated and leaving her seat walked in a very unstable manner to the bathroom to take a shower. There she noticed in the semi-darkness a pile of laundry lying on the floor, and on top of it she suddenly saw her six months old son. Let us continue in the patient’s own words. “I was unable to realize at the time that this could not be true since the baby was actually at home with his grandmother. As I kept looking the baby suddenly turned pale, then yellow, his eye-balls deviated to one side and he appeared to be on the verge of dying. Finally, before my very eyes, he started fading away and disappeared. In a wild attempt to find him I searched among the laundry and then, feeling completely desperate, I ran out to seek an injection for him. My husband prevented me from going out. I accused him of being the cause of our baby's possible death.” According to the husband there followed a short struggle and the patient was compelled to remain in the room. What occurred in the next period is covered by amnesia (that is between the twentieth and the fiftieth minute), and it is the husband alone who continues the description of the case as follows. “She showed signs of anxiety and her face held a terrified expression. Her orientation in space was altered, when she tried to seize an object she would miss it by about 20 cm, she would also miss the chair when trying to sit down. She became more.and more agitated and repeatedly tried to run into the corridor, even though she was only partly dressed, with the persistent idea of obtaining the injection for saving her child. A short time later, having managed to escape, she was found on another floor, in vain seeking an opening into a wardrobe and talking confusedly about the death of her baby. She was brought back into the room, where she became slightly calmer." The patient is able to continue the description of the events which followed (that is about an hour after the consumption of the drug), as the amnesia was lifted for this period. “I tried to understand that I could not really have seen the baby, since he was not there, but whenever I thought about him the whole situation appeared again very clearly before my eyes and I felt a terrible anxiety. At this time I partly realized that I had only suffered from a hallucination. I tried to focus my mind on my surroundings and the conversation, but my thinking was disrupted and l was unable to integrate individual notions into a logical whole, even though I did partly realize the inadequacy and incoordination of the words I used. I believe I even repeated certain phrases stereotypically.” At this time, that is between the first and second hour of 'the intoxication, the physician, who had been summoned, noted considerable psychomotor excitation, agitation, inadequate behaviour and inadequate answers to questions and diagnosed 33 ac-ra rarcu. rr NIUIOL. scan, 33, 4 �516 psychotic state. The patient confessed having taken a large dose of Benactyzin, but resolutely denied any suicidal intention. Her face was flushed and showed signs of crying, her pupils were dilated and she looked terrified, her pulse was 921 min., her blood pressure was not recorded. Caffeine and coramine Were applied hypodermically. The patient violently protested against taking the injection saying, “Do not give it to me, but to my son, who is dying.” Two hours later, when the physician saw the patient once more, there were still slight signs of psychomotor agitation and emotional instability, but the patient had just experienced a critical attitude towards the hallucination and psychotic state. In her story the patient describes her feelings during the period between the second and fourth hour after consumption as follows: “After the injection I felt roughly normal. I realized the impossibility of what I had seen, but I still remembered it with a feeling of terror.” Her husband observed that she became calmer after the injection, but her speech was still inadequate. Four hours after taking the drug she became normal, but was very tired and sleeply. An hour later, that is five hours after taking Benactyzin, she was able to ride home on the bus. Then she spent a quiet night, and the following day she was without symptoms. a EPICRISIS Ten to twenty minutes after consumption of 1300—1400 mg of pure Benactyzin a 29 year old married and mentally healthy female, a physician by profession, showed signs of indisposition, ataxia and derealisation, later there appeared psychomotor excitation and a temporary true optical hallucination showing the horrible image of the death of the patient’s baby. This experience led to great anxiety and psychomotor excitation and the whole behaviour was centered on saving the baby. In the period between the twentieth and fiftieth minute of the intoxication the patient passed into a delirious state, wih confused consciousness and followed by amnesia. This stage was characterized by the appearance of a secondary delusion about the death of the child and accompanied by aggressive behaviour motivated by the wish to save him. Thinking was incoherent, there was a feeling of blocking of the thoughts with a strong accentuation on anxiety, agitation and ataxia. The physician who examined the patient some time between the first and second hour after the intoxication, noted a psychotic state with signs of agitation, inadequate answers to questions, and the delusion about the death of her baby. Upon physical examination a flushed face, dilated pupils, and tachycardia were observed. The psychomotor agitation decreased after the application of coramine and coffeine and there arose a critical attitude towards the hallucination and delusion experienced, but the emotional bond to their memory remained. Disorders in thinking stood out foremost (blocking of the thoughts). These were apparent in the form of incoherence and perseveration. Three or four hours later the psychotic state had definitely ceased and was re9 �517 placed by tiredness and sleepiness. After this phase there were no further complications. DISCUSSION The toxic dose of Benactyzin has not been ascertained for man. Experiments on the human subject were made impossible by the marked effect of even small doses of the drug upon the central nervous system, as may be observed both clinically and on the electroencephalogram (Coady & Jewesbury 1956). After a dose of four to six mg of Benactyzin, the following unfavourable side effects were described: dizziness, apathy, relaxation of the muscles, a dull feeling of the extremities, as if they were not connected with the body, sluggish thinking and lowered attention, decreased reactivity to external stimuli, blocking of the thoughts, derealisation, ataxia. Among the symptoms of disturbance of the vegetative nervous system, it was especially dryness of the mouth and palpations which stood out. The side effects described above occur in about 40 per cent. of the patients treated, causing a marked decrease in the therapeutic value of Benactyzin. The dose used to date never surpassed 90 mg (per single dose) and were never accompanied by qualitative disturbances in thinking or hallucinations or. confusion (Jacobsen 1955). The Benactyzin intoxication described above (about 1300 mg) was characterized by a delirious psychotic episode with a brief optical hallucination, followed by a secondary delusion, confusion, and psychotic behaviour. Before and after the delirious state in our case, there were the other side effects commonly described in the literature, namely ataxia, derealisation, and blocking of the thoughts. The atropine-like visceral effects which could be expected after such a large dose of the drug were not felt by the patient herself even though they could be observed to a small extent (tachycardia, flushed face, dilated pupils). The psychotic course of the intoxication could be explained by the specific and quantitative action of Benactyzin upon the central nervous system. While the theme of the psychotic episode might well be understood psychodynamically: a sensitive mother whose main problem of life is the health of her six months old child, the optical hallucination may be the realisation of her fears. The relatively benign course and short duration of this intoxication and the negligible visceral symptoms which accompanied it, even though the dose taken surpassed therapeutic dosages more than a thousandfold, denote a relatively low toxicity of Benactyzin. On the other hand this case only accentuates the predominative action of this drug on the central nervous system. 33‘ �518 SUMMARY The clinical course of an intoxication by about 1300 mg of Benactyzin characterized by a short benign delirious psychotic state is described. REFERENCES GeseIIscha/l f. chem. Iniluslrie, Basel, Schw. Pat. No. 183065, 187825, 1936. (.‘oady, A., & E. C. 0.1ewesbury (1956): A clinical trial of benactyzine hydrochloride (“Suavitil”) as a physical relaxant. Brit. med. J. 1, 485—87. Davies, If. B. (1956): A new drug to relieve anxiety. Brit. Med. J. 1, 480—84. Jaeobsen, E. (1955): A new drug efective on the central nervous system. Dan. Med. Bull. 2, 159-160. Jacobsen, E., A. Kehler, V. Larsen, I. Munkvad & K. Skinhaj (1955): Investigations into autonomic responses during emotion. Acta psychiat. (Kbh.) 30, 607—25. Jensen, 0. ”slergaard (1955): Suavitil in the treatment of psychoneuroses. Dan. Med. Bull. 2, 14043. Munkvad, I. (1955): Treatment of psychoses and psychoneuroses with a new sedative (Suavitil). Acta psychiat. (Kbh.) 30, 729—39. Vinar, D., M. Vojté'chovskﬁ & Vinarova’ (1958) : Cas. lik. Ees. (Prague), in press. , Received April 4, 1958. Milo} Vojtéchovsk)", M.D., Praha XIV, Budéjovika 800, Czechoslovakia. �Reprinted from Psychotropic Drugs THE COMPARISON OF THE PSYCHOTIC EFFECT OF TRYPTAMINE DERIVATIVES WITH THE EFFECTS OF MESCALINE AND LSD-25 IN SELF—EXPERIMENTS S. SZARA Central State Institute for Nervous and Mental Diseases, Budapest (Hungary); Forsehungsabteilung, Psychiatrisehe und Nervenklinik der Freien Universitat, Berlin (Germany) INTRODUCTION \ Indolealkylamines have been considered for a long time as a group of active substances of rather slight pharmacological and almost no psychiatric interest. Renewed attention has been focused on them since the discovery of the presence of 5-hydroxytryptamine in blood, in the enterochromafﬁn cell system, spleen, kidney, and the central and peripheral nervous tissue. An excellent review on the pharmacology of indolealkylamines by ERSPAMER appeared in 1954, and many other reviews have appeared on 5-hydroxytryptamine or serotonin (AMIN et al.1; FREYBERGER et al.11; GADDUM et al.12; HIMWICH13; LANGEMANN17 ; PAGE2"; ROTHLIN). The tryptamine derivatives have been of interest only in connection with their effect on blood pressure. Data on their effect on the central nervous system can be found only sporadically (NIEUWENHUIZENlS; SPEETER AND ANTHONY“). Our attention towards their possible psychotic action was attracted by the works of FISH, JOHNSON, AND HORNING9 on Ptptaa’enta alkaloids among which they found bufotenine, N,N-dimethyltryptamine, and their N -oxides. In experiments on animal they found these drugs to have psychotic effects, but experiments on humans were made only with bufotenin by FABING. We therefore decided to make self-experiments and experiments on normal volunteers with N,Ndimethyltryptamine and with the N,N-diethyl compound also (Fig. I). Bufotenine HG I /\ANH/ l I l CH2CH2 N(CH3)2 C (WCHZCHz-N(CH3)2 DMT “ T—g l \ANH /\j—j— \NH CH 2 CH 2 -NCH (2 5)2 Fig. I. The chemical constitution of bufotenine. DMT and T—9. References 1). 466. �PSYCHOTIC EFFECTS or DMT, r-g, 461 MESCALINE, AND LSD-25 METHODS AND MATERIALS The N,N—dimethyltryptamine (DMT) and the N,N-diethyltryptamine (T-g) were obtained synthetically by the method of SPEETER AND ANTHONY. For the purpose of puriﬁcation the amines were distilled in high vacuum. For the experiments, sterile aqueous solutions of the hydrochloric salts were prepared and used in a concentration of 30 mg per ml. The lethal doses estimated in white mice by the usual method were 135 mg/kg in the case of DMT, and I20 mg/kg in the case of T-9. ' Although the substances have been not very toxic in mice, we were very cautious in the self-experiments. In the peroral experiments, starting from 14 mg and increasing the dose up to 150 mg no observable psychic or vegetative effects were found. After the unsuccessful peroral experiments, intramuscular experiments were made. In this titration series other physicians of the Institute of Budapest took part. The doses administered were IO mg, increasing to 150 mg (zle. 2 mg/kg body weight). Psychotic effects were observed from 30 mg, Le. 0.2 mg/kg body weight; they reached their optimum in doses about 0.7—1.0 mg/kg body weight. On further increasing the doses the psychotic symptoms were suppressed by the vegetative and organic symptoms. Therefore the further experiments on normal volunteers were made with the above-mentioned optimal dose. A detailed paper on the results obtained with normal volunteers, is to appear in Psychiatria at N eurologica (SAI—HALASZ et al.22). THE SELF-EXPERIMENTS The purpose of this report is to compare the psychotic effect of tryptamine derivatives with the well-known effect of mescaline and lysergic acid diethylamide in self— experiments. I believe that this method of experimentation is one of the best ways of obtaining direct information on subtle psychopathological phenomena, which are of great importance in understanding the schizophrenic syndrome. TABLE I THE DATA OF SELF-EXPERIMENTS Dose Substance I. Mescaline II. LSD-25 III. DMT DMT DMT DMT IV. T-9 0.35 g IOO lug 0.25 mg—I 50 mg 75 mg 75 mg 60 .mg 60 mg A dmin. Date per 05 per 05 per os i.m. Dec. 1955 Dec. 1956 i.m. i.m. i.m. March—April 19 56 April 1956 June 1956 March 1957 Nov. 1956 Place Budapest Vienna Budapest Budapest Debrecen Berlin Budapest The experiments were carried out over a period of 16 months. I took mescaline at Christmas—time 1955, and the LSD—25 was tested in Vienna at the Psychiatric Clinic of the University, by courtesy of Prof. Dr. HOFF and Docent Dr. ARNOLD, in De— cember 1956. The ﬁrst intramuscular administration of DMT occurred at the end of April 1956, and was followed by the experiments on normal volunteers. We reported References 1). 466. ' �s. szARA 462 the results at the Annual Meeting of the Hungarian Physiological Society in Debrecen. During this meeting I made the second intramuscular experiment in order to get an electroencephalographic recording. A third DMT—experiment and some biochemical investigations were made in Berlin at the Research Department of the Psychiatric and Neurologic Clinic of the Free University, by the courtesy of Prof. Dr. SELBACH. The T—g—experiment was made intramuscularly in November 1956 in Budapest. I shall not go into details about the effects of mescaline and LSD-25 becauseI am not able to add any new aspects to that well—known picture. Nevertheless, the chief features of these experiments will be mentioned later. At present I shall only describe in more detail the symptoms of DMT and T—g model psychoses, in View of the lack of such reports in the literature up to now. (a) The BAIT—experiments As mentioned above, DMT ingested per as has no observable effect. But an intramuscular injection of 30 mg could already produce some mydriasis and subjectively some perceptiOn disturbances. The larger the dose, the more striking are the symptoms. About the self—experiment made with 1.0 mg/kg, Le. 75 mg DMT in total, I can report the following: In the third or fourth minute after the injection vegetative symptoms appeared, such as tingling sensation, trembling, slight nausea, mydriasis, elevation of the blood pressure and increase of the pulse rate. At the same time eidetic phenomena, optical illusions, pseudo—hallucinations, and later real hallucinations, appeared. The halluci— nations consisted of moving, brilliantly coloured oriental motifs, and later I saw wonderful scenes altering very rapidly. The faces of the people seemed to be masks. My emotional state was elevated sometimes up to euphoria. At the highest point I had compulsive athetoid movements in my left hand. My consciousness was completely ﬁlled by hallucinations, and my attention was ﬁrmly bound to them; therefore I could not give an account of the events happening around me. After %—I hour the symptoms disappeared, and I was able to describe What had happened. In the second intramuscular DMT-experiment, the duration in time and the symptoms were mamiy the same. At the third DMT-experiment, the dose was somewhat smaller (60 mg); the symptoms were thus milder, but qualitatively the same. (b) The T—g—exyberimem The symptoms of the T-g—experiment are brieﬂy as follows. About 15 minutes after the injection of 60 mg of T-g came the same vegetative symptoms as described for DMT. The illusions, hallucinations, and the athetoid compulsive movements in the left hand were the same as for DMT. But the alteration of the surrounding world and the emotional reaction to them were strong and impressive. The mask-like faces of the' persons, the dream-like mysteriousness of the objects and the room gave me the feelnig that I had arrived in another world, entirely different and queer and full of secrecy and mystery. This wonderful but strange world attracted me at one moment, but the next moment I did not want to accept it. I became perplexed; I did not know what I ought to do. I began to walk anxiously up and down, and said: ”I ought to do something, I must!” There was a peculiar double orientation in space References p. 466. �463 PSYCHOTIC EFFECTS OF DMT, T-9, MESCALINE, AND LSD-25 and time: I knew where I was, but I was inclined to accept this strange world as a reality, too. The dusk of the room was lightened for some minutes, and again the light was switched off, and that seemed to me as if this period might be an entire epoch, ﬁlled with events and happenings, but at same time I knew that only several minutes had passed. (6) The comparison of the results I should like to compare the effects of the two tryptamine derivatives outlined above with the effect of mescaline and LSD-25. The most outstanding differences can be established in their time of duration. Intensity of symptoms T-9 DMT LSD-25 Mescalin Flg. 2. Schematic course of the self-experiments. _ In Fig. 2 it can be seen that the duration of the DMT-induced model psychosis is about one hour, that of T—g is about three hours, while the LSD— and mescaline symptoms lasted for 8—10 hours. The onset of the symptoms in the case of tryptamine derivatives is wsentially quicker than the onset of the others. The elevation of the dose of DMT did not produce a longer state of intoxication, but the symptoms were more organic. It is remarkable that in all the four model psychoses the symptoms developed and passed away in wave form. The specialsymptoms are demonstrated in Table II. TABLE II THE MAIN SYMPTOMS OBSERVED IN SELF-EXPERIMENTS Symptoms I. Vegetative symptoms 2. Athetoid movements 3- IIIUSiODS 4. Hallucinations 5. Disturbances of a. spatial perception b. time perception 6. Bodily sensations 7. Depersonalisation Emotional reaction a. euphory b. anxiety 9. Autism 10. Language changes 8. References 1). 466. Mescaline DM T LSD-2 5 T- 9 Preceded the other symptoms Coincided with the other symptoms — + + ++ ++ — _ I +++ + + ++ +++ + ++ + ++ + —_ — -— ~—— +++ ++ —|— ++ _+ ' , +++ + +++ + + + +++ ++ + + +++ ++ +++ + +++ ___ +++ _+ �464 s. SZA'RA As can be seen, the different symptoms were not equally apparent in every case. (I) The vegetative symptoms in mescaline and LSD-25 preceded the other symptoms, while in the case of the tryptamine derivatives the disturbances sensory appeared as early as the vegetative symptoms began. (2) An interesting phenomenon observed only in the tryptamine derivatives was the appearance Of athetoid, choreiform compulsive movements. As far as I know, these symptoms have not yet been described in the case of other hallucinogenic substancesf (3) The perceptional disturbances are qualitatively the same for all the substances; only quantitative differences could be observed. (4) The emotional reactions, however, were qualitatively different, viz. my reaction to mescaline and DMT was euphoric, to the LSD—25 anxious, but in the case of T-9 euphoria and anxiety alternated. These phenomena, together with the severe autism and the above-mentioned ambivalency were observed only in T-g. However, it is well—known from the literature that it can occur in the case of mescalnie and ‘ LSD-25 also (HUXLEY14, SOLM523). The comparison shows that the structure of a model psychosis, which can be considered as a form of the acute exogen reaction type (BONHOEFFER), depends on the chemical structure of the causative agent, apart from the fact that absorption, metabolic and excretion processes may determine the course in time. BIOCHEMICAL INVESTIGATIONS v ‘ The rapid onset and the short duration of the symptoms in the DMT—induced state is very interesting from a biochemical point of View, and it is probably connected with the rapid metabolism of DMT (FISH ct LIL). We know from the investigation of ERSPAMER6 that in rats the main breakdown product of DMT is 3—indolylacetic acid (3-IAA) which is excreted in the urine partly in free form, but largely bound to glycocol as indolaceturic acid. We investigated the excreted indole derivatives in the human volunteers chromatographically and photo— metrically, and obtained the same results as ERSPAMER (SZARA25). In addition, an interesting phenomenon was observed (Table III). We found in the urine after a larger dose of DMT more 5-hydroxyindolylacetic acid (5-HIAA) excreted than was normally present. Unchanged DMT was not estimated in the urine extracts. These data suggested TABLE III TOTAL 5-HIAA EXCRETED THE APPROXIMATE AMOUNT OF AND AFTER THE N 0. I 2M 3‘” 4 * Dose of DM T 150 mg I50 mg 75 mg 60 mg IN A 6 DMT EXPERIMENT h PERIOD BEFORE Amount of 5-HIAA* alter expt. 1.0 mg 1.2 mg 1.5 mg 2.0 mg before expt. 3.0 mg 3.0 mg 1.2 mg L5 mg Estimated by two-dimensional chromatography, developed with p-dimethylaminO-benzalde‘and the hyde, eluted spots measured colorimetrically. ** Self-experiments. References p. 466. �PSYCHOTIC EFFECTS OF DMT, T-g, MESCALINE, AND LSD-25 465 that the DMT is very rapidly metabolized, and perhaps displays its effects by means of serotonin. In order to obtain more information about the relationship in the blood, I made an experiment with 60 mg DMT. The extracts of I5 ml blood taken before, and IO, 30 and 90 minutes after the experiment, were chromatographically investigated, and I found qualitatively only two indol derivatives, namely tryptophan and 3—IAA, but no serotonin 5—HIAA or unchanged DMT could be demonstrated. The 3—IAA level of the blood was elevated in the 10th and 30th minute (Fig. 3). 3- 1AA lug p.c. 100 50 10 _ 30 ._+.> 90 minutes Time in after injection of DMT _ . Fig. 3. The 3-IAA level of blood during the DMT experiment. This ﬁnding did not support the presumption that serotonin plays a role in the psychotic effect of tryptamine derivatives. The evidence, however, is not sufﬁcient to allow one to draw deﬁnite conclusions in this respect. DISCUSSION In discussing the mechanism of action of tryptamine derivatives, it must be admitted that at present there is no deﬁnite knowledge about the biochemical mechanism of action. The clinical picture, however, taking the other experiments on normal volunteers also into consideration, enables us to give some information concerning this mechanism. The rapid onset of the psychotic symptoms makes it seem probable that DMT affects directly those brain structures that are affected indirectly by LSD and mescaline (BLOCKZ). The appearance of choreiform athetoid movements is possibly due to an effect on structures other than those affected by LSD or mescaline. The tryp— tamine derivatives seem to be the ﬁrst hallucinogenic substances to cause athetoid movements, and should therefore provide a new tool for investigating experimentally the exact mechanism of this phenomenon. Unfortunately, I have not enough time to develop in detail the very interesting psychopathological symptoms of T—g, which reminded me of the conception of the “schizophrene Grundstimmung”, described by WYRSCH27. It is, however, very remarkable that tryptamine derivatives without the OHgroup in the 5-position are able to produce mental phenomena. As UDENFRIEND at al. demonstrated in animal tissues, there is no enzyme that could decarboxylate trypto— phan to produce tryptamine; it is assumed therefore that only the enteral bacteria can produce this substance. ‘ References p. 466. �s. szARA 466 There is a possibility that from this tryptamine the schizophrenic organism may is It noteworthy in the enzymically. substances way hallucinogenic wrong produce in of disturbance evidence team4 a his BUSCAINO presented and recently Prof. that be desirable. would ﬁeld in this work Further in schizophrenia. metabolism indole the SUMMARY The psychotic effects of N,N-dimethyltryptamine (DMT) and N,N-diethy1tryptamine (T—9) have been compared with the effects of mescaline and LSD-2 5. The most outstanding features of DMT model psychosis are the rapid onset and the short duration Of the symptoms. This may indicate a different mechanism of action from that of LSD and mescaline. New symptoms appearing with both tryptamine derivatives are the choreiform athetoid movements. This phenomon could be a new tool for investigating experimentally the mechanism of the extrapyramidal compulsive movements. of indole and aminotoxic the theory Of derivatives supports effects tryptamine The psychotic schizophrenia. REFERENCES ]. Physiol. (London), 126, (1954) 596. A. H. AMIN, T. B. B. CRAWFORD AND I. H. GADDUM, 2 W. BLOCK, Z. physiol. Chem., 294 (1953) 1; lbid., 294 (1953) 49; ibid., 296 (1954) 1; ibid., 296 (I954) 1083 V. M. BUSCAINO, Quaderni aeta neural, (1953). 4 V. M. BUSCAINO, D. KEMALI, R. BAGNULO, Aeta Neural. (Naples), 10 (1955) 547. 5 V. ERSPAMER, Pharmacol. Rev., 6 (1954) 425. 6 V. ERSPAMER, 118. (1955) (London), 127 Physiol. ]. 7 H. D. FABING, Am. ]. Psychiat, 113 (1956) 409. 8 H. D. FABING AND J. R. HAWKINS, Science, 123 (1956) 886. 9 M. S. FISH, N. M. JOHNSON AND E. C. HORNING, ]. Am. Chem. 500., 77 (1955) 5892. 10 M. S. FISH, N. M. JOHNSON, E. P. LAWRENCE, E. C. HORNING, Blaehim. Biophys. Aeta., 18 (1955) 56411 W. A. FREYBURGER, B. E. GRAHAM, M. M. RAPPORT, P. H. SEAY, W. M. GOVIER,O. F. SWOAP AND M. J. VANDER BROOK, ]. Pharmacol. Exptl. Therap., 105 (1952) 80. 12 I. H. GADDUM AND A. HAMEED KHAN, Brit. ]. Pharmacol., 9 (1954) 240. 13 H. E. HIMWICH, Nervous Mental Disease, 127 (1955) 413. ]. 14 A. HUXLEY, The Doors of Perception, London, 1954. 15 D. KEMALI, V. M. BUSCAINO AND R. BALBI, Aeta Neural. (Naples), 11 (1956) 209. 16 D. KEMALI AND G. ROMANO, Aeta Neural. (Naples), 11 (1956) 959. 17 H. LANGEMANN, Sehwelz. med. Waehsehr., 85 (1957) 957. (9). (1936) 18 F. Amsterdam, Akad. Koninkl. Wetensehap, 39 Proc. NIEUWENHUYZEN, J. 19 I. H. PAGE, Pharmaeal. Exptl. Therap., 105 (1952) 58. ]. 20 I. H. PAGE, Physlal. Revs, 34 (1954) 563. 21 E. ROTHLIN, A. CERLETTI, A. KONZETT, W. R. SCHALCH AND M. TAESCHLER, Experientia, 12 (1956) 15422 A. SAI-HALASZ, GY. BRUNECKER AND S. SzARA, Psychiat. et Neurol., (in press). 23 H. SOLMs, Praxis, 45 (1956) 746. 24 M. E. SPEETER AND W. C. ANTHONY, Am. Chem. 500., 76 (1954) 6208. 25 S. SzARA, Experientia, 12 (1956) 441. 23 S. UDENFRIEND, C. T. CLARK AND E. TITUS, ]. Am. Chem. 500., 75 (1953) 501. Daseinwer’se. Paul 27 Psychologie. Klinlk, Studlen des zur Die Person Sehlzophrenen. WYRSCH, J. Haupt, Bern, 1949. 1 j. ' DISCUSSION A. SAI—HALAsz, I stltuto Centrale per le malattie Nervose e M entali, Budapest (Ungheria) Il collega SzARA ha avutO occasione stamane di parlare in dettaglio sugli esperimenti fatti con me Or—a vorrei richiamare l’attenzione soltanto su un normali. in soggetti la dimetiltriptamina con fenomeno, che mi sembra assai interessante dal punto di vista clinico. Su 30 persone esaminate 22, schema dello i disturbi 1e le allucinazioni, illusioni e semilateralizzati: i1 sintomi cioé 73% avevano i segni di lesioni piramidali prevalevano a anche ed atetosici i movimenti dello spaziO, e corporeo �PSYCHOTIC EFFECTS OF DMT, T-9, MESCALINE, AND LSD-25 467 sinistra. Questa differenza era netta. Per esempio un soggetto sperimentale guardando la mano sinistra diceva che essa non gli apparteneva pil‘l, aveva cambiato forma ed era divenuta luminosa e bellissima; guardando invece la mano destra, diceva. che non presentava nulla di straordinario. Abbiamo sperimentato su tre persone mancine, e in questa i fenorneni prevalevano alla parte destra. Si dovrebbe concludere che 1a dimetiltriptamina produce una Iesione semilateralizzata dell’emisfero non dominante del cervello. Questo fenomeno ﬁnora. non segnalato dalla letteratura. per gli altri farmaci psicotropi ci propone due questioni: (1) La prima sarebbe la seguente: come si pub immaginare, che una sostanza chimica abbia un effetto nocivo molto pi1‘1 forte sull'emisfero cerebrale non dominante? Sappiamo a1 contrario, che é appunto l’emisfero dominante i1 ph‘l sensibile, specialmente se danneggiato nel sistema vascolare. (2) La. seconda domanda é di carattere psicopat'ologico. Si tratta cioé di sapere se questa semilateralizzazione ci pub dire qualcosa sugli aspetti delle psicosi sperimentali. HOFF e PéTZL hanno gia‘L/dimostrato collo “Zeitrafferphéinomen”, che lesioni organiche dell'emisfero non dominante possono produrre fenomeni psicopatologici molto strani. Lo “Zeitrafferphéinomen” é stato descritto gié da BERINGER nel corso di psicosi sperimentali mescaliniche. Secondo 1a nostra. opi— nione sarebbe di grande interesse studiare ancora. 1e psicosi sperimentali gié conosciute, a1 ﬁne di evidenziare se ci sono diﬂerenze fra. 1e due parti del corpo. Ci pare probabile, che questo fenomeno non sia un eﬂetto solo della dimetiltriptamina. Ad ogni modo, conoscendo i fatti suddetti, noi possediamo ora una. nuova. sostanza per aiutarci a conoscere meglio i problemi dell’emisfero cerebrale non dominante. ‘ �Reprinted from Psychotropic Drugs SHORT COMMUNICATIONS 283 Effects of psychomimetic drugs on cerebral synapses The psychomimetic drugs allow us to elicit at will a limited, reversible, mental derangement in man and a related distorted behavioral pattern in animals. They can therefore be highly potent tools equally for the physiologist, the behaviorist, and the experimental psychiatrist. The tremendous versatility of the brain is nonetheless the manifestation of activity in a ﬁnite number of structures and of mechanisms relating them. It follows, therefore, that the multiple patterns that add up to biological behavior must share in part the available mechanisms. It is by virtue of this probability, rather than because of any exact or fancied resemblance to the clinical conditions, that the study of chemical or so-called model psychoses and the agents producing them can be expected to be fruitful. To the physiologist this suggests the need for identiﬁcation of the underlying unitary processes involved; to the behaviorist, the identiﬁcation of the combinations constituting known behavior patterns; and to the experimental psychiatrist, the comparison of natural and induced psychoses. All can proﬁtably use drugs as tools for analysis. The clinician, furthermore, can convert these ﬁndings into tools for diagnosis and the means for therapy. The high vulnerability of synapses to chemical inﬂuences makes them a natural focus of inquiry. We have utilized the synapses of the optic cortex of the cat (lightly anesthetized with sodium pentobarbital) activated by transcallosal impulses initiated in one cortex and evoking post-synaptic impulses recorded at the symmetrical point in the opposite cortex. This has proved a very convenient preparation and the data are representative of a variety of cerebral synapses, including cortical, subcortical and medullary synapsesl. By intracarotid injection we achieve an active concentration of the drug or chemical in the ipsilateral hemisphere with sufﬁcient dilution on entry into the systemic blood stream to obviate peripheral effects. The ipsilateral recording elec— trode simultaneously monitors the input and output of the terminal synapses in the system, which is submaximally activated every two seconds. In this way we have established that synaptic transmission is under the control of a delicate chemical equilibrium between cholinergic excitation reciprocating with adrenergic inhibition. It is then evident that a disturbance of this equilibrium would lead to abnormal synaptic transmission, resulting in disturbed cerebral and mental function. Among the synaptic inhibitors naturally found in the mammalian brain are adrenaline, nor— adrenaline, and serotonin. The last is by far the most powerfu13. Substances with a chemical similarity to these become candidates for the role of psychomimetic drugs. Such is indeed the case with mescaline, adrenochrome, adrenolutin, lysergic acid diethylamide (LSD-2 5) and bufotenine. Mescaline is closely related chemically to adrenaline, which on oxidation is converted initially to the indole, adrenochrome. Adrenolutin is a minor modiﬁcation of adrenochrome. Serotonin and dimethyl-serotonin, or bufotenine, are indoles, and LSD-2 5 can be regarded as built on an indole nucleus. It strengthens the argument, therefore, that we ﬁnd all of these to be synaptic inhibitors3 4. Furthermore, their ranking as synaptic inhibitors parallels the ranking as to psychomimetic potency in man. The agreement between data from the anesthetized cat and the human encouraged us to believe and test that tranquilizers, reported to be clinically effective in partially offsetting mental disturbance, would have a predictable action on synaptic inhibition by psychomimetic agents. If the synaptic inhibition so produced were truly instrumental in bringing about psychotic behavior, then the improvement of such behavior that is observed clinically might be due to antagonizing of an endogenous chemical corresponding to the exogenous psychomimetic drugs. This, indeed, turns out to be the case. The prophylactic administration of chlorpromazine, promazine, reserpine, and azacyclonol, in doses having no effect per 33 on synaptic transmission, prevents or reduces the synaptic inhibitory action of the psychomimetic drugsz. Overdoses of tranquilizers clinically produce toxic phenomena, some of them taking the form of depression, and even psychosis. Likewise, large doses of the tranquilizers produce a depression of synaptic transmission indistinguishable from synaptic inhibition. Characteristically, the tranquilizers exercise their clinical effect without a corresponding degree of depression. This is reﬂected in the ratio of depressant to prophylactic dose, or “synaptic safety margin”. This safety margin is nonexistent for phenobarbital, equals 2 for reserpine, IO for promazine and 20 for chlorpromazine and DEPARTMENT OF EXPERIMENTAL PSYCH'IIRY ‘ s “ APR wetHyTAL 30 40.59 �284 SHORT COMMUNICATIONS azacyclonol. The above data suggest the hypothesis that synaptic inhibition is one of the mechanisms responsible for some forms of mental disturbance. A perversion of metabolism resulting either in an excess of endogenous inhibitory substance or an excess susceptibility of the neurons upon which it acts, would result in abnormal patterns of activity whose variety would be determin— ed by varying thresholds and, in particular, by abnormal inhibition interrupting normal control, and thereby releasing more primitive and less adaptive —perhaps subcortical—t—patterns of activity. Such conceptions emphasize the role of naturally occurring inhibitory indoles in mammalian brain. Of these, serotonin is highly active, dimethyl—serotonin or bufotenine is twice as active as serotonin, while adrenaline and adrenolutin are relatively weak inhibitors. Psychotic manifestations have been clearly described for all but serotonin, whose powerful peripheral disturbing actions seriously obscure the picture when it is introduced by the usual routes. For this reason we are testing the effects of intracarotid serotonin injections in man. The importance of serotonin has caused us to extend our original observations of its cerebral synaptic inhibitory action with experiments designed to record the action of “in situ serotonin”. This is accomplished by the use of iproniazid, the inhibitor of monoamine oxidase (MAO), the enzyme responsible for the destruction of serotonin. With intracarotid injections of iproniazid we can reproduce the cortical action of serotonin and show that, at the height of the synaptic inhibi— tion, the MAO titer on the inhibited side is, in fact, lower than on the control side; as would be expected if iproniazid is exercising its action by inhibiting MAO and, consequently, accumulating natural serotonin at the synapses. Following the reasoning already outlined, we again assessed the pertinence of the data to possible clinical signiﬁcance by testing the action of tranquilizers against serotonin. We ﬁnd that the tranquilizers exercise a prophylactic or preventive action against the inhibitory effects of serotonin in the same way that they antagonize psychomimetic drugs. A comparison of the cerebral synaptic action of psychomimetic drugs with that of naturally occurring cerebral synaptic inhibitors and their modiﬁcation by tranquilizers produces data consistent with the hypothesis that a disturbance of synaptic equilibrium—in this case, by a preponderance of inhibitory effectiveness—is a potential mechanism for some kinds of mental disturbance, and that therapeutic results could be anticipated by various means of preventing or annulling this eﬂect. The opposite kind of disturbance or a preponderance of excitatory effectiveness seems also plausible. The prevention or annulling of this deviation in synaptic equilibrium would require different measures. The effectiveness of different tranquilizers and varying therapeutic measures might be expected to become diagnostic criteria. Veterans Administration Research Laboratories in Neuropsychiatry, V. A. Hospital, Pittsburgh, Pa. U SA. 1 2 3 4 A. A. A. A. AMEDEO S. MARRAZZI S. MARRAZZI, Science, 118 (1953) 367. S. MARRAZZI, Ann. N. Y. Acad. Sci, 66 (1957) 496. S. MARRAZZI AND E. R. HART, Science, 12I (1955) 365. S. MARRAZZI AND E. R. HART, ]. Nervous Mental Diseases, 122 (1955) 354. APR ,7 3 ‘0"!!! DEPARTMENT OF EXPERIMENTAL PEVOH‘AIRY HILLSIDE HOSPITAL GLEN OAKS, N. Y. �a hemical aspects of Psilocgpin p39 0......” “-4 cum -c£—¢h—-g-M- by A;Hofmannj Eagle psychotropic act1ve principle of Psilocybe mexic! Helm has been isolated in crystalline form. This fungus 6ne is of the so- called magic or s.a¢red Mexican mushrooms used since orecolumbian times by the indians of Mexico- dur1ng religeous ceremonies and also by soothsayers to acquire clairvoyence. The inawater, but practically unsoluble organicmost in solvents._r Analysis, Spectra and colour react10ns indicated that 1t 13 a \\ tryptamine. The spec1al structural features of psilocybin are dis~. . �to central autonomic stimulation, the study of Psilocybin on 1solated variety of organsshows Only on peripheral structures ¢ littleactivity ofshe ‘ adrug 5 ‘ ��8 MARCH 1958 . ‘ PSYCHOSIS AND TREMDR DUE TO ' \L MECAMYLAMINE . _ M. HARINGTON M.B. Cantab., M.R.C.P. SENIOR REGISTRAR AND MEDICAL TUTOR PRISCILLA KINCAID—SMITH M.B. W’srand, M.R.C.P., D.C.P. REGISTRAR DEPARTMENT OF MEDICINE, POSTGRADUATE MEDICAL SCHOOL OF LONDON ganglion-blocking agent for treat— ing hypertension was introduced two years ago (Freis 1955, Ford et a1. 1955), and since then it has been widely used in clinical practice, its chief advantage being that it is fully and regularly absorbed when given by mouth. It produces the same side-effects, due to blockade of the parasympathetic system, as do other ganglion-blocking drugs, but in addition reports have been published in America indicating that mecamylamine may also have a toxic action on the central nervous system (Schneckloth et al, 1956, Deming et al. 1957). We describe here four patients in whom tremor and mental disturbance, with confusion and hallucinations, developed while they were receiving mecamylamine, and we suggest that this may be a not uncommon complica— tion of treatment with mecamylamine given in large dosage. MECAMYLAMINE as a \ Case-reports Case l.—A man, aged 55, was ﬁrst seen in July, 1955, com— plaining of headaches. He had two years’ history of high blood-pressure and ﬁfteen years’ history of gout. Although intelligent, he was unstable and did not follow any regular occupation. On examination his blood~pressure was 230/140 mm. Hg; he had numerous retinal haemorrhages and exudates; his urine contained a trace of albumin and could be concentrated to 1.020; and his blood-urea level was 30 mg. per 100 ml. Treatment.—-—Benign essential hypertension having been diagnosed, he was treated with subcutaneous pentolinium, to which reserpine 0-1 mg. thrice daily was later added. This regime reduced his blood—pressure, and his fundi considerably improved. Mecamylamine therapy—In July, 1956, mecamylamine was substituted for the pentolinium, 20 mg. thrice daily being necessary to keep the blood—pressure down to 140/80 mm. Hg, with the patient in the erect position, for the greater part of the day. This dosage, however, caused troublesome side-effects, at ﬁrst principally constipation, but later difﬁculty in micturition associated with frequency. DR . HOBSLEY BaraEtlaésCZIS 499 ORIGINAL ARTICLES REFERENCES M. (1952) Rev. Sanid. Polie., Lima, 12, 198, cited by Ferris et al. 2 Bernstein, C., Klotz, S. D. (1952) Ann. Allergy, 10, 479. Dameshek, W., Neber, J. (1950) Blood, 5, 129. Dobson, A. M., Ikin, E. W7. (1946) 3'. Path. Bact. 58, 221. Ferris, H. B., Alpert, S., Coakley, C. S. (1952) Amer. Praetit. 3, 177. Frankel, D. B., Weidner, N. (1953) Ann. Allergy, 11, 204. Hoffmann, C. R. (1957) Surgery, 41, 491. Loew, E. R. (1950) Med. Clin. N. Amer. 34, 351. Maunsell, K. (1944) Brit. med. _7. ii, 236. Mollison, P. L. (1951) Blood Transfusion in Clinical .Medieine, p. 317. Oxford. F. M., Margolin, S., Jackson, D. (1953) 3‘. med. Soc. N. i. 50, Offegkgantz, 3 . Simon, S. W., Eckman, W. G., Jr. (1954) Ann. Allergy, 12, 182. Stephen, C. R., Martin, R. C., Bourgeois—Gavardin, M. (1955) 7. Amer. med. Ass. 158, 525. Wilhelm, R. B., Nutting, H. M., Devlin, H. B., Jennings, E. R., 0. A. (1955) ibi‘d. p.’ 529. W’inter, C. C., Taplin, G. V. (1954) Ann. Allergy, 12, 717. Wright, W. A. (1950) .Med. Times, N.Y. 78, 466. Brines, Readmission.—In February, 1957, retention of urine developed and the patient was readmitted to hospital. His bloodurea level was now 60 mg. per 100 ml., rising after ten days to 72 mg. per 100 ml., he had a urinary infection, which was treated with tetracycline. Soon after admission his requirement for mecamylamine fell: the dosage was reduced from 60 to 30 mg. daily, and his blood-pressure was maintained at 110/70 mm. Hg with the patient in the upright position. Mental and nervous symptoms.——On Feb. 19, 1957, he had a tremor of the hands. All hypotensive treatment was stopped, but next day the .tremor had increased and he became mentally confused. Two days later his condition had deteriorated further: he had a coarse generalised shaking affecting his whole body, present at rest, and accentuated on attempting any voluntary movement. His speech was slurred and jerky. There was a general increase in muscular tone and in the deep reﬂexes; the plantar responses remained ﬂexor. He was completely disoriented in both space and time and had vivid frightening hallucinations. His extreme restlessness and picking at the bedclothes suggested alcoholic delirium tremens. From time to time he had lucid intervals during which he had considerable insight into his condition. Repeated large oral doses (10-15 m1.) of paraldehyde subdued the tremor and relieved the hallucinatibns for three to four hours at a time. This striking clinical picture persisted for a week and then gradually subsided. By March, twelve days after the mecamylamine treatment had been stopped, the hallucinations had disappeared and the patient’s mental state had returned to normal. He could now remember in detail what had happened during his delirium. Slight tremor persisted for a further two days before ﬁnally clearing. During this period he had been treated with subcutaneous pentolinium because his blood— pressure had risen after the cessation of hypotensive therapy; but it was difﬁcult to keep his blood-pressure down, because he was conﬁned to bed. He was discharged from hospital on March 14, 1957, taking two injections of pentolinium daily; his blood-urea level had fallen to 38 mg. per 100 ml. Readmission.——Four months later he was readmitted with uraamia and left ventricular failure and died in ﬁve days. Necropsy There was atheroma of the blood-vessels at the base of the brain, the gyri were ﬂattened, but no localised abnormality was found on section of the brain. The kidneys showed lesions of malignant nephrosclerosis. Case 2.—A woman, aged 65, was admitted to hospital in July, 1956, with left ventricular failure. She had eight weeks’ history of exertional dyspnoea. Her blood-pressure was 300/160 mm. Hg, and she had hmmorrhages and soft exudates in her fundi. Her blood-urea level was 30 mg. per 100 ml. She was treated with digitalis, mersalyl, and hypotensives— at ﬁrst subcutaneous pentolinium and later oral mecamylamine. When ﬁrst seen at Hammersmith Hospital in September, 1956, she was very much improved symptomatically, but her bloodpressure was 200/130 mm. Hg, and the dosage of mecamyla— mine was increased from 12-5 to 20 mg. twice daily. In October the dosage was further increased to 45 mg. daily; but, although this dosage did not control the hypertension, urinary retention developed and she was admitted to hospital on Oct. 29, 1956. On admission she was cooperative and well oriented but somewhat apprehensive and overexcitable. Her blood-pressure was 290/140 mm. Hg, and soft exudates but no papilloedema were noted in her fundi. There was no sign of heart-failure. Her urine contained albumin, and her blood—urea level was 66 mg. per 100 ml. Mecamylamine therapy was continued, the dosage being slowly increased until on Nov. 6, 1956, she was having 65 mg. daily. Her systolic blood-pressure remained about 200 mm. Hg. .Mental and nervous symptoms.—ln the early hours of NOV. 11, 1956, she became agitated and confused, having hallucinations of voices and complaining of noises in the head. Her bloodpressure was 170/90 mm. Hg. She had general hyperreﬂexia. K2 �M 500 ORIGINAL ARTICLES During the succeeding days her confusion increased, and she was disoriented for most of the time but had intervals of insight and cooperation. Mecamylamine therapy was stopped on Nov. 13. On Nov. 17 she was grossly confused and hallucinated, with paranoid delusions. She also had a coarse tremor of arms and legs. Her blood-urea level had risen to 97 mg. per 100 m1. on Nov. 17 and to 140 mg. per 100 ml. on Nov. 20. She became more agitated and violent and was completely inaccessible. On Nov. 21 her condition made it necessary to transfer her to a mental observation ward. She went progressively downhill, her blood-urea level rose to 296 mg. per 100 ml., and she died on Nov. 30, 1956, without any improvement in her mental state. mid-poms. The kidneys were typical of malignant nephrosclerosis. Case 4.—An electrician’s mate, aged 46, presented in January, 1956, with four months’ history of blurring of vision and dyspnoea. His blood-pressure was 250/150 mm. Hg and he had bilateral papilltedema with scattered retinal haemorrhages. His urine contained albumin, granular casts, and occasional leuco— cytes; his blood—urea level was 155 mg. per 100 ml. There was no history to suggest previous renal disease. In view of his visual symptoms hypotensive therapy was considered advisable, in spite of the severe renal failure, and treatment was started with subcutaneous pentolinium. At the end of February his blood-urea level was 222 mg. per 100 m1. Mecamylamine therapy—At this stage he was given oral mecamylamine. He was not very sensitive to it, 60 mg. in divided doses daily being needed to keep his blood—pressure down to 160/100 mm. Hg. On April 14, 1956, six weeks after mecamylamine therapy had been started, he was readmitted to hospital with increasing trembling of his arms and legs for the previous three days. On admission his blood—pressure was 160/90 mm. Hg. He still had bilateral papilloedema. He was dyspnmic, and his jugular venous pressure was raised. Mental and nervous symptoms.—He was drowsy and mentally! confused. He had occasional spontaneous quivering of his lips and a coarse irregular tremor of his limbs. His muscular tone was increased; his lower limbs showed almost cogwheel Necropsy The left kidney was small (55 g.) with generalised ischazmic atrophy suggesting occlusion of the renal artery. The right kidney weighed 110 g., and its histology was that of ﬂorid malignant nephrosclerosis. The brain showed a small area of softening in the right internal capsule, and the cerebral arteries were considerably affected by atheroma. Case 3.—An electrical engineer, aged 53, was found in January, 1956, to have a blood—pressure of 240/140 mm. Hg, bilateral papilltedema, heavy albuminuria, and a blood—urea level of 40 mg. per 100 ml. Malignant essential hypertension was diagnosed, and he was treated with subcutaneous pentolinium and with rauwolﬁa alkaloids; but his“ blood—pressure was difﬁcult to control, and during the next six months further deterioration in the fundi and increasing cardiac enlargement were noted. On admission to Hammersmith Hospital in July, 1956, he had heart-failure, blood—pressure 260/140 mm. Hg, bilateral papilloedema, haemorrhages and exudates in his fundi, and albuminuria. His blood-urea level was 139 mg. per 100 m1. Treatment with subcutaneous pentolinium was continued, a dosage of 30—40 mg. twice daily being necessary to control his blood-pressure. Rauwolﬁa was not given. Chlorpromazine 50 mg. thrice daily was given because of vomiting. After a month the heart-failure had cleared and the blood-urea level fallen to 60 mg. per 100 ml. Mecamylamine therapy—On Sept. 10, 1956, mecamylamine therapy was started, and pentolinium was withdrawn gradually during the next few days. The blood—pressure was not satisfactorily controlled during the period of transfer, but by Sept. 17 it was down to 140/80 mm. Hg, with the patient in the erect position, for most of the day. This was achieved with a dosage of 20 mg. mecamylamine thrice daily. By now the blood-urea level had risen again to 100 mg. per 100 ml. The fundi still showed papilloedema, but there were no fresh exudates or haemorrhages. Mental and nervous symptoms.—On Sept. 24, 1956, shaking of the limbs and trunk was ﬁrst noted. This tremor also affected the face and tongue; it was coarse and present at rest but exaggerated on voluntary movement. The speech was jerky and difﬁcult to understand. There was a general increase in muscular tone; the tendon—reﬂexes were exaggerated, and knee and ankle clonus could be elicited; the plantar responses were ﬂexor. Mecamylamine was withheld after it had been taken for fourteen days, and pentolinium therapy was restarted; but the tremor increased, and four days later the patient became drowsy and confused. He was now disoriented and hallucinated, speaking to imaginary people and seeing snakes and insects crawling across his bedclothes. His body shook so violently as to rock the whole bed. Paraldehyde reduced the tremor somewhat, but he remained confused and steadily deteriorated. His blood-urea level rose to 170 mg. per 100 ml. , his urinary output fell, and he died, after repeated attacks of left ventricular failure, on Oct. 7, 1956. Necropsy The brain was overweight (1490 g.) and oedematous, with a small area of recent softening at the posterior end of the putamen on each side and a recent small haemorrhage in the THE LANCET rigidity. His tendon-reﬂexes were uniformly increased, and he had bilateral ankle clonus. His plantar responses were ﬂexor. Hypotensive therapy was stopped, and he was treated only with digoxin, but the confusion and tremor persisted, and he died on April 16, 1956. Necropsy ' The kidneys showed the changes of malignant nephrosclerosis. The brain showed cerebral oedema, but no localised lesion or other abnormality. Discussion The clinical picture was similar in each of these four patients. In three the ﬁrst neurological abnormality to be noted was a coarse tremor which affected the trunk and head as well as the limbs and caused difﬁculty with speech. It was variable in the early stages, perhaps hardly noticeable when a limb was at rest, but brought out when voluntary movement was attempted. The shaking of the trunk made it look as if the patient was shivering. The tremor was equally present on both sides of the body. At its height it was so violent in two patients as to shake the whole bed. Mental symptoms were observed before the tremor in one patient, but in the others a few days after the tremor. They consisted of a clouding of consciousness with confusion and disorientation, together, in three cases, with hallucinations which were usually visual but sometimes also of hearing or of touch. The mental state ﬂuctuated, and there were lucid intervals, with some insight, between periods of extreme delirium. Both tremor and mental symptoms were alleviated temporarily by administration of paraldehyde, in case 1 strikingly so. In this patient, who recovered from the episode, the mental abnormalities disappeared ﬁrst, the tremor persisting for a few days before ﬁnally clearing. Examination of the nervous system in these patients revealed a general increase in muscle tone, symmetrically exaggerated tendon-reﬂexes with clonus, and ﬂexor plantar responses. In no case were any lateralising signs found. Electroencephalography in three cases gave records which were difﬁcult to interpret because of arte— fact due to muscle tremor; there was complete absence of alpha rhythm, but in no case was positive evidence found �8 MARCH 1958 501 ORIGINAL ARTICLES either of a general metabolic disturbance or of a localised lesion. The patients all had severe hypertension. In two this was frankly malignant, with papillaedema; in the other two the presence of active retinitis and progressive renal failure indicated that the hypertension was in a premal— ignant phase, and at necropsy lesions of malignant nephro— sclerosis were found in the kidneys. Renal function was impaired in all. In three there was gross renal failure with a raised blood-urea level which continued to rise until death in case 1, who already had some renal impairment, shown by a failure of concentrating power, but who had a normal blood-urea level, there was a further deterioration in renal function and a temporary rise in the bloodurea level coincident with a urinary infection. This patient’s blood-urea level had returned to normal by the time that his neurological symptoms had cleared, but it rose again later, and uraemia was present at his death four months afterwards. All four patients were receiving large dosages of meca5 mylamine (60—65 mg. daily) because smaller amounts had not reduced the blood—pressure. The duration of admin— istration of mecamylamine before neurological symptoms developed varied from seven months in case 1 to fourteen days in case 3. Case 1 had the least impairment of renal function. Since cerebral arterial disease is common in hypertensive patients, the question arises whether organic brain damage due to haemorrhage or to infarction could have caused the symptoms observed. Evidence of local cerebral lesions was found at necropsy in two cases: in the right internal capsule in one case; and in both basal ganglia and the pons in the other. The whole clinical picture, however, was more like a toxic confusional reaction, bearing in its fully developed state a striking resemblance to alcoholic delirium tremens. The symmetry of the tremor, the absence of any lateralising signs in the central nervous system, and particularly the complete disappearance of symptoms in case 1 after mecamylamine had been withheld suggest strongly that this drug was to blame. In the patients who did not recover, uraemia and death supervened probably before sufﬁcient time had elapsed to allow the mecamylamine to be cleared from the body. Mecamylamine is a secondary amine and freely diffusible across cell membranes. There is evidence that this drug is concentrated within the cell (Milne et al. 1957). It is therefore likely that its mode of action differs from that of ganglion-blocking agents such as hexamethonium and pentolinium, which are quaternary ammonium compounds and are distributed only in the extracellu— lar ﬂuid. That mecamylamine has a different, and previously unrecognised, mode of action at the neuromuscular junction has been shown by Bennett et al. (1957). From this it might also be expected that mecamylamine, apart from producing the same side—effects due to parasympathetic blockade as other ganglion—blocking drugs, might also have toxic actions from which methon— ium compounds are strikingly free. There is some experimental evidence of a direct toxic action on the central nervous system. Rats given mecamylamine in large doses develop a tremor and have generalised convulsions before death (Milne et al. 1957). The frequency of this complication of treatment is not certain. Doyle et al. (1956), Smirk and McQueen (1957) and Kitchin et al. (1957), in their accounts of clinical experience with mecamylamine, do not mention any neurological symptoms related to its administration. The four cases described here occurred among ninety patients treated with mecamylamine at this hospital (twenty of them with malignant hypertension). The average daily dosage of mecamylamine in the whole series, however, was only 35 mg. , and only sixteen patients received more than 50 mg. daily. Moreover, this is a selected group of patients, including some with severe hypertension who were speciallyreferred. In addition to the cases described in detail above, three other patients treated with mecamylamine developed a tremor without mental symptoms: a woman, aged 31, with malignant hypertension and systemic lupus erythematosus and a woman, aged 51, with malignant hypertension and renal-vein thrombosis, both with moderate impairment of renal function (blood-urea level 40—70 mg. per 100 ml); and a man, aged 51, with malignant essen— tial hypertension and urxmia (blood-urea level 114 mg. per 100 ml.). The daily dosage of mecamylamine in these patients was 25, 50, and 30 mg. respectively. In the two women the tremor disappeared when the dosage of mecamylamine was reduced and pentolinium was partly or wholly substituted. It certainly seems that patients with severely impaired renal function are much more likely to develop symptoms of neurotoxicity while taking mecamylamine: of ﬁve patients in whom the blood—urea level was 100 mg. per 100 ml. or higher at the start of treatment four developed tremor and three of these mental symptoms. This complication is presumably related to the retention of mecamylamine in the body, its urinary excretion being reduced in renal failure (Milne et al. 1957). Summary Four cases are described in which a syndrome of tremor, mental confusion, and delirium developed under treatment with mecamylamine. Tremor developed in three other patients. This complication of mecamylamine treatment occurred in patients receiving large dosages thereof (60—65 mg. daily); all these patients had or subsequently developed malignant hypertension and in all renal func— tion was impaired. We thank Prof. J. McMichael and Dr. M. D. Milne for their help and advice; and Dr. I. F. Goodwin for permission to report a patient under his care. REFERENCES Bennett, G., Tyler, C., Zaimis, E. (1957) Lancet, ii, 218. Deming, . B., Hodes,M . E., Edreira, J. G., Baltazar, A. (1957) New Eng]. E.Med. 256, 739. Doyle,A ,y,Murph E A. Neilson, G. H. (1956) Brit. med. ff. ii, 1209. Mo yer,]. H. (1955)]. Lab. clm. Med. 46, 815 Ford, R. Dennis,E., Freis, E. D. (1955) Lancet, ii, 977. Kitchin, A. Lowther, C. P. Turner, R. W D. (1957) 1'b1'd. p. 605. Milne,M. D., Rowe, G. G., Somers,K., Muehrcke,R. C., Crawford,M. A. (1957) Clin. SE1. 16, 599. Schneckloth, R.E ,Corcoran, A. C. Dustan, H. P., Page, I. 3'. Amer. med. Ass. 162, 868. Smirk, F. H., McQueen,E G. (1957) Brit. med. 3‘.1, 422. H (1956) “ How then does a good physician help a patient to face death and, accepting the ways of nature, to meet it? It is not done by all the busy paraphernalia of scientiﬁc medicine, keeping a vague shadow of life ﬂickering when all hope is gone. . . . If man lives as a stranger in a lonely crowd, he dies utterly alone. Whereas his entry into the world is the ﬁrst stage of the dissolution of an intimate partnership with his mother, his ﬁnal departure is the ultimate in solitary procedures.”——WILLIAM B. BEAN, Arch. intern. Med. 1958, 101, 201. �W 502 ORIGINAL ARTICLES ESSENTIAL FATTY ACIDS AND IDIOPATHIC HYPERCALCIEMIA OF INFANCY A. T. JAMES J. WEBB Ph.D. Lond. and then after roller drying of this concentrated milk. No loss of these two acids was found, although the same experiment was repeated several times. Table I also shows the linoleic-acid + linolenic-acid contents of the same sample of milk after storage under various conditions. After three months at room temperature or at 37°C the “ essential ” fatty-acid content had fallen to two-thirds of the original value 5 after six months’ storage under similar conditions the “ essential” fatty acids had dropped to less than half their previous B.Sc. Lond. THE NATIONAL INSTITUTE FOR MEDICAL RESEARCH, MILL HILL, LONDON T. STAPLETON W. B. MACDONALD D.M. Oxon., M.R.C.P. M.D. Melb., M.R.A.C.P. ASSISTANT DIRECTOR LECTURER PEDIATRIC UNIT, ST. MARY’S HOSPITAL MEDICAL SCHOOL, LONDON ATTENTION has been‘drawn deﬁciency Of “ essential ” fatty to the possible role of a acids (linoleic and arachi— donic acids) in the genesis of idiopathic hypercalcaemia Of infancy (Lancet 1957). It has been suggested (Sinclair 1956a) that in the preparation of evaporated milks there is some loss of essential fatty acids and an even greater loss in the production of National Dried Milk made by passage over hot rollers; thus infants fed on dried milk preparations might receive a diet deﬁcient in essential fatty acids. This suggestion could have provided an additional explanation of the frequency with' which hypercalcaemia of infancy has been recognised in the United Kingdom, where dried milks are widely used, although one established factor to explain this frequency has been the extent of fortiﬁcation of infant foods with vitamin D (British Medical journal 1956). We have studied the fatty-acid composition of samples of human milk, cows’ milk before and after drying by a variety of commercial techniques, stored dried milk, and evaporated milk. Similar analytical studies of whole blood from three healthy infants have been made, as well as from three infants with idiopathic hypercalcaemia; the latter were studied both before and after treatment with cotton-seed oil (a rich source of linoleic acid). The fattyacid analyses were made with the gas-liquid Chromatogram (James and Martin 1956). value. Comparative Analyses of Various Milk Preparations used in ' Infant Feeding Table II shows comparisons of the fatty-acid composition (major components only) of two samples of human milk, fresh cows’ milk, roller-dried milk, National Dried Nlilk, and ‘ Carnation ’ evaporated cows’-milk. The difference in the levels of linoleic + linolenic acids in TABLE I—LINOLEIC-ACID CONTENT OF cows’ MILK DURING PROCESSING AND STORAGE (As PERCENTAGE OF ACIDS IN THE RANGE C3-C20) Milk Under the conditions used for the fatty-acid analyses the gas chromatogram does not differentiate between the cis-cis, cis-trans, and trans—trans forms of linoleic acid. In addition linoleic and linolenic acids (the C18 di- and tri-unsaturated acids) are not separated; so‘ the ﬁgures reported refer to the sum of these two acids. However, the linolenic-acid content of all the fats studied is likely to be low. Studies in collaboration with other laboratories have shown excellent agreement between the gas chromatographic and spectrophotometric techniques for determining (1) a combined value for linoleic and linolenic acids and (2) arachidonic acid. The linoleic acid isolated from cows’ milk by the gas chromato— gram has been shown to be 9 : lZ-octadecadienoic acid by the micro degradation procedure described by James and Webb (1957). Results Changes in Fat-composition of Milk on Processing to Dried Milk and on Storage In Table I are listed the linoleic-acid + linolenic-acid contents of fresh milk, the same milk after concentration, Powder Powder stored stored Powder 3 mos. 6 mos. stored at room at room 3 mos. 8 temp- temp- at 37° erature erature Fresh concen-. milk trated After before roller 120/ t ota(l drym dryin _ solids (21% Kincaid) so Linoleic acid + linolenic acid 3-2 s 1 3-0 3-4 2-3 1-4 2-4 Powder stored 6 mos. at 37° 1-1 human milk and cows’ milk was less than has sometimes been supposed; but the effect of diet on these levels has yet to be determined. “ Essential Fatty-acid ” Levels in Blood of Infants with Methods Each sample Of milk was extracted exhaustively with ether-ethanol overnight to remove the lipids. Samples of whole blood were similarly extracted. The lipid extracts were saponiﬁed with methanolic potassium hydroxide, and the non-saponiﬁable material was extracted with petroleum ether. The alkaline solution was acidiﬁed with 5N sulphuric acid, and the fatty acids were extracted with petroleum ether. The extract was dried over anhydrous sodium sulphate, and the acids were converted to methyl esters by reﬂuxing with anhydrous methanolic hydrochloric acid. Samples were stored in high dilution in petroleum-ether solution at +2°C, and the solvent was removed by evaporation before applying the sample to the gas-liquid chromatogram. THE LANCET . Hypercalcaemia Case 1.—A male infant, born on Feb. 21, 1956, who had well-established hypercalcaemia, was studied at the age of 9 months. He was fed cotton-seed oil containing 500/0 w/w of linoleic acid for twenty days. During the ﬁrst ﬁve days he received about 5 ml. of cotton-seed Oil a day; during the next twelve days about 8 ml. a day; and during the last three days about 20 ml. a day. The serum—calcium (table III and ﬁg. 1) had been high for so long that it seemed improbable that the fall from 15-8 mg. per 100 ml. to 9-9 mg. per 100 ml. in ten days was due to a chance variation in its level, although such variations are known to occur. Analyses were made of the fatty acids of whole blood taken from this child before, while, and after he was given cotton-seed Oil. NO signiﬁcant change TABLE II—MAJOR COMPONENTS OF MILK FATS FROM VARIOUS SOURCES EXPRESSED AS PERCENTAGE OF FATTY ACIDS IN RANGE C3-C20 Human milk Sample 1, ten days after start of lactation Acid Myristic . . Branched C15. . nC15 .. Palmitoleic .. Palmitic Branched unsat. C17 nC17 . . . Linoleic Oleic . . . . Isomers of oleig acx Stearic . . Poly-unsat. C20 (not arachidonic) Cows’ milk Sample 2, three mos. Fresh after start of lactation 5-7 0-5 0-8 3-9 26-5 1-5 9-0 0-2 0-4 2-6 20-0 0-7 5-1 38-6 Trace 4-4 46-0 0-7 3-2 23-3 12-1 1-8 7-7 10-6 1-6 1-2 2-0 16-6 2-0 1-1 36 3-5 26-1 3-1 0-6 4-1 30-4 10-0 0-8 4-4 26-0 5-1 10-3 12-0 10-5 1-0 13-8 2-0 . 0-8 1-0 2-2 26-4 1-5 Not measured Not measured National ‘ Cama— OsterDried ’ milk Milk tion ’ roller- bought tinned dried from a milk clinic 10-7 1-3 1-3 2-2 29-7 1-5 . 0- ‘ Dill"; . . . i . . . EXPERIMEI‘EIAI. r. .5 .....;-.‘a' {II HILLSIDE HOSPITAL “24.53 GLEN OAKS, N. Y. 9-4 1-8 1-4 2-4 21-8 1-5 �Effects of Pitressin Hydration on the Electroencephalogram Paroxysmal Slow Activity in Nonepileptic Patients with Previous Drug Addiction ABRAHAM WIKLER, M.D. Surgeon (R), United States Public Health Service LEXINGTON, KY. 0. s. MPMTWHT or HEALTH, tenement... MD rustic mum: sum! ﬁEPRiN‘lED WITH PERMISSION FROM “in"!!! A. M. A. ARCHIVES OF NEUROLOGY ANi} P‘S‘IQHIATRY VOL. 57-JAN. 194')" HEV-J-L’EI" KV'. �EFFECTS PITRESSIN HYDRATION ELECTROENCEPHALOGRAM OF ON THE Paroxysmal Slow Activity in Nonepileptic Patients with Previous Drug Addiction ABRAHAM WIKLER, M.D. Surgeon (R), United States Public Health Service LEXINGTON, KY. LTHOUGH hydration by forcing of ﬂuids and the use of pitressin has long been employed to precipitate epileptic seizures for diagnostic purposes in persons suspected of having idiopathic epilepsy,1 no study has been made of the electroencephalographic changes produced by this procedure, either in normal or in epileptic subjects. 'A single injection of pitressin has been reported to have no effect on the electroencephalogram,” but no data have been found on the effects of water intoxication except for the statement by Allen 3 that some experiments of this type on dogs had been attempted. The present study was undertaken in an attempt to solve a clinical problem. A patient at the United States Public Health Service Hospital was referred for electroencephalographic study because he exhibited periodic episodes of antisocial behavior. A diagnosis of psychopathic personality had been made, but it was desired to rule out epilepsy. A routine electroencephalogram was essentially normal. A pitressin hydration test was then made with a view to provoking a ﬁt, antisocial behavior or “epileptiform” changes in the electroencephalogram. Neither a ﬁt nor antisocial behavior occurred during this procedure, but paroxysmal slow activity did appear in the electroencephalogram. This was difﬁcult to interpret because of the lack of control data in the literature, and therefore further investigations were made. MATERIALS AND METHODS The subjects for these experiments were 14 male patients at the United States Public Health Service Hospital who were undergoing trearment for addiction From the United States Public Health Service Hospital. 1. McQuarrie, I., and Peeler, D. B.: The Effects of Sustained Pituitary antidiuresis and Forced Water Drinking in Epileptic Children: A Diagnostic and Etiologic Study, J. Clin. Investigation 10:915. 1931. Hilger, D. W.; Mueller, A. R., and Freed, A. E.: The Pitressin Hydration Test in the Diagnosis of Idiopathic Epilepsy, Mil. Surgeon 91:309, 1942. 2. Gibbs, F. A.; Gibbs, E. L., and Lennox, W. G.: Effect on the Electroencephalogram of Certain Drugs Which Inﬂuence Nervous .Xctivity, Arch. Int. Med. 60:154 (July) 1937. 3. Allen, F. F.: Spontaneous and induced Epilegtifo: 1n Attacks in Dogs, in "tr-rel iat. 102:67, 1945. Relation to Fluid Balance and Kidney Function, f= m. 5 �to opiates while serving sentences for violation of the Harrison Narcotic Act and who volunteered for this test. All these subjects had been in the institution six months or more and had not used opiates habitually for at least that length of time. Their ages varied from 32 to 46, with an average of 37.1. None gave a history of epilepsy, and in no case had a seizure been recorded since the patient’s admission to the institution. All were in good health. For 7 patients a diagnosis of psychopathic personality was made on admission. Electroencephalograms were made before and after pitressin hydration. Silversilver chloride cup electrodes were applied to the scalp, and bipolar recordings were made from the frontal, precentral, parietal and occipital regions. The electroencephalograph was a four channel, capacity—coupled, ampliﬁer and oscillographic apparatus with photographic recording on bromide paper. During the recording the patient lay quietly on a comfortable bed in an electrically shielded, sound— proofed, air-cooled room. An observer was always present to note movement and to make sure the patient was not asleep. Records were taken before, during and after hyperventilation. Each record was analyzed as follows: A representative thirty second sample was selected, and all waves over 5 microvolts in amplitude were measured and counted. Paroxysmal activity was not included in the strip. The mean alpha frequency was calculated by averaging all frequencies from 8 to 13 per second, and the percentage of alpha activity was determined by calculating the time occupied by such frequencies during a thirty second recording. A frequency spectrum was then plotted. The limits of individual variation from day to day were determined on several records, and, with this method of analysis, the variation in alpha frequency was found to be not more than 0.5 cycle per second, and that in percentage of alpha activity, 12 per cent. The method of hydration varied to a considerable extent because of differences in the ability of the. subjects to tolerate this procedure. In the ﬁrst few experiments, pitressin was injected hypodermically every hour for seven hours (in doses of 0.3, 0.4, 0.5, 0.5, 0.5, 0.5, 0.5 cc.), and the patient drank 500 cc. of water every hour for eleven hours. Some patients were able to tolerate this, but others suffered from vomiting and abdominal cramps. The procedure was then altered by giving smaller doses of pitressin hourly for eight hours (0.2, 0.3, 0.3, 0.3, 0.3, 0.3, 0.3, 0.3 cc.) and administering 1,000 cc. of 5 per cent dextrose in distilled water intravenously every two hours until a total of 5,000 cc. had been given during the eight hour test period. Some minor modiﬁcations were made in the dosage in individual cases. The patients were admitted to the research ward in the morning, and preliminary physical examinations and records of pulse, temperature, blood pressure, respiration and weight were made. An electroencephalogram was made in the afternoon. Pitressin hydration was begun early the next morning, and the patient was weighed at frequent intervals. Another electroencephalogram was; made the same afternoon, after maximum ’hydration had been achieved. The patients were closely observed, and records of blood pressure, pulse, respiration and temperature were made every four hours during the period of hydration. A regular' diet was prescribed, but coffee, tea and soup were excluded. RESULTS Clinical Observations—Some of the patients were fairly comfortable during these procedures, but most of them had some degree of discomfort, chieﬂy nausea, abdominal cramps and occasional vomiting. �Considerable puﬂiness of the face appeared in a few patients. In none did alarming reactions of circulatory nature appear, and there were no signiﬁcant changes in pulse rate 'or blood pressure. No epileptic seizures of any kind were precipitated. It was found that the smaller doses of pitressin (0.3 cc.) were just as effective in inhibiting diuresis as larger amounts and produced less discomfort. On the morning fol— lowing pitressin hydration voluminous diuresis took place, and the patient’s weight returned rapidly to or slightly below the control level. Electroencephalographic Observatiom.—The data are summarized in the table. The average gain in weight at the end of hydration was Eﬂects of Pitressin Hydration on the; Electroencephalogram r—A—‘M—q Total Per Cent Alpha Frequency Alpha Percentage Snb- Pitres- Gain in ject sin. Body Differ No. Cc. Weight Before After ence Before After Difference 1 3.4 5.3 9.9 10.1 +0.2 71.0 73.7 + 2 3.4 3.2 3.2 5.0 4.5 2.7 10.2 11.1 10.7 9.8 10.6 —0.4 10.5 ——0.2 83.5 47.3 42.3 82.1 40.0 63.3 — 1.4 — 7.3 2.6 5.1 11.5 11.6 10.9 11.4 ~0.6 42.7 57.4 42.2 67.8 — 0.5 3 4 5 6 3.0 3.0 4 —-0.5 —0.2 8 3.2 2.6 1.8 3.2 9.9 10.3 10.0 10.0 +0.1 —-0.3 87.1 76.2 90.8 67.7 9 2.5 7.3 10.3 9.7 —0.6 74.3 58.9 10 1.3 4.3 11.5 11.5 0.0 22.6 22.9 11 1.3 5.3 11.1 10.5 —0.6 42.9 63.9 12 1.3 4.4 10.9 10.7 —o.2 63.3 41.2 13 14 1.7 1.0 5.3 3.9 10.4 11.1 10.4 10.6 0.0 67.0 60.8 61.2 46.9 7 ——0.5 2.7 Comment Shift to slow side and paroxysmal delta activity after hydration 721.0 Shift to slow side after hydration +10.4 Shift to slow side and parox~ ysmal delta activity after + 3.7 — 8.5 hydration " Shift to slow lid-e after hydration —15.4 Shift to slow side and paroxysmal delta activity after hydration + 0.3 Paroxysmal delta activity after hydration +21.0 Shift to slow side and paroxysmal delta activity after hydration -—-92.1 Paroxysmal delta activity after hydration 5.8 —13.9 —- Shift to slow side and paroxysmal delta activity after hydration ’_—“__——-—-——————— 3 4.1 or per cent of body weight. In 3 of the subjects the mean alpha frequency was lowered 0.6 cycle per second, but in the remainder the changes in alpha frequency, although mostly in the direction of slowing, were within the range of daily variation. In half the patients the frequency spectrum showed a deﬁnite shift toward the slow side (ﬁg. 1). In the remainder no deﬁnite shift could be observed. In no case was there an unequivocal shift toward the fast side of the spectrum. The most striking change, however, was the appearance of bursts of slow activity (6 cycles per second) of moderately high amplitude in 7 of the 14 records after hydration (ﬁg. 2). All but 1 of the control recoyds were essentially normal and contained no paroxysmal slow activity, either before or after hyperventilation. In the one record Kg.,. �a scant amount; of paroxysmal 6 per second rhythm was present, and this activity was greatly increased after hydration. In those records which showed paroxysmal :3 per second rhythms, such activity appeared in short bursts of 8 to 15 waves two to six times during the entire run, which was usually about three or four minutes. The incidence of paroxysmal slow activity was not entirely the same as that of shift in the frequency spectrum to the slow side. In 2 records there was a shift but no paroxysmal slow activity. and in 2 the latter was present but there was no shift in the spectrum. There was no correlation between the incidence of paroxysmal slow activity and the degree of hydration or the total amount of pitressin injected. Nor was there a correlation between the admission diagnosis of psychopathic personality and shift in frequency spectrum or incidence of slow activity. Such changes in the electroencephalogram after pitressin hydration were present in 50 per cent of patients with diagnoses of psychopathic personality and in 50 per cent of the others. Consciousness was not grossly disturbed 5 6-7 89 IOII l2!) l4 '5'l6 I? 2| M27 30 Fig. 1 (case 1).-——Eﬂ'ects of pitressin hydration on the frequency spectrum of the electroencephalogram. The solid bars indicate values before, and the outline bars values after, pitressin hydration. On the abscissa are plotted frequencies in terms of cycles per second; on the Ordinate, the number of such frequencies in a thirty second record. Note the shift to the slow side after hydration. IS during the electroencephalographic recording so far as could be determined by the observer in. the electroencephalographic chamber. COMMENT Although none of the patients gave a history or showed clinical evidence of epilepsy, the electroencephalograms obtained on‘ half the subjects after pitressin hydration could be termed “epileptoid” because of the presence of paroxysmal slow activity. Furthermore, it is noted that this change occurred in only half the subjects and was independent of’the degree of hydration. This suggests that the appearance of “epileptoid” changes in the electroencephalogram depends on individual susceptibility. It should be emphasized here that the persons subjected to this test were not truly representative of a “normal” group, since all �had previously been drug addicts and recent studies at this institution have shown that the great majority of the drug addicts fall into either the psychopathic or the psychoneurotic group.‘ The ﬁndings provide a partial answer to the clinical problem which gave rise to this study. It is evident that the appearance of paroxysmal slow activity in the electroencephalogram after pitressin hydration cannot be considered indicative of epilepsy in the clinical sense of the W. wwmwww.WWwwmwwwwMaW A l 2 3 4 . ”NM.“.V“Mm”,rwyﬂ-MMMW‘MWﬁ«MV"V’AM'W‘W(VM/MVW‘v’w..”’V"'V’”‘tM/“ﬁ'“MP“v . WW WW",MM:A 2 3 A' ﬂ ,1 , 35‘3“” 'W ”Ki—mﬁmmwmwwm IVWWWWWM mm . A “A I .5. 1 v n________r_______,____ vwmsxwlMMWWmswwm . 4 .— . g. .l W.NWMNWJWW¢MW{MINWMMMWW N‘MMWEMWMWMMMWWwmwwwvwﬂwawwWW - 2 3 ii “WW MW M;WWWMWIW{V\I‘JNWW ”Wm-WWW h___________n_________n B I ' ‘JWMWN MMWWi‘Wlw 5‘ WWW“V““M/“V’WMWMWWW-wWWW" t 5- H 2 3 4 “W . hW‘Wmm» ‘ , n n ,- [-1 4 M'._M"‘wfw”.“f{‘wﬂgﬂ/ﬁfﬁAewMﬂWWNVI‘ﬁM'JWI/l {\VWK‘WAWMV l W“ W.’x{AMA}.A!W‘My/WWJfNUWWWW'WIl/V”NWAAfv’KVM/MM'y‘M‘fMﬁWV’V/‘N‘ F“ ' WVNVWMmtwAvW‘fPMdWWM . , M B - - '1 2-. a a I r‘v‘wAMN/WwwwwwwwMMNMWx/vvwvvwv .WW“.[it~ww’hwtwmwmmwniM”"¢"MWWWW‘MW n P Wﬁ__u—rh———nn-_ of pitressin hydration the “W- Fig. 2 (case 6_‘i.«—~-Effects on electroencephalograg: (bipolar recording from the frontal (1), pretentral (2), parietal (3) and occipital (4) leads; calibration 50 microvnlts; time in seconds). A and B are control records made before and after hyperventilation, respectively; A' and 8’, records obtained before and after hyperventilation after pitresszin hydration. Note the paroxysmal 6 per second activity gr hydration. 4. Aldrich, C. K., and Ruble, D. Addicts, to be publishsd. x." : Studizs w“ the Pe sonalities of Drug �term. However, it does suggest the possibility that the physiologic mechanism which underlies the production of clinical seizures by this method is also operant in certain susceptible nonepileptic persons and that, essentially, quantitative threshold differences determine whether or not, in any given case, clinical seizures will be precipitated. It would be illuminating, in this connection, to compare the group observed in this investigation with “normal” subjects and with persons known to have epilepsy with special reference to the incidence of paroxysmal slow activity. in the electroencephalogram after pitressin hydration. However, such studies have not yet been made. SUMMARY AND CONCLUSIONS The electroencephalograms of 14 nonepileptic men with previous drug addiction were studied before and after pitressin hydration. No clinical seizures were induced by this procedure. The alpha frequency showed a tendency to slowing after hydration, but in only 3 instances was the degree of change greater than that which could be expected from day to day variation. There was no signiﬁcant change in the percentage of alpha activity. In half the records there was shift to the slow side of the frequency spectrum. In half the records paroxysmal slow activity of moderately high amplitude appeared after hydration. There was some correlation between the appearance of paroxysmal slow activity and the shift of the frequency spectrum to the slow side, but no correlation with the degree of hydration or the amount of pitressin ' administered. The possible signiﬁcance of these observations in their relation to idiopathic epilepsy is discussed. United States Public Health Service Hospital. �Reprinted from THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 98, No. 4, April, 1950 EFFECTS OF METHADONE AND MORPHINE ON THE ELECTROENCEPHALOGRAM OF THE DOG ABRAHAM WIKLER AND SOL ALTSCHUL‘ U. S. Public Health Service Hospital, Lexington, Kentucky Received for publication January 26, 1950 | J-. .4. ‘v... The present study was made as part of a comprehensive investigation of the comparative actions of methadone and morphine on the central nervous system (1, 2). The dog has been utilized in these studies because the effects of small doses of methadone and morphine on this species are analogous to those in man (3—5). In particular, however, we wished to compare the effects of large doses of methadone and morphine on the electroencephalogram since such studies cannot be made with safety in man. Some of the observations made in the course of these investigations are also of interest with reference to the pharmaco—physiologic aspects of convulsive seizures. Electroencephalographic studies were made on eleven dogs. In eight of these animals the effects of methadone and morphine were observed without previous anaesthesia or curare. This was accomplished by the insertion of wire or “mercury cup” electrodes which made contact with the dura over the desired cortical area. The mercury cup electrode (ﬁgure 1) was inserted under aseptic conditions and permitted the recording of electroencephalograms without muscle artifacts in the same dog as often as desired over a period of several months. In one experiment a bipolar wire electrode insulated except for the tip (interelectrode distance about 1.0 mm.) waslinserted into the left anterior lateral hypothalamic area and ﬁxed in place by cementing its upper end to a metal cylinder which was screwed into the calvarium along with other screw leads which served as cortical electrodes. In these eight dogs the electrodes were inserted under sodium pentobarbital (Nembutal) anaesthesia but experiments were not made until one or more days later after full recovery from the anaesthetic. In the three remaining dogs screw electrodes were inserted into the calvarium and in the midline plane of the sphenoid bone (Via the oropharynx to a depth of 1.0 to 2.0 mm. below the ﬂoor of the sella turcica). This was done under ether anaesthesia and the animal was then curarized (“Intocostrin” 1.5 cc. I.V. initially and 0.5 cc. I.V. at about 40-minute intervals thereafter) and artiﬁcial respiration was maintained through a tracheal cannula. Experiments were not begun until the ether effects had worn off as indicated by a return of the electroencephalogram to a normal pattern. In all dogs, silver disc electrodes were also ﬁxed on the ears to serve as reference leads. In most experi— ments, a 3-channel Grass resistance-capacity coupled inkwriting electroencephalograph was used; in some, a four channel resistance-capacity coupled ampliﬁer-oscillograph was used with photographic recording. Shielding of the animal was accomplished by a wire screen grounded cage. The motor patterns of convulsive seizures produced by large doses of methadone or morphine were studied in six other dogs. After one or more seizures they were terminated by intravenous injection of Nembutal. Moving picture records were made for subsequent analysis of the convulsive patterns. The dose range for methadone was 2.0 to 75.0 mgm./kgm. and that for morphine, 5.0 to METHODS. 1 Now Resident Psychiatrist, Illinois Neuropsychiatric Institute, Chicago, 437 9 (as. is ‘ it 111. �438 ABRAHAM WIKLER AND son ALTSCHUL initial doses were given subcutaneously while subsequent doses were given subcutaneously or intravenously. 350.0 mgm./kgm. In all experiments The pre-medication resting electroencephalograms of the dogs varied considerably from dog to dog and on different days in the same dog (ﬁgure 2, control records). However, the changes produced by methadone or morphine were quite different from spontaneous variations in electroencephalographic pattern. After small doses of methadone (2.0 mgm./kgm.) or morphine (5.0 to 10.0 mgm./kgm.) irregular high voltage random slow waves appeared in cortical tracings although fast activity present in the control records persisted (ﬁgure 2). After larger doses of methadone (about 75.0 mgm./kgm.) or morphine (about RESULTS. LUGITE CUP RUBBER DAM MERCURY ,4 SILVER m: _%/ WIRE \ mLT‘T" \ ,//ﬂ\\\\\\\m&\‘ //// Hm ' . . ,l y } 2 -' ,, , J ‘ ._ _— SCALP ———MUSCLE SKULL DURA —r---CORTEX FIG. 1. Mercury cup electrode for recording E.E.G. from dura in unanesthetized and uncurarized animals. Under Nembutal anesthesia, the scalp and muscles are incised and a threaded trephine opening is made in the skull. The mercury cup is screwed in place and the scalp sutured over it. After recovery from anesthesia and healing of scalp wound, recording of EEG. is made by inserting a sharp-pointed, ﬁne but rigid needle, insulated exis The latter conthe into dam rubber and the mercury. scalp for cap the through tip, cept nected by the stout silver wire to the underlying dura. After completion of record, the needle is removed. Mercury is rescaled in cup by rubber darn. Procedure may be repeated indeﬁnitely over a period of several months. 200.0 mgm./kgm.) the earliest change (about one to three minutes after sub— cutaneous injection) was the appearance of bursts of high voltage moderately fast activity (ﬁgures 3B and 4B) in the cortical tracings. Later, high voltage slow waves appeared in the cortical tracings (ﬁgures 30 and 4C). In several exof of bursts high voltage the another change was striking appearance periments less and (ﬁgure 4D) after dome morphine mal”—like and spike sequences “petit frequently and less typically after methadone (ﬁgure 3D). These complexes apassociated not but both were from hemispheres in cortical or one tracings peared with any signiﬁcant change in tracings from sphenoid leads (ﬁgures 3D, 4D, and 4F). In some experiments bilaterally synchronous spike and dome activity in the cortical tracings could be induced by sudden loud noises (clapping hands—ﬁgure 4D). Relatively early (twenty to thirty minutes) after methadone seizure discharges spike voltage after high four morphine to hours) later (two or appeared synchronously in the cortical tracings (ﬁgures 3E and 4G). In one of .-. f? n r �438 ABRAHAM WIKLER AND SOL ALTSCHUL In all experiments initial doses were given subcutaneously while subsequent doses were given subcutaneously or intravenously. 350.0 mgm./kgm. The pre-medication resting electroencephalograms of the dogs varied considerably from dog to dog and on different days in the same dog (ﬁgure 2, control records). However, the changes produced by methadone or morphine were quite diﬁerent from spontaneous variations in electroencephalographic pattern. After small doses of methadone (2.0 mgm./kgm.) or morphine (5.0 to 10.0 mgm./kgm.) irregular high voltage random slow waves appeared in cortical tracings although fast activity present in the control records persisted (ﬁgure 2). After larger doses of methadone (about 75.0 mgm./kgm.) or morphine (about RESULTS. W /// ' LUCITE CUP RUBBER DAM / MERCURY SILVER wnRE \m+.—' \ //ﬂ\\\\\\\\\\\‘ 3W ,1 . ..,\//l 0/” V x//// W, , .. 5 ‘.,- '_' 23932,, "ww/ , .. y i . ' “‘8-//////////%m,m . J \N 1 1 2 _ SKULL DURA -————coarsx FIG. 1. Mercury cup electrode for recording E.E.G. from dura in unanesthetized and uncurarized animals. Under Nembutal anesthesia, the scalp and muscles are incised and a threaded trephine opening is made in the skull. The mercury cup is screwed in place and the scalp sutured over it. After recovery from anesthesia and healing of scalp wound, recording of EEG. is made by inserting a sharp-pointed, ﬁne but rigid needle, insulated exis con— The latter the into dam rubber and the mercury. scalp for the cap through tip, cept nected by the stout silver wire to the underlying dura. After completion of record, the needle is removed. Mercury is rescaled in cup by rubber dam. Procedure may be repeated indeﬁnitely over a period of several months. 200.0 mgm./kgm.) the earliest change (about one to three minutes after sub— cutaneous injection) was the appearance of bursts of high voltage moderately fast activity (ﬁgures 3B and 4B) in the cortical tracings. Later, high voltage slow waves appeared in the cortical tracings (ﬁgures 30 and 4C). In several exof of bursts high voltage the another change was striking appearance periments “petit mal”-like spike and dome sequences after morphine (ﬁgure 4D) and less frequently and less typically after methadone (ﬁgure 3D). These complexes apassociated not but both were from hemispheres cortical in or one tracings peared with any Signiﬁcant change in tracings from sphenoid leads (figures 3D, 4D, and 4F). In some experiments bilaterally synchronous spike and dome activity in the cortical tracings could be induced by sudden loud noises (clapping hands— methadone after minutes) to thirty (twenty early Relatively 4D). ﬁgure seizure discharges spike voltage after four high morphine hours) later to (two or appeared synchronously in the cortical tracings (ﬁgures 3E and 4G).-Irr gnepf W-." : "em 4" , ‘ .1] — *Since the publication of“ 95. paper we -nvo substitutged fdi'ﬁi's an the since Wire latter for *"z’rplatinum Silva. a Fer-i 0d of time and permits amalgam with mercury a mercury to leak throughw rel ~. _ ‘ .4 , . ‘ ‘ ‘5: 3.: �439 METHADONE AND MORPHINE ON EEG three experiments with sphenoid leads, such spike seizure discharges appeared in the basal lead as well (ﬁgure 3E) and were followed by a steady 25 per second rhythm in the latter while the cortical tracings were isoelectric or showed only l N~VAVE K..~u,,V‘.~ -. v I". fl ,' .w.”w“: ‘w‘ﬂxﬁﬂl‘ﬁ,'\" I} c V ——.—-—_—.~. .’ 1 \ .-*.*' - 9' N\W’WW§;""MJ a? u :~' .I. $15” A ,5 '—- _ FIG. 2. Dog #70. Mercury cup electrodes in left fronto-parietal and right parieto-occipital regions. No anesthesia or curare. All tracings bipolar transcortical. Time in seconds. Gain same throughout. A—control. Note predominantly fast activity. B—two and onehalf hours after methadone 2.0 mgm./kgm. subcutaneously. Note general increase in voltage and admixture of irregular slow waves. C—control, two days later. Note irregular rhythms, varying from 10—30 per second (large “spikes” are probably EKG artifacts). D—two and one-half hours after morphine 10 mgm./kgm. subcutaneously. Note changes similar to those in B. slow activity (ﬁgures 3G and 3H). In another experiment the spike seizure discharge from the cortex followed immediately after a typical spike and dome paroxysm (ﬁgure 3G). In the single experiment with hypothalamic bipolar leads, typical spike and dome discharges after morphine 20.0 mgm./kgm. (subcutane- �440 ABRAHAM WIKLER AND SOL ALTSCHUL WWW WWWW WWW/«WAN EFFECTS OF METHADON 75 MG/KG. ON E.E.G. OF DOG ”AI—um... axe SMMA’“ A ”“1 smVI WWW WWWMMW WWW . .. l \ FIG. 3. Dog #102. Curarized. Artificial respiration. Screw electrodes in left anterior- parietal, right posterior-occipital and basi-sphenoid regions. In all records, upper tracing is right occipital to right ear, middle tracing is left parietal to left ear and lower tracing is sphenoid to left ear. Calibrations on “A” apply to all records except “F” where gain was reduced as indicated. A—control. Note mixture of fast and slow frequencies of moderate voltage in cortical tracings and periodic 4 per sec. waves of moderate voltage on a back‘ ground of low voltage fast activity in basal tracing. EKG is shown to point out slow activity in basal tracing is of approximately the same frequency as heart rate. B—three minutes after methadone 75 mgm./kgm. subcutaneously. Note bursts of high voltage spikes in cortical tracings and little change in basal tracing. C—ﬁfteen minutes after methadone. Note admixture of high voltage slow waves in cortical tracing; occasional random spike in basal tracing. D—nineteen minutes after methadone. Note burst of 2 per sec. dome ously) appeared in the cortical tracing from one hemisphere; later the spike components increased progressively in voltage and the pattern assumed �441 METHADONE AND MORPHINE ON EEG EFFECTS OF METHADON 75 MG/KG. ON E.E.G. OF (CONTINUED) 006 WMWMMWWWWh MUM/MtllttﬂtttttttttttltWWW MNWWWMMWMWWW WWWMWWMWMWWWWWWWMWWW WWWWWWWWWWWMIWW [WV wwwwmwwmwwtwwmwwwwmwm I “0}N FIG. 3 (Continued) and spike discharges from left- parietal region alone. E—twenty-two minutes after metha-I done. Note very high voltage seizure discharges synchronous1n all tracings, consisting of repetitive spikes of about 8 pe1 sec. frequency, gradually becoming faster. F—twenty-eight minutes after methadone during a second seizure discharge, shown at 1educed gain. Frequency 15 per sec. G—end of seizure Note steady low voltage 25 per sec. terminal discharge in basal tracing while cortical tracings are practically isoelectric at ﬁrst, then show only irregular slow activity. H~thirty- seven minutes after methadone. EKG and basal tracings showing cardiac slowing and abrupt end of another seizure discharge followed by steady 25 per sec. low voltage activity. that of a sustained high voltage spike discharge. The tracings from the contra- lateral cortex and from the hypothalamus showed no signiﬁcant changes during this period. In all instances, after subsidence of the seizure discharges the cor- �442 ABRAHAM WIKLER AND SOL ALTSCHUL EFFECTS OF MORPHINE 238 MG/KG. ON EEG. OF 006 M'L’NMWNWNWWW WWWWW 7 lhll I fl wwMMJ‘tWJlsl .«qulllllll 'uln kW] \liiWW”"AMMWMAN'"MW,“AA . : :4 ii D respiration. Screw leads in right parieto-occipital, left fronto-parietal and basi-sphenoid regions. In all records, upper tracing is right parietois lower and tracing left to is fronto—parietal left ear middle tracing to right occipital ear, record middle Note records. all on gain refer “A” to Calibrations left on to ear. sphenoid is almost twice that on the others. A—control. Note mixture of moderately high voltage slow and low voltage fast activity. B—one minute after morphine 200 mgm./kgm. subcutaneously. Note increase in moderately high voltage fast activity in cortical tracings; there is little change in basal tracing. C—twenty-seven minutes after morphine. Note admixture of high voltage slow waves in all tracings. D—one-half hour after total of 238 mgm./kgm. FIG. 4. Dog 7% 93. Curarized. Artiﬁcial tical tracings were isoelectric for a few seconds and then high voltage slow activity appeared. In most experiments this sequence of events was repeated several times after the last injection of either methadone or morphine. The motor patterns of the seizures were similar after either drug except that �443 METHADONE AND MORPHINE ON EEG EFFECTS OF MORPHINE 238 MG/KG. ON E.E.G. OF (CONTINUED) 006 mll‘léllllijlW-“meww WSMI , FIG. 4 (Continued) of morphine (24 mgm./kgm. I.V. 3% hours, and 14 mgm./kgrn. I.V. 4 hours after ﬁrst dose). Note burst of high voltage spike and dome complexes from right parieto—occipital region alone; irregular high voltage slow activity in basal tracing. E—seven minutes after D. Burst of spike and dome complexes from right parieto-occipital region with synchronous activity in left fronto-parietal tracing, elicited by clapping hands loudly. F—eight minutes after E. Similar synchronous cortical discharges occurring spontaneously. G—continued from F. Note burst of spike and dome complexes from cortical leads followed immediately by seizure discharge of very high voltage spikes. No change in basal tracing. H—end of seizure. No change in basal tracing. they appeared sooner after large doses of methadone (ten to thirty minutes) than after large doses of morphine (two to four hours). Clonic movements were more prominent in the seizures produced by methadone. The morphine seizures were predominantly tonic. �444 ABRAHAM WIKLER AND SOL ALTSCHUL between the effects of methadone and morphine on the electroencephalogram have been reported in the cat (6). In this species small doses of methadone produced diphasic spikes with admixture of slow waves while larger doses produced seizure—like sustained spike activity. Small doses of morphine caused an increase in frequency while larger doses produced slow waves and subsequent disappearance of electrical activity. These differences appear to be peculiar to the cat for in our experiments with dogs, small doses of either drug produced admixtures of slow waves while larger doses produced seizure-like discharges. The bursts of moderately high voltage spike discharges seen early after methadone or morphine were very similar to the changes produced ab~ in of this the species cortical in the electroencephalogram rat; morphine by olition of cortical electrical activity seemed to be due to anoxia since brain waves reappeared after tracheal insuﬂiation of oxygen (7). In man also, the effects of single and repeated doses of methadone and morphine on the electroencephalogram are comparable (5, 8). Likewise in chronic spinal and in chronic decorticated dogs single and repeated doses of methadone and mor— phine produce similar effects (1, 2). However, in our present studies, some quantitative differences between the effects of these drugs were noted. Convulsions appeared much sooner after subcutaneous injection of methadone than after morphine. Also “petit mal”-like spike and dome activity in the electroencephalogram were much more prominent after large doses of morphine than after methadone. Electrical seizure discharges from subcortical basal structures of the in of in but dose methadone none experiment one after large a were seen experiments with morphine. However, this difference may not be a consistent one since a sphenoid lead was used in only three experiments. Nevertheless, some differences in the actions of methadone and morphine may be expected since these drugs appear to exert different actions on enzyme systems concerned in brain metabolism (9). Our observations are also of interest with reference to the origin of the electrical signs of convulsive activity, particularly the spike and dome pattern. Hursch (10) found that section of the corpus callosum did not alter the pattern of bilaterally synchronous “petit-mal” discharges in the cortex. Jasper and Drooglever-Fortuyn (11) and Hunter and Jasper (12) were able to produce spike and dome and sustained spike activity in both cortex and thalamus by electrical stimulation of medial thalamic structures. These observations suggest a subcor— tical origin of “petit-ma ” complexes. On the other hand, Hayne, Belinson and Gibbs (13) as a result of studies in man, concluded that “. . . The present ﬁndings do not suggest a subcortical but a cortical origin for the three per second wave and spike of petit mal, because (a) the spike registers on the cortex as neg— ative when referred to a relatively inactive area, (b) it can appear as an isolated and purely focal discharge in one cortical area and (0) no evidence was found that it is causatively related to thalamic or other subcortical activity.” Our ﬁndings are strikingly analogous to those of the latter group since after large doses of morphine electrical seizure patterns could, and most often did appear in cortical tracings without concomitant signiﬁcant changes in tracDISCUSSION. Differences �METHADONE AND MORPHINE 0N EEG 445 ings from sphenoid or hypothalamic leads, and spike and dome discharges were frequently observed in cortical tracings from one hemisphere only. However, while suggestive, our evidence is not conclusive with regard to the origin of spike and dome activity since in our experiments the two cortical electrodes were not in strictly homologous areas and our basal electrodes (sphenoid lead and bipolar hypothalamic leads) could not be relied on to pick up electrical activity in the dorsal thalamus. Our records also indicate that the spike and dome discharge and sustained spike activity are closely related since in several instances after large doses of morphine a spike and dome pattern was followed by prolonged sustained spike activity without interruption. Except for the question of the thalamic origin of these seizure discharges, these observations are analagous to those of Hunter and Jasper (12). It is also of interest to note that when a seizure discharge was recorded from the sphenoid lead, this was followed by a sustained low amplitude 25 per second discharge apparently originating in subcortical basal structures. This resembled strongly the “after seizure” discharge seen in chronic decorticated cats following electroshock (14). In the latter study, morphine appeared to alter the electroshock seizure pattern so that fast and slow sequences resembling “petit mal” discharges were seen in some records. In our present investigation, this 25 per second discharge appeared in the sphenoid lead tracings while cortical activity was absent or of a different character. Such independent activity of subcortical structures and cerebral cortex has also been noted after ﬂuoroacetate (15). SUMMARY The effects of small and large doses of methadone and morphine on the electroencephalogram were studied in unanesthetized and uncurarized dogs and in curarized dogs. The motor pattern of the convulsive seizures induced by large doses of these drugs was also observed in different dogs. 2. A “mercury cup” electrode is described which facilitates the repeated recording of electroencephalograms from the dura over the cerebral cortex in unanesthetized and uncurarized animals, without interference due to artifacts from the scalp and temporal muscles. 3. Small doses of methadone or morphine produce an admixture of fast and high voltage slow activity in cortical tracings. Large doses of either drug produce seizure discharges which may appear synchronously in cortical and basal tracings or in cortical tracings alone. The seizure discharges from cortical tracings were both of the spike and dome and sustained spike patterns. At times the former passed over into the latter Without interruption. An “after-seizure” 25 per second low voltage discharge in the tracings from the sphenoid lead was not associated with activity in the cortical leads. 4. The motor pattern of seizures induced in dogs by large doses of methadone or morphine were essentially the same, although clonic movements were more prominent in the methadone convulsions. These seizures appeared much sooner after subcutaneous injection of methadone than after morphine. 1. �446 ' ABRAHAM WIKLER AND SOL ALTSCHUL REFERENCES 99°F!" S" WIKLER, A.: Am. J. Psychiat., 105: 329, 1948. WIKLER, A., AND FRANK, K.: THIS JOURNAL, 94: 382, 1948. SCOTT, C. C., AND CHEN, K. K.: THIS JOURNAL, 87: 63, 1946. SCOTT, C. C., CHEN, K. K., KOHLSTAEDT, K. G., ROBBINS, E. B., AND ISRAEL, F. W.: THIS JOURNAL, 91: 147, 1947. ISBELL, H., WIKLER, A., EISENMAN, A. J ., DAINGERFIELD, M. A., AND FRANK, K.: Arch. Int. Med., 82: 362, 1948. LEIMDORFER, A.: Arch. Internat. Pharmacodyn. et de Therap., 76: 153, 1948. CAHEN, R. L., AND WIKLER, A.: Yale J. Biol. Med., 16: 239, 1944. ANDREWS, H. L.: Psychosom. Med., 6: 143, 1943. GREIG, M. E., AND HOWELL, R. 8.: Arch. Biochem., 19: 441, 1948. HURSH, J. B.: Arch. Neurol. Psychiat., 63: 272, 1945. JASPER, H. H., AND DROOGLEVER-FORTUYN, J .: Res. Publ. Assn. Nerv. Ment. Dis., 26: 272, 1947. HUNTER, M. B., AND JASPER, H. H.: J. Electroencephalog. Clin. Neurophysiol., 1: 305, 1949. HAYNE, R. A., BELINSON, L., AND GIBBS, F. A.: J. Electroencephalog. Clin. Neurophysiol., 1: 437, 1949. WIKLER, A., AND FRANK, K.: Proc. Soc. Exper. Biol. and Med., 67: 464, 1948. WARD, A. A.: J. Neurophysiol., 10: 105, 1947. » E‘PSDSDF'?’ Hg... 12. ~ 13. 14. 15. �EXPERIMENTAL SCHIZOPHRENIA—LIKE SYMPTOMS MAX RINKEL, M. D., H. JACKSON DESHON, M. D., ROBERT W. HYDE, M. D., AND HARRY C. SOLOMON, M. D. Boston, Mass. Reprinted from AMERICAN JOURNAL OF PSYCHIATRY Vol. 108, No. 8, February, 1952 Printed in U. S. A. �[Reprinted from THE AMERICAN JOURNAL OF PSYCHIATRY, Vol. 108, No. 8, February, 1952] EXPERIMENTAL SCHIZOPHRENIA—LIKE SYMPTOMS MAX RINKEL, M. D., H. JACKSON DESHON, M.D., ROBERT W. HYDE, M.D., AND HARRY C. SOLOMON, M. D. Boston, Mass. Printed in U. S. A. �EXPERIMENTAL SCHIZOPHRENIA-LIKE SYMPTOMS ‘ MAX RINKEL, M. D., H. JACKSON DESHON, M.D., ROBERT W. HYDE, M. D., AND HARRY C. SOLOMON, M. D. Boston, Mass. - The nature and cause of the major psychoses are still unknown. Repeated attempts have been made to reproduce experimentally psychotic symptoms in the hope to uncover their psycho—physiological relationship. In 1886, Schmiedeberg succeeded in producing cataleptic phenomena in rabbits by the use of ethyl-urethan. In 1904, Peters(II) discovered the cataleptic action of bulbocapnine; Baruk and de Jong(1, 9, Io) investi— gated this, as well as many related chemicals, more extensively and demonstrated the catatonic elfect upon man and animals. With the discovery of new chemicals and chemical compounds, new tools are made available to the psychiatrist to investigate psychoses experimentally, and a new branch, experimental psychiatry, is emerging. The experimental psychiatrist has the advantage of knowing the one factor, in the causation of psychotic symptoms, the chemical that was administered to the patient and started the chain of reactions. The psychopathological genesis, however, of the psychotic phenomena will best be investigated by methods of the inter— Read at the 107th annual meeting of The Ameri— can Psychiatric Association, Cincinnati, Ohio, May 1 7-11, 1951. From the Department of Psychiatry, Harvard Medical School, and the Boston Psychopathic Hos— pital; Dr. Harry C. Solomon, Director. Aided by a grant from the McCurdy Company, Rochester, New York. H C /8 HC \‘/ CH. \C/ /\{twin/ \/ \/ C‘ CH 572 H / */\ C _, CH. 8 > CH. \f”? /\if”?!/ \/ \/ HC N~CH;; CH_ NH \r/ HOOC .. GET—CE 5 HC Chemistry and Plu'zrmacology L.S.D., which stands for the German Ly— .vergsdure Didthylamid, is the abbreviation used for the diethylamid tartrate of lysergic acid which, according to A. Stoll, A. Hofmann, and F. Troxler(I7), is diastereomer but not structurally isomeric with isolysergic acid as seen in the accompanying formula. coon \*/ Hi pretative analytical branch of psychiatry. Of the chemicals used experimentally at present 2 are outstanding: mescaline, an alkaloid known in its crude form as peyote for hundreds of years, though only in the past few years chemically synthetized, and d—lysergic acid diethylamide tartrate (L.S.D.), a member of the ergot group. Although these chem— icals are quite different in their chemical structure, in their effect upon normal subjects and psychotic patients they show great simi— larities with regard to the production of psychotic symptoms. The schizogenic effect of mescaline has been reported in a number of articles, most recently in a brilliant experimental and psychopathological publication by Paul H. Hoch(8). Our paper is concerned essentially with the description of the effect of d-lysergic acid diethylamide tartrate (L.S.D.) upon male and female individuals who, subsequent to the administration of this chemical, responded with the production of psychotic-schizophrenic-like phenomena. +— C Hi HC CH C CH NH N—CH. CH. �- I952] M. RINKEL, H. J. DESHON, R. W. HYDE AND H. C. SOLOMON It is water soluble and administered orally. Pharmacologically L.S.D. belongs in the group of the ergonovine substances. It has a deﬁnite“ effect upon the in situ uterus of the rabbit, and causes peculiar states of motor rigidity similar to the catatonic phenomena in the dog and cat as' seen with bulbocapnine (19). In our own experiments we noted an especially strong physiological reaction in a 29-year-old very sensitive white girl who was menstruating at the time. She complained of most violent abdominal constrictions, which may have been caused by vehement uterine contractions. The peculiar psychological effect, seen as excitation in experimental ani— mals, was ﬁrst observed and described by the chemist, A. Hofmann. In his laboratory notes of April 4, 1943, he remarked that, while working with L.S.D., he noticed in himself a peculiar restlessness associated with slight dizziness. He had to interrupt his work and went home to rest. While at home, he felt as if intoxicated, a condition characterized by an extremely stimulated phantasy. After darkening his room, for the daylight bothered him very much, he had a most wonderful experience. Phantastic images of most extraordinary plasticity and intensive kaleidoscopic coloring passed before him. This state of intoxication lasted about 2 hours. Literature Following this discovery a number of au— thors investigated the effect of L.S.D. in self-experiments, on normal subjects, and on psychotics. W. A. Stoll(18), who ﬁrst systematically investigated the psychological phenomena of LSD, conﬁrmed Hofmann’s experiences and reported as the most striking psychological ﬁndings disturbances in perception that led to hallucinations, acceleration of thinking, slight dimming of consciousness, but maintenance of judgment. He regarded the psychotic condition as an acute exogenous reaction type and pathologically as diencephalosis. Condreau(4) conﬁrmed most of Stoll’s ﬁndings, but reported that in his experiments the subjects’ consciousness was not disturbed aside from the feeling of intoxication. He added that the subjects maintained their capacity of self-criticism, but showed increased distractibility andiwere less able 573 to concentrate. The basic theme of thought remained unchanged, and the changes in feeling tone he felt to be merely an intensiﬁca— tion of the previous underlying mood. He added as a new observation forced laughing and one instance of athetoid movements as suggestive of involvement of the diencepha— lon, thus contributing to W. A. Stoll’s origi— nal conception. A. M. Becker(2) essentially conﬁrmed the observations of Stoll and Hofmann and emphasized the astounding production of psychosis—like syndromes following the administration of mere “traces” of a chemical substance. He believes the psycho— logical manifestations are the result of two different basic disturbances: affectivity and impulsivity on the one hand, and intention— ality on the other. The most striking contrasts among his observations were manic— hyperkinetic and inhibited depersonalized manifestations. In contrast to Stoll, who termed L.S.D. a “Phantasticum,” Becker suggested the designation of “Psychoticum” for L.S.D. Umberto de Giacomo(6, 7), of Italy, in his experiments with rather large amounts of LSD. (300 to 500 gamma) ob— served in his patients catatonic-like phenomena, which were similar to those produced by bulbocapnine. M. Rinkel(12) and Victor H. Vogel(18) reported their experiences with diethylamide of lysergic acid, adding as new observations paranoic trends and, in contrast to previous publications, slowing of thinking and poverty of thought. Bush and Johnson( 3) used L.S.D. as an aid in psy— chotherapy, and reported that their psychotic patients responded with an increase in activity and greater verbalization of psychopathology. They noted occasional short periods of confusion and disorientation, and occasional transitory visual hallucinations. Most of their patients showed some degree of eu- phoria. Method and Procedure In our own experiments, L.S.D. was given I 7 times to 15 normal adult volunteers, students, nurses, and doctors, in the 19—48 age range, and, as freshly prepared solution, to some psychotics: dementia praecox and manic-depressive, depressive type. The observations on the psychotic patients are still in progress and will be published later. The �574 EXPERIMENTAL SCHIZOPHRENIA-LIKE SYMPTOMS normal subjects, who were kept without breakfast, received LSD. in doses ranging from 20 to 90 gamma p. 0., in most cases one gamma per kilogram body weight, while the psychotics were given 3 gamma per kilogram body weight. This increased dosage for psychotics was chosen on the basis of the unanimous reports in the literature that psychotic patients were particularly resistant to the effect of LSD. The subjects were kept under continuous observation by at least one of the authors for the ﬁrst 5 hours and, on occasions, tape recordings of the subject’s productions were made. The subjects remained under observation the same day at the hospital, and were seen again the following day. The main emphasis in our observations was on the clinical psychiatric picture. Routine neurological and circulatory system examinations were not done, but signs occurring in these areas were noted, if observed. In 9 of the experiments, electroencephalograms at or near 2 hours after L.S.D. were taken, and Rorschach tests were given to 5 normal subjects and concrete-abstract thinking tests to 2 subjects during the height of the L.S.D. reaction. Controls of EEGS and psychological tests were done while the subjects were in their normal mental state. Results I. Disturbances of Thought and Speech.— The most prominent psychological changes observed were those in thinking and speech. They were present in all our experiments. There was no cloudiness of consciousness, no intellectual weakness, but most frequently we observed difﬁculty in the power of expression. The subjects became more and more slowed down, poverty of thought became apparent, and the ﬂow of speech became increasingly diminished and blocked. One subject, a middle-aged depressed pa— tient, went into a complete stupor. In another instance occurred unwillingness to speak, a symptom similar to the negativism of the schizophrenic. Hesitancy, indecision, and impairment of abstract thinking were frequently present; also looseness of thought and actual disconnection with increased dis— tractibility were common observations. As in schizophrenic patients, some of the sub— [Feb jects exhibited such phenomena as lack of spontaneity, irrelevance, pedantic imitation, and subjectively automatic speech. In one instance, we had the impression of the formation of a neologism. Acceleration of thought with ﬂight of ideas associated with rhyming and punning; garrulity and loquacity of the hypomanic type were seen in a cyclothymic medical student within 45 minutes after the administration of LSD. In general, the effects appeared within 30-45 minutes after the oral administration of L.S.D., and disappeared gradually after 3-4 hours. II. Affect and M ood.—-Clear-cut blunting of affect and suspiciousness, as often seen in schizophrenic patients, were outstanding. These symptoms frequently led to feelings of indifference and unreality with disturb— ances in body image. The subjects experienced hostility and resentment, and on rare occasions ambivalence. The phenomena occurred about 15' minutes after the administration of LSD; feelings of indifference and blunting tended to be protracted; suspiciousness, hostility, and resentment were always more transient. Changes in mood were twofold: euphoria and depression, which occurred in about equal number. Euphoria was either of the shallow elation type with silliness, as seen in the hebephrenic, or, in a cyclothymic subject, of the jovial and infectious type, as found in hypomanic and manic states. Depression was combined with dependency, indecision, insecurity, passivity, and feelings of being “lost.” In no instance did we observe the happy and dreamy feeling of ecstasy as it has been described by other authors who experimented with L.S.D., mescaline, and other similar chemicals. III. Perceptiou.—Usually within 40 minutes after the intake of LSD. disturbances of perception were observed. Those of visual perception were most common and mainly of the illusional type. The subjects would see rippling or wavy lines on the wall that might evolve into geometrical pattern, or be associated with color such as yellow, orange, or pink. In some instances, subjects saw a thermostat on the wall as a cruciﬁx but fully realized that the experience was an illusion. None of the subjects, however, had the feeling of seeing something of extraor— dinary beauty, as it was stated in early re- �I952] M. RINKEL, H. J. DESHON, R. W. HYDE AND H. C. SOLOMON ports on L.S.D., or as it may occur under the inﬂuence of mescaline. Gustatory disturbances occurred frequently; the subjects experiencing a metallic or “funny” taste or heavy tongue. Auditory perception was changed only in a few instances. The subject would hear a sound that was either near or distant, and in one instance of a depressed patient, the noise of a typewriter in an adjoining room was perceived as music, seemingly beautiful music. The sense of time was disturbed in II out of 17 experiments. It was characterized by the feeling of time accelerated or retarded. IV. Hallucinations and Delusions—Disturbances in perception, in a complex way, often lead to hallucinations and delusions. A vivid phantasy, a pseudohallucination or illusion, in the process of mental dissociation, may ultimately appear as a real object outside the subject and thus constitute a real hallucination. By a similar process, changes in auditory perception, combined with exist— ing suspiciousness, may lead to ideas of reference and delusions of persecution. It may be stated that hallucinations, predominant under the inﬂuence of most phantastica, sub— sequent to the injection of LSD. were rather meager and never showed the quality of an extraordinarily beautiful or threatening experience. The occasional visual hallucinations consisted mainly of formed images, which occasionally were preceded by crude ﬂashes of light. Perhaps the above—men— tioned disturbances of taste perception should be mentioned here as gustatory hallucina— tions. In only one instance we noticed an auditory hallucination, which consisted in hearing bells, although there were none anywhere around. Haptic hallucinations were experienced by two subjects. One male sub~ ject had the rather vivid feeling of his trousers being wet from urine, and one female schizoid patient was convinced that she lost urine and wet her slacks and the bed. She actually, later on, did wet the bed, and it may be possible that her hallucination was stimulated by autonomic excitation of the bladder mechanism. Morbid ideas were common; they included ideas of reference and ideas of inﬂuence. One female volunteer became quite paranoic and was Still disturbed the following day. Major delusions, ideas of gran— 575 deur or persecution, as seen in the delusional states of the paranoic or paraphrenic, were not observed. That may be due, perhaps, to the fact that in our experiments on normal volunteers we used only relatively small amounts of L.S.D. V. Depersonalization.—Alteration of personality occurred rather frequently. Those changes consisted mainly in the subject’s feeling that his legs were either extraordinarily long or heavy; in one psychotic patient the feeling was that the leg between ankle and hip had disappeared entirely. Most common was the feeling of unreality as regard to the subject, himself, and the outer world. Though these phenomena were of minor magnitude, they, too, indicate symptoms particularly ob— served in the schizophrenic patient. In no instance were we able to elicit experiences, of synaesthesias, as frequently seen in mescaline intoxications. VI. Behavior.—The most and striking change consisted in underactivity, associated with lack of spontaneity and initiative. One schizoid-depressed patient went into a state of catatonia; another one became stuporous. A female schizophrenic patient, who had received 3 gamma/kg. body weight of L.S.D., became agitated; after an initial state of inertia, she suddenly stood up and went through many and various motions. She knelt down, kissing the wall, the ﬂoor, the examining table, and progressively became more and more excited. She tore off her clothes and became noisy to such an extent that the ex— periment had to be terminated by the intravenous injection of 0.5 g. of sodium amytal. In our normal subjects, overactivity or in— appropriate behavior was rarely noted, but psychomotor manifestations, such as smiling, giggling, and laughing, more often appropriate than inappropriate, were frequently observed. This was particularly so in a student of cyclothymic personality make-up. VII. Intellect—In our normal subjects, intellectual functions were never disturbed. The subjects were aware of what they were doing at every moment of the experiment. Their memory also never became disturbed; each one was able to give, in a written report, a description of all the experiences he went through. Also, the psychotic patients did not show any particular memory defect. . �576 EXPERIMENTAL SCHIZOPHRENIA-LIKE SYMPTOM S Patients Whose verbal expression became slowed down and ﬁnally completely ceased, as in the case of stupor or catatonia, were able the following morning, under sodium amytal or d—desoxy-ephedrine, to recall their thoughts or personal experiences of the day before under the inﬂuence of L.S.D. VIII. Autonomic Nervous System.—All normal subjects and also the psychotic patients had numerous subjective complaints and symptoms. Since they mostly belong in the group of disturbances of the autonomic nervous system, they are best described here. The most common symptom was change in appetite, which more often was decreased, and associated with nausea, than increased. Complaints of headiness, giddiness, faintfre— and tremulousness, shaking were ness, The subjects complained , quently expressed. of chilliness and coolness of whole or part of the body, lump and “funny” feelings in ab— domen, constriction with oppression in chest and precordial discomfort, violent cramps and constriction in the abdomen in a pa— tient who just happened to menstruate. Objectively observed were ﬂushing, sweating, shivering, and shivering with goosepimples. Tachypnoea, salivation, pallor, sighing, and obscattered micturation of were urgency servations. Changes in pulse rate and blood pressure were of minor magnitude and observed only occasiOnally. Involuntary smiling, giggling, or laughing were considered in the nature of “risus sardonicus” where the subject described these phenomena as occurring Without or against his will. One subject stated that in a smile he felt as if his facial muscles were like plastic wax being moved by some inexorable force. Pupils were often maximally dilated. Gross disturbances of the cerebrospinal nervous system were not observed, except in some instances “dysarthria,” which consisted of a transient stumbling over words and was never marked. IX. Electroencephalogram.—EEGS were taken in 9 experiments at about the height of L.S.D. reaction, and compared with the EEG of the same subject in his normal state. In general, the EEG changes were only slight. Principal changes occurred in the alpha rhythm, which was characteristically increased in rate from 1-3 cycles per second. [Feb. In one case, an individual who was very relaxed, a slowing of about 2 cycles per second was observed. Hyperventilation showed a diminished responsiveness and may be due to the subject’s reduced cooperation. X. Psychological Tests. A. Rorschach—Controlled Rorschach tests were given to 5' subjects at the height ofL.S.D. reaction. All tests given during L.S.D. reaction showed abnormalities principally of the schizophrenic or paranoic type. There was noticed autistic thinking with decreased organization, contamination responses, and lack of logical thinking, also negativism and diminished emotional inhibition indicating anxiety, depression, and aggression. One Rorschach test revealed a moderately schizophrenic picture with autistic thinking and withdrawal. B. C oncrete-Abstract Thinking—The tests consisted in employing proverbs and aphorisms and recording the subject’s reaction. On the whole, the results, especially the wide range of responses in abstraction and overgeneralized and tangential thinking, were similar to those obtained in schizophrenic patients. DISCUSSION The common denominator in all our experiments with L.S.D. on normal subjects is a profound transformation and alteration of the psychic state of the individual, as it is a common factor in all psychotic states. The various mental phenomena that we have reported were brought about by mere traces (I:I,000,000g/kg. weight) of a chemical, d—lysergic acid diethylamide tartrate. The mental phenomena show similarities to symptoms that occur in actual psychoses. We noticed, predominantly, changes similar to those seen in schizophrenic patients. The subjects exhibited preeminently difﬁculties in thinking, which became retarded, blocked, autistic, and disconnected. The affect was shallow or there was clear-cut blunting. Feelings of indifference and unreality with suspiciousness, hostility, and resentment also approximated schizophrenic phenomena. Hallucinations and delusional disturbances though present were much less prominent or striking, but together with the manifestation ' �‘ 3952] M. RINKEL, H. J. DESI-ION, R. W. HYDE AND H. C. SOLOMON of depersonalization were most reminiscent of schizophrenic dissociation. To a much lesser degree were there similarities to the confusional states. Gross clouding of consciousness was absent in our experiments, but illusional misinterpretations were not infrequently observed. A few cases showed similarities to the manic-depressive states, with changes in mood of euphoria or depression. However, only in one cyclothymic-pyknic subject the intensity was of a hypomanic or manic state. Delusions of grandiose or persecutory nature, familiar in the paranoic psychoses, were not seen. We mention the similarities of the experimental phenomena to actual psychotic states in order to caution against fallacies that may occur in the interpretation of experimental psychotic disturbances. The same caution that is warranted in the application of an animal experiment to a pathological condition in man is needed in the application of the psychiatric experiment to natural psychosis. Our experiments have brought to light the fact that, in a short space of time, under the inﬂuence of a mere trace of a chemical agent in normal subjects, a variety of mental symptoms occur that are similar to natural psychoses, and that in psychotic patients an accentuation of existing, or elicitation of latent, schizophrenic phenomena takes place. It may be possible to assume that fundamentally the mechanism of origin of natural and experimental psychotic phenomena is a similar one: a chemical agent that pathologically stimulates selectively various higher, especially perceptive, brain centers with the result of hallucinatory and delusional experiences. H. J. DeShon, M. Rinkel, and H. C. Solomon( 5) have already pointed out that the clinical effects of LSD. imply such an involvement of the higher and highest centers of the central nervous system, and perhaps of lower levels of the nervous system as well. Many authors assume that chemical endogenous substances are the cause of schizophrenic psychosis. We must bear in mind that, in addition to d—lysergic acid, a great variety of seemingly unrelated chemical substances are capable of producing transi- 577 tory psychotic-like symptoms. Although observations are still too few to allow the for— mulation of a well-founded scientiﬁc theory as to the chemical origination of psychotic symptoms, we strongly believe that this branch of experimental psychiatry is progressing in the right direction, and may some day provide an answer to the most perplexing problems in psychiatry. SUMMARY The effects of minute amounts of dlysergic acid diethylamide tartrate (L.S.D.) on normal subjects, with an age range of 19—48 years, and some psychotic patients of the schizophrenic, depressive, and paranoic type are reported. 2. Psychotic phenomena and alterations of the autonomic nervous system were observed. The psychotic phenomena were pre— dominantly schizophrenia-like symptoms that were manifested in disturbances of thought and speech; changes in affect and mood; perception; production of hallucinations and delusions; depersonalization and changes in behavior. The basic intelligence was not reduced. 3. Electroencephalographic examinations at the height of the L.S.D. reaction revealed only slight changes, principally increased alpha rhythm, except in one case where there occurred a slowing of about 2 cycles per ' second. 4. Rorschach tests showed abnormalities principally of the schizophrenic or paranoic type. Concrete—abstract thinking tests also, on the whole, showed responses similar to those obtained in schizophrenic patients. 5. N 0 scientiﬁc theory for the origination of the natural psychotic phenomena or psychoses is being advanced, but the belief is expressed that experimental psychiatry progresses in the right direction. 1. Credits Our preparation of LSD. was supplied, in ampules containing I mg. substance, by courtesy of Professor E. Rothlin, Director of the Pharmacological Laboratories of Sandoz Chemical Company, Inc., Basel, Switzerland. �EXPERIMENTAL SCHIZOPHRENIA-LIKE SYMPTOMS 578 BIBLIOGRAPHY I. Baruk, H. Psychiatric. Medicale, Physiologique et Experimental. Masson et Cie. Paris (VI), 1938. 2. Becker, A. M. Zﬁr Psychopathologie der Lysergsaure-Diathylamid-wirkung (On the psychopathology of the effect of lysergic acid diethyla— mide). Wien. Ztschr. Nervenh. 2:402, 1949. 3. Bush, Anthony K., and Johnson, Warren C. L.S.D. 25 as an aid in psychotherapy. Dis. Nerv. Syst. 11 : 241, Aug. 1950. 4. Condrau, Gion. Klinishche Erfahrungen an Geisteskranken mit Lysergsaure-Diiithylamid (Clinical experiences in mental patients with lysergic acid-diethylamide). Ejnar Munksgaard, Copenhagen, 24: 9, 1949. 5. DeShon, H. J., et 31. Mental changes experimentally produced by L.S.D. Unpublished article. 6. Giacomo de, U. Données biologiques sur l’ac— tion psychopharmacologique de la diéthylamide de l’acide lysergique (Biological data on the psycho— pathological action of Lysergic acid diethylamide). Paper read at the Symposium on “Chimie cerebrale” of the International Congress of Psychiatry, Paris, Sept. 18-27, 1950. 7. Giacomo de, U. La catatonia sperimentale. Schizofrenie, 4: 195, 1934-1935. 8. Hoch, Paul H. Experimentally produced psy— choses. Am. J. Psychiat., 107:607, Feb. 1951. 9. Jong de, H. Die experimentelle Katatonie als vielfach vorkommende Reaktionsform des Zentralnervensystems (Experimental catatonia, as a frequent reaction type of the central nervous system). Ztschr, ges, Neur. Psychiat., 139 : 468, 1932. 10. Jong dc, H., et Baruk, H. La catonie experimentale par la Bulbocapnine. Paris: Masson et Cie, 1930. Pharmacologische Untersuchungen iiber Corydalisalkaloide (Pharmacological in- II. Peters, F. [Feb. vestigation of Corydalisalkaloids). Arch f. Experi— ment, PathoLogie, 51:130, May 1904. 12. Rinkel, M. (I) Discussional remark on L.S.D.—Clinic of the American Psychiatric Asso— ciation, held at the Annual Meeting of the A.P.A. May 1, 1950, in Detroit. J. Clin. Experiment. Psy— chopathol., Jan. 1951 (Van Ophuijsen Memorial Issue). (2) Discussion at symposium on “Chimie cere— brale” of Ist World Congress of Psychiatry, Paris, Sept. 18-27, 1950. Printed in “Les comptes-rendus du Congrés.” 13. Schmiedeberg, O. Uber die pharmacologischen Wirkungen und die therapeutische Anwendung einiger Carbamin Séiure-Ester. (On the pharmacological effect and therapeutic application of some of the esters of the Carbamin acid). Arch. f. Experiment. Pathologie und Pharmakologie, 20: 203, 1886. J. E. Psychopathologie der 14. Staehelin, Zwischen-und Mittelhirnerkrankungen (Psychopathology of the diseases of the diencephalon). Schweiz. Arch. Neurol. und Psychiat. 53 : 374, 1944. 15. Stoll, A. Les Alcaloidés de L’Ergot (The alkaloids of ergot). Experientia 1:250, 1945. I6. Stoll, A., and Hofmann, A. Partialsynthese von Alkaloiden vom Typus des Ergobasins (Partial synthesis of alkaloids of the type of the ergo— basins). Helv. Chim. Acta, 26:944, 1943. 17. Stoll, A., et a1. Ueber die Isomerie von Ly— sergsaure und Isolysergsaure (On the isomery of lysergic acid and isolysergic acid). Helv. Chim. Acta, 32 (No. 2) : 506, 1949. I8. Stoll, W. A. Lysergsaure-diithylamid, ein Phantasticum aus der Mutter-korngruppe. (Lysergic acid diethylamide, a phantasticon of the ergot group). Schweizer Arch. Neurol. und Psychiat., 60: I, 1947. 19. Vogel, H. Victor. Discussional remark to Hoch’s paper (ref. 8). ‘ ��ILQMH ‘_ .1”. '_ ., z::y1;,;m.ynom 32/ [7 _ kHLLQJ-» '2 2rd, GLEN QAKS N. L CLINICAL EFFECTS OF A “STIMULANT” BARBITURATE (Sodium I :3—dimethylbutyl ethyl barbiturate) in Schizophrenics BY HARRY [Reprinted from H. PENNES, MD. T8: JounNAL or Nnnvous AND MENTAL DISEASE, Vol. 119, No. 3, Mar. 1954] �[Reprinted from THE JOURNAL OF NERVOUS AND MENTAL DISEASE, Vol. 119, No. 3, Mar. 1954] CLINICAL EFFECTS OF A “STIMULANT” BARBITURATE (Sodium 1:3-dimethylbutyl ethyl barbiturate) in Schizophrenics HARRY H. PENNES, M.D.‘x‘ central the nervous than rather depress stimulate barbiturates Many of these drugs evaluation clinical but animals in experimental system barbitu— of central—depressant Administration a limited been has (15). of amelioration transient often sodium produces such amytal as rate different symptoms' in schizophrenics (6, Io, 3). These symptom changes are usually attended by a variable degree of hynotic (sleep— producing) eﬂect which may proceed to actual sleep as the dosage is increased. In the drug therapy of schizophrenics the excessive narcosis produced by the central-depressant action of the barbiturates in common administered. be which conveniently total the limits dosage may usage It was considered possible that a central—stimulant barbiturate might of the desirable ordinary depressant the activity therapeutic possess barbiturates without the disadvantage of excessive narcosis. The stimulant barbiturate utilized to test this hypothesis was 1,3— dimethylbutyl ethyl barbiturate, sodium salt (15), (hereafter designated as DMBEB) which is similar structurally to sodium amytal (14). A small number of observations has also been included on another stimu— lant barbiturate, namely, 3,3—dimethyl allyl ethyl barbiturate, sodium salt, (supplied for research purposes by Eli Lilly and Company, Indianapolis) (16). According to reports, DMBEB produces a period of increased alertness and restlessnes in unanesthetized dogs, followed by convulsions; the seizures, which occur only in warm-blooded animals, are Violently tonic in type and the locus is probably the spinal cord; no hypnotic or anesthetic effects are noted in sublethal doses (13, 14,). The reﬂex contraction of m. tibialis anticus is augmented in spinal and barbital—anesthetized dogs; in this regard it is I/250th as active as strychnine, one—fourth as active as picrotoxin, and more active than caf— feine, cocaine, or ephedrine (9). The crossed—extension reﬂex in m. gas— trocnemicus and respiration are also augmented (8). The convulsant activity of DMBEB may be antagonized by administration of sodium amytal (14). The sodium salt of 3,3—dimethyl allyl ethyl barbiturate produces a restless, frightened, or boldly vicious animal in which con— ‘From the Department of Experimental Psychiatry (Paul H. Hoch, M.D.), New York State Psychiatric Institute. [25I] �252 Harry H. Penna: vulsions ﬁnally ensue; blood pressure and body temperature rise while respiration is stimulated (I6). Gottlieb has previously observed that DMBEB produces a euphoric effect in depressed patients after oral administration in subconvulsant doses (4). The drug was likewise maintained at a subconvulsant level in the present study in order to rule out the possible therapeutic effect of a generalized seizure. PROCEDURE schizo— administered hospitalized 20 to Patient5.—DMBEB was duraMean mean females. 8 males and was 32.5 12 years; age phrenics, tion of illness, 13.4 years; mean duration of hospitalization, 2.2 years. The diagnostic categories were as follows: pseudoneurotic, 6; catatonic, The pseudo— unclassiﬁed schizophrenic, mixed 1 II. ; or hebephrenic, 2; neurotics presented diffusely neurotic symptomatology in a basically of criteria the and to according diagnosed were schizophrenic setting schizo— unclassiﬁed and mixed of The Polatin Hoch and (7). group phrenics presented admixtures of catatonic, hebephrenic, and paranoid cata— Gross disease. of the features the well as primary as components tonic stupors or excitements and diagnostic categories other than schizo— phrenia were not included. Most of the patients were quite well pre— served. Sixteen of the 20 cases had either no or slight deterioration (6 pseudoneurotics, 2 catatonics, I hebephrenic, and 7 mixed or un— classiﬁed schizophrenics); these patients were chieﬂy short-term, volun— tary hospital admissions. The remaining 4 subjects displayed an advanced degree of schizophrenic deterioration and were long—term, state hospital patients. All but 2 patients had received at least one course of electric convulsive and/ or insulin coma therapy at some time during the course of the illness. Dru gun—DMBEB was dry—sterilized in an electric oven at I50—I60° C. for one to two hours. Immediately prior to intravenous injection the drug was dissolved in 20.0 cc. of sterile distilled water at a concentration of 5.0 mg. per cc. A colorless solution was quickly formed. The the in administered 20 of that dose 63.5 DMBEB was was mg. average subjects. An injection rate of about 5.0 mg. per minute was used in all subjects. The same procedure was followed in the administration of 3,3—dimethyl allyl ethyl barbiturate, sodium salt, to 2 patients both of whom also received DMBEB on another occasion. Each patient also independently received intravenous injection of sodium amytal (Amobarbital sodium, Eli Lilly and Company, Indianapolis), 250-500 mg. dis— solved in 10.0 cc. of sterile distilled water at a rate of about 50 mg. per minute, as well as 20.0 or 40.0 mg. of pervitin hydrochloride (Smith, �Eﬁect: of a "Stimulant” Barbiturate 253 Kline and French Company, Philadelphia) in 2.0—4.0 cc. of solution in one minute. Six patients also received intravenous sodium amytal in the same dosage and rate of administration as that of DMBEB. The drugs were administered in random orders to the various subjects. Injections were performed between 8:00 A.M. and 4:00 P.M. without limitation of food or the subject’s usual ward activities. Changes in the patient’s baseline clinical status were recorded in protocol form for a period of at least 48 hours following injection. RESULTS I. Mental Reactions.——DMBEB reduced clinical symptoms in II (55.0 per cent) of the series. Three patients (15.0 per cent) showed only increase of symptomatology and 6 (30.0 per cent) had no reactions except for side-effects to be described in section II. A. Symptom-reducing reﬂect—The therapeutic action was most pro— nounced in the pseudoneurotic group. Four out of 6 patients in this group experienced complete or almost complete relief of anxiety and tension, phobic concerns, irritability and hostility, and depressive manifestations. All 3 obsessive—compulsive patients in this group experi— enced amelioration of the disabling symptomatology, slight in I and quite complete in 2. The usual duration of relief was two to eight hours, but in 2 subjects the improvement lasted 16 to 24 hours. The symptomatic improvement began during the injection, usually concurrently with cephalic sensations described variously as “light—headed” or a “subtle feeling of relaxation.” In the 14 overt schizophrenics (hebephrenics, catatonic, mixed, and unclassiﬁed), 7 patients showed slight to mod— erate therapeutic responses which were in general less complete than those of the pseudoneurotics. The effects in the overt schoziphrenic group consisted principally of signs of personality reintegration with more normal emotional feeling and display, less self—concern and self— preoccupation, an increased tendency to contact the environment, and a somewhat higher verbal productivity. The most deteriorated cases responded least to the drug in a therapeutic sense; these patients also responded least to sodium amytal and pervitin. These therapeutic responses to DMBEB were qualitatively identical with those often produced by central—depressant barbiturates. How— ever, the therapeutic response to DMBEB was more complete than to sodium amytal administered in the same low dosage to 6 patients (30, 50, 65, 89, 100, and 100 mg.); this was particularly true in the pseudoneurotic group. Moreover, clinical signs of hypnosis with DMBEB occurred in only 4 patients in the series and consisted of transient drowsi- �254 Harry H. Pennes excessive slurred speech, and nystagmus, a sleepy expression; ness euphoria, and other signs of acute barbiturate intoxication were not feel— relieved reported no subjects present. Some of the most completely after such of signs and objective of drowsiness displayed no ings DMBEB. In addition, DMBEB produced none of the signs of psychic “stimulation” that usually occurred after pervitin, a cephalotropic sym— pathomimetic amine. Administration of pervitin was almost invariably attended by a positive “stimulation” aspect consisting of increased alert— ness and energy, feelings of optimism, and heightened psychomotor acaction the DMBEB, to therapeutically In responding patients tivity. elimina— neutralization or summarized be therefore a as symptom may tion without concomitant “stimulation” and, as described above, with occasionally a minor degree of sedation. B. Symptom—increasing eﬂects.—Symptom intensiﬁcation occurred in him— for felt copiously, follows: sorry one subject wept 3 patients as self, and complained bitterly of mistreatment by doctors; a second identi— of seizure origin hysterical subject had a brief, opisthotonic cal with the type occurring in the drug—free state; the third subject felt more perplexed, confused, and depressed. These reactions were all exacerbations of pre—existent manifestations which had also previously increased spontaneously or in response to amytal and/or pervitin. These excessive reactions appeared to be precipitated “psychologically” as a secondary reaction to the unusual side effects produced by DMBEB barbituof showed acute of these signs None subjects Section 11). (see resemble did the reactions entirely not In subnarcosis. addition, rate the exaggerated emotional discharges so often produced after pervitin, since none of the primary “stimulation” effects of pervitin on psycho— motor processes was present. C. Absent mental reactions.—Six patients (30.0 per cent) had no reac— tions to the drug in terms of pre—existent symptomatology. In 3 of these, the side-reactions to the drug were so intense that the patients were preoccupied with little else. In the 3 other subjects, there were no mental side-effects. considerable of absence the of despite signiﬁcance changes II. Side Reactions.—Practically all (18 out of 20) patients experi— enced side—reactions. The toxic effects appeared during the injection and the sequence of events was approximately the same in the majority of subjects. Tingling sensations or other paresthesias began in any part of the body, and rapidly became pruritic in nature; this was followed by or associated with hot and cold sensations and a mottled erythema in face, chest, and trunk. Pilomotor reactions often appeared on arms �Eﬁect: of a "Stimulant” Barbiturate 255 and back; less frequently there were feelings of vague abdominal dis— comfort or slight nausea; repeated, forceful sneezing; and occasionally burning of the eyes. Cephalic sensations previously referred to (Section IA) usually began early in the injection in a small minority of sub— jects; on assuming the erect position some patients complained of a vague vertigo of nonspeciﬁc nature and minimal degrees of ataxia were observed. The maximum dosage of DMBEB that could be comfortably tol— erated by the subjects was limited by the pruritis, which was the most frequent side-reaction (18 out of 20 patients). The itching usually began in scalp, face, eyes, soles of feet, or genital areas. Spread was rapid and in some cases the pruritis became generalized; some subjects rubbed and scratched vigorously and became extremely distressed, tending to disregard the other actions. All the side-reactions enumerated above were of relatively short duration, usually subsiding in IO to 30 minutes. In some cases, the pruritis persisted for several hours, although distress was always minimal after the ﬁrst 10 to 30 minutes. In 17 cases, the injection was discontinued when the above reaction deﬁnitely appeared, particularly the pruritis. The average dosage administered to these subjects was 64.4 mg. total or 1.01 mg. per Kg. of body weight. The threshold dosage for the appearance of any effect, mental or toxic, was in the neighborhood of 30.0 mg. The range of effective therapeutic dosage without toxicity was therefore quite narrow. Two patients received full dosage of 97.0 and 101.0 mg. total without side— effects and a marked symptomatic improvement in one. Two subjects displayed seizures at dosages of 59.0 mg. (0.65 mg. per Kg.) and 68.0 mg. (1.04 mg. per Kg.), although other subjects receiv— ing equal or larger dosages did not display seizures. The involuntary movements were of a jerky, nonrhythmic myoclonic type; in one subject the movements were more or less generalized and in the other limited to the right arm. The movements occurred in cycles of about 15-20 seconds duration for a period of about 10 minutes. Consciousness was not impaired during the seizures; deep reflexes were normal in the inter— seizure phases; there were no facial weakness, pupillary changes, nys— tagmus, Hoffman or Babinski reﬂexes. The seizures appeared in these two subjects after the itching had become severe and generalized. Continued experience with the drug showed that no patient developed a seizure if the injection was discontinued at or shortly after the appear— ance of the pruritis. None of the side—effects of DMBEB occurred after sodium amytal with the exception of its quite minor hypnotic action. Pervitin sideeffects were totally distinct, consisting usually of mouth and throat �256 Harry H. Penna: dryness, peripheral numbness and lightness, chest pressure, and cephalic tightness or aching. Sodium 1,3-Dimet/zyl Allyl Ethyl Barbituratc.—This stimulant bar— biturate was administered in doses of 1.26 and 1.37 mg. per Kg. to 2 subjects. The same side-effects were produced as with DMBEB and with the same apparent intensity. One subject experienced generalized myoclonic—like twitchings. No therapeutic effect on mental symptoma— tology was observed. DISCUSSION DMBEB has been classiﬁed as a “stimulant” barbiturate in animals in the experimental pharmacologic literature because of its convulsion— producing property and augmentation of spinal reﬂexes (13, I4, 8). The epileptogenic action was conﬁrmed in this clinical assay of the drug inasmuch as 2 subjects had seizures under the drug, the dosage being maintained at the subconvulsant level in the other patients. The seizures occurring in these 2 subjects were of myoclonic type, whereas Swanson and Chen reported that the drug produced severe convulsions of tonic convul— of difference This animals to as in (14). type laboratory type sion may be a species difference or reﬂect the limitation of dosage in man. The median convulsant dosage after intravenous administration to guinea pigs, rabbits, cats, dogs, and monkeys ranged from 2.0—3.0 mg. with brief the whereas episodes myoclonic (14), weight body Kg. per DMBEB in this series occurred with dosages of 0.65 and 1.04 mg. per Kg. The numerous side—reactions observed in man have not been reported in animals; some of these side—reactions are purely subjective and there— fore not observable in animals. Knoefel found that DMBEB produced a stage of increased alertness and restlessness prior to the seizures (8); dogs under sodium 1,3—dimethyl allyl ethyl barbiturate became restless and also appeared frightened or boldly vicious prior to the onset of convulsions (16). These apparent changes in emotion and behavior in animals could have been secondary to a highly distressing action such as occurred in man, mainly the severe paresthetic and pruritic response. Either a peripheral or central locus of action might underlie the typical constellation of tingling, burning or cold, pruritis, pilomotor contrac— tions, erythema and sneezing. The sneezing in man may be analogous to the respiratory augmentation observed in animals (16). Gottlieb noted that the toxic reactions to DMBEB in man were not signiﬁcantly affected by administration of antihistaminic drugs (4). Despite the motor Stimulation caused by DMBEB in man and reported in animals, there was little or no evidence that the drug acted �Eﬁects of a “Stimulant" Barbiturate 257 in stimulation” The “psychic in stimulant” term patients. as a “psychic behavioral and emotional the is exaggerated to applied generally man the to sodium amytal, or with intravenous of subnarcosis as phenomena with as mood of psychomotor processes, or “primary” heightening of these of Neither amines. types the cephalotropic sympathomimetic be the this drug In may DMBEB. after respect reactions occurred which and are potent metrazol strychnine such with as grouped agents of absence The stimulants.” weak “psychic convulsants but relatively be in DMBEB with man stimulation” may of obvious signs “psychic associated with the fact that the seizure locus in animals is apparently the spinal cord (14). have been no hypnotic or has to reported DMBEB Although observed effect weak was hypnotic animals effects a in (14), anesthetic difference This series. of the may of the present in the minority patients reﬂect species variation or technical limitations in animal experimenta— tion inasmuch as a slight degree of narcosis is often purely subjective. From the therapeutic point of view, DMBEB produced symptom effects the of the series; of cent 20 or 55.0 per amelioration in II out ob— Gottlieb were most complete in pseudoneurotic schizophrenics. 60.0 i.e., material, different in results patient the tained almost same of series IO in administration a oral after per cent improvement, schizo— of a whom as diagnosed was only one severely depressed patients, establish advisable deemed therapeutic been to has It not (4). phrenic value on more than the present preliminary tentative basis because of the high toxicity of the drug which would preclude therapeutic appli— cation. The same conclusion was reached by Gottlieb (4). The observed therapeutic activity of DMBEB cannot be explained allevia— because action weak symptom hypnotic—narcotic in terms of its tion (particularly in pseudoneurotic schizophrenics) occurred without obvious of absence and the fact this of view In action. such appreciable the of action the that is therapeutic it stimulation,” apparent “psychic drug requires another explanation. Two hypothetical explanations are the following: and stimulation” properties does “psychic DMBEB really possess I. in addition the hypnotic action of the ordinary barbiturates; the balance between these two actions is such that a net weak hypnosis is occasionally the resultant in man. In this case it would have to be assumed that the complete almost the theoretically retained is despite action therapeutic of level far effects in stimulant as and so narcotic of cancelling-out consciousness is concerned. In support of such a possibility is the clinical observation that in simultaneous administration of amytal and benzedrine to mental patients, considerable therapeutic activity may ensue �258 . Harry H. Penna: despite a fairly complete mutual neutralization of the narcotic and stimulant actions of the two drugs (11). In this connection it may be observed that Gottlieb interpreted the euphorizing action of DMBEB in mental depression as a consequence of its “stimulant” properties and from this concluded that amytal may exert its euphorizing action in the same condition by a stimulant rather than a narcotic action (4). Gottlieb did not report any hypnotic action of DMBEB in his series such as was observed in the present study; the difference may possibly be a function of the oral route of administration in his study as compared with the intravenous route in this report. His data could also be inter— preted in terms of a narcotic rather than a stimulant action of DMBEB and the beneﬁcial effect of amytal in depression still explained in terms of a narcotic action rather than a stimulant one. 2. The second hypothetical mechanism for the therapeutic action of DMBEB would be that the drug exerts this effect by a mechanism other than central depression or stimulation. Direct evidence for this interpretation is lacking. However, there are several sets of data which suggest that the ordinary central-depressant barbiturates exert their therapeutic action on mental symptomatology independently of their hypnotic-narcotic actions. These data are the following: (a) a few subjects display almost complete relief of symptomatology after intra— venous injection of small amounts of sodium amytal before any or much intoxication is apparent in the form of drowsiness, slurred speech, or nystagmus. Conversely, a few subjects show little change in the mental status even though the central-depressant action may be carried to the point of sleep (10, 5). (b) The ﬁrst effect of the barbiturates on the human electroencephalogram is the appearance of relatively rapid (20-25 sec.), medium—high voltage activity, particularly in the frontal leads (II, I, 12). The appearance of this activity coincides temporally with reduction of anxiety and tension in some patients and the appearance of a more or less euphoric state (11, 12). The physiologic signiﬁcance of this rapid activity has not been fully determined as yet but in any event it is distinct from the EEG charges which are usually accepted as manifestations of depressed consciousness, i.e., high voltage, slow activity (2). In view of these considerations, it is possible that both DMBEB and the ordinary barbiturates owe their therapeutic effect on mental symptomatology to some hitherto undisclosed feature of their action. The pharmacologic literature contains reference to a large number of motor stimulant barbiturates which have never received clinical assay. These compounds show no underlying uniformity of chemical structure and many are in the thiobarbiturate series. The possibility exists that �Eﬁ‘ects of a “Stimulant” Barbiturate 259 without these of drugs with obtainable some therapeutic action may be the excessive toxicity of DMBEB. SUMMARY bar— ethyl The “stimulant” barbiturate, sodium 1,3—dimethylbutyl various with 20 patients biturate, was administered intravenously to value. of its therapeutic forms of schizophrenia in a preliminary assay effect therapeutic occurring I. The drug exerted an irregularly in pseudoneurotic degree of complete which most was (55.0 per cent) further establish advisable to deemed been schizophrenics. It has not which toxicity the high of relatively because the therapeutic efficacy would preclude therapeutic application. in convulsant is the a that drug literature the 2. In accord with remainthe in seizures; had series myoclonic this animals, 2 patients in level. A subconvulsant maintained a at ing subjects the dosage was small minority of subjects showed weak signs of central nervous system central—depressant the drowsiness; of form the slight in depression action has not been reported in animals. occurred independently the of usually effect drug The therapeutic 3. evidence was No action. central—depressant and of its weak infrequent of the in sense stimulant” acted “psychic as a obtained that the drug heightening of mood and psycho-motor processes. action the of therapeutic mechanism the of 4. Several explanations of the stimufurther of investigation the desirability and offered were lant barbiturate series indicated. BIBLIOGRAPHY the Cerebral CorBarbiturates of Action on E.: and I. Finesinger, A. M. B., (1) Brazier, tex. Arch. Neural. 6r Frye/liar” 53: 51-58, 1945. Brain. the of Activity Electrical the Underlying Mechanisms : Physiological (2) I. Neural, Neurosurg, 6* Psych, 11: 118-133, 1948. Sodium Amytal of Intravenous Value M.: Prognostic and I. Hope, S., (3) Gottlieb, I. in Cases of Schizophrenia. Arc/z. Neural. 6' Prychiat., 46: 86-100, 1941. Acid. Arch. Barbituric 5-(1,3-Dirnethylbuty1)-5—Ethyl of Action Antidepressive (4) Neurol. 6r P5yc/ziat., 66: 318—328, 1951. and Sodium Amytal of Administration of Effect S. B: (5) Harris, M. H., and Katz, Sodium Rhodonate on Mental Patients. Am. I. P:yc/ziwt., 12: 1065-1083, 1933. NERVOUS & JOURNAL and Therapy. of Narcodiagnosis Status Present (6) Hoch, P. H.: MENTAL DISEASE, 103: 248-259, 1946. Psychiat. of Schizophrenia. Form Pseudoneurotic P.: Polatin, and (7) Hoch, P. H., Quart., 23: 248—276, 1949. by Nervous Central System the of and Depression Stimulation K.: (8) Knoefel, P. Therap., 6' Pharm. Exper. Acids. I. Thiobarbituric and Barbituric of Derivatives 84: 26-33. I945<9 Exper. Therap., 57: Pharm. Barbiturate. I. Convulsant of Action a : The (9) 130, 1936 (Proc.). Sodium Amytal, Pervitin to of Schizophrenics Reactions Clinical H.: H. (10) Pennes, ' —: �260 (11) (12) (I3) (I4) (15) (16) Harry H. Penna: Hydrochloride, Mescaline Sulfate and D-lysergic Acid Diethylamide (LSD25). (To be published.) : Personal Observation. Rubin, M. A., Malamud, W., and Hope, 1.: EEG and Psychopathological Manirestations in Schizophrenia as Inﬂuenced by Drugs. Psychosom. Med., 4: 355-361, 1942. Shonle, H. A., et 31.: Relation of the Structure of Dialkyl Barbituric Acids to the Length of Their Action. I. Am. Chem. Soc., 58: 585—587, 1936. Swanson, E. E., and Chen, K. K.: The Aberrant Action of Sodium I :3—dimethylbutyl Ethyl Barbiturate. Quart. I. Pharm. é‘r Pharmacol., 12: 657-660, 1939. Tatum, A. L.: Present Status of the Barbituratc Problem. Physiol. Rem, 19: 472502, 1939Taylor, N. B. G., and Noble, R. L.: Some Pharmacological Properties of Sodium Ethyl, 3:3 Dimethylallyl Barbiturate. Nature, 163: 447, 1949. ��W Ruth. t , mm mm.bail. Ion-r “I!“ i mammcsmmcm mmmnuﬂ.‘ iv P.hmulJ.I.lIOou ,_ «2:! "WWW“ 'thﬁ-WMW-lmw mun-nuns; MM,” mug-v.4 pawn 1...,” .»,t Proof. to: Dr.J.D.lcCou it. nonu- Ltd. but lo: 959 “on“, “a m �gnu-gotta or ﬂu «unnoand at up nun-um at»), mum». Ann; tho mm, (mm, mauuorummwgpu'wubom attache-amid. ”haul-Watt!” muunuu,nwu,mumwwu1uu vlllult. m,ud¢mlduquuonofﬁom¢nub Mr uticomamnleutboc-W mummwu,muuaoomump mm,1umovd1h-u(cmsuand,19533 Inn-r, M1955, mam, 1955. 1957; 1956; -.‘-a.-1-- ran 195‘). mmmuxtuwmtmsmtzu “mummmwmumm Min-lull. Itmmuthttumotm «rutnammuummwwmd Wan-«An m .u-.. Hum.» a.‘ “.“.".‘m' .- ‘ �4-1-1- We CN nice weighing between 1.8 and 20 gram were used; all 0.2 of :1. value a m in intraparitoneany inJected were 8201'. 80 of .experilenta were carried out at a root tcperatnre The clonio convuleion (produced ”I nicotine, pentylenetet— was taken ae tho end point and the resale, etrychnino or picrotoxinﬂ obeerved date. the frocalculated van 613,. in tern of “Jim. (LIICEI’IIID I HMO! The 1949). 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Five of of etmtaral their became selected were othere while aotice (Table I). to bemtynine relationlhip 0 obtained were and pierotoxin Pentylenetetrasole nicotine 95$ Laboratoriee; ellfate fro. 1'. l H. ﬁlth, fro- laatnen Ltd. fret in Organic Chemical-g Meat“ etryebnine �w. ‘TSE' rm-Nr‘mn '.5w-7- ‘,-v T: .viq m fouroonnlmtlbytho mutmumottbocnnoftho Mucupmatutdmm-nnndinhhlon. mow q»: u; 1“v " Input-uhthouinqunu-hcﬂihtmottbﬂgg �9i was.“ 43-3: :2 .'.w -.....< . entegonised the convulsions ea did ediphenine. end 80 525A eholished the tonic The “upload, piprsdol phase. effect of ease of the etereotios of phenoherhitel is shun in rehle III. The on the ties of fieently shortened with eech eta-pound used while the motion ves signifieestly prolonged . Further iﬂicetioe of the menus station onset use sini— antics of W ' of intuitw of this phenobdbdtslestienoenheseenieml. Thesedese-reqeeu “1;" de-oeetrete the relstive effectiveness Iillitrsl for sillin. oftheseeaepeueds. Ghleqreeesinenetheeestpetent,vhileheaee- tylilee-dﬁistolsppeeredsoneuhetsinilsrteeeohethc. Assenlonoludeepreh-eteverethelessteffeetive. heelepeofthe dose—response serve those of the other W for syn-chaste ves eon-idem}; different Ms. ft. Ietea-pretstienoftheseusultseetethesieilerityes difference of the site of eetien oh the cents-.1 eel-m get. is dqndent upon our knowledge of the feces of «tier: of the oomlsellt scents. lhile this leeelieetion of oesttel ooenlsent entice is not definitely known, it is geeenlly shoddged tht estspredoninenthontheoerehreloortez, whiletheledllhryull pontine regions ere less sensitive. Pia-atom hes its pads-insist eetion on hulher structures ehile stryehine sets st e lever level ef the oerehroepdml uis. Iieotine is believed to its outrel We convulssnt sotion We st the level of the dimephlel. Itnstheeeknovledgedthsttheoonvueentsestsinltueasly st different 1evels of th- centre]. nervous mun. 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Marmara-sin, murmur“. 0!.thqu and mute]. on Wuumlmmwwmmmmm. u«.mmmmuuatunmmmﬂﬁo Pavia”mmmuamwunuuu. nub-WWmenth-pnmottm I: Wd‘O/UO. mnummwwwmummﬁm innaundtmmutthMp-éﬂyw ,. "a I. (Wingw, WW (1957) In many Mdmtuuuu u cm. do.) an udulM-(uquu-mwaaumaw mum-g mmummwormm.“ mmamumumutuwmd Wu.utuqaumutbunuuwuunua of'utomdow. .; mmmamwwwmwmm «www.m-mwwmwmum mthmuopotuqupcumuthuuuuu. Wanna uh mm‘mrmmumuugmcm mm... nulmmmmu-mmzu- MM mumumm(m,uumm19ﬂ). �”IL-*- 1 :1. u“- 1‘ a A . . :\ 1 : 1 ~=‘-<‘Wlﬂ-me~4 a“ airﬁai’iw" .. MmmtnottmoIWNLWn-(I) (l)uluuy¢loao1(l)ondlnuuctw m1“), mu umcwwaomphmmul. .1 �m Wu,morp1nn,uprobmto,uuqmm1, nova-.1 «Ml-cum. any-um proau. utma; of Ion clouo to thMM.” tumult” nth c unpai1. Wm mun-mu, 1311.00. manual, am or 3100“...th- w ‘ 2. mule-91d um, Mnmnu,m1u, wuwmulot,hnuonndiﬁ~ityofm awmumnmtmdammuw. ummammuaummm 3. “Wham-WMuRMtme-Mdm umumd,n-¢om,mw,wmorm “ulna-mm ammotu-Wtyuw-n munu1ummnmmmwm.m1m ' A. W muamudmpoumu. to «mm. 3M0 )uuu n V « , ~ ;, s. z . 1,, .. (.9; A a.» you. man mm I Mm¢ha3a11vaé2r$imH lMMﬁAxtﬁ-m¥*-"‘m&héw«gu \ �.74).?— W in with to ﬂunk thou orpniutiom for tonal-3 tolu- "11111310 tho wm": ~WW»II"M ~ ..--M- .....,... n... .. 9.. . Ml!....; that cart“! in nun. , “I‘M“ Ia Met, IJ. m1.“ E11100 0000. 8" 525A 0000. W Pipndol m. m mm man ad to mu,m. 0.0.. “10mm 3x ,:;"'-. 55.1.6 at“ -. .iﬁmi-ﬂiaﬁ.“ .0 ‘ “a .3... W. “an,” oo;oo '5 1 W, m M .1“. n1” ‘Pun. .' 4.52. - �Box-pr, r.n.. J. m1. Borg-r, LIL. Ann. M, mu, 0., 0., 1.x. And. 11m”. Int. India, 3.,Sloro, 1954. m. “1. 301. J. nan-«1. m... mm, 413 1957, 91, 685 1955.19,?” 1956. 0.1.. n. an an Pllvu, 1.. “maxim, am, ’0, ”3‘" 8.. m. Win,nun-t.W, 1956.13.14: IO, ‘0' 3.. M m1. 1953, 23: 305 Arch. ad mun. mm, 0.11., 1:19.. 0.11., and 5m 1., Apt: Pint-001. ct renal. 1955. tended. at not: “J,‘., git ? m. 1133 m MOD», '0' 1956, run-«1. a. r..,:. at my... mama, 320 1957, tron. MI. 1. and lb :.n. sun, Wall, In 1957, and pro“. 3001.1, 1.3., aura, 9., ll», IJ. 3.3. 1955. 1949, 99 n. we n. 3&6 ��‘ .........,., 4 8n» AU 8. _ Ian-av. 8m. o8 08 so an» 8. on. a... 8. a. a. : an»? u n ,5 9.5. .3.an . “at. LED- ..,..y �CV A3 ot'oﬂg gwgong p.» aw.a.p.uv pro Acto.9.wv . a.» Au.~.w..v u.w or» Aarqnarov a o ~u...u.nv �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Files and reprints: hallucinogens and EEG, 1958 (folder title 1/2). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-002-13-014 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource Various authors Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/c577bc7f069484c31c474ab088079b96.pdf ecc528f0eb233cc9aa9e8503f0092d28 PDF Text Text OF' THE EFFECTS CERTAIN DRUGS ON CEREBRAL SYNAPSES By Amedeo S. Marrazzi Reprinted from ANNALS OF THE NEW YORK ACADEMY OF SCIENCES APR 3 0 1qt§9 ‘ ‘ Volume 66, Article 3, Pages 496—507 March 14, 1957 DEPARTMENTOF . EXPERIMENT” PSYBH‘HRY SIDE HOSPlTN- Hug-LEN OAKS. N- Y- �THE EFFECTS OF CERTAIN DRUGS ON CEREBRAL SYNAPSES By Amedeo S. Marrazzi Velerans Administration Research Laboratories in Neuropsye/ziatry, Veterans Administration II ospital, Pittsburgh, Pa. As Edward Evarts has so clearly indicated in his contribution to this volume, we are all interested in determining the neurophysiological correlates of mental disturbance in the hope of thereby gaining an inkling of its underlying mech— anisms and developing a rational therapy for it. Humphry Osmond has drawn a dramatic picture of the opportunity presented by the situation made possible by the psychotomimetic drugs, which afford us the means of inducing at will a reversible model psychosis. This model psychosis, even though it bears only a fragmentary resemblance to schizophrenia, nevertheless simulates certain aspects of mental disturbance by perhaps similar mechanisms. Furthermore, the so-called model psychosis also can be shortened and terminated is in effectiveness clinical which for schizophrenia will the tranquilizers at by claimed. The use of drugs as tools thus creates favorable conditions for studies of mental illness. Our efforts, as investigators, are directed more toward an intelligent applica— tion of the hypotheses of mechanism rather than toward simple clinical evaluation. The conditions that we wish to interpret are fully and truly exhibited in man but, before we can take full advantage of controlled conditions induced in humans, it is necessary to perform some prototype experiments in animals since, in such experiments, more procedures are permissible and in them those experiments intended for man can be constructed and rehearsed. This pur— is be humans with work before done, needed can the my groundwork pose, justiﬁcation for presenting some data on animals and making comparisons with clinical conditions and experimentally induced conditions in man. FIGURE 1 summarizes the data that led my co—workers and me to a hypothesis that served as the point of departure for studies in this ﬁeld.1 It shows that in our survey of a variety of sites in the nervous system we ﬁnd, as far as we have gone, that a consistent reciprocal relationship exists between excitation or enhancement by acetylcholine and acetylcholinelike substances, including anticholinesterases, on synaptic-transmission phenomena and inhibition by epinephrine, norepinephrine, all sympathomimetic amines in varying degrees, and related substances.2 It seemed plausible that any perversion of metabolism that would distort the balance of endogenous chemical or neurohumoral control of synaptic-transmission processes could lead to abnormal cerebral performance or mental disturbance, and that chemicals or drugs could alter the equilibrium of transmission and thereby alter cerebral and mental function in the direction of health or disease. The limitations of communication with animals make it exceedingly difﬁcult, though not impossible, to relate the behavioral disturbances that can be produced in them with mental disturbance in man. Since our basic premise, however, is that all cerebral function, including both behavior and mental proc— in series and in accumulated parallel of units is functional made esses, up 496 �Marrazzi: Effects of Certain Drugs on (‘erebrztl Synapses 497 SIMILARITY OF CHOLINERGIC EXCITATION AND ADRENERGIC INHIBITION AT VARIOUS SYNAPSES ACETYLCHOLINE ATROPINE 0R CURAFIE ANTICHOLINESTERASE TEA EPINEPHRIQJE mnzpmepuamz AMPNETAMINE Epnsonms (-) CORTEX ‘MIDBRAIN (—) ~n£spmnoav (_) CENTER PARASYMPATNETIC GANGLIA (-) svunmznc GANGLIA (_) ”c/ (-I 6.23536: * ----------- 553%? ( - 4 ENHANCEMENT 3' BLOCK ‘I HONOLOGUE OF SVMPATHETIC mcounzn OF ** GANGLION FIGURE an. , _______ (-) INHIBITION CNOLINERGIC EXPERIMENTS 2‘ DEPRESSION EFFECTS IN PROGRESS 1 combinations to form patterns, I believe it of value to study such units, that is, the synapses. The transparent model of the brain of the cat (FIGURE 2) illustrates a relatively simple synaptic* preparation that we have found convenient for study. I must emphasize, at the outset, that we consider the experiment pertinent to the extent that it deals with visual pathways, since the powerful psychotomi— metic drugs exhibit an important Visual component in the hallucinations, dramatically so with mescaline. More important than that, our ﬁndings im— press us with the similarities rather than the differences between synaptic per— formance and susceptibility to chemicals, either endogenous or exogenous (drugs). Therefore, we are really using the transcallosally activated cerebral synapses in the visual area of the cat merely as representative of cerebral synapses in general, all of these synapses having qualitative similarities and varying principally by differences of threshold. We do not intend to suggest that an alteration in this speciﬁc pathway is necessarily responsible for mental disturbanceT A little later I shall outline a general working hypothesis based ‘ “Synapse” is used throughout in the sense of designating the total complex involved the functional arat ticulation of 2 neurons, that is, presynaptic nerve ends, transmission process, postsynaptic dendrites, and soma. ’r Chronic interruption in a system such as the transcallosal. as mentioned by Edward Evarts, should not necessarily be expected to produce the same changes as an acute interruption by drugs unaccompanied by surgical trauma and subsequent degenerative processes. �498 Annals New York Academy of Sciences 93 .5“ .Qaﬁda 05 mm 399% @003 .3235 029533 33. Saginaw Qumozaumqnbv 18:38.35 gobs—Tm wagon? £35 2: we 1:58 “223359 .12.— . .N 35c 5:... ~ A 688.: . �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 499 patterns that results from alteration in amounts of synaptic regulators or in the thresholds of the neurons upon which they act. Since Edward Evarts has already outlined our technique I can be very brief in pointing out certain features. Because the brain is a communication system it seems most appropriate to measure function by recording the handling of a test message. The test message is supplied in the form of a submaximal elec— trical stimulus applied to 1 optic cortex in a cat that has received a. light dosage of pentobarbital sodium. This stimulus initiates a conducted response in the association or transcallosal tract that connects the stimulated point to a sym— metrical point in the contralateral cortex where, after synaptic. transmission, the stimulation evokes a cortical potential, as first described by Curtis and Bard.3 To help distinguish between peripheral effects that would contribute to the afferent drive constituting the background against which the impulses are elicited and the strictly central effects, we take advantage of the fact. that an intracarotid injection will achieve a transient, higher concentration of drug on the ipsilateral or recording side but, when diluted by the blood in the general circulation, the concentration of the drug is brought down to levels that are below the threshold for the peripheral effects. Under the conditions of our experiment, the amounts of the drug passing through the circle of Willis to the other cortex are unimportant. In this way it becomes possible to demonstrate (FIGURE 3) that epinephrine, a chemical natural to the body, one known to produce anxiety when accumu— lated in sufﬁcient amounts, either endogenously or exogenously, also produces cerebral synaptic inhibition, as indicated by the reduction in the signal (surface on a disruption of normal negative wave) corresponding to outflow, while the inﬂow (surface positive wave) is essentially unaltered. The same type of synaptic inhibition is shown for another cerebral neurohumor, norepinephrine, in the next line of the same IOO LIV. IOO ”\4 The cerebral synaptic action of epinephrine and norepinephrine in a 2-neuron intercortical (transcallosal) system. Potentials are evoked in the optic cortex by the electrical stimulation of a symmetrical point m the contralateral cortex. Epinephrine (10 lag/kg.) was injected into the i silateral carotid artery after A. and norepmephrine (150 lug/kg.) was injected after D. A and D are centre 5, B and E represent inhibition, and C and F show recovery. FIGURE 3. �500 Annals New York Academy of Sciences 0-9-? H I HO H0 H I OH H I H -N\ CH3 EPINEPHRINE (dihydroxy-phenyl—ethonol methyl amine) h‘h‘,“ ”'9?" HCH3H AMPHETAMINE (phmyl-isopropyl amine) _*.+ H __'.+ H CHSO MESCALINE (trimethoxy-phenyl-ethyl om'ne) FIGURE 4. Types of phenyLethyl amines producing mental effects. ﬁgure, but this action is evidently weaker than the other, requiring a larger dose to produce approximately the same degree of inhibition. In FIGURES 4 and 5 are shown some structural chemical similarities of compounds with which other contributors to this volume have already dealt. Attention is called to the close structural similarity (FIGURE 4) of epinephrine to amphetamine, which is also capable of producing anxiety, and mescaline, which does so regularly and with dramatic intensity, producing a full-blown “model psychosis.” These drugs in turn are related to the group shown in FIGURE 5, in which epinephrine15 once more presented alongside a ﬁrst— oxida— tion product, adrenochrome, which is an indole. Below these are pictured d- lysergic acid diethylamide (LSD- 25), the very highly potent psychotogen which can be considered to be built on an indole nucleus, and 5- hydroxy— tryptamine, or serotonin The epinephrinelike psychotogens thus can be chemically related to the indolelike ones, including established drugs such as LSD— 25, reputed drugs such as adrenochrome, described at the beginning of this monograph by Humphry Osmond, and by myself elsewhere,2 and the b which is 4“ in the postulated by Woolbrain, naturally occurring indole found ley and Shaw5 to be sufﬁciently related to LSD- 25 possibly either to compete with or to add to its action. We now looked to see whether there was any functional parallelism or neurophysiological correlate of this relationship by using the objective test of cerebral performance afforded by the evoked- potential ac— IS FIGUR126 the that data there an showing the c.at presents in technique tual correspondence111 structure, and that all the compounds produce synaptic �Marrazzi: Effects of ("ertain Drugs on Cerebral Synapses - EH-c-("6"3 no no on 0 ——> 0 501 N has EPINEPHRINE H CON ADRENOCHROME /\ Cat's C2H5 N-CH3 -c-c-NH2 HO N N SEROTONIN D-LYSERGIC ACID DIETHYLAMIDE (LSD-25) FIGURE. 5. inhibition identical in kind to that produced by epinephrine, but vary in degree of effectiveness, so that for the approximately equivalent effects shown it re— quired milligram amounts of mescaline, but only microgram quantities of LSD-25, which duplicates the relative potency of these compounds as found in clinical experience. The dosages used throughout our experiments are inten— tionally of a size selected to produce incomplete actions, so that recovery back‘ to the control level can be secured more readily. Very interesting is the ﬁnding with serotonin, which turns out to be the most effective cerebral synaptic inhibitor of all, being effective in as little as l—ug. doses. Accordingly, rather than being an antagonist, this indole, or something like it, may represent the type of endogenous substance that is instrumental in bringing about some forms of spontaneously occurring mental disturbance. b and is brain48h is in the serotonin since so naturally present Furthermore, highly potent (about 20 to 25 times as potent as epinephrine in the same experiment), serotonin becomes, as we pointed out over a year ago,2 an even better candidate than either epinephrine or norepinephrine, which are also found 6 1" for the role of inhibitory neurohumor.* This ﬁnding would in the brainﬁ‘“ must penetrate the blood-brain barrier at least in the small amounts required to exercise the cerebral action described. ’ Serotonin �Annals New York Academy of Sciences 502 IOO MESCALlNE IOO UV. IOO ’D 100‘: UV. / 4" A A A A '°°” A A SEROTONIN CONTROL MAXIMUM EFFECT RECOVERY FIGURE 6. point even more closely to a derangement of neurohumoral balance at synapses as a potential mechanism of cerebral or mental derangement. Unfortunately, except for the intraventricular injections described by Sherwood,7 there have been, thus far, no documented reports of serotonin—induced mental disturbance* in man that are clearly separable from the natural anxiety initiated by the profound peripheral effects such as circulatory disturbance, other autonomic effects, and emesis. There are, however, such reports for a close analogue of serotonin, dimethyl-serotonin, or bufotenin, which is used for its mental eﬁects by some primitive peoples and has been observed by Fabing8 to produce such disturbances in man experimentally. These 2 subof metabolite epinephrine that well presumed adrenochrome, a as as stances, ‘ The fact that patients with carcinoid have large amounts of circulating serotonin without showing marked has develsym toms of mental derangement could represent an adaptation to very high levels of serotoninofthat such patients ope and accumulated gradually. This suggestion would account for the relative immunity to the possible central effects of high doses of serotonin injected intravenously. �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 503 CONTROL MAXIMUM EFFECT SEROTONIN IO pg RECOVERY nomcwcnmn, N H0 /hCH- /kg. CH 3 CHEN'CH’ ./\N H BUFOTENIN 0= 0: 5 pg /kg MON / N H ADRENOCHROME 2000 pg/kg. FIGURE 7. (‘erebral synaptic inhibition by indoles in a _2-neuron intercortical (transcallosal) system. The potentials evoked in‘the cerebral cortex of the cat by electrical stimulation of the contralateral cortex every 2 seconds. The injections were given in the 1psxlateral common carotid artery. Hoffer, Osmond, and Smythies9 report as reproducing some aspects of the clini— cal syndrome of schizophrenia when injected intravenously in man, are com— pared in the cat in FIGURE 7. Again, all these compounds have the identical qualitative effect, namely, synaptic inhibition, but bufotenin, tested in the same animal, exhibits twice as much effectiveness as does serotonin, which required 10 pg. for its effect on this occasion. Adrenochrome, though it does induce synaptic inhibition, requires so large a dose, 2 mg, that it seems an unlikely candidate for the role of endogenous psychotogen responsible for a form of mental illness, although a substance somewhat like it might be responsible. The great effectiveness of serotonin not only suggests that this is the type of chemical structure implicated, with the reservations already noted, but that it constitutes 1 link, another being its natural occurrence in the brain, in the chain of evidence identifying it as a cerebral neurohumor. A required piece of information to round out this evidence would be the measurement of the actual liberation of serotonin during, or prior to, the recorded synaptic activity. This is a tedious and difficult type of experiment, and it is attended by special handicaps in work on the brain. Another approach leading to a similar conclusion, however, is quite readily followed. This approach is the accumulation of what must be naturally occurring serotonin, strategically located at the synapses, by the poisoning of the enzymes that normally lead to the destruction of serotonin and account for the ready reversibility and short duration of the action of serotonin. This is the technique that has been used so successfully in the study of the function of acetylcholine in the brain, and it is in this manner, by the use of a powerful anticholinesterase, that we demonstrated the presence and operation of acetylcholine at cerebral synapses.1 Serotonin is known to be very susceptible to destruction by monoamine oxidase, which is abundantly �504 Annals New York Academy of Sciences CONTROL EFFECT RECOVERY FIQURE 8. The cerebralsynaptic action of iproniazidin a 2-ncuron intercortical ttranscallosal) system. potentials evoked in the optic cortex of the cat by electrical stimulation of the contralatcral cortex every onds. The iproniazid (S mg./lu;.) was injected into the ipsilateral carotid artery. MAXIMUM The 2 sec- present in the brain.10 We therefore attempted to inhibit. this enzyme by iproniazid (Marsilid). FIGURE 8 shows the result of a preliminary experiment in which we injected iproniazid into the common carotid artery of the cat. in the same way that we had done previously with serotonin. The effect produced duplicated the serotonin effect as if, indeed, the serotonin at the synapse had been preserved by the inhibition of monoamine oxidase by the iproniazid. I believe this ﬁnding offers another piece of important evidence that serotonin is present naturally, not only in the brain, but at strategic sites where it is capable of inﬂuencing synaptic transmission. We have not as yet measured, as we need to do, how much this dose of iproniazid, given in this way, inhibits cerebral monoamine oxidase in the cat. We believe that the somewhat discouraging attitude of some investigators toward basing clinical prediction on animal experimentation is not, entirely justiﬁed, since this procedure is a natural result of the comparison of objective criteria such as we have just described with clinical evaluation based upon questionnaires and much undoubtedly shrewd clinical observation, both of these types of data being very difficult, indeed impossible, to quantitate. Ac— cordingly, we are more impressed by the degree of correspondence obtainable rather than by the discrepancies that are to be found. Thus our evoked-potential experiments in the cat rank the psychotogens and psychotomimetic substances studied so far, in general, in the order of clinical effectiveness, and they suggest that at least part of the mechanism responsible for mental disturbance is to be found in an imbalance in the regulation of synaptic transmission. One such imbalance we have already described. If this hypothesis is truly useful, and if the animal preparation used bears other than a merely empirical relation to the clinical data, we should expect that. the various tranquilizers for which varying degrees of clinical success have been claimed would have some action here also. “'e proceeded to test this extension of our thinking, and we found that all of the several types of tranquilizers are capable, when administered prophylactically to cats, of partially preventing, in the doses used, the cerebral synaptic inhibition of a test dose of mescaline. this reaction, using chlorpromazine ('l‘horazine). 'l‘he figures now read from top to bottom instead of from left to right, as in the previous FIGURE 9 shows �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 505 MESCALNE 2.5mg/kg MESCALINE AFTER CHLORPROMAZINE CHLORPROMAZNE 0.05mg./kq. CONTROL MAﬂMUM EFFECT RECOVERY 60’\. 200 UV. The_prevention of the mescaline effect by chlorpromazine in a 2-neuron_intercortical (transcallosal) system. The potentials evoked in the cerebral cortex ofthe cat by electrlcal stimulation of the contralateral cortex every 2 seconds. The injections were made in the 1psrlateral common carotid artery. FIGURE 9. The ﬁrst column shows the control, the mescaline inhibition at B, and the recovery at C. After this, chlorpromazine is given in doses which, per se, have no apparent effect on synaptic transmission, as shown by the new control D in the second column, but now when mescaline is given again, the synaptic inhibition E is much reduced when compared to B. Without the tranquilizers, the same degree of inhibition of mescaline can be repeated several times in succession, provided that complete recovery is allowed between in— jections. Records G and II show again that this dose of chlorpromazine did not impede synaptic transmission despite the ability of the drug to protect against mescaline. If the dose is increased twentyfold it does have a depressant ﬁgures. MESCALINE A 2.5 mg./kq. MESCALINE AFTER RESERPINE D CONTROL B MAXIMUM EFFECT C RECOVERY n E RESERPINE 0.lmg./kg. G m I The prevention of the mescaline effect by reserpine in a 2-neuron intercortical (transcallosal) system. The potentials evoked in.tlie cerebral cortex of the cat by electrical stimulation of the contralateral cortex every 2 seconds. The anCCtlonS were given in the ipsilateral common carotid artery. FIGURE 10. �506 Annals New York .‘Xcademy of Sciences MESCALINE CONTROL MAXIMUM 2.5m/llq. MESCALINE AFTER FRENOUEL FRENOUEL tqu/kq. m The prevention-of the mescaline effect by It‘renquel in a Z-rieuron intercortical (transcallosal) system. The potentials evoked In the cerebral cortex of the cat by the electrical stimulation of the contralateral cortex every 2 seconds. The unections were given in the ipsilateral common carotid artery. FIGURE 11. action on synaptic transmission. The same prophylactic action is obtained with reserpine (Serpasil), as shown in FIGURE 10, and with azacyclonol (\lt‘renquel), as shown in FIGURE 11. Another point of correspondence with clinical findings is that the margin of safety, in this case the range between the prophy— lactic and the synaptic-depressant, dose, is large, the depressant dose being 15 to 20 times the prophylactic. dose with both chlorpromazine and azacyclonol, but the factor is only 2 with reserpine. The latter drug approximates the action of the barbiturates, which can reduce the degree of demonstrable inhibition from mescaline by reducing synaptic transmission in the ﬁrst place. I feel justiﬁed in saying, then, that the preparation described is pertinent to the clinical situation in that it ranks the psychotomimetic substances in the order of their clinical eli'ectiveness, and that the action of mescaline, the only drug that we have tried so far, is prevented by the tranquilizers. By use of the evoked—potential technique, we have demonstrated that: (1) There exists an equilibrium of neurohumoral control of transmission at cerebral synapses and throughout the nervous system, as far as I have surveyed it, that is susceptible to distortion and imbalance by disturbance in the amounts of chemical regulator or the susceptibility of neurons. (2*) The psychotogens and psychotomimetic substances discussed. structurally and functionally resemble the actions of the fairly well-established inhibitory synaptic neurohumors, epinephrine and norepinephrine, and of sero— tonin, the new one that we have described. (.3) Serotonin or its dimethyl derivative, bufotenin, comes close, even closer than does LSD-25, to representing the type of endogenous psychotogen that might be a natural cause of some forms of mental disturbance. We speculate that such disturbance can be produced by direct perversion of normal patterns of neuronal activity by the undue inﬂuence of synaptic inhibitors or, indirectly, by such inhibitors impeding the ﬂow of impulses from higher controlling centers and releasing the more 1,)rimitive, simpler, and less well—adapted patterns of activity that we call abnormal. �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 507 References 1. MARRAzzr, 118: 367. A. S. 1953. Some indications of cerebral humoral mechanisms. Science. E. R. HART. 1955. Relationship of hallucinogens to adrenergic cerebral neurohumors. Science. 121: 365. 3. CURTIS, H. J. & P. HARD. 1939. lntercortical connection of the corpus callosum. 126: 2. MARRAZZI, A. S. & 473. B. B. CRA\\'F()RD & J. H. GADDUM. 1954. The distribution of substance P and 5—hydroxytryptamine in the central nervous system of the dog. J. Physiol. 126: 596. 4}). PAGE, I. H. 1954. Serotonin (5—hydroxytryptamine). Physiol. Revs. 34: 563. 5. WOOLLEY, D. W. & E. SHAW. 1954. A biochemical and pharmacological suggestion about certain mental disorders. Science. 119: 587. 6. VOGT, M. 1954. The concentration of sympathin in different parts of the central nervous system under normal conditions and after the administration of drugs. J. Physiol. 123: 451. 7. SHERWOOD, S. L. 1955. The responses of psychotic patients to intraventricular injections. Proc. Roy. Soc. Med. 48: 855. FABING, H. D. 1955. Personal communication. 99° HOFFER, A., H. OSMOND & J. SMYTHIES. 1954. Schizophrenia: a new approach. II. Result of a year’s research. J. Mental Sci. 100: 29. 10. KOELLE, G. B. & A. DE T. VALK, JR. 1954. Physiological implications of the histochemical localization of monoamine oxidase. J. Physiol. 126: 434. 4a. AMIN, A. H. T., '1‘. �APR 23 ‘959 DEPARTMENT OF EXPERIMENTAL PSYBHMIRY HILLSIDE HOSPITAL GLEN OAKS, N. Y. �PSYCHOTOMIMETICS, CLINICAL AND THEORETICAL CONSIDERATIONS: HARMINE, WIN-2299 AND NALLINE 17%;»4” M :9 HARRY H. PENNES, M. D., PHILADELPHIA, PA., AND PAUL H. HOCH, M. D., NEW Reprinted from AMERICAN JOURNAL OF PSYCHIATRY Vol. 113, No. 10, April, 1957 YORK CITY �PSYCHOTOMIMETICS, CLINICAL AND THEORETICAL 1 WIN-2299 AND CONSIDERATIONS: HARMINE, NALLINE HARRY H. PENNES, M.D.,2 PHILADELPHIA, PA., AND This report describes the clinical effects of 3 psychotomimetics in mental patients. The results will be related to nosological and certain biological aspects of the “model psychoses” in general. The agents are (I) harmine, an alkaloid present in plant prepara— tions ingested by some South American tribes(1) ; (2) Win-2299, a synthetic cholinolytic(2) and (3) N-allylnormorphine (Nalline), a synthetic morphine antagonist (3, 4, 5). MATERIAL AND METHODS Single dosages of the drugs were given to 32 voluntary, physically normal mental patients, at the New York State Psychiatric Institute; 29 were in the 18-35 year age range; 19 were males and I 3 females. Twenty-two were schizophrenics of the pseudoneurotic and other nondeteriorated types, with only the primary symptoms of the disorder. Five additional schizophrenics had auditory hallucinations or delusions be— fore the drugs. The remaining 5 subjects had severe psychoneuroses or recurrent depressions. No patient had clouding of consciousness. Each drug was given about 9: 00 and breakfast after a 48-hour light a am, medication-free period. Examination by the authors and nurses were made for the remainder of the day in a shaded private room and also in the succeeding 72 hours. No patients were informed of the probable effects of the procedures. Most subjects showed excellent cooperation in reporting drug effects. In most cases, each patient received one drug of the 3 tested, but some received different doses of harmine on differRead at the 112th annual meeting of The American Psychiatric Association, Chicago, Ill., April 30May 4, 1956. 2 Director of Clinical Research, Eastern Pennsylvania Psychiatric Institute, Philadelphia, Pa. 3 Commissioner of Mental Hygiene, New York State. The actual study was performed at the New York Psychiatric Institute, New York, Department of Experimental Psychiatry. 1 PAUL H. HOCH, M. D.,3 NEW YORK CITY ent days. Each drug was given in salt form but for brevity will be referred to as the base. RESULTS GENERAL Since the new manifestations under the drugs were not present in the pre-administration period, they were clearly distinguishable from the patients’ baseline symptoms. At low dosage, each drug produced slight drowsiness, either with or without other symptoms. With medium or high dosage, the reactions qualitatively resembled those in a former series of similar subjects who received mescaline or LSD(6, 7, 8). Thus, diffuse alterations usually occurred in many realms—autonomic, motor, perceptual, emotional, intellectual, and be— havioral. Unlike mescaline or LSD (cf. Discussion for dosages), the present drugs regularly elicited some degree of clouding of consciousness in addition to the preceding changes. The characteristic reaction at medium or high dosage was a semidelirioid or confusional state with intermittent drowsiness or sleep. The confusional periods were cyclic. Their intensity and time of occurrence correlated only partly with drowsiness or sleep. Major symptoms were impairment of contact, attention, grasp, responsiveness, and concentration, with general “dreamy” or twilight quality. Full delirioid reactions occurred in 2 subjects at the highest dosages of 2 drugs (Win-2299, Nalline). Most subjects had intermittent amnesia during the reaction itself but were able to provide adequate descriptions of the major events. A spotty defect in recall was usually present in the 72-hour follow-up period. Visual hallucinations (cf. Discussion for alternative terminology) occurred at medium or high dosage with all 3 drugs. Subjects were easily roused after the onset of drowsiness or sleep and reported some of the hallucinations that had occurred in the “dream887 �888 CONSIDERATIONS OF PSYCHOTOMIMETICS ing” state. In all cases, the hallucinations occurred only with eyes closed and disappeared promptly when the eyes were opened. Hallucinations other than visual were infre— quent. Perceptual distortions of body and environment were moderately frequent. Neurological changes included varying degrees of subjective vertigo, light—headedness, subjective and objective ataxia, and sluggish speech. Like mescaline and LSD, these drugs produce a variable degree of intensiﬁcation of different types of baseline symptoms. Harmine also occasionally produced a shallow euphoria. Nalline often produced relaxation of rather marked degree. After a few initial hours of peak intensity, reac— tions usually subsided gradually between the fourth to eighth hours, often with ﬂuctuations in degree before complete remission. No subject reported effects after 24 hours except for minor, nonspeciﬁc “hangover” feelings. INDIVIDUAL DRUGS Harmine.——Turner, Merlis, and Carl have recently pointed out that the alleged hallucinogenic activity of pure harmine is a complicated issue on the basis of the previous literature on crude plant extracts(9). The threshold hallucinogenic dose of the pure drug in the present study ranged from I 50.0— 200.0 mgm. intravenously. With this route, 5 of 11 subjects reported visual hallucinations of varying degrees of complexity and organization. Bradycardia and hypotension occurred with all doses of intravenous harmine despite a 20- to 30-minute injection time, thereby limiting maximum dosage to 300.0 mgm. Average maximum changes were a pulse rate of 18 beats per minute and systolic blood pressure fall of 16 mm. mertermi— in was one subject Injection cury. nated at 210.0 mgm. because pulse rate dropped from 82 to 48 per minute and blood pressure from 118/78 to 88/60. Recovery occurred in about 30 minutes. The drug was not hallucinogenic by the oral or subcuta— neous routes. However, ingestion of crude plant extracts by natives does produce visual hallucinations according to ﬁeld observations(10, 11, 12). In an experimental study by Cardenas(13), normal subjects also reported visual hallucinations and other effects [Apr. noted here, after ingestion of an aqueous solution of yahé (Banisteria caapi, a source of harmine). Visual hallucinations might have occurred in the present study with higher oral (loses, the maximum oral amount (960.0 mgm.) being 4.8-6.4 times greater than the intravenous threshold hallucinogenic amount (150.0-200.o mgm.). The amounts of harmine taken orally under ﬁeld conditions and in Cardenas’ study are unknown, precluding comparison with the present study. Further analysis of the hallucinogenic activity of harmine is complicated by nu— merous botanical and chemical considerations(1, 10, 11, 14). Additional reactions to harmine which occurred frequently were: nausea and vomit— ing; slow, coarse, spontaneous tremor of the extremities of an “extrapyramidal” appear— ance; humming and buzzing noises (no voices); “waviness” of the environment; “sinking” sensations of the body; subjective sense of body vibration; and subject numb— ness, accompanied by objective evidence of reduced sensitivity to light touch and pinprick. These reactions, plus all the preceding, occurred in almost every patient with the intravenous route; and (except for hallucinations) some occurred with oral dosages higher than the threshold of 3000-4000 mgm. The reactions were generally more intense by the former route. Win-2299.—The mental effects of Win2299 in man have apparently not been described previously. The 2 subjects receiving 2.0 mgm. had the sedative effect. One of these subjects in addition became “hypersensitive” to light and sound, and spots on the wall moved and changed form. At the 6.0 mgm. level, all 4 subjects had severe mescaline- or LSD-like reactions plus a confusional state of moderate degree. These mescaline-like effects included bizarre perceptual distortions of soma and environment, unreality feelings, and synesthesias in one case. The single subject at 10.0 mgm. had a full delirioid episode with complete loss of contact, disorientation for time, place, and person, and responses to complex, organized visual and auditory hallucinations. This reaction occurred in brief but cyclic episodes; partial contact and lucidity were restored after persistent comments and questions. �I957] HARRY H. PENNES AND PAUL H. HOCH Most subjects had a moderate degree of mydriasis; blood pressure and pulse rate changes were insigniﬁcant. Nall-ine.—The results with Nalline in the main conﬁrmed previous observations of others in different types of subjects, includ— ing normals( 3, 4, 5). Past and present ﬁndings included varying degrees of relaxation or euphoria, anxiety and dysphoria, miosis, nausea, drowsiness and sleep, thought disturbances, feelings of heaviness or lightness of limbs, and visual hallucinations. In the present series, visual hallucinations occurred in the single subject receiving 10.0 mgm., in 7 of 8 at 20.0 mgm., and in 2 of 3 at 30.0 mgm. In 4 cases (and in 2 with harmine) the hallucinations were Lilliputian in type, a not infrequent feature of acute toxic psychoses in general. So far as can be judged from the literature, a possible major difference from previous observations consisted in the occurrence of frank mescaline-like or delirioid reactions. At 20.0 mgm, 3 subjects had typical diffuse, bizarre per— ceptual disturbances, severe unreality feelings, and other signs of psychic disorganization. At 30.0 mgm., a similar reaction occurred including auditory hallucinations and synesthesias. In another subject at this dose the effect was overtly delirioid, with a strong resemblance to the Win—2299 toxic psychosis previously described. The intravenous route probably accounts in part for the appearance of these reactions, since previous reporters of the mental effects of Nalline have used the subcutaneous route, usually at dosages of 10.0-15.0 mgm. and sometimes higher( 3, 4, 5). DISCUSSION Relatively high doses of harmine by the intravenous route were required to produce the full psychotomimetic effect with visual hallucinations. The same was probably true of Nalline. It is conventionally stated that acute toxic psychoses occur in apparently normal individuals after high dosages of various other drugs, for example, atropine and cocaine(I5). There is a dearth of precise data on the number of such drugs, dosages required, and regularity of effects. However, not all drugs in relatively high dosage produce the diffusely abnormal men- 889 tal changes which are the criteria of psychotomimetic action. For example, clinical differentiation may be made between a confusional-hallucinatory state and a simple, progressive depression of level of consciousness elicited by narcotics and other agents. High dosage alone would therefore not preclude the classiﬁcation of the present or other drugs as psychotomimetic in a selective or speciﬁc sense. Transient cerebral anoxia could have resulted from the hypo— tension and bradycardia with intravenous harmine or a respiratory depressant action of Nalline, which has been reported at dosages used in this study(3, 5). The ﬂorid and diffuse reactions elicited by these 2 drugs would certainly not appear to be characteristic of those in cerebral anoxia. In addition, the circulatory effects of harmine usually disappeared about 20 minutes after termination of injection, whereas the mental re— actions lasted at least several hours at peak intensity. Harmine, Win—2299, and Nalline fundamentally produced an acute organic reaction type, because of the basic mental clouding and confusional effects. Harmine and Nal— line each produced mental clouding together with systemic toxicity (cf. above) ; on the other hand LSD and mescaline elicit neither clouding or toxicity in major form within a certain dosage range. However, Win-2299 did not display this association of the 2 effects, since severe mental clouding occurred without obvious systemic toxicity. It is possible that confusional aspects may be more prominent for a given agent whose threshold psychotomimetic dosage is high relative to threshold dosage for any effect. Quantitative data relevant to this proposition are lacking for any psychotomimetic but are obtainable in principle. It is very probable, however, that absolute dosage thresholds for psychotomimetic activity correlate poorly with mental clouding. In ascending order, these dosages are very approximately: LSD (oral or intravenous) under 100 micrograms; Win—2299 (oral) and Nalline (subcutaneous or intravenous) 55.0-20.0 mgm.; harmine (intravenous) and mescaline (oral or intravenous) over 100.0 mgm. LSD and mescaline are at opposite extremes of an enormous absolute dosage range, and produce �89o CONSIDERATIONS OF PSYCHOTOMIMETICS practcially no clouding whereas the 3 intermediate agents elicit frank clouding at near threshold. There is evidence, however, that LSD and mescaline may produce clouding of consciousness at dosages well above threshold. Pennes has previously reported a sedative effect of LSD in 26.0% of a series of schizophrenics(8). The drug less occasionally (about 10.0% of cases) produced a confusional state(7). MacDonald and Galvin more recently reported a 58.0% incidence of mental clouding and confusion after LSD in 50 subjects. The psychotic subjects in their series apparently received the drug in dosages (per kilogram of body weight) up to 6.0 micrograms as compared with 1.0-2.0 micrograms orally in Pennes’ series(16). Mescaline sulfate (4oo.o—6oo.o mgm., intravenously) often produces slight drowsiness throughout the entire reaction and occasional confusional states(7). There may be an underlying similarity for all the drugs under discussion in the relationship of the visual hallucinogenic response to visual restriction and hypnagogic mechanisms. First, it will be recalled that visual hallucinations with the present drugs always disappeared when the eyes were opened. Wikler noted the same in post-addicts under mescaline(4). The authors have not noted this effect in frank form with either mescaline or LSD but have occasionally observed that hallucinations are reported as less distinct and vivid when the eyes are opened. Darkening of the room does initiate or intensify visual hallucinations with eyes open under mescaline or LSD. If eye closure and reduction of intensity of external light affect drug-induced hallucinations by the same mechanism, then the difference with respect to this mechanism may therefore be negligible between the present drugs and LSD. Such a mechanism may be related to that presumably operative in hallucinations and other mental disturbances recently reported as occurring with generalized restriction of sensory input(17). Secondly, the abnormal visual phenomena with the present drugs are probably best categorized as hypnagogic hallucinations or even more broadly as hypnagogic imagery or visions. This term is used because of the [Apr. invariable drowsiness (cf. Results, General) ; disappearance on eye opening is also consistent with the hypnagogic quality of the response. According to Ardis and McKellar, spontaneous visual hypnagogic images in normals are usually experienced in the drowsy state and with eyes closed. These authors also found strong resemblances in detail between mescaline visual hallucinations and normal visual hypnagogic imagery (18). Previous workers with Nalline have variously used the terms visual hallucinations, day-dreaming, vivid visual fantasies in a dreamy state, or nightmares. The apparent differences between the present drugs and mescaline or LSD may therefore be quantitative rather than qualitative. The conclusion would be that mescaline and LSD may also basically produce an organic reaction type. It is a familiar ob— servation that the visual hallucinations which are so characteristic of the drugs under consideration are relatively infrequent in chronic schizophrenia. These considerations obviously do not preclude various possible relationships between psychotomimetics and a possible endogeneous “toxic factor” or metabolic disturbance in the “functional” psychoses. Hoch and Wikler have recently and independently summarized the other implications of the drugs and the “model” psychoses for experimental psychiatry(19, 20). The indole nucleus, alleged to be speciﬁc for psychotomimetic activity(2I), is absent in mescaline, Win-2299, and Nalline. How— ever, with the exception of mescaline, the remaining 4 psychotomimetics contain a tertiary nitrogen grouping (2 in LSD). Since these compounds are otherwise grossly dissimilar in molecular conﬁguration (ﬁg. I), the entire structure undoubtedly has to be taken into account. Despite this well-known factor and the very small series of drugs, there are certain indications that the tertiary nitrogen grouping may contribute to psychotomimetic activity. In brief, some of the evidence relates to effects of apparently minor changes in the LSD molecule, effects of quaternization of VVin-2299 on its CNS potency(2), and comparison of the actions of serotonin with those of its tertiary amine derivative, bufotenine(22). However, in ad— dition to mescaline, the literature reports �HARRY H. PENNES AND PAUL H. HOCH I957] 891 other psychotomimetics without the tertiary nitrogen groupings: marijhuana, which is n0n-nitr0geneous(9) and 3,4,5-trimethoxy— amphetamine, a mescaline derivative(23). 9 W: "5 Some types of centrally acting drugs other OCH3 \ c2 “5 than psychotomimetics also possess the terFuther of OCH: analysis grouping. tiary nitrogen IE SCALINE on, these relationships will be presented elsewhere(24). There is no apparent common neurophar— macological basis for the psychotomimetic action in general and for harmine, Win—2299, and Nalline in particular(2, 5, 25). Win2299 is qualitatively similar to atropine in animals by virtue of its peripheral cholinolytic and central actions(2). The mechanism of production of abnormal mental effects ‘HCL HO- 0" C- 0' CH2. CH2- / similar be both for N\ drugs, Win—2299 apmay \°2"5 parently having a lower threshold dosage. 2299 (2 2 to recent speculations, some psy— According —-— chotomimetics may produce their effects as antagonists of cerebral serotonin(26, 27'). N-CH20H=CM2 The mental effects of oral LSD and intravenous harmine (both indoles and peripheral antiserotonins) differ in many respects (Results, General and Harmine) . The difference in route of administration is not a factor in 0n View of the ﬁnding of Hoch that oral and 0 "CL ' intravenous LSD have the same qualitative effects(28). However, differences in relative Structures of Some Psychotomimetics. levels contribute the to dosage apparent may FIG. I.—Harmine was supplied in 2 forms: as the base isolated from Banisteria caapi(I) and as the dissimilarities between the 2 drugs. c—N CH35 \ \ HARMINE NH LYSERGIC ACID DIETHVLAMDE C2 H5 6- D5 WIN- DIETHYLAMINOETHYL GLYCOLATE CH N CYCLOPENTYL THI‘ENVL) HYDROCHLORIDE G“ CH2 H ALLYLNOHMCRPHINE synthetically-prepared HCl-zHaO. The following dosages refer to hydrochloride form in each case. Harmine: oral, II patients, zoo-960.0 mgm.; subcutaneous, 6 subjects, 40.0-70.0 mgm.; and intravenous, II patients, 100.0-3oo.0 mgm. Win-2299 tablets: 7 patients, 2.0-I0.0 mgm. Nalline: intravenous, 12 subjects, 10.0-30.0 mgm. Intravenous harmine and Nalline were injected over a 20-30 minute period. Mescaline and lysergic acid diethylamide (LSD) were not given in this study. LSD and harmine contain the indole nucleus whereas the remainder do not. The tertiary nitrogen grouping is present in LSD (both in aliphatic chain and cyclic constituent), harmine (non-indole member), Win-2299 (aliphatic side chain), and Nalline (linking allyl side chain with ring member). Cf. Discussion. Both forms of harmine were supplied as the dry compound by Dr. K. K. Chen, Eli Lilly Laboratories, Indianapolis, Indiana. For parenteral administration, solutions in pyrogen-free distilled water, 20 cms.,3 were used several hours after autoclaving. Win-2299 was supplied by Sterling-Winthrop Research Institute, Rensselaer, N. Y., as the racemic mixture of the hydrochloride salt. Nalline was supplied by Merck and Co., Rahway, New Jersey, N- SUMMARY Harmine, Win-2299, and Nalline in single dosage produce many new mental effects in schizophrenics grossly similar to those elicited by mescaline and LSD. Many of the same effects are reported in normals after harmine and Nalline (other workers). Unlike mescaline and LSD at usual dosage levels, the present psychotomimetics regularly produce drowsiness and sleep along with the aberrant mental effects. The resultant state is partly that of “hypnagogic” visual hallucinations or imagery. The results with increased dosage suggest that the basic Allylnormorphine HC1= Nalline HCI; ampoules of distilled, pyrogen-free water containing sodium bisulfate, 0.2% and sodium citrate, dihydrate 1.5%. For intravenous administration, ampoule contents were diluted up to 20.0 cms.3 with pyrogen-free distilled water. �892 CONSIDERATIONS OF PSYCHOTOMIMETICS effect of these agents is to produce an acute toxic reaction type. The difference between them and mescaline or LSD with respect to clouding of consciousness and certain aspects of the hallucinogenic response may be quantitative rather than qualitative. The indole nucleus is not necessary in the structure of psychotomimetics since Win-2299 and Nalline are non-indoles. The tertiary nitrogen grouping may contribute to certain aspects of psychotomimetic action. BIBLIOGRAPHY 1. Chen, A. L., and Chen, K. K. Quart. J. Pharm. Pharmacol., 12:30, 1939. 2. Luduena, F. P., and Lands, A. M. J. Pharm. Exper. Therap., 110:282, 1954. 3. Wikler, A., Fraser, H. F., and Isbell, H. J. Pharm. Exper. Therap., 109: 8, 1953. 4. Wikler, A. J. Nerv. Ment. Dis., 120: 157-175, I954. Lasagna, L., and Beecher, H. K. The Analgesic Effectiveness of Nalorphine and NalorphineMorphine Combinations in Man. J. Pharm. Exper. Therap., 112: 3 56-363, 1954. 6. Hoch, P. H., Cattell, J. P., and Pennes, H. H. Am. J. Psychiat., 108: 579, 1952. 7. Hoch, P. H., Pennes, H., and Cattell, J. P. Proc. Assn. Res. Nerv. Ment. Dis., 32: 287, 1952. 8. Pennes, H. H. J. Nerv. Ment. Dis., 119:95, 5. 1954- 9. Turner, W. J., Merlis, S., and Carl A. Am. J. Psychiat., 112:466, 1955. Perrot, Em, Raymond-Hammett. Bull. Sci. Pharmacol., 34: 337; 417; 500, 1927. 10. 11. 1941. 12. 195513. [Apr. Iberico, C. C. Bol. mus. Hist. Nat., 5:313, Schultes, R. E. Natural History, 64: 120, Cardenas, G. F. Estudio Sobre el Principio Activo del Yagé. Thesis, Universidad Nacional, Facultuaa de Medicina y Ciencias Naturales, Bogota, 1923. 14. Albarracin, L. Contribucion al estudio de los Alcaloides de Yagé. Thesis, Bogota, 1925. 15. Goodman, L., and Gilman, A. Pharmacological Basis of Therapeutics. 2d Ed. New York: MacMillan, 1955. 16. MacDonald, J. M., and Galvin, J. A. V. Am. J. Psychiat., 112:970, 1956. 17. Bexton, W. H., Heron, W., and Scott, T. H. Canad. J. Psychol., 8:70, 1954. 18. Ardis, J. A., and McKellar, P. J. Ment. Sci., 102:22, 1956. 19. Hoch, P. H. Am. J. Psychiat., 111:787, I95520. Wikler, A. Am. J. Psychiat., 112 : 961, 1956. 21. Hoffer, A., Osmond, H., and Smythies, J. J. Ment. Sci., 100: 29, 1954. 22. Fabing, H. D., and Hawkins, J. R. Science, 123: 886, 1956. 23. Peretz, D. I., Smythies, J. R., and Gibson, W. J. Ment. Sci., 101 : 317, 1955. 24. Pennes, H. H. In preparation. 25. Gunn, J. A. Arch. Internat. de Pharmacodynam.. 50 : 379, 1935. 26. Gaddum, J. H. Drugs Antagonistic to 5- Hydroxytryptamine. Ciba Foundation Symposium: Hypertension. pp. 75-77, London, 1953. 27. Wooley, D. W., and Shaw, E. Proc. Natl. Acad. Sci., U. 5., 40: 228, 1954. 28. Hoch, P. H. Studies in Routes of Adminis— tration and Counteracting Drugs. Lysergic Acid Diethylamide and Mescaline in Experimental Psy— chiatry. New York: Grune & Stratton, 1956. ��Psychiatria et Neurologia Internationale Monatssehrltt tiir Psychiatrie und Neurologie Revue Internationale Mensuelle de Psychiatrie et de Neurologie International Monthly Review at Psychiatry and Neurology Editor: J. KLAESI, SchloB Knonau Redactor: E. GRUNTHAL, Bern S. KARGER Basel (Schweiz) New York Printed in Switzerland Vol. 135. No. 4/5, 1958 Separatum Sal-Hulda, 11.; Brunecker, G. 11nd Szdra, SL: Psychiat. Neurol., Basel 135: 285—301 (1958) Aus dem Staatl. Zentralen Neurologisch-Psychiatrischen Institut in Budapest (Frau Dr. M. Gimes) Dimethyltryptamin: ein neues Psychotieum Von A. SAI-HALASZ, G. BRUNECKER und ST. SZARA Einleitung Die ohere Stufe des Entwicklungsprozesses der Fachwissenschaften, die sogenannte experimentelle Stufe, beginnt die Psychiatrie fast als letzte der medizinjschen Féicher nur neuerdings zu erreichen. Den wirklichen Anfang bedeutet Beringers Monographie ﬁber Meskalin [1927], mit welcher zu gleicher Zeit die HaschischBeobachtungen von Frdnkel und Joel erschienen. Den zweiten groBen Fortschritt auf diesem Gebiet bildete die Entdeckung der Lysergséiurediéithylamid (LSD 25) durch Stall und Hoﬁmann [1943]. Der erste ausfiihrh'che Bericht Stalls [1947] bedeutete den Anfang einer groBen Anzahl von Publikationen. Das Ziel dieses Artikels ist die Bekanntgabe eines neuen Psychotikums bzw. dessen Wirkung auf normale Personen. Die Bewohner Haitis benutzten schon seit J ahrhunderten bei religiﬁsen Festen ein narkotisch wirkendes Schnupfpulver, das «Cohoba» genannt wurde. Mit Hilfe dieses Mittels konnten sie angeblich mit ihren «helfenden Geistern» in Verbindung treten, sogar auch von diesen Ratschlﬁgen erhalten. Das «Cohoba» wurde aus der Frucht der Piptadenia Peregrina gewonnen und enthjelt unter anderen Alkaloiden auch verhéiltnisméiﬁig groBe Mengen Bufotenin und N-N-Dimethyltryptamin (DMT), wie dies auch von Stromberg und Fish et al. bewiesen wurde. Bufotenin und DMT sind beide Indolamine und in naher Verwandtschaft mit dem biologisch hﬁchst aktiven Serotonin: �Sai-Halész, Brunecker und Széra 286 {\/\NH) /\——-—-—CH2—CH2—NH2 0H II |' OH A— 1 n —CH2—CH2—N/CH3 :1 \/\NH/ \cm. Bufotenin Serotonin /CH3 /\————CH2—CH2—N \CH3 b“ J \ \NH N-N-Dimethyltryptamin Bufotenin ist daher ein N-Dimethyl-Derivat des Serotonins, beim DMT fehlt jedoch vorigem gegenﬁber eine 5-OH-Wurzel. Das Bufotenin isolierte Handovski aus der Haut von Kroten [1920], Wieland hat es synthetisch hergestellt. Raymond Hamet gab Hunden intravenos Bufotenin und stellte voriibergehende BlutdrucksteigeAﬂ'en intravenos fest. gréBere Evarts, Tachypnoe Apnoe, spiter rung, Dosen Bufotenin und LSD-25 verabreichend, stellte bei jenen eine beinahe identische Wirkung der zwei Chemikalien fest: voriibergehende Erblindung, Ataxie und ein Zahmwerden. Er erklﬁrte dies alles durch eine Hemmung der sensiblen Reiziibertragung. Evarts nahm die Wirkung des Bufotenins und LSD-25 als Analog des Serotonins an. Nach Fabing ist Bufotenin ein in der Natur weitverbreitet vorkommendes halluzinogenes Indolderivat, dessen eine Hauptquelle die sogenannten Amanita-Pilzarten bilden. Fabing experimentierte an jungen, intelligenten Verurteilten: er injizierte intravent‘is wéihrend 3 Minuten Bufotenin. Es traten Erroten, Gesichtsperspiration und Kribbelgefiihl im ganzen Korper sowie Oppression in der Brust auf. Die Versuchspersonen sahen einige Minuten lang purpurne Flecke, die Storung der Raumwahrnehmung und Konzentration, daneben Depersonalisationsgefiihl und psychomotorische Unruhe dauerten fort. Bei groﬁeren Dosen war Erbrechen, Nystagmus und Mydriasis zu beobachten, deshalb hielt Fabing das Mittelhirn zum Teil als Angriﬂ'spunkt des Bufotenins. Die kardiovaskulﬁre Wirkung des Mittels war verhiiltnisméiBig gering. Die Versuchspersonen berichteten wéihrend 6 Stunden nach der Injektion iiber angenehmes Relaxationsgefiihl. �Dimethyltryptamin: ein neues Psychoticum 287 Material und Methode Unseres Wissens nach wurde die Wirkung des DMT am Menschen zuerst durch uns gepriift. Das DMT wurde von uns selbst synthetisiert nach der von Speeter und Anthony angegebenen Methode. Die salzsﬁurige Losung wurde als Injektion angewandt: die wirksame Dose war 0,7—1,0 mg/kg intramuskuléir, meistens gebrauchten Wir 0,8 mg/kg. DMT wurde an 30 normalen Personen, meistens Arzten, gepriift (I7 Manner, 13 Frauen; Alter zwischen 20 und 42 J ahren). Jede Versuchsperson wurde vorerst somatisch untersucht, und nur jene erhielten DMT, die vollkommen gesund waren und keine starkere vegetative Labilitéit zeigten. Auf den Blutdruck wurde sehr geachtet, da das DMT leicht starke Hypertonie erzeugen kann. I6 Versuchspersonen wurden vor und wéihrend des Versuches mit Rorschach untersucht. (Auf dessen Ergebnisse gehen wir hier nicht ein, da einer von uns1 auf dem III. Internationalen RorschachkongreB in Rom 1956 iiber diese berichtete.) Wﬁhrend dem Versuch wurden parallel zwei Protokolle aufgenommen und die Versuchs2—3 Tagen die subjektiven Erlebnisse nach aufgefordert, personen aufzuzeichnen; die Protokolle wurden dann durch diese Aufzeich5 Fallen wurde wiihrend des Experimentes EEG In ergéinzt. nungen durchgefiihrt. (Bisher noch nicht veroﬂ'entlicht.) Ergebnisse Schon nach 3—5 Minuten nach der Injizierung fﬁngt das DMT zu wirken an, und innerhalb einer Stunde léiuft die ganze experimentelle Psychose ab. Die Wirkung ist plotzlich und intensiv, mehrere Versuchspersonen berichten anfangs V011 einem weltuntergangsé‘thnlichen Erlebnis mit Starker Todesangst. In einigen Fillen war jedoch die Angst nicht so ausgepréigt, und die éiuBerst intensiven Illusionen und Halluzinationen fesselten die Aufmerksamkeit. Die Angstperioden wechselten mit solchen Starker Euphoric ab. Wéihrend des ganzen Versuches war das wellenartige Auftreten bzw. die Intensitﬁtsschwankung der gesamten pathologischen Phéinomene sehr charakteristisch. Wahrnehmungsstﬁrungen bzw. solche des Korperschemas, Depersonalisationserscheinungen, extrapyramidale Hyperkynesien, objektive Reﬂex- und Sensibilitﬁtsstﬁrungen fﬁrbten oft das Bild. Natiirlich waren bei den Versuchen auch die kultu1 A. S.-H. �288 Sai-Halész, Brunecker und Széra rellen und Pers6nlichkeitsunterschiede bemerkbar. Bevor wir die einzelnen Symptome naher betrachten, geben wir hier einige typische Protokolle wﬁrtlich wieder: Dr. J.N., Arzt, 28 Jahre. 10. 5. 1956. 50 mg DMT i.m. P.: 78/Min., RR 130/100 Hgmm. 3! Starker Schwindel und Kribbeln im ganzen Kiirper; hauptsiichlich sind die Lippen gefﬁhllos-eingeschlafen. 4/ «Alles ist glﬁnzender, die ganze Welt ist bedeutend heller.» 5/ «Als ob meine Stimme aus einer tieferen Kehle kﬁme. Das Zimmer ist gespensterhaft. Mir schwindelt. Ich amﬁsiere mich darﬁber, wie Ihr mich belauert.» «Ach, wie herrlich sind die Far-hen!» Er lacht und spricht andauernd. (Zwangslachen, Logorrhoea.) Maximal erweiterte Pupillen. RR: 160/120 Hgmm, P: 88/Min. Rhythmische Bewegung des linken FuBes. «Ach, neue Welle! Die Bilder kommen in solchen Mengen, daB ich gar nicht weiB, was ich mit ihnen anfangen soll! Zuvor waren sie noch angenehm, doch jetzt ist es schon zu viel!» Er lacht wiederum auf. «Alles ist so komisch. Die Farben leuchten ganz fantastisch. Die Gesichter sind auch ganz anders. Warum beobachtet Ihr mich so verdachtig ? » 10' «Ich sehe eine Farbenorgie, doch in mehreren Schichten nacheinander. Die Welt bewegt sich immer mehr.» 11' Er schmunzelt, spricht inkohéirent, bewegt sich viel und gestikuliert lebhaft. RR: 165/120 Hgmm. P: 88/Min. Er klagt ﬁber Dyspnoe. 12' «Ich fiihle in meinem Bauch Leere und trotzdem Fﬁlle, dorthin hat sich alles Schlechte verzogen.» «Hoﬂ'entlich kommt es nicht wieder.» «Man sieht seltsame Sachen, und trotzdem ist alles schnell vorﬁber, so wie auf der Wellenbahn.» «Die Wand bewegt sich auch, marchenﬁlmhaft. Ich fﬁhle mich ganz so, als ob ich geﬂogen ware.» RR: 155/120 Hgmm. P: 88/Min. Assoziationen aufgelockert, sucht nach Ausdriicken. Keine Dyspnoe. «Das Zimmer beginnt seine normale Form wieder zurﬁckzugewinnen! Nein, doch nicht . . . » Er setzt sich auf und sieht zum Fenster hinaus. «Nur wenn ich hinausschaue, fﬁhle ich, daB ich auf der Erde bin. Mir ist, als oh wir bis jetzt geﬂogen wﬁren! » «Ich habe das Gefﬁhl, daB dies ﬁber allem ist, ﬁber der Erde. Es ist beruhigend, zu wissen, daB ich wieder auf der Erde bin.» Pupillen noch maximal erweitert. RR: 145/110 Hgmm, P: 84/Min. Bewegt sich andauernd, gestikuliert viel. Sprache ist ﬁfters inkoh'arent, kaum verfolgbar. «Ich habe inneres Zittern, meine Gefﬁhle kann ich nicht gut ausdrﬁcken. Ich fﬁhle mich so, als ob ich hetrunken ware.» Er zittert. «Dieses Zittern ist gar nicht so unangenehm, es bedeutet, daB die Reise zu Ende ist, aber alles ist noch nicht vorﬁber.» Rhythmische Zuckungen des linken FuBes. «Jeder Anwesende hat gleichmiiBig gelbe Zﬁhne.» �Dimethyltryptamin: ein neues Psychoticum 289 28' «Alles hat einen ﬁberirdischen Stich und ist doch so real. Schade, daB alles in einem geschlossenen Zimmer geschieht. Mir scheint, daB ich zusammen mit dem Zimmer ﬂiege. Erlebnis der Reise. . .» Pupillen miiBig erweitert. RR: 140/100 Hgmm, P: 80/Min. «J etzt habe ich schon das Gefiihl, daB alles vorbei ist.» Ziindet sich eine Zigarette an. Die ZigaIette sieht er grﬁBer und umfangreicher. «Ich habe das Gefiihl, als oh ich lande. Die gehobene Stimmung léiBt nach.» Assoziationen noch immer gelockert. Hort in der Mitte angefangener Séitze auf, vergiBt was er sagen wollte, spricht iiber anderes. «Alles scheint gelb zu sein, hauptsﬁchlich die Schatten. Ich weiB, daB dieser Zustand aufhéirt, und doch. fiirchte ich mich, daB er weiterbesteht.» «Ich bin so nervos, als ob ich ﬁebrig wire. Es ist beruhigend, daB ich dauernd bei BewuBtsein war.» Klagt ﬁber Miidigkeit. «Alles ist voriiber, nur meine Gedanken schwirren durcheinander.» «Alles ist grau und farblos. Die Welt ist jetzt ganz ode.» AuBer leichter Miidigkeit beschwerdenfrei. Assoziation schon normal. «Ich hatte stets das Gefiihl, daB sich nur die AuBenwelt und nicht ich selhst mich verwandelte.» Dr. Z.J., Arzt, 30 Jahre. 1. 6. 1956. 60 mg DMT i.m. P: 72/Min., RR: 110/70 Hgmm (linkshﬁndig). 5' Er fiihlt sich ein wenig schwach. «Kollapsartiges Gefiihl.» 6' Ausgesprochenes Schwindelgefiihl. 7' RR: 130/90 Hgmm, P: 84/Min. Pupillen etwas erweitert. 8' Schwache Dyspnoe. «Das ganze ist eher angenehm.» 9' «Die Farben sind unveréindert. Mir schwindelt sehr. Leider geht es mir auch so mit dem Alkohol: mir schwindelt, ohne daB ich mich wohl fiihle.» 10' «Ich habe einen beklemmenden Druck auf der Brust, aber es kommt mir vor, daB ich auch ohne Luft existieren konne.» 11’ «Das silherne Muster der rechten Wand des Zimmers ist ganz reliefartig. Das Beklemmungsgefiihl nimmt ab.» 12' RR: 135/80, P: 88/Min. Rechter Patellarreﬂex verstﬁrkt, rechtsseitig Babinski13' 14’ 15’ 16' 17' 18' 19' Tendenz. «Die Gesichter haben sich veréindert, sind ganz mephistoéihnlich geworden.» «Uberall dominiert die silberne Farbe! Die Gesichter sind auch aus Silber und teuflisch. Die silberne Farbe ist schon, nur ein wenig furchterregend.» «Der eine Gummischlauch des Blutdruck-MeBapparates ist violett, der andere silbern.» (In Wirklichkeit schwarz.) «Die Gesichter sind asymmetrisch wie im Kino. Alles verandert sich im Raum, auch die Gesichter und Gegenstéinde.» RR 130/85 Hgmm, P: 88/Min. Reﬂexdiﬁerem der unteren Extremitiiten ist auch weiterhin vorhanden. «1111' schwebt alle im Raum. Bis J'etzt habe ich noch nicht die Rﬁumlichkeit der Dinge bemerkt. Die Anschauung des Menschen veréindert sich vollkommen.» «V01: ungefiihr einer halben Stunde konnte ich die Injektion bekommen haben. Mir kommt es vor, als ob diese Minuten viel reicher wﬁren, deshalb erscheinen sie mir linger.» �Sai-Halész,Brunecker und Széra 290 20' «Mein Uhelsein verstﬁrkt sich wieder, ich fiihle mich sehr schwach. Mir ist, als ob ich keinen Atemreﬂex hﬁtte; wenn ich nicht daran denke, wiirde ich zu atmen vergessen. » 21’ «Alles ist statuenhaft. Die Gesichter sind teuflisch.» 22' RR: 130/80 Hgmm, P: 84/Min. Pupillen mﬁBig erweitert. 23' «Mir fallen solche Details auf, die ich bis jetzt noch nicht bemerkt babe.» 24' «Ich fiihle mich vollkommen gewichtslos, gar nicht, als ob ich 75 kg wiege.» 25' «Es ist merkwiirdig, daB mir meine Hinde vollkommen fremd sind, als ob sie gar nicht mir gehorten.» 26' «Ich kann die Réiumlichkeit der Dinge besser beobachten; ich glaube, die Kiinstler sehen sie immer so. Wenn es so bliebe, wﬁrde ich Maler werden.» 27' RR: 130/85 Hgmm, P: 80/Min. Rechtsseitge Babinski-Tendenz besteht weiter. 28' «Die Gegenstéinde haben gar kein Gewicht. Ich glaube, ich konnte viel grijBere Gewichte heben als zuvor.» 29' «Die Gesichter sind noch immer statuenhaft.» 30' Er verlangt schwere Gegenstéinde und versucht, sie aufzuheben. «Die haben alle kein Gewicht.» 331' Er hort Musik mit geschlossenen Augen und lichelt. 32' RR 125/85 Hgmm, P: 80/Min. Keine Reﬂexdiﬂ‘erenz. Pupillen mﬁBig erweitert. 33’ «Die Musik ist schon und fesselnd. Als ich diese (Abendsternarie aus Tannhéiuser) letztes Mal horte, schwebte die Musik ﬁber mir, ich war jedoch auf der Erde. J etzt schwebe ich zusammen mit der Musik.» 34’ «Die Nebengerﬁusche storen mich sehr, schade, daB es Grammophonmusik ist.» 35' «Alles wird schon natiirlicher. Das ganze ist sehr angenehm.» 37' RR: 125/75 Hgmm, P: 76/Min. Pupillen méiBig erweitert. 40' «Ich fiihle mich schon halbwegs in Ordnung. Meine Hand gehort wieder mir.» 45' RR: 120/70 Hgmm, P: 80/Min. 50' «Ich bin ein wenig miide, sonst ist alles voriiber. Das Gewicht der Gegenstéinde kam auch zurﬁck. Es war merkwiirdig, daB sich am Anfang Angenehmes und Unangenehmes vermischte, in der zweiten Halfte jedoch war alles schon und I gut.» Von den retrospektiven Erinnerungen ist folgende ihres lyrischen und subjektiven Charakters halber von Interesse: Dr. E.Ch., Arztin, 27 Jahre. 50 mg DMT i.m., 27. 8. 1956. Teils fiirchte ich mich, teils bin ich sehr gespannt, was eigentlich auf mich wartet. Mein SelbstbewuBtsein mochte ich gem durchwegs behalten. Was werde ich wohl erfahren? Mit 16 Jahren hitte ich gerne Gott gesichtet — wird das jetzt kommen? Oder wird sich eine andere Zeit meiner Vergangenheit verlebendigen? «Guten Tag, Ihr Versuchskaninchen ist angekommen», begrﬁBte ich die zwei jungen Minner. «Ich messe IhIen Blutdruck, dann gehen wir ins andere Zimmer hiniiber. Der Blutdruck 120/90. Sie fﬁrchtet sich gar nicht», sagt der eine. Ich fiihle einen Stich, jetzt gibt es schon kein Zurﬁck mehr. «Sehen Sie sich gut im Zimmer um», hore ich, «sehen Sie auch aus dem Fenster.» Fliichtig schaue ich auf den Schreibtisch, die Stiihle und die monotone Wand. Alles ist kahl. Ich schaue durch das eisenvergitterte Fenster und sehe die groBen alten Baume. Ich sehe den déimmerigen Himmel, und auf einmal ﬁng es an... �Dimethyltryptamin: ein neues Psychoticum 291 Mir schwindelt entsetzlich, es trommelt in meinen Obren, mit meiner rechten Hand greife ich zum Hals, da ich dort einen ziehenden Schmerz fiihle. Mir schwindelt. — In diesem Augenblick bedauere ich, mich in dieses Experiment eingelassen zu haben. Ich sehe auf meine Uhr, es sind noch kaum einige Minuten vergangen. GroBer Gott, wann wird dieser Versuch ein Ende nehmen? Der Kopf des einen Kollegen zieht sich in die Lange, er bekommt Schlitzaugen. Das Gesicht des anderen wird ﬂacher und vierkantiger. Dieses eigenartige Licht, als ob der Schein einer Quarzlampe dammere. Meine Hand ist ganz zyanotisch. Ist sie wirklich so ? Ich ho're Sausen. Ich bin irgendwohin unterwegs, aber wohin? «Blutdruck 160», hﬁre ich, «Puls 100.» Das ist jetzt der Tod. Wie einfach alles ist. Das Sausen hat aufgehort, ich bin angekommen. Vor mir zwei stille, sonnenbeschienene Gﬁtzen. Freundlich nickend beobachten sie mich. Ich glaube, sie begriiBen mich in dieser neuen Welt. Es herrscht dumpfe Stille, wie in der Wﬁste. Ich wage nicht, sie anzusprechen. Das ist doch Agypten, diese die Siihne der Sonne, und ich bin endlich zu Hause. Zu Hause in jener wirklichen und schonen Welt, wo binter den zwei Gotzen sich heitere Menschen zwischen den hohen, gelben Sﬁulen und Statuen bewegen. Wie vornehm und einfach sie sind. Ihre sonnengebraunten Gesichter sind verklart, ihre Bewegungen frei und grazios. Weiter drinnen singen die Priester mit brausenden Stimmen. Der eine Gotze — nur seine Augen leben spricht mich an: «Geht es Ihnen besser?» «Es wird mir sehr gefallen, wenn das Ubelsein, welches der hohe Blutdruck verursacht, aufhiirt», antworte ich. Ich sehe mir meine Hand an, ein von mir ganz unabhéingiges, selbstandiges Wesen und dazu sehr schon. Die Form ist so wie zuvor, doch als ob sie mit einem goldbraunen Staub gepudert ware. Und die N age] sind rosa Muscheln. «SchlieBen Sie die Augen. Was sehen Sie ?» Ich gehorche. Aus der Dunkelheit sehe ich durch schwarze Eisengitter in den hellen Tempe]. Griiner Ranch qualmt darin und der Gong tont. China! Ich kann meine Augen nicht geschlossen halten, da mir schwindelt. J etzt zeigt man mir die RorschachTafeln. Ich kann mich so schwer darauf konzentrieren, es ist so langweilig. Jetzt erheben sich die hellen, metallschimmernden Wande, dann sinken sie wieder nieder. Es ist, als 0b das Zimmer atme. Auf der ganzen Flache kreisen vielfarbige — gelbe, hellgriine, rosa und blaue — Fischschuppen. Die glanzende Kugel der Lampe beugt sich kreisend naher. Ich sehe wiederum das Gitter, doch ist jetzt dahinter kein Ranch, sondern nur glatte runde grﬁne Steine. Auf meinem linken FuB kriecht etwas, doch sehe ich dort gar nichts. Alles bewegt sich und wogt. Im F ensterglas kreisen farbige Kranze und Fackeln mit ungeheurer Schnelligkeit. Ich mochte gerne erklaren, was ich sehe, doch .. . An den Wanden sehe ich das zischende, weiBgekronte, wogende Meer. Einige Wellen erreichen mit gedﬁmpftem Brausen den Strand. — «Debussy» — sage ich. Ich bin ein ganz kleiner Punkt, wie eine Bliite auf dem Wasser von den Wellen geschaukelt. Doch ich weiB, daB mir kein Leid geschehen kann. «Pupillen sind verengt, Blutdruck sinkt», bore ich. J etzt ist es schon still, die Schuppen kreisen immer langsamer, endlich bleiben sie stehen und verschwinden. Nur die seltsame Beleuchtung wéihrt fort. Das WeiB �292 Sai-Halasz, Brunecker und Szara ist noch auffallend weiB, alle Linien scharfe schwarze Konturen. Die Dimensionen sind sonderbar. Die ganze Welt ist furchterregend realistisch. Das ist die wahre Farbe und Form der Dinge. Geféihrliches Spiel, es ware so leicht, nicht zurﬁckzukehren. Ich bin mir dunkel bewuBt, daB ich Arzt bin, das ist aber gar nicht wichtig; Familienbeziehungen, Studien, Plane und Erinnerungen sind von mir sehr weit entfernt. Nur diese wirkliche Welt ist wichtig, ich bin frei und ganz allein. Zuriick, zuriick, drange ich mich. Ich muB den Weg zur realen Welt zuriickﬁnden. Auf dem Weg nach Hause treﬂ'e ich einen Bekannten im Bus. Ich beginne mjt ihm zu plaudern, damit ich die Realitéit der Beziehungen zu spiiren bekomme. Die am Wege stehenden Baume erscheinen grau und verblichen. Das Leben ist stumpf, unfreundlich und gleichgﬁltig. Ich bin ein anderer Mensch geworden, erfahrener und freier. J etzt verstehe ich schon viel mehr. Wenn wir die einzelnen Symptome der DMT-Psychose betreﬂ's Hauﬁgkeit untersuchen, finden Wir folgendes: 1. Vegetative Symptome wurden in allen 30 Fallen beobachtet. Das bestandigste Symptom war die Steigerung des Blutdruckes, die im allgemeinen 20—40 Quecksilber-mm erreichte, manohmal sogar noch mehr. Die hochste von uns beobacbtete Blutdruckerhohung betrug 70 mm, in einem Falle, wo der systolische Druck vor dem Versuch 140 mm zeigte und sich wéihrend des Experimentes bis auf 210 mm steigerte. Der diastolische Druck erhohte sich regelméiBig, doch in kleinerem MaBe als der systolische (meistens 10—20 mm, in einem Falle sogar 40 mm). Fast regelmaBig war die Pupillenerweiterung. Die Mydriase schien parallel mit den farbigen Halluzinationen zu erscheinen. Ob jedoch zwischen diesen ein kausaler Zusammenhang bestand, ist kaum wahrscheinlich. Eine Pulsbeschleunigung geringeren MaBes war auch in fast allen Fallen festzustellen. Objektive Atmungsstorungen fanden wir nicht, doch wurden von 23 Versuchspersonen (76 0/0) ﬁber Atemnot berichtet; diese wurde von einem Oppressionsgefiihl des Herzens begleitet. Dieses klinische Bild erinnert stark an das durch Serotonin hervorgerufene; es konnte vermutet werden, daB die molekuliire Ahnlichkeit der zwei Substanzen diese Erscheinung erkléirt: DMT verursacht auch wie Serotonin einen Krampf der pulmonalen Arteriolen. Die sympathicomjmetische Wirkung des DMT unterstiitzt diese Vermutung. Zur volligen Klarung dieses Mechanismus miiBten natiirlioh weitere Tierexperimente durchgefiihrt werden. Die sympathicomimetische Wirkung des DMT konnte nicht an allen Organen nachgewiesen werden. So fanden wir z.B. keine be- �Dimethyltryptamin: ein neues Psychoticum 293 deutende Hyperglykéimie und Tachypnoe. Die ganze vegetative Wirkung des DMT iihnelt mehr derjenigen des Serotonins als der des Adrenalins. 2. Sinnestiiuschungen wurden in 27 F ﬁllen (90%) beobaohtet. Diese waren in der Mehrheit optischen Charakters: helleuchtende, farbige Illusionen und Halluzinationen, die sich stets im schnellen Wechsel befanden. Bei geschlossenen Augen vermehrten sich die Halluzinationen und nahmen szenenhaften Charakter an. Eine unserer Versuchspersonen erzéihlte mit geschlossenen Augen: «Ich sehe F elsen, Téiler, méirchenhafte Gegenden, mit kaum einem Schein von Rot als belebende Farbe. Watteau-artige Bilder, dort sind jedoch die Gestalten griiBer. Diejenigen, die ich sehe, sind ganz winzig und verlieren sich in den Felsenrissen, kleine Anhiinger der furchterregenden Umgebung.» Oder spéiter: «Orthodox-griechische Einsiedler, die in F elsen gehauenen dunklen Hﬁhlen leben. An den Wéinden leuchten Ikone. Man spiirt, daB ihr ganzes Leben auf diese Heiligenbilder zentriert ist.» AuBer den optischen fanden wir auch — wenn auch seltener — akustische und haptische Halluzinationen ﬂiichtigen Charakters, die ebenso plﬁtzlich verschwanden, wie sie erschienen. 3. Stb'rungen der Raumwahrnehmung wurden in 22 Féillen (73 %) beobachtet. Die Dimensionen des Zimmers ﬁnderten sich am auffallendsten. Nahes und F ernes verschmolz ineinander. Die Form des Zimmers wurde ganz neu: oval oder vielkantig. Es konnte festgestellt werden, daB sich eben jene Dimensionen ﬁnderten, auf welche die Aufmerksamkeit gerichtet wurde. Wie auch in Meskalinund LSD-25-Psychose veréinderte stets jene Mauer die Lage, die eben angeschaut wurde. In einigen Fallen, in denen die Versuchspsychose Starker ausgeprﬁgt war, gingen die Raumdimensionen vallig verloren. Es stellte sich dann immer ein subjektives Erleichterungsgefiihl ein, sobald die richtige Riumlichkeit der Dinge wieder wahrnehmbar wurde. 4. Stb‘rungen des Kb'rperschemas erschienen fast immer gleichzeitig mit denen des Raumes. Es handelte sich um Symptome, die an den parietalen Symptomenkomplex erinnerten: die Versuchsperson bemerkte z.B., daB ihre Hand schon nicht ihr gehiire; oder wenn auch die GewiBheit bestand, daB es doch ihre eigene Hand sei, hatte diese doch etwas Selbstéindiges und Seltsames an sich. 0ft waren die St6rungen des Kérperschemas halbseitig; in 4 F ﬁllen dehnte sich die St6rung auf die ganze linke Kiirperhﬁlfte aus. �294 Sai-Halész, Brunecker und Széra 5. Zeitstc'irung war in geringerem MaBe in allen Fallen vorhan- den, erreichte aber nie eine grijﬂere Intensitéit. Solche Erscheinun— wie beim Meskalin-Versuch berichtet — daB Zeitsinn der ganz gen, verlorengegangen ware, haben wir nicht bemerkt. Die Dauer des Versuches wurde immer etwas ﬁberschﬁtzt. Eine Versuchsperson fiihrte das «auf die reichere Fiille der Minuten» zuriick. 6. Denkstb'rung. In 21 Fallen (70 0/0) fanden Wir eine ausgesprochene Auflockerung der Assoziationen. Die Sprache wurde inkohéirent, angefangene Siitze konnten nicht beendigt werden, da schon der néichste Gedanke im Vordergrund stand. Diese Inkohéirenz verursachte auch beim Protokollfiihren Schwierigkeiten. 0ft schwiegen die Versuchspersonen fiir einige Minuten, antworteten auch nicht auf Fragen; sie erkléirten spéiter, daB sie ihre Gedanken nicht genug beherrschen konnten, um etWas Verstéindiges zu antworten. In 5 Fallen hatten wir es mit paranoiden bzw. wahnéihnlichen Gedanken zu tun. Diese Versuchspersonen berichteten erst 1—2 Tage spater, daB sie wéihrend des Versuches ﬁberzeugt waren, man wolle sie tﬁten bzw. vergiften. DMT war das Gift, die Versuchsleiter die Mﬁrder. Eine Versuchsperson wurde Wéihrend des Experimentes sehr unruhig und muBte mit Gewalt niedergehalten werden. Sie erkléirte am néichsten Tage folgendes: «Ich fiihlte, daB ich vergiftet wurde und sterben werde und schon nichts dagegen tun konnte. Trotzdem kéimpfte ich einen seelischen Kampf, ob ich bis zum letzten Moment am Leben hé’mgen Oder ruhig sterben soll; das letztere war sehr verlockend, da ich mich sehr wohl fiihlte. Dieser seelische Kampf éiuBerte sich in meinem Motorium als Unruhe; ich spiirte und wuBte alles.» In anderen Fillen waren die Beziehungsideen nicht so ausgeprﬁgt, doch berichteten die Versuchspersonen nach einigen Tagen, daB sie betreﬁ's der Aufrichtigkeit und Zuverléissigkeit der Versuchsleiter ein wenig unsicher waren. Am nichsten Tage war dieses Gefiihl mit den eventuellen aggressiven Einstellungen zusammen verschwunden. 7. Aﬁ'ektive Verdnderungen. Euphorie ist eine verhﬁltnismﬁﬁig 0ft zu beobachtende Erscheinung der DMT-Psychose. In 8 Féillen (27 0/0) war sie stark ausgeprﬁgt, in 12 Fallen (40%) milderen Grades Oder nur auf kiirzere Zeit bemerkbar. 0ft trat sie zusammen mit Zwangslachen auf, in anderen Féiﬂen war sie mit Introversion verbunden; letztere wurde durch ein «verkléirtes» Lﬁcheln begleitet, das manchmal fast wéihrend dem ganzen Versuche dauerte. Die �Dimethyltryptamin: ein neues Psychoticum 295 Versuchsperson lag mehrere Minuten lang wortlos mit geschlossenen Augen und léichelte; manchmal jedoch weinte sie vor Seligkeit und seufzte: «Oh, wie wunderbar ist doch alles!» Wie schon bemerkt, ist die Angst eine der héiuﬁgsten Erscheinungen der DMT-Psychose. Am stéirksten ist sie einige Minuten nach Verabreichung der Injektion bemerkbar, wenn sich die Umwelt so plﬁtzlich und intensiv veréindert, daB die Versuchsperson die feste Umgebung verliert. Nur 4 Personen berichteten, keine Angst gehabt zu haben. In der zweiten Héilfte der Psychose tritt Angst Viel seltener auf. Nur eine Versuchsperson klagte wﬁhrend des ganzen Versuches iiber Angst und sagte: «DaB es nur nicht zuriickkomme ! » Was nicht zurﬁckkommen sol], konnte sie nicht erkléiren; sie antwortete: «Na ja, das Ganze!» 8. Bewuﬁtseinstb’rungen. Nur in 7 Fallen (23 0/0) haben wir eine BewuBtseinstriibung beobachtet. Sie war stets am Anfang des Experimentes bemerkhar, d.h. 8—15 Minuten nach Verabreichung der Injektion und dauerte nicht léinger als 2—5 Minuten. Wéihrend dieser Periode sprechen die Versuchspersonen nichts, und auch spéiter bestand eine Amnesie der Ereignisse, die inzwischen geschahen. Es blieb ihnen nur das Gefiihl, daB etwas Schreckliches vorging. 9. Neurologische Verc‘inderungen. Die Reﬂexe waren wéihrend des Versuches 0ft (63 %) erhtiht oder lebhaft. Voriibergehende pathologische Reﬂexe (Babinski usw.) fanden wir nur in 3 Fallen (10%). Im Motorium zeigten sich ausgepréigte Veréinderungen. Fast alle Versuchspersonen hatten eine hyperkynetische Zeitspanne, in der sich unwillkiirlich-extrapyramidale und Willkiirliche Bewegungen mischten. Nur einmal war die Hyperkynesie so stark, daB Gewalt angewandt werden muBte, um einen Unfall zu verhiiten. Sensibilitéitsstﬁrungen gesellten sich oft zur Stﬁrung des K6rperschemas. Meistens waren die Fehlleistungen seitens der Tiefensensibilitéit, Gewichtsschﬁtzung, Kﬁrperlage usw. zu beobachten. Die Oberﬂﬁchensensibilitéit war relativ viel besser erhalten. Sensibilitéitsstﬁrungen fanden wir in 18 Féillen (6000). 10. Halbseitigkeit der Symptome. Eine der interessantesten Beobachtungen beziiglich der DMT-Psychosen war, daB in Mehrzahl der F ﬁlle die Symptome halbseitig ausgepréigter waren. Dies war ebenso bei den neurologischen Symptomen wie bei den Halluzinationen und Kﬁrperschemastﬁrungen bemerkbar. Die linke Seite war stets die stéirker betroﬂene. Wir hatten Gelegenheit, 3 Linkshéindige unserem Experiment zu unterziehen; bei diesen dominierten �Sai-Halész, Brunecker und Széra ___—____—_——_—————————————-—-———~ 296 Abb. 100 % 1 80% 40% 20% s-aaa°a°-Eaa°a:a°§-Eé°-EE g be :1 :5 a; s: >., a "-4 0 '8 A: H m "‘ {-11 o I: cu 3'3 E,” H o9-1 >5 no 3:: g: .H .0 gcu 8 0 .=: :2 53 Q '8 au :5 uo .5.” 0 aa o 0 m C121 :o ‘53 a:3 (I) 1 :1 '-' :5 an .... f:O m ﬂw m a a)” ‘ M o CIT-I o a: ‘9 '8 w "" ho” s 2": cc 94 aH :o 2; 4.: '-' ﬂ tan 5:: 5 4:: 0 m F ‘3 w Q 5 E75 b; <‘. :1 H :o E E :1 «a p: '5cs o :1 g 3 g .... < g v-c an E o A4 v “-1 = 4 Q. m :1 I- :o gm 4-» ' 53 rd a a E :3 .ao _. g m o "=1 ° [—1 an g g c: "" ‘9 *8 6) u m g cc a 5.0 c: .2 s m die Symptome rechtsseitig. (Auf diese Erscheinung kommen wir in der Besprechung noch zuriick.) 11. Nachwirkungen. Alle Versuchspersonen klagten am Experiment folgenden Tage iiber Miidigkeit. Diese dauerte manchma] nur einige Stunden, bei einigen jedoch 1—2 Tage. Wéihrend dieser Periode 2 Nach ein 7 Tagen depressiv. %) (23 wenig Versuchspersonen waren Die in betreﬂ's alle 30 Ordnung. Personen vﬁllig Stimmung waren 1 der in wir Abbildung einzelnen der gehen Symptome Hﬁuﬁgkeit wieder. Besprechung Durch die DMT-Versuche ergeben sich 3 Tatsachen, die fiir das weitere Verstéindnis der sogenannten Modell-Psychosen éiuBerst interessant sind: und kurze Dauer der DMT-Psychose. 2. Halbseitigkeit gewisser Symptome. 3. Nahe chemische Verwandtschaft zwischen DMT und Serotonin. 1. Pliitzlicher Anfang �297 Dimethyltryptamin: ein neues Psychoticum Wirkung des DMT ist etwas ganz Neues unter der Psychotica. Meskalin fingt nach fast einer Stunde zu wirken an, Haschisch und LSD-25 wirkt noch langsamer. Aber auch die Dauer der Psychose ist beim DMT auffallend kurz, und zwar 40~60 Minuten. Um diesem Problem nﬁherzukommen, haben wir — wie schon berichtet - die Ausscheidung von DMT und 3-Indolessigséiure wéihrend und nach dem Versuch untersucht. Wir fanden, daB nach Verabreichung von DMT die Quantitéit der 3-Indolessigséiure im Harn stark zunjmmt und in den ersten 6 Stunden schon ungeféihr das Zehnfache der normalen Ausscheidung erreicht; ebenso erhﬁht sich — jedoch nur in geringerem MaBe — die Ausscheidung der 5-hydroxy-3-Indolessigséiure, was auf einen Zusammenhang mit dem Serotonin-Stoffwechsel hinweist. Im Harn fanden wir jedoch kein unveréindertes DMT, was bezeugt, daB das DMT im Korper sehr schnell und vollig abgebaut wird. Dies kann uns erkléiren, warum die Wirkung so schnell abléiuft und auch das DMT peroral unwirksam ist: wahrscheinlich wird es in der Leber abgebaut, bevor es die psychische Wirkung ausiiben konnte. Es bleibt aber noch immer die Frage oﬂ'en, warum das DMT so schnell wirken kann. Nach der Theorie von Rothlin und Patzig veréindert sich das Meskalin und LSD-25 im Organismus, bevor es eine Wirkung ausiiben konnte; es wéire eigentlich ein Umbauprodukt dieser Substanzen, das die psychotische Wirkung habe. Beim DMT kann kaum von so einer Transformation die Bede sein; das plotzliche Auftreten der Symptome unterstiitzt die Vermutung, daB das DMT selbst die psychotische Wirkung ausiibt. DMT wéire demgemﬁB das erste Psychotikum auBer Bufotenin — das selbst ohne Abbau oder Umbau die experimentelle Psychose verursacht. 2. Die Halbseitigkeit einiger Symptome ist eine der interessantesten Erscheinungen der DMT-Psychose. Es treten gleich zwei Fragen auf: a) wie ist es moglich, daB eine chemische Substanz auf eine Hemisphﬁre stéirkere Wirkung ausiibt als auf die andere, und warum stets auf die nichtdominante Hemisphéire ? b) hat die nichtdominante Hemisphéire eine wichtige Rolle im Auftreten der experimentellen Psychose oder wenigstens einiger Symptome ? Diese Fragen kann man heute noch kaum beantworten. Es wﬁre zu oberﬂéichlich, sich auf die erste Frage mit der Antwort zu begniigen, daB die nichtdominante Hemisphéire chemischen Intoxi1. Die rasche -— Psychiat. New-0]., Basel. Vol. 135, No. 4—5 (1958) 20 �298 Sai-Halész, Brunecker und Széra kationen gegeniiber mehr «verwundbar» wire; dies sollte sich doch dann auch bei anderen Vergiftungen zeigen. Oder aber ist der Kreislauf der dominanten Hemisphéire im Notfall zu besserer Regulation fﬁhig ? Die zweite Frage, 0b néimlich die rechte Hemisphﬁre im Auf— treten psychopathologischer Syndrome eine wichtige Rolle habe, wurde schon in anderen Zusammenhéingen beriicksichtigt. Hoﬁ und Pﬁtzl fanden, daB das Zeitraﬁ'er-Phéinomen nur bei rechtsseitiger Lﬁsion zu beobachten war and meistens bei parieto-okzipitalen Schﬁdigungen. In der DMT-Psychose zeigt sich ein groBer Tei] der Erscheinungen eben als parieto-okzipitale F unktionsstﬁrungen (visuale Halluzinationen, Kﬁrperschemastﬁrungen, Raumwahrnehmungs-Stﬁrungen usw.). Es scheint, daB die Halbseitigkeit bei der DMT-Psychose uns einen weiteren Beweis bietet, die Theorie von Hoﬂ und Pb’tzl zu unterstiitzen: eine rechtsseitige Gehjrnschéidigung iibt eine «bahnende» Wirkung beim Auftreten gewisser psychopathologischer Phﬁnomene ans. 3. In den letzten J ahren héiufen sich die Publikationen, die eine zentrale Rolle des Serotonins in der Funktion des zentralen Nervensystems annehmen (Brodie et al.). Es wurde auch angenommen (Woolley), daB der Serotonin-Stoffwechsel in der Genese der Psychosen, hauptséichlich der Schizophrenic, einen wichtigen Anteil habe. Wie schon erwéihnt, fanden wir im Harn der Versuchspersonne ungeféihr 4—5mal mehr 5-hydroxy-3-Indolessigséiure als bei Normalen; diese Substanz ist, wie bekannt, das Hauptabbauprodukt des Serotonins. Es gibt wiederum zwei Mﬁglichkeiten: entweder wird die 3-Indolessigséiure, also das Abbauprodukt des DMT, sekundﬁr oxydiert, oder aber mobilisiert das verabreichte DMT eine bedeutende Menge des gebundenen Serotonins. Im letzteren Falle ware die experimentelle DMT-Psychose im strengsten Zusammenhang mit dem Serotonin-Stoﬂ'wechsel verbunden. Hier k6nnte man nach gewissen Analogien einen in den zentralen Synapsen abspielenden kompetitiven Antagonismus der zwei Aminen vorstellen. Es miissen noch weitere mit radioaktiven Isotopen gezeichnete DMT-Experimente vorgenommen werden, um diese Fragen zu lﬁsen und auch damit einen Wichtigen Schritt zum biochemischen Verstéindnis der psychotischen Zustéinde im allgemeinen zu tun. Durch unsere ohigen Beobachtungen kﬁnnen wir auch feststellen, daB auBer dem Bufotenin das DMT auch eine bedeutende R0116 in der Gesamtwirkung der Piptadenia-Extrakte zu spielen habe. �M“— Dimenthyltryptamin: ein neues Psychoticum 299 Insofern unsere Ergebnisse mit den spﬁrlichen an Menschen gewonnenen Bufotenin-Beobachtungen zu vergleichen sind (diese sind wegen der intravenosen Anwendung des Bufotenins kaum moglich), ist es auffallend, daB das DMT eine periphere-vaskulﬁre, serotoninartige Wirkung in geringerem MaBe als das Bufotenin ausiibt. Dies kann vielleicht der strukturelle Unterschied, d. h. die beim Bufotenin vorhandene 5-OH-Wurzel erkléiren. Diese und die iibrigen Detailfragen konnten bloB weitere, an denselben Personen und unter gleicher Anwendung der 2 Indolamine durchgefiihrte Versuche kliiren. Z usammenfassung Dimethyltryptamin wurde synthetisiert, und dessen psychotische Wirkung untersucht. Nach intramuskuléirer Verabreichung von 0,7—1mg/kg Dimethyltryptamin tritt schon nach 3~5 Minuten ein psychotischer Zustand auf, der in vielen Erscheinungen denen ahnelt, die durch Meskalin und LSD-25 verursacht wurden. Die Dimethyltryptamjn-Psychose lauft innerhalb einer Stunde ab. AuBer der Beschreibung der Symptome werden 3 Probleme nﬁher untersucht: 1. Was kann die Ursache des plotzlichen Auftretens und schnellen Ablaufes der Dimethyltryptamin-Psychose sein. 2. Welche Rolle spielt die Halbseitigkeit der Symptome, also die stiirkere Schiidigung der rechten nichtdominanten Hemisphéire beim Auftreten der psychopathologischen Erscheinungen. 3. Welche F olgerungen konnen beziiglich der Bedeutung des Serotonin-Stoﬂ'wechsels im zentralen Nervensystem betreﬂ's der nahen cliemischen Verwandtschaft zwischen Dimethyltryptamin und Serotonin gezogen werden. Die Ahnlichkeiten und Unterschiede zwischen den Bufoteninund Dimethyltryptamin-Psychosen sollen weitere Experimente klarstellen. Re’sumé On a synthétisé la diméthyltryptamine et étudié son action psychotique. Aprés une administration intra-musculaire de 0,7—1 mg/kg de djméthyltryptamine, un état psychotique est apparu aprés 3 a 5 minutes déja. Il ressemhlait par beaucoup d’aspects a ceux qui sont �300 Sai-Halasz, Brunecker und Széra provoqués par la mescaline et le LSD 25. La psychose a la diméthyltryptamine dure une heure. A part la description des symptﬁmes on a étudié de plus pres 3 problémes: 1. Quelle peut étre la raison du début brusque et de la ﬁn rapide de la psychose a la diméthyltryptamine. 2. Quel role joue la latéralisation des symptémes ainsi que l’atteinte prépondérante de l’hémisphére droit, non dominant, lors de l’apparition des symptomes psychopathologiques. 3. Quelles conclusions on peut tirer de la proche parenté chimique entre la diméthyltryptamine et la sérotonine pour la signiﬁcation du métabolisme de la sérotonine dans le systeme nerveux central. D’autres expériences montreront les ressemblances et diﬂ'érences entre les psychoses a la Bufotenine et a la diméthyltryptamine. Summary Dimethyltryptamin was synthesized and its eﬁ'ect on psychosis investigated. An intramuscular injection of 0.7—1 mg/kg Dimethyl3—5 minutes a psychotic condition after and was given tryptamin was induced which in many respects resembled those phenomena induced by mescalin and LSD 25. This Dimethyltryptamin psychosis lasted less than an hour. Besides a description of the symptoms we have investigated three problems: 1. The reason for the swift start and rapid departure of the psychosis. 2. What is the signiﬁcance of the one-sided nature of the in of the disturbance the right degree is, that greater symptoms, non-dominant hemisphere when the psychopathological phenomena begin to show. 3. Having regard to the close chemical afﬁnity between Dimethyltryptamin and Serotonin, what conclusions could be drawn as to the import of serotonin metabolism in the C.N.S. Further experiments should clarify the similarities and differences between psychoses induced by Bufotenin and those by Dimethyltryptamin. LITERATUR Beringer, K.: Der Meskalim'ausch, Springer, Berlin 1927. — Brodie, B. B. et al.: Science 122, 968, 1955. — Erspamer, V.: Pharmacol. Rev. 6, 425, 1954. — Evarts, E. V.: Arch. Neurol. Psychiat. 75., 49, 1956. — Fabing, H.D.: Amer. J. Psychiat. 113, 409, 1956. — Fabing, H.D. and Hawkins: Science 123, 886, 1956. — Fish, M. S., �m Dimethyltryptamin: ein neues Psychoticum 301. N. M. Johnson and D. C. Homing: J. amer. chem. Soc. p. 77, 1955. — Fraenkel, F. und E. Joel: Z. ges. Neurol. Psychiat. 111, 84, 1927. — Hoﬁ, H. und 0. Po'tzl: Z. Neurol. 151, 599, 1934. — Page, I.H.: Physiol. Rev. 34, 563, 1954. — RaymondHamet: Compt. rend. Soc. biol. 135, 1414, 1941. — Rothlin, E.: Experientia 12, 154, 1956. — Speeter, M.E. and W. C. Anthony: J. amer. chem. Soc. 76, 6208, 1954. — Stall, A. und A. Hoﬂmann: Helv. chim. Acta 26, 944, 1943. - Stromberg, V.L.: J. amer. chem. Soc. 76, 1707, 1954. — Stoll, A.: Schweiz. Arch. Neurol. Psychiat. 60, 1, 1947. — Szdra, SL: Experientia 12, 441, 1956. — Wieland, H. und H. Mittasch: Ann. Chem. 513, 1, 1934. — Woolley, D. W.: Brit. med. J. 1954, 122. Adresse der Autoren: Dr. A. Sai-Halész, Dr. G. anecker, Zentrales Neurologisch-Psychiatrisches Institut, Budapest-Lipétmezb‘ (Ungarn). Dr. St. Széra, 113 Hesketh Street, Chavy Chase 15, Md. (USA). �, u '1‘ �Copyright, 1958, by the Society 'for'Experimental Biology and Medicine. Reprinted from PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE, 1958, v97, 4837486 A New Group of Psychotomimetic L. G. ABOOD, A. M. OSTFELD Agents.ale AND (23782) JOHN BIEL Divisions of Psychiatry and Preventive Medicine, University of Illinois College of Medicine and Lakeside Laboratories, Milwaukee During the past few years, much interest has developed in psychotomimetic agents, particularly with regard to LSD 25 and mescaline. At the same time, considerable emphasis has been placed on the possible role of adrenalin and serotonin in psychoses, particularly because they are structurally related to the psychotomimetic agents and are pharThe, role Of macologically antagonistic. acetylcholine and acetylcholine- like sub'stances, on the other hand, has received relatively little attention. Knowledge of the hallucinogenic properties Of cholinergic blocking agents,,such. as atroh pine and hyoscine, dates back to thetime of the ancient Hindus. Recently, a group of piperidyl benzilates possessing anticholinergic properties were synthesized by Biel and associates(l) as possible antispasmodics in the treatment Of duodenal ulcer(2). In the course of therapeutic trials, it was found that the tertiary amine hydrochlorides of the benzilate esters, although active anticholinergics, produced undesirable side effects, particu- larly hallucinations. The quaternary ammonium salts, on the other hand, were entirely devoid of such effects. We have recently, Obtained a series of such substances and examined their psychotomimetic effects on animals and human subjects(3). Methods. The psychotogenic effects of the N—methyl-3-piperidyl benzilate and related congeners were tested on over 40 human volunteers who were either normal or patients complaining of minor disorders. Although some of the patients had limited knowledge of the psychotogenic action of the drugs, the majority of subjects were completely unaware Of their nature. Ceruloplasmin determinations were made on many subjects, employing a method described previously(4). All of the agents were tested for their behavioral effects in animals, including some 30 Siamese ﬁghting ﬁsh, 50 rodents, and 5 cats. The action of these agents on the Siamese ﬁghting ﬁsh is comparable to those described 'for LSD by Abramson(5). In rodents there were marked behavioral changes, such as initial excitement and marked' hyperactivity, spon* Supported by grants from Mental Health Fund, taneous squealing, lack Of ”responsiveness to State Of Illinois, and Teagle Fn. stimuli, muscular weakness, (and lethargy. , _ 4 _ �NEW PSYCHOTOMIMETIC AGENTS The anticholinergic effect of the agents was determined on isolated smooth muscle preparations and the rectus abdominus according to the method of Chang and Gaddum(6). Results. Experimental ﬁndings have indicated that the compounds are extremely powerful hallucinogens, in many respects more interesting than LSD and mescaline. When administered in 5-15 mg doses, orally, to human volunteers, distinct auditory and visual hallucinations occurred within one hour in for recurred and periodically individual every periods up to 10 hours after administration of the drug. Hallucinations were accompanied by gross distortions of visual images and severe alterations in feeling state. A number of subjects exhibited paranoid and megalomanic delusions, while the affective states ranged from a feeling of unpleasantness to extreme terror. Some of the subjects actually carried on conversations with imaginary individuals involving situations dating back 10-20 years. The following are almost exact quotations from different subjects: “People from India are standing outside a tent. They have turbans and those are camels.” “I see six people sitting around a table playing cards . a monkey is over the table hanging by his tail.” “I am walking down a narrow corridor and suddenly stop and cannot move is beating . . . a band is playing . . . a drum 3/4 rhythm.” The subjects receiving 10 mg (orally) of N-methyl-3-piperidyl benzilate were in complete loss of contact with the environment for vis— dramatic While hours experiencing many ual and auditory hallucinations. In many respects these anticholinergic agents come closer to simulating clinical psychoses than do mescaline and LSD. Thus far, a number of congeners have been tested for both hallucinogenic properties and anticholinergic effect on the isolated colon (Table I). Of all the compounds tested for hallucinogenic properties, N-methyl-3-piperidyl benzilate is the most potent, with the Nethyl derivative being somewhat less effective. The tetramethyl derivative is considerably less effective than the N—ethyl derivative. The quaternary derivative is devoid of , psychotogenic effects. As for the antispasmodic potency, although the 3 substances possessing psychotogenic properties are perhaps the most potent, the remaining compounds are still quite effective. Ceruloplasmin determinations were made on all subjects, since this enzyme was shown to be increased in the serum of acute schizophrenics(4,7). The method used has been described previously(4). Preliminary observations have indicated that as much as a 50-75% elevation in the blood ceruloplasmin accompanies the hallucinatory episode produced by these agents. The enzyme increased only when marked psychogenic disturbances were apparent, returning to normal shortly after the psychogenic effects disappeared and while peripheral autonomic effects, such as mydriasis, muscular weakness, and dryness of the mouth, still persisted. A rise in ceruloplasmin has been shown to accompany changes in affective or feeling states, regardless of the mechanism by which the effects are produced (3 ) . Discussion. A discussion of the relative antispasmodic properties of this group of compounds appears elsewhere(1). It is apparent from the present study that in this series of compounds there is no direct relationship between the anticholinergic effect on smooth muscle and psychotogenic potency. The presence of the hydroxyl group in the acid moiety to yield the diphenylacetate ester is undoubtedly essential for hallucinogenic effect, while only slightly enhancing the anticholinergic effect. Since both the diphenylacetate and the benzilate derivatives penetrate the blood brain barrier, it would appear that the hydroxyl group is an absolute require— ment. The presence of a quaternary nitrogen in the piperidine ring only slightly inﬂuences the anticholinergic effect, but apparently pre— vents the compound from penetrating the blood—brain barrier. As a rule, quaternary ammonium compounds are not able to enter the central nervous system through the blood stream. Preliminary observations have shown that intrathecal injections of the quaternary compound into rats produce much the same kind of neurological and behavioral disturb- �_,,' _ a \ 4 l NEW PSYCHOTOMIMETIC AGENTS TABLE I. Structure-Activity Relationships of. Some Piperidyl Benzilate Congeners. Anticholinergic effect was determined on isolated rat colon with concentrations of about 10“ M. \ / Ill/Q ox R—O—C—C \ \/\O — Relative Relative halantilucinogenic cholinergic potency potency Name R X N—methyl-3-piperidy1-benzilate m 0H ++++ ++++ OH +++ +++ OH — + +++ I \N/ CHs N -ethyl-3-piperidyl—benzilate \/ N 02115 1,2,2,6 tetramethyl-4-piperidyl benzilate CH3 \N/(CHS) 2 CH3 N-ethyl-3-piperidyl-diphenylacetate \/ H 0 +++ OH 0 +++ N 02H5 m \/ /\ N-dimethyl—3-piperidyl benzilate N+ CH3 ances observed with the tertiary benzilates. At present, numerous other congeners are being examined for their hallucinogenic properties. Future synthetic work is contemplated in an effort to explore other structureactivity relationships from the point of view of hallucinogenic effect. In view of the work of others on anticholinergic substances, it may be predicted that the distance between the hydroxyl group and the piperidyl nitrogen is critical( 8,9). Introduction of alkyl groups into the molecule would, therefore, presumably diminish the anticholinergic potency, and it will be of interest to determine the relationship of such a change to hallucinogenic effectiveness. Summary. A series of synthetic anticholin- C'H3 ergic agents have been shown to possess potent psychotomimetic properties. Chemically, the agents are esters of piperidine and benzilic acid. Among the effects produced are megalomanic and paranoid delusions, visual and auditory hallucinations, and a partial loss of contact with the environment. A number of congeners of the compounds have been examined with regard to structure-activity relationships. J. H., Sprengler, E. P., Leiser, H. A., Horner, 1., Drukker, A., Friedman, H. L., J. Am. Chem. 1. Biel, Soc., 1955, v77, 2250. 2. Ewing, P. L., Seager, L. D., Keller, G., Dodson, D., J. Pharmacol. Exp. Therap., 1954, v110, l7. 3. Ostfeld, A. M., Abood, L. G., Marcus, D. A., �NEW PSYCHOIOMIME’TIC AGENTS Arch. Neurol. Psych. in press. 4. Abood, L. G, Gibbs, F. A, Gibbs,E ., ibid., 1957, v77, 643. 5. Abramson, H. A., Evans, L. T., Science. 1954. V120: 9906. Chang, v79, 255. H. C., Gaddum, J. H., J. Physiol., 1933, . t ' ' 7‘Akerfeldt, M., J. Pharmacol. Exp. Therap., Lands, 8. S., Science, 1957, v125, 117. A. 1951, v102, 219. 9. Goodman, L., Gilman, A., The Pharmacological Basis of Therapeutics, ed. Macmillan Co., N. Y., 1955. Received December 23, 1957. P.S.E.B.M., 1958, v97. DEPARTMENT OF EXPERIMENTAL rsvcumm HlLLSlDE HOSPITAL GLEN OAKS. N. v. MAY1 4'53 '- �Reprinted from the A. M. A. Archives of Neurology (5“ Psychiatry March 1958, Vol. 79, pp. 317-322 Copyright 1958, by American Medical Association Studies with Ceruloplasmin and a New Hallucinogen ADRIAN M. OS'I'FELD, M.D.; LEO G. ABOOD, Ph.D., and Knowledge of the hallucinogenic prop—erties of atropine—like compounds is cer— tainly as old as that concerning the effects of mescal and marihuana. It has been pos— tulated that the oracle at Delphi induced her prophetic vision with belladonna. Hughes and Clark1 quote a lively description of a 17th century American epidemic of atro— pine poisoning. Readers of English detec— tive novels or American Western stories are familiar with the deadly nightshade and Jimson weed, respectively. The recent synthesis of N-ethyl-3-piper— idyl benzilate hydrochloride, JB 318*,2 an agent chemically related to atropine (Figure), led to the present studies. Originally intended as an autonomic—blocking agent in the treatment of peptic ulcer, the drug exhibited hallucinogenic properties, so prominent as to merit further investigation.3 At the close of the conference of the Brain Research Foundation on blood tests in mental illness in 1957,4 several unan— swered or partly answered questions were raised or implied. What are the serum ceruloplasmin levels in disturbed behavior not of psychotic proportion? Does the con— centration of this protein vary with the severity of the mental disorder? Is its concentration in the blood increased during Submitted for publication Sept. 16, 1957. Department of Preventive Medicine and Division of Psychiatry, University of Illinois College of Medicine. Now at the Institute for Psychosomatic and Psychiatric Research and Training, Michael Reese Hospital (Dr. Marcus). This research was supported in part by the Mental Health Fund, State of Illinois; the Brain Research Foundation, and the Dan Crego Fund. *The material was supplied by Drs. John Biel and H. L. Daiell, of Lakeside Laboratories. Dr. John Biel cooperated in the study and made helpful suggestions. DAVID A. MARCUS, M.D., Chicago N—ETHYL—B-PIPERIDYLBENZILATE (JB 3l8) CHz—7CH—CH2\ N—CH: \ CHz——- CH——-CH2 / CHzOH l CH—O-C H ATROPINE drug—induced psychoses? And, ﬁnally, since ceruloplasmin attacks certain pyrocatechol (catechol) amines in vitro, what effect does an increase in these pyrocatechol amines in the blood have on ceruloplasmin? The present study, then, had the dual purpose of examining the psychotomimetic properties of ]B 318 and assaying the effects on serum ceruloplasmin of (1) JB 318—induced “psychoses,” (2) intravenous infusion of some pyrocatechol amines, and '(3) naturally occurring behavior disturb— ances of moderate severity. Experimental Methods and Results Studies with J B 318.—In all, 45 volunteer nonpsychotic subjects were studied. JD 318 was administered orally to nine subjects in doses of 10 or 15 mg. Three who took the agent were professional persons employed in the hospital; six were medical ward patients, selected only because their general state of health was satisfactory. The three 317 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY professional persons had prior knowledge of anxious to repeat the experience. Seven the effects of the drug, whereas none of experienced visual hallucinations, and four the patients were told what to expect. Blood of these also described auditory hallucina— was drawn for serum ceruloplasmin deter— tions, which were especially prominent in mination before and at the peak of the three. The visual hallucinations usually consisted hallucinatory phase. Ceruloplasmin was measured by the method of Abood5 in of amorphous colored forms, whereas eight of the nine subjects. brightly colored, elaborate images were inThe determination was done as follows: frequent. In the ﬁve cases in which animal One-tenth milliliter of fresh serum was and human forms were reported the images incubated with 0.1 ml. of 0.1% p-phenylene— were usually related to speciﬁc events in the diamine and 1.0 ml. of 0.2 M tris(hydroxy— recent past experience of the subject. Most methyl)ethanolamine buffer (pH 6.8) for hallucinations lasted only a few seconds, al— a period of one hour at 37 C. After the though one subject reported images persist— addition of 2 ml. of distilled water the mix- ing for many minutes. Generally, but not ture was read at 490m“ on the spectro- always, the maximum hallucinatory effect photometer. An optical density reading of was attained when subject was kept alone 0.100 corresponds to an activity of IOMM in a darkened, quiet room. The auditory hallucinations consisted of substrate (p—phenylenediamine) oxidized of musical such mainly sounds, stand— 0.1 as whistling, hour ml. The of one serum. per ard curve was determined by oxidizing the singing, and band playing. A few reported substrate with puriﬁed human cerulo~ noises, such as sirens and hammering or banging radiators. Emotional disturbances, plasminrt such fear and as bewilderment, seem to acReactions related to the autonomic activ— visual whereas hallucinations, the company the 30 of about minutes ity drug began after oral administration and consisted of auditory experiences were not usually disthe following: dry mouth, blurred vision in turbing. Two be subjects to appeared paranoid all cases, usually tachycardia, facial ﬂushing, hallu— the during or immediately following and disappearance of the carotid sinus re— ef— While the cinatory central responses. ﬂex. There was no appreciable effect on fects ofthe drug persisted, the subjects blood pressure. Nausea occurred in two pa— showed reduction of intellectual a capacity, tients, vomiting in one. The autonomic recharacterized rela— short attention by span, actions began 15 to 60 minutes before the tive and anomia, inaccurate time grossly hallu— and outlasted the psychic phenomena All remained in judgment. contact with cinations by l to 24 hours. The peak auto— the actual environment, but the presence of nomic effects preceded the peak psychic familiar a person or object was required to effects in every case. enhance orientation and allay apprehen— Perceptual responses were characterized sions. by distortion of Visual images, visual and The following are taken essentially verauditory hallucinations, and alterations in batim from the comments of dur— a patient feeling state. All nine subjects reported dis— ing the period of hallucinogenic effect: tortion of visual images and an initial change “My arms are heavy and everything feels far in mood, characterized by apprehension and away. My head feels light. I’m very weak. . . .” “Lots of people are talking incoherently. I think lethargy. The general feeling tone was re— it’s Spanish.” ported as unpleasant by eight of the nine “The room feels distant. I wish I could lift my subjects, and none of the subjects were left is arm but I can’t. The and Dr. G. D. Cummings, of the Michigan Department of Health, supplied the puriﬁed human cerulo— plasmin. 1' 318 room a narrow, band is playing. The rhythm is M. . . .” “The room is a long corridor, and I’m in it and I’m 8 or 9 years old. I wonder how I’ll get out. I Vol. 79, March, 1958 �I CERULOPLASMIN AND NEW HALLUCINOGEN of .18 318 on Serum Ceruloplasmin’l‘ of Normal Volunteers TABLE l.——Eﬂect Before JB Ceruloplasmln Approximately Two Hours After J B 318 Subjects Who Hallucinated 318 230 242 304 224 188 230 241 2l 1 115 120 155 315 * 160 170 Subjects Who Did Not Hallucinate _ «——~ - _ _ -_ . __ -_ 143 296 The values are expressed as optical density X10 8. know I’m in bed and also in that other place. There must be more than one of me, and one is a little girl.” “People from India are standing outside a tent. They have turbans, and those are camels.” An electroencephalogram taken on one subject revealed no abnormality, even dur— ing a series of vivid hallucinations. Ceruloplasmin levels uniformly increased in the six subjects who experienced hallucinations and decreased slightly in the two who did not (Table 1). The parallelism of ceruloplasmin levels in schizophrenic psy— choses and those induced by JB 318 is evident. There was, however, no propor— tionality between the per cent increase in ceruloplasmin and the severity of the psy— choses. Nor were the ceruloplasmin levels during the drug psychoses as high as commonly occurs in acute schizophrenics?6 Studies with Pyrocatechol Amines and Human Subjects.—Pyrocatechol amines and their breakdown products have been increas— ingly implicated in schizophrenic psychoses. Since ceruloplasmin has been shown to at— tack epinephrine and serotonin in vitro,7 it was deemed worth while to infuse certain pyrocatechol amines intravenously and to gauge their effects on behavior and serum ceruloplasmin. There was a uniform slight decrease in serum ceruloplasmin with each agent, as well as with control dextrose in— fusion. The subjects were general medical patients who were either convalescing or not seriously ill. None had rheumatoid arthri— tis, liver disease, acute infections, or known carcinoma, conditions sometimes associated Oxtfeld at (11. with high cerulopla51nin.4'6 The infusions were all administered by an unfamiliar physician in a new setting. Apprehension was initially evident in the behavior and Speech of each subject. Common were such comments as “We’re on the same side, aren’t we, Doc. . .you won’t hurt me”; or “lf the test comes out bad, will I have to stay here [in the hospital] longer?” With a single exception, the subjects were relaxed, beginning about 15 minutes after perfusion was started. About half slept, and nearly all commented on how comfortable and tranquil they felt. None of the subjects on levarterenol, serotonin, or dex— trose reported any unusual sensation. The subject on isoproterenol U. S. P. and the two who received epinephrine experienced a rapid heart rate but no emotional disturb— ances. One subject who received epinephrine grimaced, tossed about, and was agitated during the infusion. Since the effects of the infusion on ceruloplasmin were identical regardless of the agent administered, the parallel decline in anxiety and in ceruloplasmin attracted our attention. It was postulated that if there were a parallelism between feeling state and ceruloplasmin, then both would be ex— pected to undergo an increase during peri— ods of disturbed behavior. 2.—E[fect of Various Agents“ onSerum Creruloplasmin of Normal Human Subjects TABLE Agent Levarterenol Epinephrine Dosage 10 jug/min. 10 jig/min. 20 jig/min. 5 pg/min. 10 ug/min. 10 ug/min. 15 Isoproterenol Serotonin Iproniazid 5% dextrose with water jig/min. pg/min. ng/min. 15 15 5 ug/m‘m. mg/min. mg/ min. 100 mg. orally 0.25 0.50 Ceruloplasmin Control 186 213 292 228 350 144 235 220 188 211 222 196 During Drug Eﬂect 140 232 225 191 347 102 205 200 214 189 224 1' 177 230 225 240 278 182 228 236 160 187 170 __- 141 150 TThis subject alone was markedly agitated during the infusion. N onpsychotic at present, he had been previously hospitalized six times for acute schizophrenic episodes. 319 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY Ccruloplasmin* of Disturbed and Tranquil Subjects Who Were Not Psychotic TABLE 3.——Serum Disturbed Tranquil 262 250 220 222 136 157 154 272 240 lVlean * S. l). 348 230 282 410 263 202 170 181 118 186 156 230 170 120 166 The values are expressed in terms of optical density X10 5. This thesis was tested in 26 consecutively referred clinic patients. Previously, one pa— tient who could not speak English and three whose psychological states were not clearly discernible to the observer were not included, leaving a group of 22 patients. Each subject was interviewed in order to determine his general psychological state. Eleven exhibited disturbed behavior, such as weeping, pacing the ﬂoor, sweating, and tachycardia and/0r admitted to prominent feelings of anxiety and depression. An equal number whose illnesses were not viewed by them as unduly threatening were calm in the clinic setting. Ceruloplasmin levels for the two groups are shown in Table 3. No attempt was made to determine a pre— cise psychiatric diagnosis, but the behavior disturbances in the one group were of neurotic proportions. Increased ceruloplasmin levels in the disturbed group are evident and are signiﬁcant at the 0.001 level of probabil— ity. Comment The correlation of elevated ceruloplasmin with particular types of behavioral disturb~ ances apparently involving an alteration in “feeling state” raises the problem of the mechanism of ceruloplasmin production. In- asmuch as hallucinogenic agents, such as the present one (see also Alkerfeldtﬁ Abood“) seem to stimulate ceruloplasmin production only during the hallucinatory or psychogen— ically disturbed phase, a central mechanism would appear to be involved. It is of par— 320 ticular signiﬁcance that the onset of the enzyme elevation is within minutes after the occurrence of hallucinations or anxiety, suggesting a rather unique mechanism for enzyme production. Contrary to our origi— nal expectations, an elevation in blood pyrocatechol amines, which are apparently endogenous substrates for ceruloplasmin, was not, in itself, a stimulus for increased production of ceruloplasmin, but, rather, caused a decrease in many instances. What increases were noted in the infusion studies were apparently related to anxiety reactions to the manipulative procedures involved’in handling the subjects. Since, in the present studies, no noticeable alterations in feeling state resulted directly from the pyrocatechol amines, it remains to be seen whether in those instances in which such reactions have been attributable to infused epineph— rine8 an elevation in ceruloplasmin does occur. Future studies are aimed at the clariﬁcation of many of these points. The suggestion that changes in cerulo— plasmin may reﬂect alterations in emotional state has been proposed by others. Leach and associates9 have postulated that many environmental factors, including stress, can alter the enzyme level. Meduna4 described a patient who exhibited a high serum cerulo— plasmin >during an acute schizophrenic psychosis and a normal value during a lucid interval. Hoffer10 has noted an increase in a serum pyrocatechol oxidase (presum— ably not ceruloplasmin) during the acute phase of a schizophrenic attack. Schizophrenia is a genetic limitation involving par— ticular enzymes within the brain or elsewhere in the organism. In the face of environmental stress, such limitations be— come prominent, and metabolic products with psychotomimetic properties accumu— late." The psychosis itself is ushered in by the sensory distortions, altered feeling state, and hallucinations so induced. Sub— sequently, when the patient attempts to reconcile his present state with his past ex— perience, the disorganization of cortical function begins. Vol. 79,‘ March, 1958 �CERULOPLASMIN AND NEW HALLUCINOGEN Numerous reports”12 are available on the psychogenic properties of the bella— donna alkaloids, but the effects were quite variable and difﬁcult to interpret because of the many peripheral side-effects, particularly with atropine. JR 318 possessed about one—third of the cholineric—blocking effect of atropine on smooth muscle,‘3 and at the doses used in the present study produced a slight, if any, effect on blood pressure, heart rate, or gastrointestinal tract. Even the more superﬁcial peripheral effects ob— servable with atropine, such as mydriasis and dryness of the mouth, were occasion— ally absent with the doses of JB 318 used. With regard to the possible mechanism of JR 318 and other cholinergic—blocking agents on the central nervous system, very little'can be said. Although the evidence in support of the role of acetylcholine as a chemical transmitter in the central nervous system is not convincing“:15 disturbances in its concentration or action within the central nervous system result in a wide variety of psychic and neurological symp— toms. Many cholinergic agents, such as isoﬂuro— phatef“,17 produce central nervous system disturbances which are apparently associated with the accumulation of acetylcholine in the brain. The observations of Pfeiffer et al.18 that the “muscarinic” component of acetylcholine—like agents, such as arecoline and physostigmine, are of value in the treat— ment of catatonic schizophrenia, suggest a role of acetylcholine in mental disease. There would appear to be a conﬂict between the argument that a cholinergic agent is beneﬁcial in schizophrenia, while a choliner— gic—blocking agent is psychotomimetic; but the neural mechanisms involved in psycho— genic phenomena are much too obscure to justify the comment on this apparent dis— crepancy. What is signiﬁcant is the fact that acetylcholine does seem to inﬂuence psychogenic phenomena and may be of im— portance in the study of mental disease. Ostfeld at al. Summary A recently synthesized atropine—like compound, N-ethyl—3—piperidyl benzilate, induced altered feeling states, visual and auditory hallucinations, and increased se— rum ceruloplasmin in seven of nine patients. Infusion of four pyrocatechol amines— epinephrine, levarterenol, isoproterenol, and serotonin—appeared to have no effect per se on serum ceruloplasmin. Iproniazid, an amine—oxidase inhibitor, was likewise inef— fective. Serum ceruloplasmin undergoes small, but signiﬁcant, increases during psychiatric disturbances of neurotic type and proportions, and decreases by a similar amount during periods of tranquility. Department of Preventive Medicine, University of Illinois College of Medicine (Dr. Ostfeld). REFERENCES Hughes, J. D., and Clark, J. H., Jr. Strontium Poisoning: A Report of 2 Cases, J. A. M. A. 112: 1. : 2500, 1939. J. H.; Sprengeler, E. P.; Leiser, H. A.; Homer, J.; Drukker, A., and Friedman, H. L.: Antispasmodics: II. Derivatives of N—Substituted— 3-Piperidols, J. Am. Chem. Soc. 77:2250, 1955. 3. Biel, J. H.: Personal communication to the authors. 4. Brain Research Foundation, papers read at Medical Conference, Chicago, Jan. 12—13, 1957, by Akerfeldt,5 Abood,8 and Meduna. 5. Akerfeldt, S.: Oxidation of N,N-Dimethyl—p' plienylenediamine by Serum from Patients with Mental Disease, Science 1252117, 1957. 6. Abood, L. G.; Gibbs, F. A., and Gibbs, E.: Comparative Study of Blood Ceruloplasmin in Schizophrenia and Other Disorders, A. M. A. Arch. Neurol. & Psychiat. 772643, 1957. 7. Holmberg, C. G., and Laurell, C. B.: Investigations in Serum Copper: IlI. Ceruloplasmin as an Enzyme, 'Acta chem. scandinav. 5:476, 1951. 8. Hoffer, A.: Epinephrine Derivatives as Potential Schizophrenic Factors, Quart. Rev. Psychiat. & Neurol. 18:27, 1957. 9. Leach, B. E.; Cohen, M.; Heath, R. G., and Martens, 8.: Studies of the Role of Ceruloplasmin and Albumin in Adrenaline Metabolism, A. M.A. Arch. Neurol. & Psychiat. 762635, 1956. 10. Hoffer, A.: Conference on Biochemistry and Mental Disease, University of British Columbia, Vancouver, B. C., Canada, June, 1957. 2. Biel, 321 �A. M. A. ARCHIVES OF NEUROLOGY AND 11. Quigley, J. P.: Mental Disturbances from Atropine or Novatropine to Subjects Under the Inﬂuence of Insulin, J. A. M. A. 10921363, 1937. 12. Wangeman, C. P., and Hawk, M. H.: The Effects of Morphine, Atropine and Scopolamine on Human Subjects, Anesthesiology 3:24, 1942. 13. Ewing, P. L.; Seager, L. D.; Keller, G., and Dodson, D.: Cardiovascular Effects of Some Derivatives, J. Diphenylacetate 3-Piperdy1 Pharmacol. & Exper. Therap. 110217, 1954. 14. Eccles, J. C.: The Physiology of Nerve Cells, Baltimore, Johns Hopkins Press, 1956. 15. Feldberg, W. S.: Central and Sensory Trans— mission, Pharmacol. Rev. 6285, 1954. 322 PSYCHIATRY Koelle, G. B., and Gilman, A.: The Chronic Toxicity of Di—Isopropylﬂuorophosphate (DFP) in Dogs, Monkeys and Rats, J. Pharmacol. & 16. , Exper. Therap. 872435, 1946. 17. Rowntree, D. W.; Nevin, S., and Wilson, A.: The Effects of Diisopropylﬂuorophosphonate in Schizophrenia and Manic Depressive Psychosis, J. Neurol. Neurosurg. & Psychiat. 13:47, 1950. 18. Pfeiffer, C. C., and Jenney, E. H.: The 111- hibition of the Conditioned Response and the Counteraction of Schizophrenia by Muscarinic Stimulation of the Brain, Ann. Nevv York Acad. Sc. 662753, 1957. '- Printed and Published in the United States of America �DEPARTMENT OF PSYCHIATTY EXPERIMENTAL HILLSIDE HOSPITAL GLE. CAKS. MAY-1 4's; N Y. �Vol. 167, No. l MEDICAL LITERATURE ABSTRACTS neuralgic pain from herpes zoster, and in patients with tabetic crisis. R 875 was then given to 8 patients with psychalgia in whom a diagnosis of cenesthopathia associated with depression had been made. In these patients the drug proved to be ineffective; it was tolerated badly and the cenesthopathia frequently was increased. Thus, the effectiveness of the drug in patients with organic syndromes contrasted with its complete ineffectiveness in those with psychalgia. R 875 may be administered orally or subcutaneously; the intravenous route of administration is contraindicated because of the risk of respiratory accidents. Certain undesirable side-effects of the drug, such as malaise, nausea, vomiting, and oc— casionally drowsiness, require care in administering it; rest in bed is advisable, at least for the initial phase of the treatment. the Hearing Level Following Severe Poliomyelitis. R. Batson and F. McConnell. A. M. A. J. Dis. Child. 95:139-145 (Feb.) 1958 [Chicago]. A Study of The authors report on 87 selected, extensively paralyzed patients, between the ages of 5 and 37 years, with poliomyelitis who underwent detailed audiological assessment in order to determine the precise status of auditory acuity. The audiograms obtained from these patients were compared with those obtained during the same period from 2 groups of young adults without poliomyelitis. Near— ly all the pure-tone thresholds in the patients with poliomyelitis departed from the zero decibel reference level by more than 10 db., indicating some depression of hearing acuity as compared with the levels in the control subjects, which adhered ex— tremely closely to the zero decibel reference level, denoting normal threshold of audibility. Inspection of the pure-tone and speech thresholds in the patients with poliomyelitis revealed that more than 75% (28 patients) showed at least a slight depression of acuity which would be considered deviant from the norm. Numerous factors were considered in an effort to clarify the causative signiﬁcance of the reduction in sensitivity to auditory stimuli in the patients with poliomyelitis. Factors such as age, sex, and possible drug therapy were not thought to inﬂuence these results. It was believed that depressed hearing responses could not be attributed to emotional disturbances or lethargy accompanying serious illness, since the patients gave oral responses to speech-hearing tests which required more physical energy than the effort required for signaling in response to pure-tone stimuli. It was found that the duration of disability did not correlate well with the extent of hearing loss. Several patients who were ambulatory and others who were in a wheelchair throughout the day demonstrated the same defect. A signiﬁcant correlation, however, was observed between loss in hearing and loss in 117 vital capacity, in that patients with marked decrease in vital capacity were apt to show signiﬁcantly greater hearing loss. The signiﬁcance of this is not clear, and it may be only a reﬂection of the severity of the disease in a particular patient. Because there are many other clinical symptoms more distressing to the patient and the physician, and since communication with such patients is usually at close range, reduction in sensitivity to auditory stimuli can be easily overlooked even when it reaches moderate proportions of severity. The causative signiﬁcance of this ﬁnding is not clear. New Group of Psychotomimetic Agents. L. C. Abood, A. M. Ostfeld and J. Biel. Proc. Soc. Exper. Biol. 8: Med. 97:483-486 (Feb.) 1958 [Utica, N. Y.]. A group of piperidyl benzilates possessing anticholinergic properties were recently synthesized as possible antispasmodics in the treatment of duodenal ulcer. In the course of therapeutic trials, it was found that the tertiary amine hydrochlorides of the benzilate esters, although active anticholinergics, produced undesirable side-effects, particulary hallucinations. The quaternary ammonium salts, on the other hand, were entirely devoid of such effects. The authors recently obtained a series of such substances and examined their psychotomimetic effects on animals and human subjects. The psychotogenic effects of the N-methyl-S-piperidyl benzilate and related congeners were tested on more than 40 human volunteers. Although some of the patients had limited knowledge of the psychotogenic action of the drugs, the majority of the subjects were completely unaware of their nature. All the agents were tested for their behavioral effects on animals, including some 30 Siamese ﬁghting ﬁsh, 50 rodents, and 5 cats. The action of these agents on the Siamese ﬁghting ﬁsh is comparable to the action described for lysergic acid diethyl amide (LSD) by Abramson. In rodents there were marked behavioral changes, such as initial excitement and marked hyperactivity, spontaneous squealing, lack of responsiveness to stimuli, muscular weakness, and lethargy. The compounds proved to be extremely powerful hallucinogens, in many respects more interesting than LSD and mescaline. When administered in oral doses of 5 to 15 mg. to human volunteers, distinct auditory and visual hallucinations occurred within 1 hour in every individual and recurred periodically for periods up to 10 hours after administration of the drug. Hallucinations were accompanied by gross distortions of visual images and severe alterations in feeling state. A number of subjects exhibited paranoid and megalomanic delusions, while the affective states ranged from a feeling of unpleasantness to extreme terror. Some of the subjects actually carried on conversations with imaginary individuals involving situations datA _ �118 MEDICAL LITERATURE ABSTRACTS ing back 10 to 20 years. The subjects receiving 10 mg. (orally) of N-methyl-S—piperidyl benzilate were in complete loss of contact with the environment for many hours while experiencing dramatic visual and auditory hallucinations. In many respects these anticholinergic agents come closer to simulating clinical psychoses than do mescaline and LSD. Of all the compounds tested for hallucinogenic properties, N-Methyl-S-piperidyl benzilate is the most potent, with the N-ethyl derivative being somewhat less effective. The tetramethyl derivative is considerably less effective than the N-ethyl derivative. The quaternary derivative is devoid of psychotogenic effects. As for the antispasmodic potency, although the 3 substances possessing psychotogenic properties are perhaps the most potent, the remaining compounds are still quite effective. Recurrence of Glioma of Cerebral Hemispheres: Histological Features and Therapeutic Possibilities. I. Papo and R. Tritapepe. Minerva chir. 12:144-31446 (Nov. 30) 1957 (In Italian) [Turin, Italy]. A second surgical procedure was performed on 34 patients with a recurrent supratentorial glioma. At the ﬁrst operation this tumor appeared to be an astrocytoma in 7 patients, an oligodendroglioma in 7, a glioblastoma in 16, and a changing type of tumor in 4. Histopathological changes from astrocytoma to glioblastoma were observed in 1 patient 11 months after the ﬁrst operation. It is possible, however, that areas of glioblastoma were originally present. Atypical areas were found in sections of the oligodendroglioma in 4 patients, who were operated on, from 35 to 103 months after the ﬁrst operation. This phenomenon could justify the differentiation of the oligodendroglioma. The immature and atypical features of glioblastoma became more evident at the second operation. A type of glioma, which originally appeared to be oligodendroglioma with atypical areas, changed into glioblastoma in 1 patient 25 months after the ﬁrst operation. The longest postoperative survival period in patients with astrocytoma was 19 months, in those with oligodendroglioma 21 month, in those with glioblastoma 26 months, and in those with a changing type of glioma 6 months. The authors point out that in most instances there is reappearance of the symptoms of glioma rather than its recurrence. Astrocytoma and oligodendroglioma often change into glioblastoma. There is no evidence to show whether this is due to the intrinsic character— istics of the tumor, to the surgical intervention, or to the x-ray therapy. A gradual higher degree of malignancy seems to develop even in those gliomas which did not originally present a neoplastic structure. Surgical therapy, with rare exceptions, affords no beneﬁt to patients with recurrent glioblastoma but may be considered in patients with recurrent astrocytoma and oligodendroglioma. ].A.M.A., May 3, 1958 GYNECOLOGY & OBSTETRICS Induction of Ovulation in the Human: Therapeutic and Diagnostic Importance. H. S. Kupperman, J. A. Epstein, M. H. G. Blatt and A. Stone. Am. ]. Obst. 8: Gynec. 75:801-309 (Feb.) 1958 [St. Louis]. The authors explain on the basis of a diagram the current status of knowledge of the normal cyclic functioning of the pituitary-ovarian axis. A defect or alteration in any one of this normally sequential series of interactions can result in menstrual irregularities, ovulatory failure, and/0r amenorrhea. It was felt that speciﬁc hormone therapy in properly selected cases of failure of ovulation might artiﬁcially trigger the defective ovulatory mechanism. Since the proposed therapy theoreti— cally was to be speciﬁc for an isolated defect in ovulation, patients with other hormonal imbalances that secondarily inﬂuence the pituitary-ovarian axis were not included in the series. The patients who were euthyroid with normal adrenal function and who menstruated fairly regularly or who menstruated after therapy with progesterone and showed an absence of pregnanediol with a ﬂat basal body temperature were judged as having ovulatory failure and fulﬁlled the criteria established for the “potentially responsive” cases. Those whose only endocrinopathy was failure of ovulation received 20 mg. of conjugated estrogens (equine), administered intravenously as a single dose, not sooner than the 18th day of the menstrual cycle. Of the 40 patients treated, 31 were barren, and 9 were either single women with menstrual irregularities or married women practicing contraception. Nine pregnancies resulted among the 17 infertile patients in whom ovulation was induced after no more than 2 injections of estrogens given intrave— nously at intervals determined by the patients’ own basal body temperature charts. The history of infertility in the 9 women in whom treatment resulted in pregnancy ranged from 2 to 7 years. One of the nonpregnant patients had her ﬁrst spontaneous ovulatory menses in 3 years in the cycle subsequent to the menses induced by estrogens given intra— venously. Three other patients with a history of only infrequently occurring spontaneous ovulatory menses also had normal 28-day cycles for 1 period after that induced by estrogen. Moreover, 4 of the 9 pregnancies occurred during the cycle subsequent to the estrogen-induced ovulatory response. The negative responses were due to mechanical inability of the ovaries to respond to pituitary stimulation, i. e., polycystic ovaries of the Stein-Leventhallike syndrome, where the thickened ﬁbrous tuniCa presents a mechanical barrier to ovulation. Surgical exploration with bilateral ovarian wedge resection was advised in 8 of 12 infertile patients who were negative responders. In each of the 8 patients op- �COUNCIL ON DRUGS 1634 Orphenadrine Hydrochloride.—N,N-Dimethyl-2(o-methyl-a-phenylbenzyloxy) ethylamine hydrochloride—The structural formula of orphenadrine hydrochloride may be represented as follows: [CH3 CH Cy 0 CH2CH2N\ CH3 ' HCI CH3 ~ Actions and Uses.—Orphenadrine hydrochloride, the o-methyl analogue of the antihistamine, diphenhydramine hydrochloride, produces a reduction of voluntary muscle spasm. The effect is central, presumably by an inhibitory action on cerebral motor areas, and resembles the central effects of atropine. Orphenadrine exerts only weak antihistaminic and sedative eHects. It is not primarily a peripherally acting anticholinergic agent since, in therapeutic doses, it produces few of the typical effects on smooth muscle, the eye, or secretory glands which characterize atropine and other peripheral para— sympathetic blocking agents. The skeletal muscle relaxation is not of the type produced by mephenesin or zoxazolamine, since there is no evidence that it interrupts transmission through peripheral neuromuscular pathways. Nor is there any indication that it acts at the myoneural junction in the manner of the curariform drugs; it does not cause ganglionic blockade. Orphenadrine has been used for the symptomatic management of paralysis agitans (Parkinson’s disease). Subjective observations seem to indicate that the drug may bring about beneﬁcial effects in approximately half of the patients so treated. Rigidity is apparently relieved much more readily than is tremor; in occasional patients with severe spasticity, tremor may even be accentuated as the spasticity is relieved. Other salutary effects ascribed to the action of the drug include relief of oculogyria, sialorrhea, diaphoresis, blepharospasm, and disturbances in gait and balance. The drug also exerts a euphoriant effect which is useful in combating the depression and fatigue that frequently accompany this syndrome. In common with other antiparkinsonian drugs, the therapeutic effectiveness of orphenadrine diminishes with prolonged use. For this reason, and because it is considered somewhat less active than other antiparkinsonian drugs, orphenadrine is probably best employed as an adjunct to such other agents as procyclidine, trihexyphenidyl, cycrimine, or benztropine for the treatment of paralysis agitans. It may, however, be tried alone for patients who have become refractory to the other antiparkinsonian drugs. Because of its antispastic effect on voluntary muscle, orphenadrine has been proposed for use in a variety of clinical conditions which may be unrelated in etiology but in which pain due to J.A.M.A., July 26, 1958 skeletal muscle spasm is present. These have been described as sprains, strains, ﬁbrositis, whiplash injuries, noninﬂammatory rheumatic and arthritic states, and torticollis. Although such use might be considered a logical clinical application of the drug’s pharmacological action, the evidence available to date is not adequate to permit a sound conclusion as to the ultimate effectiveness of such therapy. Further studies are also needed to conﬁrm the possible usefulness of orphenadrine in the treatment of the extrapyramidal involvement associated with high doses of reserpine or phenothiazine-type tranquilizing agents. The clinical toxicity of orphenadrine hydrochloride appears to be low, at least with therapeutic doses. Thus far, side-effects have been limited to nausea, dryness of the mouth, dizziness, mild excitation, and occasional hallucinations. Most of these effects tend to subside or disappear with a reduction in dosage. Because of its anticholinergic classiﬁcation, orphenadrine should be administered cautiously to patients with glaucoma, tachycardia, or urinary retention. Dosage—Orphenadrine hydrochloride is administered orally. The usual initial dose is 50 mg. given three times a day. This dosage should then be ad— justed according to the clinical response of the individual patient and the appearance of sideeffects. Preparations: tablets 50 mg. Applicable commercial name: Disipal. Biker Laboratories, Inc., cooperated by furnishing scientiﬁc data to aid in the evaluation of orphenadrine hydrochloride. Pancreatic Dornase.—A stabilized preparation of the enzyme, deoxyribonuclease, prepared by fractional precipitation of aqueous acid extracts of beef pancreas followed by dialysis, sterilization by ﬁltration, and lyophilization. The activity of pancreatic dornase is determined by measuring the rate at which it reduces the viscosity of thymus deoxyribonucleic acid, potency being expressed in terms of units. One unit is an amount of enzyme which causes a drop of one viscosity unit in 10 minutes at 30 C, where the flow-time of water is taken as one viscosity unit. Actions and Uses—Pancreatic dornase is derived from beef pancreas, and, in contrast to the deoxyribonucleases produced by hemolytic streptococci (streptodornase), it is a single nuclease. Like streptodornase, it acts directly upon a substrate of deoxyribonucleoprotein (and deoxyribonucleic acid). The action of pancreatic dornase has been characterized as one of rapid depolymerization, with a resulting decrease in viscosity of purulent material. Pancreatic dornase degrades deoxyribonucleoprotein to relatively large-sized fragments, thus differing from streptodornase, which continues �Vol. 167, No. 13 COUNCIL ON DRUGS Mepazine Hydrochloride. — 10—[(1-Methyl-3—piperidyl ) methyl] phenothiazine hydrochloride—The structural formula of mepazine hydrochloride may be represented as follows: N-CH; < CH2 (II) .3 - HCI Actions and Uses—Mepazine hydrochloride is a phenothiazine derivative with actions and uses similar to, but not identical with, those of chlorpromazine. Although less potent, mepazine is not merely a weak chlorpromazine. Pharmacological studies indicate that it differs from chlorpromazine in that it does not lower the body temperature in rats as does chlorpromazine; it does not antagonize the waltzing syndrome in mice as does chlorpromazine; and it augments carotid sinus reﬂexes in cats whereas chlorpromazine inhibits them. The signiﬁcance of these differences with respect to its clinical usefulness is, at present, unclear. The drug is used principally for its calming or tranquilizing action in the management of neuroses and psychoses in which anxiety, tension, agitation, and increased psychomotor activity are predominant; it is said to exert a selective action to normalize the thinking process of mentally or emotionally disturbed patients. Because mepazine is less potent than chlorpromazine, it does not produce the excessive sedation, drowsiness, and depression which frequently accompany therapy with the latter drug. On the other hand, the diminished potency of mepazine makes it less effective than chlorpromazine for the long—term control of the most severe forms of agitation and tension; it has little or no immediate effect on acute psychotic disturbances. In terms of over-all psychotherapeutic effectiveness, mepazine might be considered to be intermediate between the most potent agents such as chlorpromazine and the milder agents such as meprobamate. Like chlorpromazine and other phenothiazine derivatives, mepazine hydrochloride exerts an antiemetic effect and may be used for the control of nausea and vomiting from a variety of causes. The drug has also been used for its calming effects in surgery, in obstetrics, and in anesthesia. Other reported clinical applications include use in narcotic withdrawal to control restlessness and agitation, in chronic alcoholism to lessen anxiety and tensions, and in advanced neoplastic states to reduce the 1633 quantity of narcotics needed for control of pain. However, sufﬁcient evidence is not available to establish its usefulness for the latter purposes. The acute toxicity of mepazine hydrochloride in experimental animals is less than that of chlorpromazine hydrochloride, and, in general, its clinical use is followed by a somewhat lower incidence of side-effects and untoward reactions. As already indicated, the usual doses produce a calming effect, with little sedation and drowsiness. Although jaundice has not as yet been observed with administration of mepazine, physicians should be alert to its possible occurrence. The drug should not be given to patients with a history of jaundice or liver damage. The most frequent side-effects of mepazine are atropine-like in nature and include blurring of vision, dryness of the mouth, and constipation. Since constipation can lead to more serious forms of intestinal obstruction, it should not be neglected; if necessary, laxatives should be prescribed. Less frequent side-effects include occasional dizziness, tremor, urinary retention, and transient hypoten— sion. The most serious toxic reaction to mepazine is referable to hematopoietic depression. As with chlorpromazine, the drug can produce leukopenia and granulocytopenia. It should, therefore, be used with discretion; peripheral blood cell counts are indicated at frequent intervals during therapy, and patients should be advised to report to the physician immediately upon the onset of fever, sore throat, or marked weakness. Because it potentiates the action of other central nervous system depressants, mepazine is contraindicated in patients under the inﬂuence of large doses of narcotics, barbiturates, or unknown large quantities of alcohol. Dosage.—Mepazine hydrochloride is administered orally. For the treatment of ambulatory neurotic patients, the usual initial dose is 25 mg. three or four times daily. This dosage can be increased every week by increments of 25 mg. per day until the desired effect has been attained. For those psychiatric conditions which are severe enough to require hospitalization of the patient, the initial dose is 100 mg. per day; this may be increased by 50 mg. every ﬁve to seven days. Maintenance dosage for such patients is usually 400 mg. per day or more. For the treatment of nausea and vomiting, the dosage ranges from 50 to 100 mg. per day. Dosage for use in surgical and obstetric patients has not been ﬁrmly established; single doses ranging from 50 to 200 mg. or more have been employed. Preparations: tablets 25, 50, and 100 mg. Applicable commercial name: Pacatal Hydrochloride. ’ �COUNCIL ON DRUGS 1632 the bacteria, as such, responded to the antibiotics, i. e., a transformation of the original bacterial arthritis into a chemical arthritis occurred. If the nodules were originally situated only in the skin (as clinically described) and only later appeared in the subcutaneous fat tissue (as described in the biopsy specimen and at autopsy), one could postulate that originally circulating trypsin caused vascular alterations in the deeper layer of the corium, with resultant skin nodules, and later the circulating lipase resulted in subcutaneous fat necrosis and subcutaneous nodules. Summary A chronic alcoholic patient had episodes of abdominal pain for two years, on the basis of a relapsing pancreatitis. Four weeks prior to his death, he developed swelling and tenderness of the various joints, with chills and fever. This could have been due to a bacterial polyarthritis associated with an acute pulmonary lesion such as pneumonia. The bacterial infection could have precipitated an acute pancreatic fat necrosis, on the basis of a Schwartzman phenomenon. Excessive amounts of circulating enzymes (trypsin and lipase) caused a striking involvement of the extrapancreatic fat tissue, cutaneous and subcutaneous nodules of fat necrosis, and necrosis of the periarticular fat tissue, initiating a chemical polyarthritis. The abdominal symptoms that appeared later were due to extensive J.A.M.A., July 26, 1958 mesenteric fat necrosis. The terminal jaundice was due to hepatocellular damage (toxic hepatitis) secondary to the pancreatic and extrapancreatic fat necrosis. The depression of blood calcium level was characteristic for extensive pancreatic fat necrosis and was due to saponification of the fatty acids liberated from neutral fat by the enzymatic action of pancreatic lipase. References 1. Roberts, N. J.; Baggenstoss, A. H.; and Comfort, M. W.: Acute Pancreatic Necrosis: Clinicopathologic Study, Am. J. Clin. Path. 20:742-764 (Aug) 1950. 2. Balser, W.: Ueber Fettnekrose, eine zuweilen todtliche Krankheit des Menschen, Virchows Arch. f. path. Anat., 90:520-535, 1882. 3. Hansemann, D.: Discussion in Verhandlungen arzt- licher Gesellschaften, Berl. klin. Wchnschr. 26:1115, 1889. Blauvelt, H.: Case of Acute Pancreatitis with Subcutaneous Fat Necrosis, Brit. J. Surg. 34:207-208 (Oct.) 1946. 4. Ponﬁck, E.: Ueber die sympathischen Erkrankungen des Knochenmarkes bei inneren Krankheiten, Virchows Arch. f. path. Anat. 56:534-556, 1872. Scarpelli, D. 0.: Fat Necrosis of Bone Marrow in Acute Pancreatitis, Am. J. Path. 32: 1077-1087 (Sept-Oct.) 1956. 5. Vogel, F. S.: Cerebral Demyelination and Focal Visceral Lesions in Case of Acute Hemorrhagic Pancreatitis, with Consideration of Possible Role of Circulating Enzymes in Causations of Lesions, A. M. A. Arch. Path. 52:355-362 (Oct) 1951. and Brakney, E. L.: Acute Hemorrhagic Pancreatic Necrosis Produced by Local Schwartzman Reaction: Experimental Study on Pancreatitis, J. A. M. A. 1553569574 (June 5) 1954. 7. Richman, A.: Acute Pancreatitis, Am. J. Med. 21:2466. Thal, A., 274 (Aug) 1956. COUNCIL ON DRUGS NEW AND NONOFFICIAL DRUGS Monographs and supplemental statements on drugs described here and in subsequent editions of New and Nonofﬁcial Drugs are based on the evaluation of available scientiﬁc data and reports of investigations. H. D. KAUTZ, M.D., Secretary. Mepazine Acetate.—10-[ ( l-Methyl-S-piperidyl) methyl]phenothiazine acetate—The structural formula of mepazine acetate may be represented as follows : N " CH3 < 0 CH2 ‘ u CH3C OH Actions and Uses.—Mepazine acetate has the same actions and uses as mepazine hydrochloride, except that it is administered parenterally. (See the monograph on mepazine hydrochloride.) Dosage—Mepazine acetate is administered by intramuscular or intravenous injection. For severely agitated psychotic patients, the dose by either route is 50 mg. three or four times daily. For the treatment of severe nausea and vomiting, daily doses of 25 to 75 mg. are injected intramuscularly. Dosage for use in surgical and obstetric patients has not been ﬁrmly established, but single intramuscular or intravenous doses ranging from 50 to 200 mg. or more have been employed. Mepazine acetate may be injected parenterally either as the full-strength solution or as a diluted solution. Chloride or alkaline solutions should not be used as diluents since they cause precipitation of mepazine acetate. Oral therapy with the hydrochloride salt should be substituted for parenteral injection as soon as possible. Preparations: solution (injection) 50 mg. in 2 cc. Applicable commercial name: Pacatal Acetate. �1631 DIAGNOSTIC PROBLEMS Vol. 167, No. 13 with antigenic properties may cause a Schwartzman reaction, and antigenic speciﬁcity is not involved, i. e., the provocative antigen need not be identical with the sensitizing antigen. It may be recalled that, in the case under discussion, the joint involvement was conspicuous early in the course of the disease. There was no deﬁnite evidence of rheumatoid arthritis, either clinically or pathologically. Bacterial polyarthritis, speciﬁcally of gonorrheal origin, should be considered, although a most careful search failed to reveal any evidence for a gonorrheal infection of the genital organs. Gonorrhea] polyarthritis in the early stages shows a serous type of synovitis, and cultures of synovial fluid may be negative. The association of polyarthritis with periarticular fat necrosis and pancreatic fat necrosis raises the following possibilities: 1. There may have been a rheumatoid of coincidence polyarthritis a pure with pancreatic fat necrosis, whereby the peri- The interesting feature of this case was the onset, with polyarthritis followed by the appearance of disseminated subcutaneous nodules, while the abdominal symptoms appeared later. The involvement of the pancreas proper, revealed at autopsy, TABLE 3.—Etiology of Acute Pancreatitis“ I. The common channel theory: reﬂux of bile into pancreatic duct secondary to obstruction of ampulla of Vater a. Calculus at ampulla of Vater b. Spasrn of the sphincter of Oddi c. Edema II. Obstruction of pancreatic ducts by 1. Stone 2. Spasrn of sphincter of ampulla of Vater 3. 4. 5. 6. Fig. 5.—Relatively well-preserved body and tail of pancreas. Large hemorrhagic, chalky, mesenteric mass extends downward from pancreas. III. Alcohol A. Acute B. Nutritional IV. Metabolic disturbances 1. Malnutrition (as it has been produced experimentally by ethionine) was not too extensive; it is possible that extrapancreatic involvement occurred early and was limited to the retroperitoneal space, enabling the escape of pancreatic lipase into the circulation by way of the lymphatics, circumventing the enterohepatic circulation. The resultant high lipase levels may account for the extensive involvement of the joints and skin. The various theories about the etiology and 2. Site Trauma VI. Vascular changes (Necrotizing arteriolitis; periarteritis nodosa) VII. Infection (e. g. mumps, scpticemic, acute cholecystitis?) VIII. Allergic a. Schwart7m3.n phenomenon * Extrapancreatic Fat Necrosis In Literature In Our Case + + ....................... Retroperitoneal fat tissue .................. + + Mediastinal tat tissue ...................... + — Subepicardial fat tissue .................... + Subcutaneous fat tissue ................... + + — Bone marrow ............................... + Central nervous system + (perivascular demyelinization) ........... + — Periarticular fat tissue ..................... + necrosis at the site of the original intradermal Mesenteric fat tissue Hyperlipemia V. pathogenesis of acute pancreatitis are summarized in table 3. An interesting recent theory6 relates acute pancreatitis to the Schwartzman phenomenon, whereby intradermal injection of a cell-free ﬁltrate of Salmonella, followed by intravenous injection of the same ﬁltrate, results in hemorrhagic TABLE 2.—-Sites of Edema of papilla of Vater Tumor of pancreas Squamous metaplasia of the epithelium in the ducts Surgical ligature —— V injection. Using this principle, injection of a bacterial endotoxin in sublethal doses into a pancreatic duct, with a subsequent provocative intravenous injection of the same endotoxin, has produced a fulminating pancreatitis in rabbits. Any substance Richman" (modiﬁed). articular fat necrosis occurred in a site of decreased resistance; but, despite the high incidence of rheumatoid arthritis and the relative frequency of pancreatitis, such a coincidence of these with periarticular fat necrosis has never been reported. 2. The pancreatic fat necrosis in the early clinically latent phase of the disease, with liberation of lipase into the circulating blood, may have led to a chemical polyarthritis due to extensive periarticular fat necrosis. 3. A bacterial (gonorrheal?) polyarthritis preceding pancreatitis cannot be excluded, despite the negative bacteriologic ﬁndings. One might speculate, on the basis of morphologic evidence of a chronic pancreatitis, that the pancreas was already sensitized. A bacterial polyarthritis could then have provided an antigenic provocation for a Schwartzman phenomenon, which led to an acute pancreatic fat necrosis, in the course of which large amounts of circulating trypsin and lipase were liberated. The circulating lipase caused a peri— articular fat necrosis, which in turn caused a proression of the polyarthritis, despite the fact that DEPAR MENT OF EXPERIMENIAL PSYCHIATRY HILLSIDE HOSPITAL GLEN OAKS, N. Y. JUL3 1 ‘5. �elements. 3. The rhythm of 4 -6 cycle/sec in the sub- cortical area disappears completely following administration of chlorpromazine in the dosage of 7.5—10 mg per kg, and does not appear even in response to painful stimulation with electric current; which undoubtedly indicates an inhibitory effect of chlorpromazine on adrenergic elements of these structures. 4. Administration of epinephrine against a background of a pronounced chlorpromazine effect produces a temporary decrease in symptoms of the chlorpromaaine effect on the organism. Accompanying this, there is a tendency to activation of electrical activity in all parts of the brain. 5. Comparison of our data with those in the literature leads us to the conclusion that the adrenergic substrate of the reticular formation exerts a complex inﬂuence on individual structures within the reticular formation as well as on the cerebral cortex. This action is apparently associated with metabolism of adrenergic substances, and for this reason it changes in a reciprocal manner as a result of the action of epinephrine and chlorpromazine. RE FERENCES 1. 2. AGAFONOV, V.G., Zhurn. nevropatolog. ipsikhiatr., 56, ANOKHIN, P.K., No. 2, 94, 1956. XX Mezhdunarodnyi kon— v Briussele (Collected gress fiziologov papers, 20th International Congress of Physiologists in Brussels), 151, M. , 3. 4. 5. 6. ’ 7. 8. 1956; Fiziolog. zhurn. USSR, 43, No. 11, 1072, 1957; Zhurn. vyssh. nervn. deiat.. 9, No. 4, 489, 1959. ANOKHINA, I.P., Zhurn. nevropatologi psikhiatr., 56, No. 6, 478, 1956. BAN'I‘SEKINA, M.M., Biull. eksper. biolog. i med., No. 8, 3, 1959. VERSHININ, N.V., Farmakologiiamchobnik) 137, M., 1952. GAVLICHEK, V., Fiziolog. Zhurn. USSR, 44, No. 4, 305, 1958. DOBRZHANSKAIA, A.K., Zhurn. vyld. nervn. deiat.. 9, No. 1, 22, 1959. POPOV, E.A. and T.A. NEVZOROVA, Zhurn. nevropatolog. No. 7, 559, 1956. 9. SHUMILLNA, 11. 12. 13. 14. 15. 56. A.I., Zhurn. nevropatolog. ipsikhiatr, 56, 10. ipsikhiatr.. No. 2, 118, 1956; Kinf. po vopr. elektrofiziolog. ts. n. s.. Tez. dokl. (Abstracts of Confsnnes on Problems of Electrophysiology of the C.N.S.), 144, M., 1958. BRADLEY, P.B. and A.I. HAUCE, EIG clin. Neurophysiol., 9, 2, 191, 1957. DELL, P., M. BONVALLET and A. HUGELIN, Journ. Physiol., 48, 403, 1956. GANGLOF‘F, H. and M. MONNIER, Physiol. et Pharmacol., acta, 15, l, 83, 1957. RINALDI, F. and H. HIMWICH, Dis. Nerv. System, 16, 5, 1955. ROTHBALLER, A.B., EEG clin. Neurophysiol., 8, 603, 1956. VOGT, M., Journ. Physiol.. 123, 451, 1954. THE ANTAGONISTIC ACTION OF CHOLINOMIMECTIC AND CENTRAL CHOLINOLYTIC AGENTS ON THE EEG OF THE RABBIT P.P. DENISENKO, Division of Pharmacology, Institute of Experimental Medicine, Um}! Academy of Medical Sciences, Leningrad (Received January 21, 1959) Today the presence of cholinerglc synapses in the central nervous system, particularly in the cerebral cortex, is considered an estab— lished fact. The cerebral cortex can be stimulated with acetylcholine (Markosian, 1937; Feldberg, 1950) and various "cholinopositive" substances — cholinomimetics (nicotine, arecoline) and anticholinesterases (physostigmine and diethyl p-nitrophenyl phosphate, or phos- phacol) — which, like acetylcholine, are capable of causing excitation of choline-roactive systems (Rizzolo, 1929; Miller, 1037; Stewart, 1952; Michaells, Finesinger, Ver— ster, Erickson, 1954). The rate of proﬁle- tion of acetylcholine in the cortex depends on the functional state of the cortex (Macintosh and Oborin, 1953). The establishment of the role and significance �of aeetylcholine in the activity of the cortex and other parts of the brain has aided in the under— standing and the correct evaluation and interpretation of the inﬂuence of cholinolytic drugs such as atropine, scopolamine, etc. upon psychic activity. ()1 the other hand, it has given rise to the synthesis and investigation of new sub- stances with cholinolytic action, inasmuch as this opens up an opportunity for entirely new methods in drug therapy of psychic and nervous diseases and increases the armamentarium of sedative and anticonvulsive drugs, as well as antidotes for poisoning with anticholinesterases. Among the cholinolytics known today there are a considerable number of substances capable of exerting a blocking inﬂuence chiefly on cholinergic structures in the central nervous system. Owing to the obvious predominance of central cholinolytic action over peripheral, substances of this type have, at the suggestion of S.V. Anichkov, been classed in a separate group — central cholinolytic agents.1 In chemical structure, central cholinolytic agents in most cases are complex esters of amino alcohols and aromatic acids, such 'as diethylaminoethanol and diphenylacetic acid. Pharmacologic studies of central cholinolytic agents are conducted by various methods, especially the methods of conditioned reﬂexes and electroencephalography; among others are experiments with convulsions produced by nicotine, arecoline, pentylenetetrazol, and other ' drugs. As research, electroencephalography is being increasingly widely used. However, out of the large group of cen— tral cholinolytic agents, this method has been used only for partial investigation of caramiphen (Pentaphen, Parpanit), benactyzine (IEMa method of 22, Diazil), and Z—diethylaminoethyl diphenylacetate (Diphacil, Trasentine) (Schallek and Smith, 1952; Paskov, 1958). In the current study an electrophysiological investigation was made of five new substances synthetized by S. F. Torf in the chemical lab— oratory of the Division of Pharmacology, In— stitute Fxperimental Medicine, USSR Acad— emy of Medical Sciences: Preparation IBM263 (benzene sulfonate 0f l—diethylaniinoisopropyl methoxyd l pheny lacetate . Preparation IEM-265, or Methyldiphacil (racemic l—diethylaminoisop ropyl diphenylacetate hydrochloride), Preparation [EM—268 (racemic 1-dimethyl aminoisopropyl diphenylacetate hydrochloride), Preparation [EM—273 (benzene— sulfonate of 2-methylcholine diphenylacetate), Preparation IBM—275, or Methyldiazil (racemic l «timethylaminoisopropyl benzilate hydrochloride». We also made a comparative study of the influence of certain other central cholino1 ‘The term "central cholinolytic agent" was approved and accepted at the 9th All-Union Conference of Physiologists, Biochemists, and Pharmacologists in 1959. 125 olytic agents, namely Diphacil, Diazil, Pentaphen, Aprophen (ﬂ-diethylaminoethyl diphenylpropionate hydrochloride), Diprophen w—di-Npropyl thiodiphenylacetate hydrochloride), and Tropacin (tropine diphenylacetate hydrochloride) upon the bioelectrical activity of the brain. METHOD Experiments were conducted on rabbits weighing 3 —4 kg with implanted nichrome or platinum electrodes. Potentials from the cortex (temporal and occipital areas), thalamus, and hypothalamus were recorded unipolarly. Experimental equipment consisted of a differential amplifier from the Moscow experimental shop and either an ink-writing or a type MPO—2 oscillograph. The amplitude—frequency characteristic of the ink-writing apparatus in the O — 70 cycle/sec range was flat to within 20%. The inﬂuence of the central cholinolytics, as well as of acetylcholine and cholinomimetics (nicotine and arecoline), on the spontaneous electrical activity of various parts of the brain was investigated. In addition, electroencephalography was used to show the existence of antagonism between these two groups of substances. No substance was administered to the same animal more than once a week. EXPERIME NT A l. RESULTS Before proceeding with the study of the in— ﬂuence of central cholinolytic agents on the electrical activity of various parts of the brain, we considered it necessary to determine how it changes under the influence of acetylvholine and cholinomimetics (nicotine and arecoline). This was essential because one of the tests in the study of substances of central cholinolytic action involves a determination of their anticonvulsive activity in nicotine and arecoline convulsions (Bovet and Longo, 1951; Kharauzov. 1954; Artem'ev, 1955. 1957; Zeimal', 1955, 1957; Golikov, 1956; Liberman, 1956; Sokolova, 1957; Smirnov, 1957; Fedorchuk, 1958; Jacobson, 1958). Intravenous injection of nicotine and arecoline (0.4 mg/kg) produces tremor and convulsions in the animal due to the stimulating effect of these substances on the choline—reactive systems of the brain. For further evaluation and analysis of the influence of central cholinolytic agents on the bioelectrical activity of the brain it was important to compare the picture of general excitation of the animal with the changes in the electrical potentials of the brain. Normally, the electrocorticogram of the rabbit was made up chieﬂy of waves of medium amplitude (30 -60 uv) and a rate of 4 —9 per second. Superimposed on these we re fast small waves with an amplitude of up to 15 av. Occasionally single high-amplitude waves appeared (5 —8 per min). As a rule, potentials �large doses (0.4 -0.5 mg/kugi. 1.9. .dosos which usually cause a convulsive seizure is animal. In the last case we recorded simultaneously the champs in brain potentials and of the thalamus and hypothalamus, were faster than those of the cortex but of considerably smaller amplitude (Fig. 1. 1-3; Fig. 2, 1-3; l-‘ig. 3). .l FIG. 1. Influence of nicotine and Diphacil on the RH; - - - somatosensory cortex; B hypothalamus. l normal EEG; 2 — 3 min after intravenous administration of nicotine in a dose of 0.43 mg/kg; 3 — prior to administration of Diphacil (6 days after the initial application of nicotine); 4 — 5 min after intravenous administration of Diphacil in a dose of 5 rug/kg; 5 — absence of stimulating action of nicotine (0.43 mg/kg) administered after Diphacil; 6 — 4 hours after administration of the preparations. A Cholinomimetics (nicotine and arecoline) were used in small doses (0.25 mg/kg) and the contractions in the hind limb. After the administration of choiinomimstios 126 �no FIG. 2. Antagonism of cholinomimetic arecoline and choline— lytic Methyldiazil displayed in the rabbit EEG. A — - somatosensory cortex, B thalamus. 1 — normal EEG; 2 — 3 min after administration of arecoline in a dose of 0.45 mg/kg; 3 restoration of original state; 4 — 5 min after intravenous- administration of Methyldiazil (0.5 mg/kg); 5 — absence of stimulating influence of are coline in the same dose after Methyldiazil; 6 — 8 hours after administration of the preparations. - the animal's behavior changed abruptly, espe— cially if administration occurred against a background of general depression which was usually observed after the rabbit had temporarily been in a darkened room. Whereas prior to the ad— ministration of the preparations the rabbit lay quietly in its stand with its head between its paws and at times even semi-asleep, following administration of nicotine or arecoline it exhibited unrest, turned its head, jerked, pricked up its ears and reacted keenly to any external stimulation. Mter epinephrine was given intravenously in the dose of 0.4 mg/kg, severe convulsive movements were observed lasting, with interruptions, for several min— utes. Along with the changes in the behavior of the animals already mentioned, there were also marked changes in the spontaneous elec— trical activity of the brain (Figs. 1 and 2). These changes took the form of an increase in amplitude and number of the high—frequency potentials and quantitative diminution, to and including complete disappearance, of high- �FIG. 3. EEGs in various parts of the rabbit brain before (upper oscillograms) and 5 min after (lower oscillograms) intravenous administration of central cholinolytic agents in the following doses: Diazil 0.5 mg/kg (A), Diphacil 5 mg/kg (B), Aprophen 2 mg/kg (C). Left, cortex; right, subcortical structures. amplitude slow waves. Changes in the EEG appearing after administration of nicotine evidently are not the result of induction of muscle currents but reflect changes in the electrical activity of the brain. inasmuch as they precede motor excitation of the animal. Such a supposition appears to be even more probable because 10 — 15 min after the strongest general excitation produced by administration of nicotine, the rabbit calms down (muscle tone becomes normal, movements decrease or disappear, and the animal reposes quietly in its stand) . Simultaneously with this, lowering of general EEG activity is observed, with an increase in the number of abrupt high waves and a diminution of the high-— frequency discharges. Comparison of changes in the EEGs of different parts of the brain discloses that follow— ing administration of nicotine cortical potentials show the first and strongest changes. Changes in the EEGs of the hypothalamus, thalamus, and other subcortical structures are less pronounced and appear later than the cortical changes. The other cholinomimetic, arecoline, in doses of 0.4-0.5 mg/kg also had a stimulating action: it caused unrest. convulsions, and tremor, which, as is generally recognized, are the result of the stimulating action of are— coline on the choline-reactive systems of the brain. The stimulating action of arecoline on ~ 128 the brain is reﬂected in the EEG to the same extent as is that of nicotine. As shown in Fig. 2, the amplitude of the fast oscillations, especially in the subcortex, rises sharply and the number of oscillations increases appreciably. Typical changes characteristic of excitation appeared in the EEG following intravenous injection of acetylcholine in doses of 0. l - 0. 8 ‘y/kg. In doses of 1 ~50 'y/kg acetylchouno produced such changes only du ring the first, very brief timevinterval after the injection; this was followed by a pronounced depression of electrical activity. Thus, in experiments with cholinomimetics (nicotine and arecoline) and acetylcholine. a characteristic picture of EEG changes a» crease in amplitude and number of fut rhythms and a decrease in slow waves) was produced which in combination with changes in the general condition and behavior of the rabbits (excitation, tremor, convulsions) permits us to regard, with a high degree of probability, the observed picture of EEG changes as a roll..tion of cerebral excitation. In addition, a clear—cut distinction was observed between the action of nicotine and arecoline on the cholinergic systems of the brain: the first and most marked changes uder the inﬂuence of nicotine are in the cortical EEG, but under the inﬂuence of arecoline, in the subcortical structures. The changes produced by �arecoline and nicotine are not identical in duration. The intensification of activity prochiced by administration of nicotine lasts a maximum of 10—15 min and is often succeeded by a general dqreesion of electrical activity. Potentials of normal magnitude and rhythm appear in l - 1 1/2 hours, but the sensitivity of the cholinsrgie systems to nicotine and mani— festation of the corresponding reaction to nicotine are not restored for 4 -—5 days. Arecoline a more lasting excitation which is succeeded by the normal EEG picture. 0n repeated one hour after the first injection, one may observe complete restoration of sensitivity b arecoline. Ahinistration of central cholinolytic agents gave opposite results. General calming of the animal was observed following administration of cholinolytic agents. This was manifested especially prominently when central cholinolytic agents were administered to animals which had not yet become accustomed to the stand and the experimental conditions, or when the prepara— tions were administered at the very beginning of the experiment when the rabbit remained somewhat excited. In such instances the ad— ministration of a cholinolytic agent caused jerking of the paw, attempts to escape the stand, head movement, and reactions to external stimuli (noise, light, and sound) to disappear immediately. Two to five minutes following admin— istration of Diphacil, Diasil, Pentaphen, Aprophen, and other substances in the group under investigation, the state of unrest was succeeded by general depression. of an intensity which depended on the dose of the cholinolytic agent. The rabbit lay quietly in the stand and reacted feebly to external stimulation. Simultaneously with the change in the state and behavior of the animal, characteristic changes were also observed in the electrical activity of the brain: slow waves (1 - 2 per sec) lg) to ”0 v predominated in the EEG. High— a potentials disappeared entirely or marke‘y decreased in number (Figs. 1, 2, 3). These cheapo in electrical activity following the injection of central cholinolytic agents could be registered in all portions of the brain which were under study. The intensity and duration of theee depended on the dosage of the agents admhistened as well as on their properties. This. similar changes could be observed following intravenous administration pm Motion frwy We of Diphacil. 5 mar/ks. Wen, Mammal-oil. 2 mar/ks; mg/kg; Diaail, 0.6 mg/kg; Methyl— easu. 0.1 mg/kg; and Diprophen, 15 mg/kg. other hand, intravenous administration cholinolytic agents in identical heee redted in dissimilar changes in the thalamus. and hypothalad cortex, such as Diazil and Methylmus. Motions dis-ll greater changes in the potentials of the structures than of the cortex. whereas administration of Methyldiphacil and Diﬂlacil renlted in greater changes in the cortex. Under the influence of Pentaphen. 1 it.eeet ~ ‘ I” h a“ Meal 129 131’ Aprophen, and to some extent Methyldiphacil, changes in the EEGs cf the cortex and subcortex were approximately identical (Fig. 3). Duration of the action of the preparations under study varied between 2 and 30 hours depending, apparently, on the dosage and their physico-chemical properties. The strongest and most lasting effect was observed after the administration of Diazil and Methyldiazil, and the weakest and shortest after administration of [EM-268 and Diprophen. Thus, experiments with central cholinolytic agents showed that they cause general depres— sion of the animal, a decrease in reﬂex activity and characteristic changes in the EEG (predominance of slow, high-amplitude potentials). Comparison of changes, following administra— tion of central cholinolytic agents, in behavior, general condition, and EEG, which were oppo— site to those seen after administration of cholinomimetics (nicotine and arecoline), per— mits the conclusion that the EEG changes produced by central cholinolytic agents reﬂect a state of cerebral depression due to blocking of the cholinergic systems of the brain. From our own and published data we knew of the antagonistic relationships between cholino— lytic and cholinomimetic agents that have been demonstrated on peripheral structures as well as in experiments with conditioned reﬂexes and with nicotine and arecoline convulsions. It was of interest to find out whether these antagonistic relationships are exhibited in the EEG. A special series of experiments were therefore carried out for the purpose of investigating the influences of central cholinolytic agents on the EEG already altered by the administration of cholinomimetics, and vice versa. It was found that central cholinolytic agents in definite doses prevent and cancel the action of cholinomimetics. As shown in Fig. 1, Di— phacil prevented the action of nicotine administered in a dose which usually produced a pro— nounced rise in electrical activity. Convulsions were the external manifestation of the stimulating inﬂuence of nicotine on the brain. Nicotine administered after Diphacil, Methyldiphacil, Pentaphen. and other preparations never pro— duced convulsions. Similar results were obtained wiﬂi arecoline: preliminary administra— tion of Methyldiazil prevented the effect of a convulsive dose of arecoline (Fig. 2). Figs. 1 and 2 show that normally both of these cholinomimetics exerted a pronounced inﬂuence on the EEG. Their administration in the same doses against a background of action by central cholinolytic agents was without effect; the EEG remained the same as after administration of central cholinolytic agents Diphacil and Methyldianil. In these experiments there were also data indicating a certain preferential antagonism batman arecoline and Diazil or Methyldiazil and between nicotine and Diphacil or Methyldiphsoil. Preparations such as Pentaphen and Aprophen prevent and cancel the action of - �arecoline and nicotine equally effectively. as application clinical for agents tion of these cholinolytics and tranquilizers. DISC U$ION REFERENCES experi— the of the course in clear It became experito an administration following ments that (Diphacil, preparations older of animal mental as and others) Aprophen. Pentaphen, Diazil, S.V.. In the book: Novye i eksperimente v sredstva lekarstvennye 1. ANICHKOV. and in experiments klinike (New drugs clinic), 5. L.. 1958. protivosudo— Izyskanie V.S., ARTEM'EV, 2. rozhnykh sredstv metodom eksperimental'anticonvulsive for search (A noi terapii agents by the method of experimental 1955; L. Dissertation. , therapy). i atsetilkholina rol' Fiziologicheskaia izyskanie novykh lekarstvennykh of role physiological (The veshchestv new for search the and acetylcholine drugs), 1. L.. 1.957. soveshch. dokl. Tez. GOLIKOV, S.N., 3. i claim. strukt. mezhdu sviazi p0 probl. the of (Abstracts veshchestv lekarstv. between Connection the on Conference 13, of Drugs), Action and Structure Tarw, 1956. dokl. Tez. iref. 4. DENISENKO, P.P., deiat. nervn. vyssh. probl. soveshch. p0 Problems on Conference the of (Abstracts of Higher Nervous Activity). No. 1, ‘6, 1... 1958. 1 mom. 5. ZEIMAL‘, E.V., Biuli. eksper.book: the in 1955. 42, 1, 39, med., Fiziologicheskaia roi' atsetilkholinai izyskanie novykh 106m rstvennykh of veshchestv (The physiological role new for search the and acetylcholine drugs), 79, 1... 1957. itoksiFarmakolog. LIBERMAN, 5.8., 6. kolog.. 6, 10, 1956. bioBiull. eksper. A.A., MARHEIAN, 7. 1937. 4 119, (2), med., log. Farmakoiogicholtm D.S., PASKOV', 8. GEM-275), Methyldiazil — agents well as newer — sigIBM-268 and (IBM-265), Methyldiphacil slow EEG: large the in develop nificant changes be— waves medium and waves appear and small be may changes These come less numerous. of cere— state of a manifestations regarded as confirmed interpretation an bral depression, the of experibehavior and condition the by mental animals. The depressant effect of central cholinolytic nature, cholinolytic of a is brain the agents on action the cancel and prevent inasmuch as they (nicotine, cholinomimetics and of acetylcholine stimu— a exert themselves which by arecoline), some is There brain. the on influence lating already which was antagonism, preferential discussed earlier. more one as serve hand, one on These data, synapses cholinergic of existence the of proof other the on system; nervous in the central the that proof convincing hand, they provide not characteristic is central cholinolytic effect of an but agents, cholinolytic individual only of of esters (complex entire class of compounds acids) which have amino alcohols and aromatic been called "central cholinolytic agents." and new that hope to Our data permit us found be posmay agents cholinolytic powerful Two action. central sessing a predominantly —- [EM-265 (Methyl— of the preparations studied — are (Methyldiazil) IBM-275 and diphacil) and tranquilizers as trials undergoing clinical cholinolytic drugs. 1 CONC LU SION'S to used was Electroencephalography 1. of properties cholinolytic establish the central complex representing of substances a number and aromatic diethylaminoethanol of esters acids. in manifested 2. A pronounced antagonism, central between exists EEG, their action on the agents. cholinomimetic and cholinolytic be— interdependence 3. There is a definite of action the and tween the chemical structure to the degree cholinolytic agents. According study under the preparations of vigor of action, of diminorder following the in may be arranged ishing strength: Methyldiphacil, and Aprophen phen, Diprophen. and IBM—268, Preparation chocentral the 4. The EEG data regarding esters complex of series of this ytic action recommenda— the which permits investigations u kharakteristika alkaloids Mann antikholinesteraznogv sredstva (Pharma— alkaloid of the characterizatmn cological Disantichoiinesterase), an nivaline as sertation, L.. 1958. rol' Fiziologicheskaia 9. SOKOLOVA, LA. . atsetilkholina i izyskanie novyldl vennykh veshchestv (The phydol“ role of acetylcholine and the 1957. 122, L., drugs), new 1 Parmakolog. 10. FEDORCHUK, IU. G.. 130 imh m ' toksil<olog., 4, 52, 1953. 11. KHARAUZOV, giperkine zov N.A., Farmakoterapﬂl tsentral'nogo proiskhoal- hyper“ deniia (Pharmacotherapy of of central origin). Dissertation. L.. 1954; Izbiratel'noe vliianie lekar not.” tsentral'nuiu na veshchestv nykh of influence (Selective nuiu sistemy -_., L.. system). nervous central the on ' ‘ �13. FELDBERG, W., Brit. Med. Bull., 6, 11, 312, 1950. 14. JACOEON, E... Antibiot. Med. a. Clin. Therapy, 5, 2, 89, 1958. 15. MACINTOSH, F. and P. OBORIN, Abstr. Comm. XIX Intern. Physiol. Congr. 580, Montreal, 1953. 16. MICHAELIS, M., J.E. FINESINGER, F. VERSTER and R.W. ERICKSON, Journ. Pharmacol., III, 2, 169, THE EFFECTS OF 17. 18. 19. ' 20. 1954. MILLER, F.R.. Journ. Physiol., 91, 2, 212, 1937. RIZZOLO, A., Arch. Farmacol., sper.,50, 16, 1929. Tsit. p0: Chem. Abstr., 24, 1158, 1930. SCHALLEK, W. and 1LT. SMITH, Journ. Pharmacol., 104, 3, 291, 1952. STEWART, W., Brit. Journ. Pharmacol., 7, 2, 270, 1952. HYPOCAPNIA ON THE FUNCTIONAL STATE OF THE RESPIRATORY CENTER G.L. FEL’DMAN, Department of Human and Animal Physiology, State University, Rostov-on-Don (Received January 8, 1960) METHODS The question of the physiological mechanism and biological function of sleep has long interested investigators (Legendre and Pierron, 1913; von Eoonomo, 1925; Hess, 1949; and others) and has also been the subject of syste— matic study in experiments conducted at the Pavlov Laboratory (Pavlov, 1911, 1923, 1935; Krasnogorskii, 1911; Rozhanskji, 1913; Petrova, 1941; Asratian, 1953; Anokhin, 1958). Ole method adopted for exploring the nature of sleep inhibition and its effect on normal behav— ior of the brain is that of artificial sleep depri— vation. Thus, as early as 1891, M.I. Manasseina demonstrated that keeping puppies awake for a period of 4 to 5 days will lead to death by degeneration of the nervous tissue of the brain Legendre and Pierron (1913) described histo— logical changes of the neurons in the region of the motor analyzer in the cerebral cortex of adult dogs deprived of sleep for 7 days. Prolonged sleep deprivation produces severe derangement of brain function, manifested in a derangement of the processes regulating biochemical activity (Fedorov and Sikolskaia, 1M1), nervous breakdown (Ukolova, 1959), and so on. Reports by N. Kleitman (1923), N. Kleitman and M. Li (1923), Tyler (1955), Bredlend (1955), and others, describe changes during experiments in sleep deprivation in The present study was conducted on 34 ani— mals (10 kittens between 18 and 30 days old, 13 kittens between 35 and 55 days old, 6 adult cats, and 5 puppies between 25 and 40 days old), with electrodes chronically implanted according to the method described by A. B. Kogan (1952). The electrodes were implanted in the region of the motor and visual analyzers of the cortex and in the subcortical sections of the brain. Potentials were recorded bipolarly with an interval between the electrodes of 3 mm for the surface electrodes, 1.5 mm for the depth electrodes. Recording was done with a two—channel electroencephalograph with optical recording or a four—channel ink-writing electro— encephalograph. Physiological tests were made of the effects of a sound stimulus (intermittent siren twice per second) and a tactile stimulus (an air current). Parallel with this, and with the same chronically implanted electrodes, determinations were made of the thresholds for direct electrical stimulation of the correspond— ing points in the brain. For purposes of comparison, we studied the intensity relationships for the motor components of the natural conditioned food reflex (Varukha, 1954) and coordination tests in which we analyzed the placement of the footprints made by the animals in walking. Throughout the period of wakefulness the animals were permitted to move about without restraint and were constantly observed under natural light by day and bright elect‘ric illumination at night. We kept the humans. Thus a study of the effects extended wake— fulness has upon brain function as revealed in the EEG and other indicators of. the functional state of the brain is a matter of definite interest. 131 �may be somewhat wider than the actual distribution, due to analytical errors and biological variation in the ratio of single bone to whole skeleton. It is predicted that in 1966 the average young child in the world will have a skeletal concentration of strontium-90 of about 4 MIC of strontium-90 per gram of calcium; that 10 percent may have a concentration of 8 one; that 1 percent may have a level of 20 uuc; and that none will have a level exceeding 80 one of strontium-90 per gram of calcium. References and Notes 1. Lamont Geological Observatory Contribution No. 347. This research is being supported by the Division of Biology and Medicine of the U.S. Atomic Energy Commission. Many individuals have contributed valuable suggestions and criticism. These include E. C. Anderson, C. L. Dunham, M. Eisenbud, H. Hollister. W. H. Langham, W. F. Libby, J. F. Loutit, L. Machta, W. G. Marley, N. G. Stewart, H. L. Volchok, and H. Q. Woodard. We also express our gratitude to the many medical doctors around the world who have assisted in essential sample procurement. Rieta Slakter is in charge of the Lamont analytical laboratory. R. Alley, W. Blake, T. Bott, J. Brokaw, D. IO :55» 5. 6. 7. 8. 9. 10. 11. 12. Harlin, M. Mandel,.._G. Markle, J. Rippey, J. Sonderburg, and R. lWoehr assisted in various aspects of the techniCal and secretarial work. J. L. Kulp, W. R. Eckelmann, A. R. Schulert, Science 125, 219 (1957). W. R. Eckelmann, J. L. Kulp, A. R. Schulert, ibid. 127, 266 (1958). The two commercial laboratories were Isotopes, Inc., Westwotid, N.J., and Nuclear Sci— ence and Engineering Corp., Pittsburgh, Pa. H. L. Volchok, J. L. Kulp, W. R. Eckelmann, J. Gaetjen, Ann. N;.Y. Acad. Sci. 71, l, 293 (1957); H. L. Volchok and J. L. Kulp, Nucleonicr 13, 49 (1955). D. L. Thurber, J. L. Kulp, E. J. Hodges, P. W. Gast, M. Warhpler, Science 128, 256 ' (1958). A. R. Schulert, E. A. Peets, D. Laszlo, H. Spencer, M. Charles, J. Samachson, Intern. ]. Appl. Radiation and Isotopes 4, 144 (1959). A. R. Schulert, E. J. Hodges, E. S. Lenhoff, J. L. Kulp, Health Phys., in press. J. L. Kulp and R. Slakter, in preparation. F. J. Bryant, A. C. Chamberlain, G. S. Spicer, M. S. W. Webb, Brit. Med. ]. l, 1371 (1958). Health and Safety Lab. U.S. Atomic Energy Comm. Publ. No. HASL—42 (16 June 1958). J. L. Kulp and R. Slakter, Science 128, 86 (1958). D. V. Booker, F. J. Bryant, A. C. Chamberlain, A. Morgan, G. S. Spicer, Atomic Energy Research Establ. (G. Brit.) Publ. No. HP/R 2182 (1957); F. J. Bryant, A. C. Chamberlain, A. Morgan, G. S. Spicer, Atomic Energy Research Establ. (G. Brit.) Publ. No. HP/R 2056 (1957). H. H. Mitchell, T. S. Hamilton, F. R. Steg~ 13. 14. Isosterism and Competitive Phenomena in Drugs q_ A study of structure-activity relationships in agents acting upon autonomic effector cells Daniel Bovet Making use of the considerable means offered by organic synthesis, many investigators have directed their efforts to the ﬁeld of therapeutics and have sought to lay the groundwork for a pharmaceutical chemistry or, better, for a chemical pharmacology. If such an ambitious program has not yet been fully realized, nevertheless, during the last ﬁve decades, one can notice the emergence of a few basic concepts whose usefulness continues to be conﬁrmed. This is particularly true of the concepts of isosterism and of competition. Numerous drugs were ﬁrst derived from products of biological origin, par- ticularly the alkaloids. The elucidation of their structure helped chemists to embark on syntheses of analogous compounds. In this respect cocaine, atropine, 8 MAY 1959 and morphine are good illustrative examples. The molecules synthesized according to their models exhibited clinically useful anesthetic properties, spasmolytic activity, or pronounced analgesic effects. In each case, chemical similarity produces in-some-way-related physiological properties. Analogous observations have subsequently been gathered in many other ﬁelds, but it has also become evident that sometimes very different, even antagonistic, pharmacological properties may be found in chemically similar molecules. Despite the fact that the concept of “antimetabolite” is based on rather old experiments, it was deﬁned essentially in the ﬁeld of “antivitamins”; the work of Woods (1940) and Fildes (1940) on 15. 16. 17. 18. gerda, H. W. Bean, J. Biol. Chem. 158, 625 (1945). H. Spencer, D. Laszlo, M. Brothers, ]. Clin. Invest. 36, 680 (1957); “Deposition and Retention of Ingested Strontium-90 in the Skeleton" (Washington, D.C., 23 Apr. 1957), committee report (ofﬁcial use only). C. L. Comar, R. H. Wasserman, M. M. Nold, Proc. Soc. Exptl. Biol. Med. 92, 859 (1956). C. L. Comar, I. B. Whitney, F. W. Lengeman, ibid. 88, 232 (1955). Consumer: Repts. 24, No. 3, 102 (March 1959). 19. J. L. Kulp, A. N. Kaufman, R. S. Slakter, W. R. Eckelmann, in preparation. 20. Health and Safety Lab. U.S. Atomic Energy Comm. Publ. No. HASL-5I (10 Nov. 1958). 21. L. Machta and R. J. List, “Stratospheric data and meteorological interpretations,” paper presented at a meeting on “ABC—sponsored Research and Development Related to the Collection and Classiﬁcation of Atmospheric Particulates,” held in Minneapolis, Minn., Oct. 1958. 22. W. F. Libby, Proceedings symposium on Noxious Eﬂects of Low Level Radiation, Schweizerischen Akadcmie der Medizinischen Witsenschaften 27-29 Mar. 1958, p. 309. 23. R. S. Russell, Nature 182, 834 (1958). 24. Unpublished data from the Lamont Geologi8—9 25. 26. 27. 28. cal Observatory, Palisades, N.Y. A. M. Brues, Science 128, 693 (1958). M. P. Finkel, ibid. 128, 637 (1958). E. B. Lewis, ibid. 125, 969 (1597). F. J. Bryant, E. H. Henderson, G. S. Spicer, M. S. W. Webb, Atomic Energy Research Establ. (G. Brit.) Rept. No. C/R 2583 (May 1958). the antisulfonamide component of yeast and its identiﬁcation as p-aminobenzoic acid found a large acceptance. The idea that a compound structurally similar to one normally present in the organism is able to interfere with the function of this metabolite could be applied in many ways. Its success, especially in enzymology [where, for the ﬁrst time, it was clearly formulated by Quastel (1925— 1928)], in chemotherapy, in vitaminology, and in endocrinology, obviates a detailed discussion of the underlying physi-L cochemical and biological principles. Instead, I would like to draw your attention to the importance of studies of competitive phenomena in pharmacodynamics, especially in the pharmacology of drugs of the autonomic nervous system. I would like to show how a very large part of therapeutical chemistry depends on the relations between many alkaloids or synthetic compounds and a few hormones, chemical transmitters, and products of tissue metabolism of rather simple chemical structure: epinephrine and norepinephrine, acetylcholine and propionylcholine, histamine, and 5-hydroxytryptamine (Table 1). Dr. Bovet is head of the department of therapeutic chemistry at the Istituto Superiore di Sanita, Rome, Italy. This article is a translation of his Nobel lecture, presented 11 December 1957, when he was awarded the Nobel prize for medicine and physiology for 1957. It is reproduced here with the permission of the Nobel Foundation. We are indebted to Dr. Ernest Schoffeniels of the department of neurology. College of Physicians and Surgeons, Columbia University, for the translation. 1255 �Drugs of the Autonomic Nervous System The history of the research in this ﬁeld is one of the most spectacular and successful chapters in the chemistry and physiology of the alkaloids and hormones. As far as transmitters of the sympathetic system are concerned, one may recall that the isolation of epineph— rine by Takamine (1901) was preceded both by empiric application of ephedrine-rich mahuang by the Chinese, and by the fortuitous discovery of the properties of tetrahydronaphthylamine by Bamberger (1888). The exact signiﬁcance of norepinephrine has been established only recently, by von Euler (1946). In the ﬁeld of parasympathomimetic agents, the observation of the properties of muscarine (1811) and the synthesis of acetylcholine (1866) preceded, by a century and a half century, respectively, the discovery of acetylcholine of Loewi (1921) and its isolation from tissues (1931). Histamine was synthesized (1907) shortly before its identiﬁcation in the products of animal and plant origin and before Dale and Dudley (1910) began their well-known studies of its pharmacological properties. The recent discovery of 5-hydroxytryptamine (Rapport, 1949) is the culmination of the work of Erspamer on enteramine isolated from enterochromaﬂin cells (1937—1952) and the work of Rapport, Green, and Page (1947— 1948) on the vasoconstrictor factor of serum, serotonin. The relationship between epinephrine, (CH2) /COO.CH2.CH2.N(CH3)31 “\COO.CH2CH2N(CH3)3 1 £5 E I34 8 0- 3 7 a% 2 w .=‘ - 3 g . 0 Fig. n=12345 Curarizing effect of choline esters 8 1. and dicarboxylic aliphate acids with normal chains. Curarizing activity was established in rabbits by measuring the “head dro P ” dose of the various compounds given intravenously. Curarizing activity reaches a maximum with succinylcholine and decreases with higher homologues of the series. [Bovet, Bovet-Nitti, Guarino, Longo, and Marotta, 1939] 1256 Table 1. Drugs with a competitive action with respect to epinephrine, acetylcholine, histamine, and 5-hydroxytryptamine. Adrenaline (noradrenaline) H \ CH0H.CH2rN/ , CH 0H Hydroxytrypt amine . . Histamine Acetylcholine CH 3 K CH3.COO.CH2.GH2.N\ 6213 CH/ H H \\N—c CH3 ’H NH-CH . OH CH 2. CH 2. H- cHz.CHz.N\H N/ \H H Sympatholytic Antihistaminics : Parasympatholytic Antihydroxytryptaagents : agents : .mines ” Ergotamine 929 F Atropine (spasmolytic Yohimbine 2339 R.P. (Antergen) agents ) Benzodioxane Curares: Pyrilamine d-Tubocurarine (933 F) Diphenhydramine Dibenamine Gallamine Antazoline Phentolamine Decamethonium Promethazine Succinylcholine Ganglioplegic agent: Hexamethonium Central ganglioplegic agents: Antiparkinson agents Antiphobic agents _ , tissue acetylcholine, and the nervous system was recognized early. In 1904, Elliot, struck by the similarity existing between the pharmacological action of epinephrine and the effect of stimulating the sympathetic system, proposed the hypothesis according to which epineph- rine is released from sympathetic nerve endings and transmits the impulse from nerve cell to smooth muscle ﬁber. Wieland in 1912 and Le Heux in 1919 tried to demonstrate that choline and acetylcholine were local hormones. Their hypothesis, we know, was successfully developed by Loewi, Dale, Cannon, and Bacq, whose experiments established the concept of chemical transmitters. The hypothesis of chemical transmission by acetylcholine ﬁrst proposed for viscera innervated by the parasympathetic system was later extended by Dale, Feldberg, and Vogt (1936) to the neuromuscular junction. Recent investigations on the physiology of the end plate have, in sum, conﬁrmed this mechanism. The reaction between acetylcholine and its receptor located at the postsynaptic mem— brane can now be integrated within the framework of electrophysiological ﬁndings, particularly those demonstrating electrical nonexcitability of this membrane and its great sensitivity to the transmitter (Kuﬂler, 1948; Castillo and Katz, 1956). To turn now to substances antagonizing these various hormones and transmitters, models for the synthesis of adrenergic and cholinergic blocking agents were furnished by compounds of biological origin, such as ergotoxine, atropine, and curare. The antihistaminics were studied later and represent syn- ' thetic products of completely original design. In practice, these drugs have been widely used in the symptomatic treatment of dysfunction of organs which are dependent on the activity of the autonomic nervous system: heart, blood vessels, bronchi, gastrointestinal tract, and uterus. The antagonists of epinephrine found their major application in the treatment of vascular disorders and hypertension. The antagonists of acetylcholine are used primarily as spasmolytic, mydriatic, and muscle-relaxing Table 2. Structural relations between and sympathomimetic Sympatholytic agents. [Raymond-Hamet, 1937; Bovet and Simon, 1936; Druey, 1936; Bovet, de Lestrange, and Fourneau, 1942; de Beer and Fassett, 1938; Hartmann and Isler, 1939; Gross, Tripod, and Meier, 1951] SYMPA'HOMIMEIIC AGEN’S /’ H0 \0H SYMPAYNOlVYIC AGENYS CHOHCHZNHCHg ACHECHENHE CH2CH2N(C2H5)2 V AC CH2CH2NHCH3 \v OCHZCH2N(C2H5)2 OH ANHCHECHzNH: N< V CH 2 mm L c (2115).? 93*” HUM HOMNH CH3 NCH3 o/\I~1chzc{r\m-<':H2 CHJDV OCH3 \N—CH; N CH2 C<NH—(IIH2 \N—CHg CH3 0H SCIENCE, VOL. 129 �agents. The antihistaminics are most useful in the treatment of urticaria, rhinitis, asthma, and other allergic diseases. For speciﬁc illustrations, I shall use examples from three different pharmacological groups. For the epinephrine group, I will consider ergotamine; for the antiacetylcholine group, curare; and for histamine, I will consider the syn— thetic antihistaminics. “ifssﬁm " , '" CH? C3 Synthetic Sympatholytic and Ergotamine-Like Compounds Sympatholytic drugs form a group characterized by common pharmacological properties. They act as competitors—or blocking agents, in AngloSaxon terminology—by opposing the effects of epinephrine and norepinephrine. Most characteristically, they block the hypertension and vasoconstriction produced by epinephrine. As is often the case, various drugs of this class were introduced empirically into therapeutics long before their pharmacological actions were established. As long ago as 1909, Froelich noticed that animals pretreated with small doses of the dextrorotatory isomer of epinephrine became resistant to the effects of the natural isomer. Today we explain this observation as resulting from a partial block of the receptors by a pharmacologically much less active enantiomorph of the compound. Later Loewe (1927), Kiilz (1936), and Raymond-Hamet (1937) described N-alkyl derivatives of phenylethylamine with sympatholytic properties; analogous properties were described in the phenoxyethylamine series (Anan, 1930; Levy and Ditz, 1933; Bovet and Maderni, 1933; Bovet, Simon and Druey, 1937), the phenylethylenediamine series (Bovet, de Lestrange, and J. P. Fourneau, 1942), the isoquinoline series (Hjort, de Beer and Fassett, 1938), and the phenylaminoethylimidazoline series (Meier and M'Liller, 1939; Hartmann and Isler, 1939). In each of these groups the structural similarities between the antagonistic molecules with either sympathomimetic or sympatholytic properties are evident (Table 2); the degree of substitution on the amine, the suppression or displacement of the phenolic function, the closing of a ring, are sufficient to reverse the pharmacological action. It is very important to notice that while the distance betWeen the amine function and the aromatic ring remains constant in both sympathomimetic and sympatholytic agents, the inhibitory 'molecule has always, in con: 8 MAY 1959 {gags seems i} {We casing mag, Fig. 2. Pachycurares. (Left) d-Tubocura- rine; (above) gallamine. Table 3. Classiﬁcation of the main groups of sympathomimetic and sympatholytic agents. ©-c-c—N ©—o-c—c—N ©mc-c-n Phenylethylamines Phenoxyethylamines Phenylethylene diamines Tiiii r i Sympathomimetic agents Phenolic derivatives of Phenylethylenediamine and Epinephrine its phenolic derivatives Phenylethylamines and their phenoxyethylamine phenolic derivatives Sympatholytic agents (aromatic series) N-Diethyl-N’-propyl-N’N-Diethylphenylethylamine N-Diethylphenoxyethylamine phenylethylenediamine Dibenamine Dibenzyline Tetrahydronaphthylamines, N-substituted Sympat/tolytic agents (heterocyclic series) N -MethyltetrahydroBenzodioxane: Phenylpiperazine Phentolamine isoquinoline Prosympal Benzylimidazoline Piperoxan Sympatholytic alkaloids Yohimbine Ergot alkaloids Table 4. Structural relations between sympathomimetic and sympatholytic agents: from epinephrine to ergotamine. [Marini-Bettolo, Chiavarelli and Landi, Vittory, 1950—1953; Bovet, Bovet-Nitti, Virno, Longo, Marotta, and Sollero, 1953] [NH _ CH3 CHOH-CHZ NH 2 ,NH2 / (31+2<:H2 NH2 GHz'ct' 0H3 OH OH Adrenaline Phenylethylamine Amphetamine Tetrahydronaphtylamine CH30H‘I3H2 IcorchH5 CH3 _ 843 LS alibi-c co C H2 -0H \Nz—CH 2 H 5-» 3 9| 6 1.5. _ CIH2 CH\ N/CHZ c,o\lI NH— N\ COG N‘ X30 ERGOTAMINE 1257 �The most active natural and synthetic tradistinction to the excitatory one, an amino group substituted by more, and heavier, radicals. Generally the inhibitory molecules also have a more stable structure and a higher molecular weight. sympatholytic compounds, whose effectiveness is sufﬁcient to permit their use in the clinic, are generally polycyclic or heterocyclic, with structures analogous Table 5. Investigations of synthetic oxytocic agents, derived from phenylglycinamide. [Bovet-Nitti, 1952, 1954] CH CH 3 3 NH- CH- CHZOH co- CONH-CIZHCHZOH CH2' CH2 N— CH3 CZ H5 NHCOCH2N< c2*‘5 8331.8. Ergometrine 62' " s CZ H5 NHCOCH2 N 1048 I €sz 1.3. ,6sz NHCOCHZN. H 0sz‘N- co- CHz-N c ’2 5 |062 |058I.S. 1.5. Table 6. Natural and synthetic curares: d-tubocurarine (King, 1935; Wintersteiner and Dutcher, 1943); 3381 RF. (Bovet, Courvoisier, Duclos, and Horclois, 1946) ; gallamine (Bovet, Depierre, and de Lestrange, 1947) ; succinylcholine (Bovet, Bovet-Nitti, Longo, and Marotta, 1949; Fusco, Palazzo, Chiavarelli, and Kniisli, 1949). “3‘0 <300 H 3 ‘ E"? 06H; on / ;.. C2H5 \ /"x I 1‘ ————©—o O—(CH2)5-—-0 I °2H5 3381 R.P. d-Tubocurarine ' O‘CHZ-CHZ'N(CZH5)3I ' on 2coocnzc H2N(CH3)BC! - , . o-cwcwmcm-I' 2 2. 253 or 0 Hz- CH2*N(CZH5)3'I ] _ . CHz-COOCHZCH2N(CH3)3C!‘ Succinylcholine Gallamine Table Subject Mammals Birds Amphibians (rectus abdominis) 1258 7. Pharmacodynamic properties of synthetic curares. Pachycurares (competing agents) : tubocurarine, gallamine Curarization Curarization Antagonism to acetylcholine Leptocurares (depolarizing agents) : succinylcholine, decamethonium Curarization (muscular ﬁbrillation) Contracture followed by curarization Acetylcholinic contracture to the above-mentioned compounds despite their complexity. Benzylimidazoline (Meier and Miiller, 1939) and dibenamine (Nickerson and Goodman, 1947) are related to the phenylethylamines; the aminomethyl-benzodioxanes (Fourneau and Bovet, 1933), to the phenoxyethylamines; and phentolamine (Gross, Tripod, and Meier, 1951) to phenylethylenediamine derivatives (Table 3). Studies conducted at the Istituto Superiore di Sanita by Marini-Bettolo and Chiavarelli, on the chemical aspects, and by F. Bovet-Nitti, Longo, Marotta, and Guarino on the pharmacological aspects, illustrate the usefulness of the concepts of isosterism and of competition in this kind of investigation. When the isolation and structural determination of the ergot alkaloids was achievedwresearches for which we are largely indebted to Stoll and Jacobs—— much work was done to prepare derivatives by partial or total synthesis; thus, dehydrogenated derivatives (Rothlin, 1947) and oxytocic derivatives closely related to ergometrine (Rothlin, 1947) were prepared, and the diethylamide of lysergic acid with hallucinogenic properties was discovered (Stoll). Since we proposed to investigate the structureactivity relationships of ergotamine, we used as our working hypothesis the con— cept relating structure to antagonistic action. At ﬁrst sight, the structure of the ergot alkaloids seems to be very different from that of epinephrine or of sympathomimetic derivatives of the phenylethylamine series. Nevertheless, since the skeleton of B-tetrahydronaphthylamine (2-aminotetralin) can be recognized in'the structure of lysergic acid, we decided to study compounds of this group (Table 4). Pharmacological tests with derivatives of relatively simple structure demonstrated the sympatholytic activity of 2-diethylaminotetralin (843 1.5.). Studies with more complex molecules, in particular the amide and amine derivatives of 2-tetralin, are a new step in the attempt to reproduce the essential portion of the lysergic acid skeleton. Using molecules of increasing complexity, one may go by successive stages from phenylethylamine to tetrahydronaphthylamine or to N-(2-tetra1yl) -N-methyl-N’-ethylB-alaninamide (916 LS.) and the ergot alkaloids, with a resulting progressive diminution at each stage of sympathomimetic properties and the appearance of sympatholytic properties. Oxytocic activity was observed in a large number of synthetic derivatives, SCIENCE, VOL. 129 �and this class of compounds seems very broad compared to that of adrenolytic substances (Table 5). In the course of experiments performed on rabbit uterus, isolated or in situ, several derivatives of aminotetralin and of aniline and even some aliphatic compounds showed strong activity. We may single out such examples as N,N-diethyl-N’- ( 2-tetralyl ) glycinamide (621 I.S.); N,N-diethyl-N’-3( 1048 4-dimethylphenylglycinamide LS.) ; and N,N,N’,N’tetraethylglycinamide (1062 LS.) (Bovet-Nitti, 1953). The main difﬁculty, apparently encountered also by other investigators, was the lack of parallelism between effects observed in laboratory animals and in man. Generally speaking, a satisfactory solution to the problem of syn— thetic oxytocies has not yet been reached, and the question is still under study. Antagonists of Acetylcholine: Synthetic Curares The problem of competitive agents that antagonize acetylcholine activity is rather complex, due to the multiple functions of this transmitter. Acetylcholine is the chemical transmitter in viscera innervated by the parasympathetic system; it has a role at the neuromuscu— lar junction, and it is liberated in ganglia during the passage of a nerve impulse. A surprising fact, which has been proﬁtably exploited in pharmacological investigations of competitive agents, is that compounds antagonizing acetylcholine differ according to the site of action of the local hormone. Thus, atropine and benzoylcholine neutralize the muscarinic effects of acetylcholine on cardiac receptors, on the intestine, or on secretions; tetraethylammonium iodide or hexamethonium block the nicotinic action of acetylcholine on sympathetic and parasympathetic ganglia. Finally, curares are speciﬁc antagonists of acetylcholine in striated muscle. With respect to the structure of antagonists, synthetic curares furnish us with a succession of examples comparable to those we have reviewed in the sympatholyticgroup. These investigations were begun in 1946, after King’s elucidation, in 1935, of the structure of one of the physiologically active constituents of Amazonian curares, and after the introduction by Grifﬁth and Cullen in 1942 of the chemically pure alkaloid as an adjuvant in anethesia. d-Tubocurarine, which is extracted from a menispermum, Chondodendron tomentosum, is found in curares prepared by the natives of the Upper Ama8 MAY 1959 , emcageugcagcagefcam Mammengmécm {1:39} CHQCG B Ci‘iéci‘ig ‘ ’ R;C8313 (CH333NCHgCRgu C0 CHg Fig. 3. Leptocurares. (Left) Decamethonium; (right) succinylcholine. zon. It is an alkaloid of the group bis ( benzyltetrahydroisoquinoline) , whose molecule has two quaternary ammonium ity, and this was also true for polyphenol ethers and aromatic esters. The latest investigations on the path to ultimate simpliﬁcation are concerned’ with the activity of aliphatic derivatives. In England, Barlow and Ing and Paton and Zaimis (1948) reported extremely interesting observations on the curare-like effect of decamethylene—w- functions. In research done with our colleagues, Viaud, Horclois, and de Lestrange, we ﬁrst looked for molecules structurally close to the selected model. By successive transformations, we were able to synthesize relatively simple derivatives with analogous properties (Table 6). From a series of new compounds with two quinolinic rings bearing quaternary ammonium functions, we ﬁrst selected the diiodoethylate of 8’ ,8’ ’ -diquinolyloxy1,5-pentane (3381 R.P.). This was the ﬁrst synthetic compound with curarelike action in mammals showing a speciﬁcity comparable to that of natural alkaloids isolated from curare (1946). It was then found that aminophenol derivatives which have neither quinoline nor isoquinoline rings had similar activ- bis-trimethylammonium hydrate (decamethonium). In our Laboratory of Therapeutical Chemistry at the Istituto Superiore di Sanita, the curare-like action of succinylcholine was ﬁrst recognized. This compound was synthesized by Hunt in 1911. The number and variety of compounds with curare-like action, the relative simplicity of their mode of action, and the possibility of precise pharmacological assay permitted a careful study of structure-activity relationships of synthetic curares. Solveni front D Iodine Carboxylic reagent Bromothymol blue 0 000 @%s + 60 O Enzymic hydrolysis (5%) 01 cm.{ R; 1 o O o @ @s....,...ho.... @ @ @ ® + a 2 § § Choline Succinylmonocholine Succinate 3 20 Control Non-enzymic hydrolysis (96) Fig. 4. Chromatograms of (a to e) succinlycholine at various stages of enzymic hydrolysis; (f) a mixture of succinylcholine and its products of hydrolysis; (g) 0.1 mg of succinylcholine after nonenzymic hydrolysis. [Whittaker and Wijesundera, 1952] 1259 �Fig. 5. Comparison between curarizing effects of d-tubocurarine (left) and of succinylcholine (right) given intravenously as a single fol— muscle of the Contraction anesthesia. gastrocnemius chloralose under (First line) the dog, continuous perfusion on injection or by lowing the.rhythmic stimulation of the sciatic nerve; (second line) control of the speed of injection; (third line) blood pressure. The record shows clearly the difference between the duration of neuromuscular paralysis following a single injection of succinylcholine (370 1.8., 0.05 mg/kg) and of d-tubocurarine (0.1 mg/kg). Also, on comparing the effect of a single injection of d—tubocurarine with continuous perfusion of succinylcholine (initial injection of 0.05 mg followed by repeated injection of 0.0062 mg at each signal), one sees that, for the duration of subtotal and reasonably uniform eurarization (about 80 percent, for 20 minutes), the reversibility of the effect is quick (about 10 minutes) after infusion of succinylcholine while it is slowly progressive (about 50 minutes) after injection of d-tubocurarine. [Reuse, 1953] I will mention only two important factors which inﬂuence the activity of bis-quaternary derivatives: the distance between the quaternary ammonium groups and the massiveness of the molecule. The ﬁrst factor is illustrated by comparison of polymethylene-bis-trimethylammonium derivatives (Barlow and Ing; Paton and Zaimis, 1948) as well as of aliphatic diesters of choline (Bovet, Bovet-Nitti, Guarino, Longo and Marotta, 1949) (Fig. 1). Careful pharmacological study showed that the action of new synthetic derivatives was sometimes quite different from that of the natural alkaloids. The differences between the action of decamethonium iodide and succinylcholine iodide on the one hand and the action of d-tubocurarine and of the tri— iodethylate of gallamine on the other were carefully studied by Paton and Zaimis, Brown and Dias and in our own laboratory. The British authors have proposed calling these two groups depolarizing agents and competitive curares. We proposed designating decamethonium and succinylcholine as leptocurares, and tubocurarine and gallamine as pachycurares (Figs. 2 and 3; Table 7). The advantage of our nomenclature lies in the fact that it does not presume the mechanism of action. The main differ— ence between the pharmacodynamic effects produced by the two types of curares is determined by the responses of amphibian and bird muscles. In birds, the pachycurares are typical curarizing agents, while leptoeurares induce con- ESHWEH H . CH, C“Cf~iLCHNH }; fag; \g‘fsfmwx ‘ as? N 1260 y 2‘ ecu, '2 CHECHEMCHM Fig. 6. (Left, top) Histamine; (left, bottom) pyridylethylamine; (above) pyrilamine. tracture that is followed by eurarization. In mammals the differences between the two groups are less sharp. The responses of muscle from different species or of different muscles from a single species are not always comparable. Also, intermediary steps seem to exist between depolarization and curare competition. The distinction between the groups, though relative with respect to the mechanism of action and the type of preparation used, are, nevertheless, useful if we want to compare relations between chemical structure and pharmacological activity. Clinically, the most important factor in classiﬁcation of curares is duration of effect. In this respect, the introduction of a short-acting curare, particularly succinylcholine, is an important step forward. The relative ease with which suc— cinylcholine is hydrolyzed by pseudocholinesterase and the very low toxicity of the products choline and succinic acid account for the brevity of action and the remarkable tolerance of the organism for this curare (Fig. 4; Table 8). The ﬁrst clinical observations concerning short-acting curares were published by Valdoni (1949) and Scurr (1951) and deal with suxethonium. The introduction of succinylcholine into anesthesiology was ﬁrst proposed in Sweden, by Thesleff (1951), Holmberg and Thesleff ( 1951), Tammelin and Low (1951 ) , and von Dardel (1951), and in Austria, by Briicke et al. (1951), Mayrhofer and Hassfurther (1951), and Holzer (1951). In the light of these various investigations, one may today recognize two methods of using succinylcholine: single injection when very short action is required (as for endoscopy or electroSCIENCE, VOL. 129 �Table 8. Hydrolytic products of succinylcholine. (CHgaN‘CiECi-izococ Hacib c OOCHZC HZN ’(c 1493.1’ -Succiny|choline 1'. (CH3)? CHZCHZOCOCHZCI‘ECOOH + OHCHZCHZN (cl-1‘3)3 I Choline Succinylmonoct‘oline l lrl(.7H3)3N CH2 CH 2OH+ HOOCCHZCHZCOOH Succinic acid Choline shock) or continuous infusion in surgical procedures of long duration. Two recordings from a study in our laboratory demonstrate results obtained with the two types of application. They show the superiority of continuous infusion of short-acting curares over the classical technique (Fig. 5). Antihistamines The last example I will use to illus— trate the concept of competition is concerned with compounds that antagonize the third local hormone, histamine. This particularly rich ﬁeld since the usefulness of these compounds has stimulated a great many investigations within a very few years. In 1937, in Fourneau’s laboratory, we began—A. M. Staub and I—to look for compounds antagonistic to histamine. Considering the number of features that histamine, acetylcholine, and epinephrine have in common, we looked for antagonism comparable to that exhibited by sympatholytic compounds toward epinephrine and by parasympatholytic compounds toward acetylcholine. We obtained the ﬁrst positive results in 1939 with thymoxyethyldiethylamine (929 F). Our experimental work was then directed toward deﬁning criteria for antihistaminic activity. Staub (1939) extended her observations to phenylethylenediamine derivatives. In 1942, the syntheses by Mosnier, the pharmacodynamic studies of Halpern, and the ﬁrst therapeutic results of Cuilleret, Thiers, Gaté, Celice, Perrault, Decourt, and Durel with dimethylaminoethylbenzylaniline, or Antergan, deﬁnitively established interest in compounds of this group. The role played by histamine in many allergic affections assures a broad area of clinical application of these compounds. After the pio— neers (Maderni, de Lestrange, and Benoit in Fourneau’s laboratory in Paris; is a Table 9. Principal groups of synthetic antihistaminics: 929 F (Bovet and Staub, 1937) ; Antergan (Halpern, 1942); antazoline (Meier and Bucher, 1946); diphenhydramine (Loew, Kaiser, and Moore, 1945); promethazine (Halpern and Ducrot, 1946); chlorphenamine (Tislow, La Belle, et al., 1949) ; pyrilamine (Bovet, Horclois, Walther, and Fournel, 1944); tripelennamine (Mayer, Huttrer, and Scholz, 1945) ; thonzylamine (Reinhard and Scudi, 1947). Antihistaminics related to: Sympatholytic agents onQ [OHS CH ocnac H2N(62H5)2 CH3 929F ”Q CH ‘0H 2 0H 2 Maria) 2 Antergon Q Spasmolytic agents 0 \ZCH CH Diphanhydramine O cuzcnmcusiz N \ N-CH2 _ Antozoiine 8 MAY 1959 :EH GHZCH2N(CH3)2 Chlorphenamino 2N(CH3) Pyrilamine N‘cnacnzmchu 3 CH— @001 ECHocH ZCHZNKSH 3’2 Promethazine \C Histamine Tripulennominc ﬂZOOCHS N/ \ZCHZCHZNCHa) Thonzylamino Table 10. Structural relations between histamine and antihistamines. [Walter, Hunt, and F osbinder, 1941; Nieman and Hays, 1942; Bovet and Walthert, 1943] NH /\ / / ’I CH2 CH2 NHZ , I, HISTAMINE Histamine action 2. N I Antihistamine action HQ": CH2 CHZN: (/\n-CH2.GH2.NHZO KEV) /J Nona \ ,/<CH 2 .0H 2 .NH 2 \ "[0142 A" (7N1ii KN 6H2 ii; N’0 2 ‘01:: CH 0 o \N ~ /-CH2CH2. NH2 “3 + K I R N: N [CH3 CH2.CH .N\ * CH% Viaud, Horclois, Mosnier, and Charpentier in French industry; Hartman and Hofman in Switzerland; Rieveschl, Scholz, Huttrer, and Roblin in the United States; Cavallini in Italy), about 500 chemists synthesized, in less than ten years, more than 5000 compounds in the antihistaminic group. Pharmacologists were easily able to recognize the competitive nature of the antagonism exerted by these antihistaminics toward histamine. Chemists, however, could not perceive any relation between the structure of antihistaminics and histamine which logically might explain such activity, nor could they ﬁnd a relationship among the various active compounds. It was therefore impossible to escape the conclusion that most of the results were rather empirical. From the pharmacological viewpoint, it was possible to distinguish three groups of substances (see Table 9) with antihistaminic action and relate them to (i) the sympatholytic group; (ii) the parasympatholytic-sympatholytic group; and (iii) histamine itself. To the ﬁrst group belong the phenolic esters (929 F) and the phenylethylene— diamine derivatives (1571 F) studied at the Pasteur Institute, Halpern’s Antergan, and the antazoline of Meier and Bucher. The compounds of the second group, from a chemical point of view, have more homogeneous structures, in 1261 �common with atropine-like drugs and other spasmolytics; some of these are, in fact, spasmolytic as well as antihistaminic (diphenhydramine). In derivatives of a-aminopyridine, which form the third group, the antihistaminic action is more speciﬁc and almost free of secondary effects. It is interesting to note in this group the isosteric reactions which account for the pharmacological activity. Walter et al. (1941) and Niemann and Hays (1942) have shown that a-pyridylethylamine derivatives have histamine-like activity, and that a fundamental difference exists between a-, [3-, and y-substituted pyridines in this respect. In this case, the analogy of structure which is not evident between histamine and pyrilamine (Neo-Antergan) may be seen between the groups a-pyridylethylamine and (it-pyridine ethylenediamine (Table 10, Fig. 6). A typical compound from this group is pyrilamine (see Fig. 7), but many other synthetic compounds of similar design have also proved to be active. Central Action of Transmitters The compounds considered so far do not exhaust the ranks of competitive agents. Pharmacologists are to some extent les enfants terrible: of physiology. They did not wait for the battle of the neuromuscular junction to be won before engaging in a more difﬁcult encounter. They proposed that the available evidence suggested the action of a chemical transmitter in the central nervous system, exactly as in the autonomic nervous system. Analyzing the collective results from various laboratories, Feldberg (1950) concluded that the theory ascribing a transmitter role to acetylcholine in the central nervous system was the only one able to offer convincing and satisfactory interpretations. Even if intervention of noncholinergic chemical transmitters in the central nervous system is not excluded, we must admit that our knowledge about the probable roles of norepinephrine, epinephrine, histamine, and 5-hydroxytryptamine is still quite incomplete. The physiological role of the reticular formation in the brain stem has been clearly deﬁned by Moruzzi and Magoun (1949). In the last few years, a considerable number of investigations have shown that compounds affecting the autonomic nervous system also affected this formation. Paradoxically enough, cholinergic as 1262 HISTAMINE 0.001 cm/H 0 20 .mm/Hg 200 100 0 15 PYRILAMINE HISTAMINE 1.0 0.001 “ j 1 V. 10 5 0 0 ‘_3lOsec Fig. 7. Antagonistic action of pyrilamine with respect to the vasodilating effects of histamine in cerebral circulation. The subject was a dog under chloralose anesthesia. (A) Blood pressure, femoral artery (mm-Hg); (V1) pressure recorded through a catheter introduced in a centrifugal direction into the external maxillary vein (mm-H20) ; (V2) pressure in the internal maxillary vein (mm-H20). Injection was made into the saphenous vein; dosages are given in milligrams per kilogram. [Virno, Gertner and Bovet, 1956] well as adrenergic substances affect the electrical activity of the cortex in the same way that direct electrical stimulation of the reticular formation does. Under well-deﬁned experimental conditions, acetylcholine (Bonnet and Bremcr, 1937) and epinephrine itself (Bonvallet, Dell, and Hietzel, 1954) provoke a transient activation in the electroencephalogram. The administration of either an anticholinesterase (eserine, diisopropyl ﬂuorophosphate) or of amphetamine (Bradley and Elkcs, 1953) produces an intense and prolonged desynchronization. From a strictly pharmacological viewpoint, the major interest in this type of investigation stems from the similarity in observed antagonisms between various groups of drugs in the central nervous system and in viscera innervated by the autonomic nervous system. As early as 1947 we suggested that in extrapyramidal syndromes some relation might exist between the central, “antiparkinson,” effect of certain tertiary amines and their ganglioplegic properties in peripheral ganglia (Sigwald and Bovet; Dumont; 1947). “Antiparkinson” drugs form a relatively homogeneous group comprising diethazine (Diparcol), isothazine (Parsidol), caramiphen (Parpanit), and trihexyphenidyl (Artane), as well as some antihistaminics (diphenliydramine and promethazine). Electroencephalographic studies (Fig. 8) have shown that three groups of compounds produce an electroencephalogram similar to that recorded during sleep: the parasympatholytics (scopolamine and atropine), the central ganglio— plegic or “antiparkinson” drugs (Table 11), and the neuroleptics (chlorproma- w; mwgwmmwww W MWMvM 51mm ‘ . -..,: p‘, 51%; g‘ﬁ‘kﬁﬁg‘ﬁ’?‘ “if“?'9““(high ‘) K $3.)wa ai’zfiig'f$6,133?3.25% “ if: (3:1‘331“ ii 4, ,. “‘ ;.§l(¢t {brave-112m}? Fig. 8. Antagonistic action of diethazine against convulsive patterns caused by nicotine on the electroencephalogram of curarized rabbit. (A) Blocking reaction after acoustic stimulation (black line). (B) Convulsive seizure by nicotine (2 mg/kg) in normal animal. (C) After injection of diethazine (5 mg/kg) a second injection of nicotine no longer produced the electrical changes observed previously. and the acoustic stimulus fails to produce the blocking reaction. [Longo and Bovet, 1952] SCIENCE, VOL. 129 �zine, reserpine). These also antagonize the cortical reaction elicited by external stimuli (stress) or by desynchronizing agents (eserine and amphetamine) (Bovet and Longo, 1956). The effect of such synchronizing agents may, as a ﬁrst approximation, be localized in the reticular formation and thus be comparable to the importance of chemical transmitters at this level. Many observations suggest that speciﬁc receptors fOr epinephrine, acetyl- choline, and histamine are speciﬁc proteins with a structural conﬁguration complementary to that of the transmitter. This concept was ﬁrst proposed by Fischer, who illustrated it with the now famous model of key and lock. his mechanism has been invoked to explain observations in physiological and chemical studies of taste and smell. Recently, Landsteiner and Pauling applied this idea of “complementary conﬁguration” in the ﬁeld of immunological reactions. At this point it would not be possible to consider the various aspects of reactions between chemical transmitters, inhibitors, and receptor proteins without taking more space than is available. The particularly simple case of binding acetylcholine with cholinesterase has been studied by Nachmansohn (1953— 1954) and Wilson (1954). They consider acetylcholine to be attached at two points, one electronegative and the other elcctropositive, and have drawn valid conclusions with respect not only to various anticholinesterases but also to a new group of drugs that reactivate the phosphorylated enzyme. If I cared to develop the extensive areas covered in this article I could include other topics and point out that different groups of compounds affect the metabolism of mediators because they are precursors or because they inhibit synthesis, slow down or accelerate liberation, or interfere with destruction. In every phase, investigations have been successful and the results appear to be very promising. Conclusion The composite picture I have tried to present, at the risk of relating many al— ready well-known facts, appears, despite inevitable gaps, very certain. If, in concluding, we rapidly retrace our path, we will see that in covering the vast ﬁeld of pharmacology, the structures of a small group of remarkably simple biogenic amines have led us, like the thread 8 MAY 1959 Table 11. Central ganglioplegic agents: diphenhydramine (Loew, Kaiser, and Moore, 1945) ; diethazine (Sigwald, Bovet, and Dumont, 1946; Bovet, Fournel, and Charpentier, 1947); caramiphen (Domenjoz, 1946; Griinthal, 1946); trihexyphenidyl (Doshay and Constable, 1949). / \ / \ CH-O-CHz-CH2~N(GH3)2 Diphenhydramine (Benadryl) -GO'O‘ OHZ'GHZ'N(02H5)2 Caramiphen <// \\> S N'CH2'CH2N(02H5)2 :COH'CHZCHZN > Diethazine Trihexyphenidyl of Ariadne, through the labyrinth of very a name always well-known and sometimes very close to us. The future of pharmacodynamics is, nevertheless, so rich and promising, and diverse physiological actions and chemical structures. It has been said that the art of the orator is to speak about what he knows and to hide his ignorance. I do not feel any need to resort to such an artiﬁce in presenting the current picture of the chemical pharmacology, because it is, in ﬁnal analysis, only a kind of “natural history” and classiﬁcation of organic molecules. I would say that the results obtained so far give rise to optimism because they let us catch a glimpse of the pharmacology to come as a well-ordered and well-deﬁned science in which foods, drugs, and poisons will be integrated in the metabolism of the simplest constituents of living matter. Finally, in recalling the great names associated with studies of the pharmacological agents that made it possible for us to reach our present level, I can only speak with emotion of all those who preceded me, particularly of my teacher, Ernest Fourneau, who wrote such a great and glorious chapter of therapeutic chemistry and whose name will forever be written in the history of this science. My feelings are sincerely divided between the immense pleasure I feel at the honor which is bestowed on me and my sense of inadequacy at being unable to repay my teachers and colleagues all that I owe them. This feeling is the more vivid because therapeutic chemistry is a very young science that has developed amazingly during the past half century; perhaps in no other domain does the part played by each individual appear so clearly and with such continuity as in our studies, where every formula bears it bears so many theoretical and prac— tical possibilities, that I cherish the hope that my future work will justify not only the marvellous distinction I have received today but also the conﬁdence and the friendship of my teachers and colleagues, whose works cannot be separated from those I pursue with confidence, enthusiasm, and love. Bibliography The following bibliography includes mainly general reviews; concerning studies published prior to 1948, the reader is referred to the work published in collaboration with Mme. F. Bovet-Nitti. Z. M. Bacq, “La pharmacologie du systeme nerveux autonome, et particuliérement du sympathique, d’apres la théorie neurohumorale,” Arm. physio]. physicochim. biol. 10, 467 (1934). D. Bovet, “Introduzione allo studio ﬁsiologico e farmacologico del curaro,” Boll. soc. ital. bio]. sper. 25, 539 (1949). , “Introduction to antihistamine agents and Antergan derivatives,” Arm. N.Y. Acad. Sci. 50, 1089 (1950). , “Some aspects of the relationship between chemical constitution and curare-like activity,” ibid. 54, 407 (1951). and F. Bovet-Nitti, Structure et Activite’ pharmacodynamique des Médicaments du syrtéme nerveux vége’tatif (Basle, 1948). “Curare,” Experientia 4, 325 (1949). , “Rapports de structure entre sympathomimétiques et sympatholytiques. De l’adrénaline a l’ergotamine,” Actualités pharmacol. N0. 6 (1953), p. 21. , “Le chlorure de succinylcholine, agent curarisant a breve durée d’action,” Sci. Med. Ital. 3, 509 (1955). , S. Guarino, V. G. Longo, R. Fusco, “Recherches sur les curarisants de synthése. III, Succinylcholine et dérivés aliphatiques,” Arch. intern. pharmacodynamie 88, 1 (1951). D. Bovet and V. G. Longo, “Pharmacologie de la formation réticulée du tronc cerebral,” Oomph-rend. 20éme Congr. intern. physiol. Bruxeller (1956), pp. 306—329. D. Bovet and P. Viaud, “Curares synthése: Chimie et pharmacologie,” Aneslhésie et analgésie 8, 328 (1951). F. Bovet-Nitti and D. Bovet, “Recherches sur les ocytociques de synthése: dérivés de la phenylglycinamide,” Arch. intern. pharmacodynamic 6, 327 (1954). F. Briicke, “Dicholinesters of -dicarboxylic acids ‘ 1263 �and related substances,” Pharmacol. Revs. 8, 265 (1956). W. B. Cannon and A. Rosenblueth, Autonomic Neuroeﬂector System (New York, 1937). J. Castilljo and B. Katz, “Biophysical aspects of neuro—muscular transmission,” Progr. in Biophys. and Biophys. Chem. 6, 122 (1956). H. H. Dale, “Transmission of nervous effects by acetylcholine,” Harvey Lecture Ser. 32, 229 (1937). L. Donatelli and U. Seraﬁni, Gli antistaminici di sintesi (Naples, 1951). J. C. Eccles, “The electrophysiological properties of the motoneurone,” Cold Spring Harbor Symposia Quant. Biol. 17, 175 (1952). V. Erspamer, “Pharmacology of indolealkylam~ mines,” Pharmacol. Revs. 6, 425 (1954). U. S. von Euler, “The nature of adrenergic nerve mediators,” ibid. 3, 247 (1951). S. M. Feinberg, S. Malkiel, A. R. Feinberg, The Antihistamines (Chicago, 111., 1950). W. Feldberg, “The role of acetylcholine in the central nervous system, Brit. Med. Bull. 6, 312 (1950). R. Fusco, G. Palazzo, S. Chiavarelli, D. Bovet, “Ricerche sui curari di sintesi, IV,” Gazz. chim. ital. 79, 836 (1949). L. S. Goodman and M. Nickerson, “Clinical ap- plication of adrenergic blockade,” Med. Clin. N. Am. 34, 379 (1950). H. R. Grifﬁth and G. E. Johnson, “The use of curare in general anesthesia,” Anesthesiology 3, 418 (1942). B. N. Halpern, “Les antihistaminiques de synthese, essais de chimiothérapie des états allergiques,” Arch. intern. pharmacodynamie 68, 339 (1942). , “Sur le mécanisme d’action des antihistaminiques de synthése,” Presse Med. 57, 949 (1949). H. R. Ing, “The curariform action of onium salts,” Physiol. Revs. 16, 527 (1936). S. W. Kuﬂler, “Physiology of neuro-muscular junctions: electrical aspects,” Federation Proc. 7, 437 (1948). O. Loewi, “Problems connected with the principle of humoral transmission of nerve impulses,” Proc. Roy. Soc. (London) 1188, 299 (1936). G. B. Marini~Bettolo, “Contribution a l’étude des alcaloides des Strychnos du Brésil,” Festschr. Arthur Stoll (Basel, 1957), pp. 257—280. , S. Chiavarelli, D. Bovet, “Ricerche sui simpatolitici di sintesi della serie dell’ergotammina,” Gazz. chim. ital. 80, 281 (1950). A. R. McIntyre, Curare. Its history and clinical use (Chicago, 111., 1947). D. Nachmansohn, “Metabolism and function of Manuel Luz Roxas, Agricultural Chemist Manuel Luz Roxas was one of the foremost scientists in the Philippines. His valuable services to the University of the Philippines as a teacher of chemistry in the College of Agriculture and the important role he played in the creation and organization of the National Research Council of the Philippines will be long remembered. Almost immediately after Dr. Roxas’ graduation from the University of the Philippines in 1911, with a BS. degree Hg? ‘ \ ._ Manogmmm OF in Agriculture, his ﬁrst research work appeared in the Philippine Agriculturist and Forester under the title “The pandan industry in Majayjay.” This was soon followed by three other articles in the same journal: “The cultivation of coconut,” “The effect of some stimulant upon rice,” and “The coffee industry in the island of Luzon.” Dr. Roxas pursued further studies in his chosen ﬁeld and in 1913 obtained his MS. degree at the University of the Philippines, where he then served as instructor in chemistry until he was appointed a university fellow to the United States. Evidently this appointment was in recognition of his unusual endowment with the “divine spark” to perform research. He enrolled in the University of Wisconsin and received his Ph.D. there in 1916. On his return to the Philippines, Dr. Roxas resumed his position in the Col-' lege of Agriculture in the University of the Philippines, where he was later appointed assistant professor, then professor of chemistry, and ultimately, professor emeritus of agricultural organic chemistry. He was also named Distinguished Alumnus of the University of the Philippines in 1932 for achievement in scientiﬁc research. All these deserved 11111111111111 131111111111 HILLSIDE HOSPITAL QLEN omsm. v. ' recognitions were due to his active labor in the ﬁeld of research, especially in agricultural chemistry and food technology; his 95 scientiﬁc papers were published in various journals, including the Philippine Agriculturist and Forester, the [ournal of Biological Chemis— try, Sugar News, and the Journal of the Philippine Islands Medical Association. The National Research Council of the Philippines owes its origin to the leadership of Dr. Roxas. He headed a committee that worked continuously in preparing the draft of the bill for its creation which was introduced in the House of Representatives. With the support of Manuel L. Quezon as Senate President and other leaders of the Philippine Legislature, and the cooperation of the then Governor General Frank Murphy, Act 4120 creating a National Research Council for the promotion of research along scientiﬁc lines was approved on 8 December 1933. Elected as ﬁrst chairman of the National Research Council, Dr. Roxas did a great deal in the organization of the different divisions integrating the Executive Committee of the council. For his distinguished and outstanding contributions in scientiﬁc research in the Philippines, Dr. Roxas may well be considered the “father of the National Research Council of the Philippines.” Manuel Luz Roxas was a man of sterling character, a good Filipino and patriot, simple and humble; all these qualities enhanced his merit as a true man of science. Our country can never repay what it owes him for his scientiﬁc labor and devotion to research. ANTONIO G. SISON National Research Council of the Philippines, Quezon City SCIENCE, VOL. 129 _ 3.1u1111959 the nerve cell,” Harvey Lecture Ser. 49, 57 (1956). W. D. M. Paton and E. J. Zaimis, “The methonium compounds,” Pharmacol. Revs. 4, 219 (1952). M. Protiva. “Chemie antihistaminovych latek a histaminové skupiny,” Nakladatelstvi L'eskolovenske’ Akademie véd (Prague, 1955). M. M. Rapport, “Serum vasoconstrictor (serotonin) : IV,” ]. Biol. Chem. 180, 961 (1949). Raymond-Hamet, “Sur un nouveau cas d’inversion des eﬂets adrénaliniques,” Compt. rend. acad. sci. 180, 2074 (1925). Rend. ist. super. sanita‘ 12, 1-264 (1949) (numero speciale sui curari di sintesi). Ibid. 15, 723—1040 (1952) (numero speciale sugli ergotamminici di sintesi). E. R. Rothlin, “The pharmacology of the natural and dihydrogenated alkaloids of ergot,” Bull. schweiz. Akad. med. Wiss. 2, 249 (1947). A. M. Staub, “Recherches sur quelques bases synthétiques antagonistes de l’histamine,” Ann. inst. Pasteur 63, 400 (1939). S. Thesleﬂ', “Succinylcholine iodide. Studies on its pharmacological properties and chemical use,” Acta Physiol. Scand. Suppl. 99, 1 (1952). D. W. Woolley, A Study of Antimetabolites (New York, 1952). �Cultural Determinants of Response to Hallucinatory Experience ANTHONY F. C. WALLACE. Ph.D. PHILADELPHIA �Reprinted from the A. M. A. Archives of General Psychiatry July 1959, Vol. 1, pp. 58-69 Copyright 1959, by American Medical Association Cultural Determinants of Response to Hallucinatory Experience ANTHONY F. C. WALLACE, Ph.D., Philadelphia Hallucination attracts the attention of the anthropologist for several reasons: First, because, as one of the most ancient and most widely distributed of the modes of human experience, most, if not all, human cultures provide deﬁnitions of and responses to it which are of interest to the descriptive ethnographer; second, because a vast quan— tity of content has been introduced into the cultural repertoire of mankind by halluci— natory ideation in dreams, visions, and hypnogogic imagery, and hallucination must therefore be considered in relation to culture change; and, third, because hallucination is often deﬁned in Western societies as a symptom of mental and/or physical disease, and anthropologists play a role in medical research in these societies. It is in the last context, particularly in the area of mental health research, that the present inquiry is undertaken. Cross—cultural materials on hallucination may be of interest in a mental health re— search context in at least two ways. First, and rather obviously, both psychiatrist and anthropologist will expect the manifest con— tent of hallucination to vary, as does the content of other behavior, to some degree with cultural setting, and they may be interested in the range, frequencies, and associations of various types of manifest content. Differences of opinion exist in Submitted for publication Sept. 3, 1958. This study was in part supported by Grant M-1106 from the National Institute of Mental Health, U. S. Public Health Service. Research assistants were Fred Adelman, Josephine Dixon, Joan K055, and Robert J. Smith. The writer has beneﬁted from discussion of methodological problems in psychopharmacology with Dr. Harry Pennes and Dr. Harold Rashkis, of the Eastern Pennsylvania Psychiatric Institute. 74/58 regard to the supposed variability of latent content: Lincoln, in his study of dreams in primitive cultures, and other psychoanalyti— cally oriented scholars have emphasized the universal presence in dreams of Oedipal themes and the classic “Freudian” sym— bols 13; less strictly psychoanalytic ethnolo— gists have not emphasized the presence of these themes so much as culturally and personally idiographic onesﬁ2'3 In any case, however, we shall not be primarily concerned with the content per se of hallucina— tions. Rather, we shall deal with the problem of the deﬁnition of and response to the experience, by the society, by the scientiﬁc observer, and by the hallucinator himself. The rationale for such an approach, in a mental health context, is twofold: First, knowledge of the range of deﬁnitions and response, and their cultural associations, may help in diagnosis and in communication with patients; and, second, it is likely that in some cultural subgroups in our society the nature of deﬁnition and response to hallucination entertained by hallucinator and his associates may aggra— vate or precipitate other mental disabilities in the hallucinating person. Indeed, the mental patient may suffer from added anx— iety precisely because of the nature of the deﬁnition of hallucinatory experience which he entertained prior to experiencing it him— self. Certainly among hospitalized patients in our society, the attempt to conceal halluci— natory experiences from the staff is both chronic and, in one sense, realistic: Staff members frequently take a negative View of hallucinations, and hallucinating patients are subject to measures which, from the pa— tient’s standpoint, may be punishments (de- �RESPONSE TO HALLUCINATORY EXPERIENCE lay in discharge, restriction of privileges, questioning on sensitive issues, subtle contempt, and even ridicule, from both staff and other patients) .23 Problems of Deﬁnition Uncertainties of deﬁnition impede re— search in the area of hallucinatory experi— ence. Although hallucination is commonly treated by psychiatrists as a symptom of mental disorder, its occurrence is neither a necessary nor a sufﬁcient condition for such a diagnosis. Most psychiatrists, furtherword the restrictions two on impose more, “hallucination,” excluding from its exten— sion those ideational experiences which oc— cur during sleep and assigning to it a generally negative valence. These restric— tions are useful in psychiatry in our own cultural setting, but they are not helpful in establishing a cross—culturally applicable deﬁnition (nor need they be, for a Western psychiatrist’s deﬁnition is to be regarded as only one cultural variant), since in some societies dreams and waking visions may be for many purposes treated as equivalent. For the purposes of this study, “hallucina— tion” will be deﬁned, very broadly, as pseu— doperception, without relevant stimulation of external or internal sensory receptors, but with subjective vividness equal to that aroused by such stimulation. Included in its extension, therefore, are dreams, the ter— of “hallucinations” psychiatric waking minology, and hypnogogic imagery; excluded is the fainter audiovisual imagery of reﬂective thought. There remains a some— what dubious category, occasionally referred to as hallucinations in the psychiatric lite-ra— ture, of perceptions whose subject matter is unambiguously provided by external stim— ulation but whose form displays subtle or gross distortion. The most familiar exam— ples are the undulating ﬂoors, stretched perspectives, echoing sounds, and other dis— tortions experienced by some subjects on administration of the so—called hallucino— genic or psychotomimetic drugs, and by normal subjects who have consumed nar— Wallace or alcohol, have been breathing anesthetics, or are in process of losing consciousness (fainting). We shall leave these phenomena out of the range of our deﬁnition, on the ground that a “hallucina— tory” dimension already exists, of vividness of subjective imagery in the absence of sensory stimulation, at all points of which the pseudoperception may be equally undis— torted, and relate these dubious cases, rather, to a logically independent dimension of perceptual distortion. The relationship between the two dimensions may, of course. be investigated empirically. A second major problem, in addition to the concept of hallucination itself, is that perennial ﬂower of confusion, the word “possession.” Casual observers and many anthropologists alike use this word in two very different senses: as a label for some person’s overtly observable behavior, and as a label for a native theory to explain this be— havior. These two uses are, unhappily, often confused. It may be best to state ﬂatly, at the outset, that I shall use the word “possession” to denote any native theory which explains some event of human behavior as being the result of the physical presence, in a human body, of an alien spirit which takes over certain or all of the host’s executive functions, most frequently speech and control of the skeletal musculature. A phe— nomenon of possession does not, therefore, for me exist; the word merely labels a theory. Now the possession theory happens to be frequently applied, in folk beliefs, to three very different classes of phenomena, for each of which other terms exist. One of these is hallucination; the second is hysteri— cal dissociation (including multiple personality, fugues, somnambulism, conversion hysterias, and hypnotic states); the third is obsessive ideation and compulsive action. Clinically, these are distinguishable phenom— ena. But any one, or group, of them can be, in folk theory, explained by the mecha— nism of possession. Unfortunately, some observers have, in their eagerness to empa— thize with their subjects, used the word cotics, 75/59 �A. M. A. possession to denote not only a type of folk theory but also whatever phenomenon their folk happen to use the theory to explain. In other words, if a people use the concept of “possession” to explain certain hysterical dissociations (such as the stereotyped fugues which are so commonly induced in many religious rituals), the anthropologist tends to say that the dancers in the ritual are “possessed”; similarly, if a people use the theory to explain hallucination (which is, incidentally, a less common use of the concept), the anthropologist may refer to hallucinators as “possessed” persons. Even more confusingly, the ethnographer may use the word to denote any person who is thought to be persistently inﬂuenced by a supernatural being, whether located inside or outside the person’s body. A third problem of conceptual ambiguity is the notion of trance. There would seem to be at least two major uses of this term: (1) to denote physiological collapse with coma or the occasionally concomitant delirious hallucinations; and (2) to denote (again) states of dissociation. The possi— bilities of semantic confusion are manifest. Problems of Methodology At ﬁrst, it was hoped that the Human Relations Area Files (HRAF), including the old Cross—Cultural Survey Files at New Haven and the completed portions of HRAF at New Haven and Philadelphia, would provide a sample of societies various of whose cultural features could be sta— tistically related to the phenomena of hallucination. The data contained in HRAF, however, even when supplemented by mate— rial from sources not tapped by HRAF, and by data on societies not included in HRAF, proved to be not amenable to statistical treatment, for three reasons: A sample which included representative cul— tures from all major culture areas was not available; the data were not comparable from society to society, because of the extreme unevenness of the reporting (rang— ing from no report at all to careful, exten— 76/60 ARCHIVES OF GENERAL PSYCHIATRY sive, and psychiatrically informed study), and the data provided were usually too crude to permit the discriminations which I regarded as signiﬁcant for statistical cate- gories. N0 quantity of time or money spent in HRAF and other library compilations can remedy all of these defects of the eth— nographic literature, and only a vast expenditure of funds in ﬁeld work could amass new and adequate data on a sufﬁcient num— ber of societies. The inference to be made is, rather, that the ethnographic literature available for areal or world samples, of the sort envisioned by Murdock 14 and others in connection with HRAF, is not suitable for statistical analysis with respect to all dimensions of anthropological interest, but is suitable only with respect to certain highly formalized and conventionally re— ported dimensions, such as kinship and subsistence activities. The cultures on which data were collected from HRAF in the abortive statistical phase of the study are the following: Abipone Achewa Ainu Andamanese Apiaca Apinage Aranda Arikara Assiniboin Balinese Bena Blackfoot Buka Bushman—Hottentot Canella Chuckchee Creek Crow Cuna Dahoman Easter Island Gros Ventres Hopi Ifugao Indian Yoga Kamilaroi Kwakiutl Lamba Maori Marshallese Plateau area (North America) Sherente Since nontrivial and signiﬁcant statistics appeared to be unachievable, the obvious next step was to consider what prestatistical manipulations of the data were possible and whether any of these might yield formulations of interest. Experimentation along these lines brought me to construct a rather tedious list of “existence theorems,” which I shall not reproduce here, but which proved later to be valuable in setting up the matrix of concepts. Existence theorems are Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE eminently prestatistical, but they are neces— statistical of description, sort to any sary since they deﬁne the relevant and nontrivial categories. An existence theorem is merely a statement that of the class A: there is at least one member concerning which the statement [9 in true; thus, for instance, the theorem where “there exists at least one (x) such that . . .” (3x)=df and (x):df “society” and A ber of the society as meaningless concatenations of visual and/or a u d i to r y pseudo-perceptions.” The whole of the theorem would read: “There exists at least one society such that hallucinations are deﬁned by some members of the society as meaningless concatenations of visual and/or auditory pseudopercep— tions.” From the existence theorems, derived from the HRAF cross—cultural ma— terials and from my ethnographic knowledge, the dimensions of hallucinatory experience shown in Table l were con— structed. These dimensions are offered as a formal frame of reference within which to observe cultural deﬁnitions of hallucina— tory experience, and as a rough statement of the range of cultural variability evident in the ethnographic record. With the foregoing semantic and methodological considerations in mind, we may proceed to discuss, informally and nonstatistically, certain implications of the ethno— graphic data. Conditions of Hallucination If one were to design an electronic brain which behaved in all respects like a normal human brain, one would have to include in its speciﬁcations both a capacity for hallucina— tion and a capacity to distinguish halluci— nation from sensory perception. Most human beings hallucinate (in the broad sense of the term which is employed in Wallace Communication Contains no information but is a meaningless pattern of auditory or visual images (:2 Contains information in the form of observation of phenomena that really exist somewhere (but are not messages) (1. Contains message from a supernatural being (ghost, soul, demon, divinity, etc.) located outside Ego’s body a . Contains message from, or is the experience of, a supernatural being (ghost, soul, demon, divinity, etc.) located inside Ego’s body ((5 Contains message from one part of self (e. g., own soul, conscience, memory, Id, subconscious, etc.) to another (6. g., consciousness, ego, etc.) or to other person as Contains message from a natural being communicating by means of radio, telepathy, or other means of telecommunication (1 1 B p12“hallucinations are deﬁned by some mem- 1.—Dimensiom of Hallucinatory Experience TABLE Mechanism of control Can be controlled by hallucinator and/or hallucinator’s fellows by manipulating physical condition and/or foreign biochemical factors ()2 Can be controlled by hallucinator and/or hallucinator's fellows by nonphysical means (such as will, prayer, ritual, worry, suggestion, autosuggestion, psychotherapy, etc.) I). Can be controlled by will of alien supernatural or natum being b I) 1 t b5 b. b1 b3 b 1A0 2 0 [Ab 3 b 2N) a I) 1A0 2A1) . Other (ﬁll) [Vb sz 3]) 0 Induction c. Hallucinator seeks to induce or repeat experience C 2 /—"C 1 D Concealment d1 Hallucinator conceals experience from group or denies oc- currence d 2 ,—/d 1 Punishment E e. Group institutes punishment and/or social extrusion e 2 He 1 Therapy 1“ Group or individual institutes therapeutic and/or prophy— lactic measures f1 fz Hf! G Role assignment g1 Experience qualiﬁes individual for valued social role (adult hood, shaman, healer, diviner, priest, etc.) g2 My 1 H Behavior guidance hi Content of experience may be taken as guide for individual and/or group action (other than therapeutic) irrespective of social role of hallucinator h: Content of experience taken as guide for individual and/or group action (other than therapeutic) only when hallucinator already ﬁlls certain social roles (e. g. shaman, prophet) h , Content of experience not taken as guide for individual and/ or group action (other than therapeutic) 77/61 �A. M. A. this paper), in one way or another, quite frequently; and there is no society, to my knowledge, in which hallucinatory experience is unknown. Hallucination is, in fact, one of the most widely distributed of the modes of human experience. Explicit re— ports of dreams, visions, and the hearing of voices are found in the sacred literature of the pre—Christian Near East; if mythology, ritual, and other religious behavior be re— garded as in part the legacy of such experi— ences passed on by oral or written tradition, we may suspect an antiquity measured in tens or hundreds of millenia. Under the general rubric of hallucination, however, there can be assembled a wide range of types of experience, from the Vivid and realistic supplanting of reality in ec— static visions and auditory revelations, to a relatively pallid verbal or visual imagery which blends imperceptibly into ordinary “thought.” These experiences are known from Western clinical observations to be prompted by the most various circum— stances: sleep, anoxia, pharmacologic agents, brain tumors, psychological stress, fatigue, sensory restriction, and others. Relatively little seems to have been done to relate the conditions precipitating and surrounding an event of hallucination to the content of the experience; ethnographic investigation may offer a few clues here. The speciﬁc conditions under which hal— lucinations have been reported in the ethno— graphic literature may be divided into the following categories : Sleep Fatigue Hunger and thirst Prolonged physical pain Extreme physical illness Social isolation Special exercises (breath control, posture, sensory restriction) Drugs Emotional stress in normal persons Mental illness It should be noted that these conditions are not logically independent, and that frequent— ly (and especially in voluntarily induced hallucination) two or more of the conditions are realized at the same time. Three observations are pertinent. First, in many societies relatively little signiﬁcance 78/62 ARCHIVES OF GENERAL PSYCHIATRY is attached to differences in the conditions under which hallucination occurs. In par— ticular, dreams during sleep, spontaneous waking visions, and induced hallucinations under drugs or stress may be given equal status and comparable evaluation. Western society is remarkable for the importance it assigns to differences in the precipitating conditions of hallucination; the most strik— ing example, of course, is afforded by the profound distinctions we draw among dreams (in sleep), delirium (in illness or intoxication), and “hallucination” in the restricted sense (in the waking state). Second, we must take note that, although not all hallucinatory experiences are regarded as desirable in any society, in primitive socie— ties it is very common for hallucinations with desirable content to be not only ac— cepted with pleasure but deliberately sought with the aid of such devices as hallucino— genic substances (e. g., some American Indians ingest parts of the cactus peyote and Paleo—Siberians, the mushroom ﬂy agaric) and various sorts of personal disciplines, ranging from breathing and posture exercises, through hunger, thirst, and isola— tion, to prolonged physical self—torture. The tendency to minimize discrimination among hallucinations on a criterion of precipitating condition of course does not imply any inability to discriminate between hallucina— tion and sensory perception; the preferential status of hallucinatory experiences is possible only when it is clearly differentiable from normal experience. Third, it appears that both the subjective feeling tone and the speciﬁc content of the hallucination are heavily inﬂuenced by a still more pervasive condition: the cultural milieu in which the hallucination, and particularly the voluntary hallucination, takes place. The latter point is worth elaborating here, although it anticipates some of the material to follow, because it is relevant to the methodology and evaluation of clinical research with hallucinogenic compounds under varying experimental conditions. Typically in such research the clinician administers Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE to a group of healthy urban adults, often medi— the with identiﬁed themselves persons cal or an auxiliary—medical profession, a substance which induces various instrumentally measurable physiological changes and observable alterations in behavior. The subjects are asked also to report verbally on their subjective experience. These verbal reports reveal a considerable variety of experience: Some subjects are euphoric; some are entranced by the intensity of esthetic pleasure they achieve in the contemplation of color, form, and movement divorced from meaning; many complain of anxiety, physical discomfort, various un— welcome perceptual distortions, and attitu— dinal changes; some hallucinate and some do not. These various reports and observa— tions are taken to indicate the psychological actions of the drug. Similarly variable re— sults, but usually with transient intensiﬁcation of chronic symptomatology, are given by mental patients from roughly comparable cultural backgrounds (but, of course, by virtue of illness occupying a very different social status). But no cultural controls are employed; and it is possible that to an unknown degree the subjective experience, and hence even the physiological measures, is inﬂuenced by the negative attitude toward any distortion of normal sensory and cognitive experience which many members of our society share, at least those people who do not customarily seek such special experi— ences as are afforded by narcotics and alcohol or by mystical or esthetic preoccu— pations. Some indication of the quality and mag— nitude of the possible effect of differing cultural attitudes toward hallucinatory ex— perience under differing conditions of drug administration is given by the differences in the experiences reported by normal white subjects after administration of mescaline and by American Indians after consumption 0d of introduction, and of intragroup per— sonality differences: ﬁrst, the inﬂuence of tains mescaline). The literature on the mescaline experi— ences of normal subjects is rather scattered, Wallace and some of it, particularly if it has an early date of publication, is unsatisfying because of the inadequacy of sample description and the disjointed and anecdotal style of presen— tation conventional at the time. Neverthe— less, the consultation of several prime sources “'25 reveals a reasonably consistent pattern of described phenomena, which con— trasts with the pattern described (also, unfortunately, sometimes in undeﬁned sam— ples) by anthropologists’ American Indian informants.”12'1“"!24 The fact of major contrast has been brieﬂy remarked in print by one of the—foremost anthropological stu— dents of peyotism, Slotkin,21 who observed in the course of discussion of attempts of white persons to suppress peyotism that “the responses described in clinical experi— ments on Whites are so different from the responses described by Indian Peyotists . as to fall into completely different catego— 2.—Contrasts in Prevailing Character of the Responses 0f_Climcally “Normal” White and Indian Subjects of M escaline Intoxication TABLE White Indian Variable and extreme mood shifts (agitated depression, anxiety, euphoria, depend— ing on stage of intoxication and personal characteristics) Initial relative stability of mood, followed by religious anxiety and enthusiasm, with tendency toward feel— Frequent breakdown of social inhibitions and display of Maintenance of orderly and “proper” behavior (“revivalistic" enthusiasm is socially proper in context) No report of suspiciousness “shameless” sexual, aggressive, etc., behavior Suspiciousness of others present in environment (reported to be uniformly present by Guttmann and noted in self by Kliiver) Unwelcome feelings of loss of contact with reality, depersonalization, meaningless“split-personality," ness, etc. Hallucinations largely idiosyncratic in content No therapeutic beneﬁts or permanent behavioral changes ings of religious reverence and personal satisfaction when vision achieved, and often, also, expectation of “cure” of physical illness Welcome feelings of contact with a new, more meaningful, higher order of reality, but a reality preﬁgured in doctrinal knowledge and implying more, rather than less social participation Hallucinations often strongly patterned after doctrinal model Marked therapeutic beneﬁts and behavioral changes (reduction of chronic anxiety level, increased sense of personal worth, more satisfac» tion in community life) 79/63 �A. M. A. ries; they do not seem to be talking about the same thing.” The salient differences in the reports are displayed in Table 2; the reader should note that a meaningful statis— tical presentation of frequencies of response types, while desirable, is precluded by the nature of the data available. These marked differences would seem to be plausibly explained by two related fac— tors which are independent of possible differences in racial physiology, of chemical action of the drug owing to variations in dosage, mixture with other agents, of meth— od of introduction, and 0f intragroup person— ality differences: ﬁrst, the inﬂuence of the setting in which the drug is taken (the white subject’s experiences occur usually in a hospital or university research setting; the Indian experiences, in a ceremonial lodge during a solemn religious ritual); and, second, differences in the psychological meaning of the primary drug effects when experienced. Certainly, gross enough situ— ational and semantic differences exist: White normal subjects generally take mes— caline once or twice, in a clinical research setting, with deﬁnite knowledge of an ex— perimental or a clinical purpose in the investigation, and without any commitment to or interest in peyote, or to mescaline in any form, as a personal religion; Indian peyote users take mescaline repeatedly, in a solemn religious setting to the accompaniment of serious ritual, with deﬁnite knowledge of a religious purpose in the usage and, often, with hope for per— sonal salvation, of which the vision is the evidence. The former factor—the setting— 5 been has reported by Fernberger to yield differences in content, which can to some degree be affected both by suggestion by the experimenter and by autosuggestion. The latter, the semantic, factor would seem to be signiﬁcant at the present stage of theory concerning the action of the hallucinogens, since it is recognized that both personal character and, perhaps, personally or cul— turally determined values concerning the “homeostasis of subjective—experience” may 80/64 ARCHIVES OF GENERAL PSYCHIATRY affect response to experimentally induced changes in sensation and perception.19 We quote the work of Hoch, Cattell, and Pennes 8 in this connection. We have pointed out that the alterations in the vegetative nervous system appear ﬁrst under the influence of mescaline, lysergic acid, pervitin, etc. This is usually followed by alterations of per— ception, bodily sensations, and changes in body image. In many patients it would appear that the perceptual alterations are conducive in producing anxiety, uncertainty, and, at times, rage. Seemingly, the perceptual alterations lead to a lowering of reality control, thence to tension and anxiety, which in turn lead to depressive, aggressive, and paranoid manifestations. Schizophrenic patients whose reality contact is already impaired are seemingly more vulnerable to drugs that have a disorganizing effect on reality perception. As yet it is unclear whether the emotional alterations seen in these patients are due to a physiological action of the drug per se or due to the experiencing of an alteration of reality and other changes on a psy— chic level. Interpretation of Content In most primitive societies, even if (on other grounds) the hallucinator is regarded as being ill, or the hallucination itself is unpleasurable, the content will not be re— garded as a meaningless concatenation of pseudoperceptions. The content of hallucination is sometimes interpreted as a message introduced directly into the subject’s consciousness by a supernatural being, directed either to the hallucinator himself or to the community through him as an intermediary. More frequently, hallucination will be in— terpreted as a real perceptual experience by the soul, which has wandered from the body and is seeing and hearing events involving real or supernatural persons which are occurring in another place, or which is able to see and hear events and supernatural beings present but imperceptible to others. The message—intrusion theory tends to blend into primitive theories of possession; in our society, it is expressed in the conventional telepathy, radio, radar, brain—washing, and electrical—current delusions and is classed as a paranoid mechanism, while the spiritual— perception theory is associated with extreme Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE religious enthusiasm. But in both theories, the content of hallucination is interpreted as signiﬁcant information. In at least two culture areas, that of the 17th—century Iroquois Indians of what is now New York State,26 and of Western society after the advent of psychoanalysis, a third theory also has existed as an alterna— tive explanation for hallucination. In this theory, the hallucination conveys an emo— tion—laden message from the soul, or some unconscious part of the mind, to the conscious self, and thus is a process of thought. This view, like the others, regards the content of hallucination as a message containing information. It appears to be a rare idea that the content of hallucination is mean— ingless, and one may hazard the guess that this notion is largely conﬁned to psychiatri— cally unsophisticated, nonparanoid, and tepidly religious, or nonreligious, members of Western society. If a hallucination is regarded as a mes— sage, there are evidently two approaches to its interpretation: to take the manifest con— tent literally, and to regard the manifest con— tent as a symbolic expression of signiﬁcant underlying ideas. The latter approach may entail various techniques, such as guessing and devices of free association, the consul— tation of a formal list of symbols and their meanings, and the more or less standardized derivation of meaning from the context of circumstances (such as ritual, illness, situ— ational stresses, and the like) in which the hallucination occurred. It is not important here whether or not there are, in truth, universal themes and symbols expressed in dreams and other hallucinatory experiences, as psychoanalytic theory and data suggest. The important point is that most human beings, in most societies, outside Western civilization, regard hallucinatory content as communication bearing signiﬁcant informa— tion which can be understood either directly or by the use of special methods of interpretation. Now this belief in hallucinatory content as communication, particularly when it is Wallace coupled with the conviction that the com— munication is not merely intrapsychic, seems to have an effect both on the content of hallucination and on the hallucinator’s, and his community’s, response to it. Halluci— nation in itself is not frightening, either to hallucinator or to his community, al— though the content may be; but even if the content is frightening, it is valuable knowl— edge. Hence the overt response to halluci— nation will very likely be markedly affected by its classiﬁcation as communication. It is to the topic of response to hallucina— tion that we now turn. Response to Hallucination The difference in response between Eng— lish white and Australian black to a course of hallucinations in a mourning woman is vividly illustrated in the following anecdote, reported by Parker,15 the author of a study of the Euahlayi tribe of Australia. Our witch woman was rather a remarkable 01d person. When she was, I suppose considerably over sixty, her favourite granddaughter (lied. Old Bootha was in a terrible state of grief, and chopped herself in a most merciless manner at the burial, especially about the head. She would speak to no one, used to spend her time about the grave, round which she ﬁxed upright posts which she painted white, red, and black. All round the grave she used to sweep continually. More and more she isolated herself, and at last discarded all her clothes and roamed the bush 5. la Eve . . . as she had probably done as a young girl. She dug herself an underground camp, roofed it over, and painted enormous posts which she erected in front of her “Muddy wine,” as she called her camp. She never came near the house, though we had been great friends before. She used to prowl around the outhouses and pick up all sorts of things, rubbish for the most part, but often good utensils too; all used to be secreted in the underground camp. She never talked to anyone, but used to mutter continually to herself and her dogs in an unknown tongue which only her dogs seemed to understand. We thought she was quite mad. One day, while we were playing tennis, she sud— denly, muttering her strange language and dancing new corroboree steps, clad only in her black skin, came up. Matah told her to go away, but she only corroboreed round him and said she wanted to see 81/65 �A. M. A. She danced round me for a little time, then sidled up to me and said: “\Nahl [negative or “no”] you frightened, wahl me hurt you. I only womba—mad—all yowee— spirits—in me tell me gubbah— good—I lib ‘long a youee: bimeby I come back big feller wirreenun [as a medicine woman] wahl you frightened? I not hurt you.” And after crooning an accompaniment to her steps, off she went, a strange enough figure, dancing and crooning as she went towards her camp; and not until the spirits gave up possession of her did she come near the house again. I used to tell the other blacks to see that Bootha had plenty of food. They said she was all right, the spirits were looking after her. Lunatics, from their point of view, are only persons spirit-possessed. Gradually old Bootha, clothed as usual, came back about the place. Strange stories came through the house back to me of old Bootha. She was very ill for a long time, then suddenly she recovered, not only recovered but seemed rejuvenated. We heard of wonderful cures she made; how she always consulted the spirits about any illness; how there were said to be spirits in some of her dogs; how she was now a rainmaker, and, in fact, a fully ﬂedged witch. me. . . . The reader will note a typical Western attitude toward the “lunatic,” a blend of amused contempt, pity, and anxiety, and also the native woman’s awareness of the attitude, and her effort to clarify the white man’s misunderstanding by explaining that her hallucinatory experiences were “good.” Noteworthy also is the satisfactory (both to the woman and to her associates) social remission, which was achieved in the course of becoming a shaman: a remission which, I suggest, was facilitated by her anxiety— free acceptance of hallucinatory experience. This anxiety—free acceptance of, and willing— ness to describe, hallucinatory experience contrasts vividly with the common shamed, fearful, self—doubting attitude of Western patients, who frequently try to conceal the fact that they “see things” or “hear voices,” and sometimes “confess” (as the psychi— atrist puts it) to hallucinations only under very careful questioning. Response to hallucination may be considered both as a matter of the hallucinator’s response to the experience and as a matter of the response of his group (and the two, 82/66 ARCHIVES OF GENERAL PSYCHIATRY of course, may be equivalent). As I have indicated, in primitive societies the fact of hallucination per se is seldom disturbing; but the content itself may be disturbing or not, depending on the nature of the socially appropriate response. Dreamers or vision— aries may resist strenuously the hallucinated suggestion that they undergo an arduous process of becoming a shaman, or that they accept the role of berdache (an institutional— ized inversion of sexual role among the Plains Indians), or that they commit some act, like murder or incest, which violates social norms; they may be stricken with panic at learning of approaching community disaster, or that they have been bewitched, or that they will be captured, tortured, and killed in a future war. Similarly, the hallu— cinator’s associates may respond with dismay, or with enthusiasm, to the wishes of his soul, and may institute protective meas— ures to avert harm from him or from them— selves, may induct him into the special social relationships indicated by his vision, may conduct the indicated medical treatment, or may take his revelation as a code for social reform. The signiﬁcant point is that it is the content of the communication which is the focus of interest and the fulcrum of action rather than the fact of hallucination itself. Let us now consider, by contrast, the responses to hallucination typical in Western societies. In some social groups, particularly religious sects, hallucinatory experience with supernatural ﬁgures ap— parent in the manifest content is interpreted as divine, 0r Satanic, revelation, and is responded to either by acceptance of in— junctions discovered in the content or by repression, or even punishment designed to drive out “possessing” devils. In psycho— analytically inﬂuenced groups (which prob— ably include a considerable proportion of the urban population of Western countries), dreams are interpreted and used as a basis for psychotherapeutic action, but waking hallucinations are regarded as symptoms of serious psychic illness. And in the rest of Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE the population at large, waking hallucina— tions are probably regarded primarily as indications of “nervous breakdown,” or even “insanity.’ The latter unfavorable social diagnosis is very commonly followed by the social extrusion of the hallucinator, with or without prior medical advice, into a mental hospital or some other socially restricted environment, or at the very least into a quasiostracism at home or in lodgings. Police force is available and not uncom— monly used to sanction and to effect this extrusion. In medical circles, despite recog— nition that hallucination in many conditions is a secondary symptom, and despite the insistence of workers like Boisen that “what the voices say is the important thing, not 1 hallucina— the mere fact of hearing voices,” tion is commonly taken to be a grave sign. In some of the research literature, indeed, hallucination is treated as if it were the essential feature of psychosis. Now it is reasonable to suppose that most persons, when they hallucinate for the ﬁrst time (certainly when the ﬁrst waking hallu— cination occurs), are aware of the culturally standard interpretation of and response to hallucination in their society. Even if they do not accept this interpretation and re— sponse as wise or proper, they will be aware of its probable evocation in others. If this is the case, then it is likely that the person’s interpretation of, and response to, the fact of his own hallucination in a given context (as well as its content) will be a function of the way in which the fact (and content) of hallucination is deﬁned by his culture. The function should determine in part his ’ emotional experience both during and after the event, and possibly (by cultural suggestion) its perceived content as well. 'We may ask, at this point, how much anxiety, self—depreciation, and cognitive dis— tortion are added to the miseries of mental patients by the circumstance that they have learned to fear waking hallucination in the course of living in a society in which waking hallucinatory experience is almost uni— formly negatively valued? (The scientiﬁc validity of the valuation is irrelevant.) Furthermore, we must question the completeness of any research into the psychophysiological action of the so—called psychomimetic drugs, of sensory restriction, and of other hallucinogenic procedures which fails to weigh not only the magnitude but also the direction of the probably mas— sive contaminating effect of cultural sug— gestion upon the subjects. For what is measured is not just the action of a drug or other procedure, but the action of the procedure plus the subject’s interpretation of and response to this action, plus the feedback effect on the continuing action itself (Figure); and all of these actions, inter— pretations, responses, and effects are factors with direction, as well as magnitude. There may be much that the therapist can do to alter the internalized cultural deﬁni— tions of hallucinatory experience in his patients, if he wishes. But it is research problems that chieﬂy concern us here. It would be possible in clinical research to con— trol for the direction of cultural effects by employing as control subjects persons whose subculture differs sharply from that of the Hallucinatory pseudo— perception SPECIFIC HALLUCINOGENIC STIMULUS CONDITION cognition of Situation -””'“°'°‘ , . -39. “—3). _____ Musculofure 1’ Vaugned'gme" "em”s ' . WWW / ‘ . personal-3y . 2‘ .. dynamics , Internalized cultural 15" definition of situation 9 MOTOR vEggAL *{ RESPONSE Mediation of response , , to hallucmOgenic stimulus by facets 0m; subjectlve experience. _ - - 9 NERV° Wallace 83/67 �A. M. A. experimental subjects in its deﬁnition of the expected experience, and by ensuring that the experimental conditions for the controls were sufﬁciently close to culturally normal conditions for them to permit generalization from past learning. Furthermore, it would be possible to select subjects systematically on criteria of personality, of past experi— ence, and of attitude toward the expected events; and it would be possible to vary deliberately the general situational structure with other variables held constant, both by physical manipulation and by deliberate in— struction and suggestion to the subjects. Such procedures, incidentally, should also be considered in relation to other than halluci— nogenic compounds; they evidently would apply to such drugs as tranquilizers, sedatives, and energizers, which on other evidence also depend in part for their effects on relatively unexplored interactions with personal dynamics and sociocultural milieu.18 Methodologically, such manipulations are the reverse images of the controls imposed by the placebo—and—blind (or double—blind) techniques and of analysis—of—variance tech— niques involving multiple pharmacologic agents; whereas the placebo-plus—blind, or variance—analysis, design varies the chemical agent and holds situation constant either by randomization or by laboratory control, the method of cultural and situational controls would hold the drug constant and vary such aspects of situation as the physical experi— mental conditions, instructions to personnel, and character and background of subjects. Drug and cultural controls should ideally be combined in one design. Summary The paper brieﬂy examines the range of cultural variation in conditions inducing, interpretations of, and responses to, hallu— cinatory experience. The published data suggest strongly that internalized cultural deﬁnitions of hallucinatory experience have a profound effect on the responses both of mentally ill and of normal persons. Meth— odological controls for cultural differences 84/68 ARCHIVES OF GENERAL PSYCHIATRY are indicated in research with hallucinogenic substances. Eastern Pennsylvania Psychiatric Institute. REFERENCES Boisen, A. T.: The Exploration of the Inner World, New York, Harper & Brothers, 1936. 1. Eggan, D.: The Manifest Content of Dreams: A Challenge to Social Science, Am. Anthropologist 2. 54 :469, 1952. Eggan, D.: The Personal Use of Myth in Dreams, J. Am. Folklore 68 :445, 1955. 4. Fernberger, S. W.: Observations on Taking Peyote (Anhalonium lewinii), Am. J. Psychol. 3. 34 :267, 1923. Fernberger, S. W.: Further Observations on Peyote Intoxication, J. Abnorm. & Social Psychol. 5. 26:367, 1932. Guttmann, E.: Artiﬁcial Psychoses Produced by Mescaline, J. Ment. Sc. 82 2203, 1936. 6. Hoch, P. H.: Experimental Induction of Psychoses, in The Biology of Mental Health and Disease, 27th Annual Conference of Milbank Memorial Fund, New York, Paul B. Hoeber, Inc. (Medical Book Department of Harper & 7. Brothers), 1952. Hoch, P. H.; Cattell, J. P., and Pennes, H. H.; Effect of Drugs: Theoretical Considera— tions from a Psychological Viewpoint, Am. J. Psychiat. 1082585, 1952. 8. Huxley, A.: The Doors of Perception, New York, Harper & Brothers, 1954. 10. Klﬁver, H.; Mescal Visions and Eidetic Visions, Am. J. Psychol. 371502, 1926. 11. La Barre, W.: The Peyote Cult, in Native American Culture, Yale University Publications in Anthropology, No. 19, New Haven, Conn, Yale University Press, 1938. 12. La Barre, W.: Primitive Psychotherapy: Peyotism and Confession, J. Abnorm. & Social Psychol. 42:294, 1947. 13. Lincoln, J. S.: The Dream in Primitive Cul— tures, Baltimore, Williams & Wilkins Company, 9. 1935. Murdock, G. R: World Ethnographic Sample, Am. Anthropologist 592664, 1957. 14. 15. Parker, K. L.: The Euahlayi Tribe, London, Archibald Constable & C0., 1905. Petrullo, V.: The Diabolic Root: A Study of Peyotism, the New Indian Religion, Among the Delawares, Philadelphia, University of Pennsyl— vania Press, 1934. 16. Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE Radin, P.: The Winnebago Tribe, Washington, D. C., Bureau of American Ethnology, 37th Annual Report to Secretary of Smithsonian In— stitute, 1915-1916, 1923. 17. Rashkis, H. A., and Smarr, E. R.: A Method for the Control and Evaluation of Sociopsychological Factors in Pharmacological Research, Psychiat. Res. Rep. 9:121, 1958. 18. Rubin, L. S.: The Psychopharmacology of Lysergic Acid Diethylamide (LSD—25), Psychol. 19. Bull. 54:479, 1957. 20. Slotkin, J. S.: Menomini Philos. Soc., n. 5. 42:4, 1952. Peyotism, Tr. Am. J. S.: The Peyote Religion: A Study in Indian—White Relations, Glencoe, 111., Free Press, 1956. 21. Slotkin, Wallace 22. Smythies, J. R.: The Mescaline Phenomena, Brit. J. Philos. Sc. 3:339, 1953. 23. Smythies, J. R.: A Logical and Cultural Analysis of Hallucinatory Sense—Experience, J. Ment. Sc. 102:336, 1956. D.: Personality and Peyotism in Menomini Indian Acculturation, Psychiatry 15: 24. Spindler, G. 151, 1952. 25. Stockings, G. T.: A Clinical Study of the Mescaline Psychosis, with Special Reference to the Mechanism of the Genesis of Schizophrenia and Other Psychotic States, J. Ment. Sc. 86:29, 1946. 26. Wallace, A. F. C.: Dreams and the Wishes of the Soul: A Type of Psychoanalytic Theory Among the 17th Century Iroquois, Am. Anthropologist 602234, 1958. Printed and Published in the United States of America 85/69 �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Files and reprints: hallucinogens and EEG, 1959 (folder title 2/2). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-002-15-015 Date A point or period of time associated with an event in the lifecycle of the resource 1959 Creator An entity primarily responsible for making the resource Various authors Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/18207735ad5546b08aac89618232e7bc.pdf 66f756c9dd21d0500a4b4e9773773d3e PDF Text Text ��Wm « . . ”1%! W3 l/W W "79"! - duh [cow ~ 4444...; n— wlamaZu-ﬂ nag ‘3 073 /3 W _———_—_é¢%0u_LL__p_J_ 1w... mug: . j” / 3 H4 Ito :98 ��'VfJii MMud‘vue I7M¢2+ ? la Mal. .max Q ,4”; . 9:19 M00 4/73 ,“ K We; /a¢/If ,, (14.2...e‘23m,“ L DF/Wdﬁ ﬂan" 714 - “7‘ 44.4.5 44W r M , %W(“ W77 27/56:.) xéa/av-p 2/3“; 413»; Ma... 7w,» #1W 1‘ I; a.“ me: ‘M‘M w 4‘ 7‘ WWW/3,1:I/7 w»! AWL—«awe; CK’S") mm) M �7 7 4%? % ,4» 014/.- a‘,‘” __n ”ViV W ,, (A. 2‘ MW "5 11M; r W ��‘ WMA (“Av/Jaw AJa—lnw.m.5¢nﬁ¢ ��M Wf - I7 ‘70 [Lav/2.». 5’52 31 ,9: d3: ��ﬁbrw Dr? ' D.- £44415" Iv ~43 VP-’YV MED-thaw Masha“. -6” 'DFP- m 51am JV 1 ‘ ��\ \-_' <f/ e4 AM (3 ��73/4 r 4/»! / 4? ��" ,; . “A; 7 m 7V ��Ph. i74800 MECHOIYI® CHLORIDE (METHACHOLINE CHLORIDE U.S.P., MERCK) a SHARP DOHME MECHOLYL* Chloride produces the same physiologic response as does acetylcholine, which, when released at nerve endings, produces parasympathetic stimulation. In therapeutic doses, MECHOLYL slows the heart rate, lowers blood pressure, constricts the bronchioles, dilates the peripheral blood vessels, constricts the pupils, Increases intestinal tone and peristalsis, causes salivation and ﬂushing, and stimulates the detrusor muscle of the bladder. In general its eﬁects are the opposite of those produced by epinephrine. Its action is much more prolonged than that of acetylcholine and it is, moreover, devoid of the nicotine-like effect of that substance. METHODS OF ADMINISTRATION MECHOLYL Chloride is a potent substance and careful consideration should be given to Its dosage and method of administration. For *MECHOLYL is the registered trade-mark of MERCK & CO., Inc., for its brand of methacholine. [i] stopping an attack of paroxysmal auricular tachycardia it should be given by subcutaneous iniection (never by intravenous or intramuscular injection), and the same method of administration may be used in treating scleroderma, chronic ulcers, Raynaud's disease and other vasospastic states, although in the latter conditions better and more prolonged eﬁects are obtained when it is administered by the method of ion transfer For administration by mouth (iontophoresis). the less hygroscopic MECHOLYL Bromide is supplied in tablet form. Atropine intravenously immediately terminates the action of MECHOLYL. A syringe containing a suitable dose of atropine sulfate [0.6 milligram (l/iOO grainI] should be available for immediate intravenous iniection if the dose of MECHOLYL Chloride causes undesirable symp- MECHOLYL Chloride is supplied in ampuls Since MECHOLYL constricts the bronchioles containing 25 milligrams (0.025 gram) of the powder. Solutions for subcutaneous iniection are prepared by dissolving the drug in sufﬁcient sterile distilled water to make it possible to measure accurately and administer easily the dosage desired. WARNING Injections of MECHOLYL Chloride should be given subcutaneously only. lniections should never be given in- travenously or intramuscularly. PRECAUTIONS The patient should be lying down during the administration of MECHOLYL Chloride to minimize the effects of lowered blood pressure. [2] toms. Overdosage of MECHOLYL may produce momentary cardiac arrest. The Trendelenburg position, to give the cardiac center the beneﬁt of any circulation present, is sometimes beneﬁcial in such an emergency. and may produce an asthmatic attack in those subiect to this condition, it should be used with extreme caution, if at all, in cases where there is a history of asthma or hypersensitivity. Substernal pain following the administration of MECHOLYL is said to be rare. However, the use of this drug in patients subiect to angina pectoris is not recommended. USE IN PAROXYSMAL AURICULAR TACHYCARDIA One of the most efﬁcacious uses of MECHOLYL Chloride is in terminating attacks of paroxysmal auricular tachycardia. It is, however, not effective for prophylaxis or for continued treatment in cases of frequent recurrence of the arrhythmia. [3] �not recommended for the treatment of auricular fibrillation, auricular ﬂutter, or paroxysmal ventricular tachycardia. It is DOSAGE The initial subcutaneous dose of MECHOLYL Chloride should be limited to IO milligrams (0.01 gram) to test the patient's tolerance. Careful preliminary testing of the patient with a small dose will not nullify the effect of a subsequent dose, and is advisable if there is any doubt of the patient's ability to tolerate the drug. treating paroxysmal auricular tachycardia in patients under twenty years of age, IO milligrams given subcutaneously usually terminates an attack. In older patients, 20 to 40 milligrams may be required; obese patients sometimes require more. In Slow absorption of the drug due to inadequate local circulation may interfere with the therapeutic response. If the attack is not terminated in two minutes, compression of the vagi, together with gentle massage at the site of iniection to promote absorption, is suggested. Conversely, if absorption is found to be too rapid, further absorption may be retarded by applying a tourniquet above the site of iniection. The eﬁects of MECHOLYL may be terminated immediately by atropine. [4] and larger dose (if that given ﬁrst fails to interrupt the attack) may be given 20 to 30 minutes later, providing no severe reaction has occurred following the ﬁrst dose. Quinidine in moderate doses (not more than 0.2 gram four times a day) usually does not impair the MECHOLYL effect. Larger doses tend to inhibit its action, although MECHOLYL has been known to “break through" the depresr slon of quinidine. 174800 For oral administration or administration by the method of ion transfer (iontophoresls)—Ph. A second I Gm. bottles. 10 Gm. bottles. MECHOLYL BROMIDE (for oral administration only) is supplied in Boxes of 24—200 mg. (0.2 Gm.) tablets Bottles of 500—200 mg. (0.2 Gm.) tablets OTHER USES OF MECHOLYL CHLORIDE been used (by suba number of other condi- MECHOLYL Chloride has cutaneous iniection) in tions, particularly in certain vasospastic diseases, such as Raynaud’s disease, in chronic ulcers, and in scleroderma. If a test dose of IO milligrams of MECHOLYL Chloride has been well tolerated, the subsequent dose may be increased cautiously up to 25 milligrams (0.025 gram). In these conditions, however, the much more prolonged eﬁect produced by MECHOLYL Chloride administration by the method of Iontophoresis (ion transfer) or by the oral administration of MECHOLYL Bromide Tablets is preferred. MECHOLYL CHLORIDE is supplied ,snm DOHME SHARP 8: DOHME as follows: Philadelphia, U. S. A. For subcutaneous iniection— DIVISION OF MERCK a: CO. Inc. Boxes of 6 ampuls each containing 25 mg. (0.025 Gm.) of the dry powder. I 5 I P- IB-413 [6] Printed in U.S.A. �For the Medical Profession only ‘ANECTINE’® CHLO RIDE BRAND SUCCINYLCHOLINE CHLORIDE INJECTION 20 mg. in each cc. Multiple-dose vials of IO cc. (for intravenous use) ; n’l ' ix, use 'v 6’ ‘ " ' e .,'alysis. While respiratory depression is usually a r single dose of the drug, or following ’M‘uV-r-mtous administration, cessamore prolonged respiratory there may on occasion be depresoion requiring adequate respiratory exgen by the administration of supplemental or controlled . - -. . ‘ANECTIN E’ Chloride brand Succinylcholine Chloride Injection is an ultra-shortactmg skeletal muscle relaxant; that is, following intravenous injection of small procedures. The quick return of spontaneous respiration is a deﬁnite For more prolonged relaxation advantage. ‘ANECTINE’ may be given by continuous intravenous drip; tachyphylaxis does occur and cumulative action is not seen. The degree of relaxation not be ordinarily may controlled by the solution. Upon stopping the intravenous drip, adjusting the rate of ﬂow of narily resumes within a minute and spontaneous respiration ordirecovery is complete within 5 minutes. CHEMICAL PROPERTIES Succinylcholine chloride, also to as diacetylcholine chloride, is odorless, crystalline substance referred a white, which'is readily soluble in succmic acid bis (ﬂ-dimethyl—aminoe‘thyl) water. Chemically it is ester dimethochloride, and its formula is as follows: i ' ' ’ Cl CH2COOCH2CH2iV(CHa)3 CH2COOCH2€H2N(CH3)3 :I'he ester linkage is rapidly hydrolyzed in alkaline solutions but is in acrd solutions. In order to relatively stable promote stability, solutions should be refrigeration. It appears that succinylcholme is rapidly hydrolyzed kept-under followmg its PHARMACOLOGICAL ACTION ‘ANECTINE’ causes muscular transmission at the myoneural paralysis by producing a blockage of nervous junction.This action was ﬁrst reported et al.1 Independent studies by Bovet The at Wellcome Research Laboratories have been conducted on the synthesis2 and pharmacology“7 of the drug. de Beer and his associates3-7 have found that doses as low as 0.05 mg./Kg. given cats are effective in producing intravenously to muscular relaxation, and that intravenous doses of 0.1 mg./Kg. or more produce and complete muscular characterized by short durationprompt paralysis which is of and action extremely rapid recovery. Repeated injections produce reproducible and phylaxls nor signiﬁcant cumulative predictable muscular paralysis, neither tachyeffects being seen. When given by intravenous drip, a predetermined degree (scratic of relaxation in a cat nerve-gastrocnemius muscle) could be closely approxrmated by adjusting �The administration of doses of ‘ANECTINE’ sufﬁcient to produce complete neuromuscular blockade has not caused any signiﬁcant. ghange in blood pressure (except for the typical asphyxial pressor response in the absence of adequate respiration). No,evidence of any histamine-like depressor action has been found, thus differing from observations with d-tubocurarine. The ECG of the caﬁ was unchanged during a 2-hour infusion maintaining complete paralysis. ' ‘ ‘ Acute toxicity studies in albino mice showed the intravenous L.D.5o to be 0.55 to 0.59 mg./Kg. Complete paralysis resulted, with marked dySpnea and anoxia; death was apparently due to respiratory failure. Those mice which survived the initial symptoms exhibited disappearance of anoxia and dyspnea in 2 minutes and had completely recovered within 30. minutes. Chronic toxicity studies on albino rats showed that the intraperitoneal injection of -1' mg./Kg. or less, twice daily over a period of 4 weeks, produced no evidence of toxicity. important.diﬂ‘erence‘between ‘ANECTINE” and d-tubocurarine is that the former is not antagonized by anticholineste'rases. On the comrhlti’, 5.14.911 drugs as physostigmine, lThis rostigmine (neostigmine) and procaineaapnoli‘asgmthg 5;th 1:8 :11 would support the theory that syuccinylcholine'is hydrogze succinylcholine. by cholinesterases and that interference with this enzyme actiOn results in per- -. sistence of activity of the drug. Edrophonium (Tensilon) also prolongs the action of succinylchohne. An- ' ,. ' CLINICAL INDICATIONSUKNI) DOSAGE ‘ 1 Short Duration: ‘ANECTINE' Chloride brand Succinylcholine Chloride Injection is indicated for the production of muscle relaxation during surgical procedures, 3,9,13il5-17 and in conjunction with electroshock therapy.13,14,16 In view of its very short duration of action (usually about 3 minutes following a single intravenous injection) succinylcholine is ideally suited for procedures ;requiring 'only brief relaxation, .such as endotracheal intubation, endoscopic examinations, orthopedic manipulations, short surgicalvprocedures such as tonsillectomies, and electroshock therapy. As described previously, intravenous administration of the drug produces relaxation within a minute, which lasts about 3 minutes and is quickly followed by recovery of spontaneous respiration in those cases where apnea hasoccurred. Dosage for. Short Procedures: The average dose for’relaxation of short duration is 20 mg. (1"cc.) ‘ANECTI‘NE’ Injection given intravenously (Foldess)... The optimum'doSe will vary among individuals and may vary from =10 to 30 mg." for adults (0.5 to 1.5 cc.). Following administration of doses in this range, relaxation develops in about 1 minute; maximum muscular paralysis may persist for about 2 minutes, after which recovery rapidly takes place within the next few minutes. However, very large doses may result in more prolonged apnea. ”-21 Obviously, facilities for supplemental or controlled respiration with ,adequate exchangeoi oXygen should be available at all times. In order. to'avoid carbon dioxide accumulation and hypoxia, supplemental or controlled respirationgshould b? provided during respiratory depression without waiting for the development 0 apnea.. , Prolonged Relaxation: Although ‘ANECTINE’ isfshort—acting, prolonged relaxation may be obtained by repeated injections or, preferably, by maintaininga continuous intravenous drip.8,3o By adjusting. the rate of ﬂow, the desired degree of relaxation may be obtained and maint‘air‘ie'd‘, and the degree of relaxation can be changed within 30 seconds by changing the rate of ﬂow. Upon stopping the ﬂow of the intravenous drip solution, relaxation. quickly disappears. In those cases where respiration has been depressed it usually returns to normal_within a. few minutes upon stopping the intravenous drip, V. Dosage for Long Procedures: The-'aVerage dose for continuous intravenous infui‘ sion is 2.5 mg. per minute for adult patients. For convenience'in preparingsolutions for intravenous drip there are available ‘Anectine’ Chloride Solution, 50 mg. per cc., 10 cc. ampuls and 100 mg. per cc., 10 cc. ampuls. The, contents of one 500 in mg. 10 cc. ampul may be added to SOD-ecstetileiisotonic saline solution to an prepare (1 0.1% mg. per cc.) ‘Anectine’ Chloride Solution; the contents of one 1 Gm. in ’0 cc. ainpul‘maybe added to 1,000 cc. to prepare an 0.1% ‘Anectine" Chloride Solution. This concentration is suitable for continuous intravenous infusion, See literature accompanying ‘A‘u‘ectine' Chloride Solution,’5_0fn‘1g./cc., 10 cc. ampuls, and 100 mg:‘]cc.,«10 c‘c‘. animals for details regarding use of'r'this‘product for obtaining ' ' r‘elaxatiOn. Solutions for prolonged intravenous drip jay also be‘ prepared. for a dilution of‘An‘e’ctine’ Injection, 20 mg./cc. in appioprrate proportions. ‘ NOTE: Succinylcholine is rapidly hydrolyzed by alkaline'solutions and therefore loses potency rapidly. it mixed with thiopental sodium (pentot‘hal sddium). Such mixtures, if used at all, must be used within a few minutes ofvprepatationq however, separate injection of ‘ANECTINE’ is preferable. Succinylcholine chloride is quite stable when storedqunder refrigeration. 0n long standing at room temperature potency gradually decreases; however; solutions may be kept as long as 3 months at room, temperature without signiﬁcant loss of potency as determined by biological assay. , , ' !~- ‘ �.m . . CONTRAINDICATIONS AND PRECAUTIONS The drug should be used only by those skilled in‘ the administration of sppplemental *oecontrolled. respiration and facilities for this procedure, including adequate respiratory exchange with oxygen, should always be immediately .. available. “'V ' 'ANECTINE’lis not an anesthetic agent and should not be regarded as a substitute for anesthesia; 'its‘Ause“ does not take the place of givmg an adequate amount of anesthetic agent. Some anesthesiologists believe that rapid injection is responsible for the muscular twitching that is seen just prior to relaxation. These fascrculations may be due to the‘rate’of injection of the drug, and may be minimized or avoided ‘by giving the injection more slowly/,8,”8 While respiratory depression is usually of very short duration following a 'single dose of the drug, d" following cessation of continuous intravenous administration, ‘LiiCl‘C may‘e..-.§ribcc{i.iongespeaially with excessive doses, more prolonged respiratory depression 1.9-2]- requiririg controlled respiration and the administration of oxygen. The duration of the effect of ‘ANECTINE’ may depend on plasma-cholinesterase activity.94,2°,27 Patients’with severe'liver disease, severe anemia, severe malnutrition, and possibly those suffering from' polyphosphate insecticide poisoning may have a decreased plasma-cholinesterase activity which may intensify and prolong the action of ‘ANECTINE’, especially if large'doses are used.23,29 In such cases, in addition to the usual measures of controlled respiration and administration of oxygen, it may be desirable to administer plasma or whole blood for the purpose of restoring cholinesterase activity,” Neostigmine and other anticholine’sterases, as well as edrophonium (Tensilon), do not antagonize the action ,of~‘ANECTINE’, but on the prolong its contrary eﬁ'ect. They are therefore contraindicated as antidotes for ‘ANECTINE’. Intravenous injections of proCaiiie likewise may prolong and intensify the action of ‘ANECTINE’. There is evidence that intraocular pressure is increased slightly following injection of ‘Anectineflﬂ “This effect is seen immediately after the injection and during the fasciculatory phase; it' subsides as complete paralysis supervenes; it appears to be the result of brief contraction of the extraocular muscles. This suggests that ‘Anectine’ should ’be usedl‘with caution, if at all, in intraocular surgery. The opinion is expressed that the effect is probably not sufﬁcient to contraindicate the drug in general, surgery or electroshock therapy for patients with "' glaucoma. ‘ r‘ .- .KBIBIZIOGRAPHY 1. 2. Bovet, D., Bovet—Nittl, F., Guarino, 3., Longo, V.G., and Marotta, M.: Pharmacodynamical property of certain derivatives of suc’cin'ylcholine with curate-like action: esters of trialkylethanolamine of dicarboxylie aliphatic acids. Rendieonti Istituto Superiore di Sanita 12:106, 1949. Phillips, A.P.: Synthetic curate substitutes from aliphatic dicarboxylic acid aminoethyl esters. J. Am. Chem. Soc. 71:3264, 1949. Castillo, J.C., and de Beer, E.J.: Poteii‘tiationbl' curarizing action of diacetylcholine (succin lcholine) by aliphatic dicarboxylic acid aminoethyl amides. Federation Proceedings 9:262, 19 0. Castillo, J.C. and de Beer, E.J.:_The neuromuscular blocking action of succinylcholine (diacetylcholine). J. Pharmacol. 6: Exper. Therap. 99:458, 1950; de Beer, E.J., Castillo, J.C.,1.Phillips, A.P.,3Fanelli, R.V., Wnuck, A.L., and Norton, S.: Synthetic drugs inﬂuencing neuromuscular activity. Ann. New York Acad. Sci. 541362, 1951. Wnuck, A.L., Norton, 5., Ellis, C.H;, and- de Beer, E.J.: Production of controlled neuromuscular block by infusion of diacetylcholine. Federation Proceedings 11:403, 1952. Ellis, C.H., Norton, 3., and Morgan, W.V.: Central depression by drugs which block neuromuscular transmission. Federation Proceedings “11:42, 1952. Foldes, F.F., and McNall, P.G.: Succinylchélinei A new’a‘ppréach to muscular relaxation in anesthesiology. New England J. Med. 247596, 1952. Brucke, H., Ginzel, K.H., Klupp, H., Piaffenschlager, F., andWerner, 6.: Muscle relaxing effect: of bis'echoline e'sterof dicarboxylic‘acid in narcosis. Wien. klin. Wchnschi‘. 63 :464, 1951. Ginaiel, K.H., .Klupp,.H.,; and Werner, G.: Pharmacology of ”bis—quaternary Yammonium a, compounds. Comparative tests withisome aliphatic dicarboxylic acid esters. Arch. int. Pharmacodyn. and Therapy. 87:79, 1951. 7Gi'7nzzei,9§(l‘.H, Klupp, H., and Werner, G.: A‘dicholine ester with greater curare effect. Experentia . a. Arnold,‘0.H., Bock-Greissau, W., and Ginzel, K.H.: Wien. med. Wchnschr. 101:492, 1951. Thesleﬁ‘, S.; Pharmacological and clinical tests with LT 1. (0.0—succinylcholine iodide). Nordiak ’ Med. 46:1045, 1951. Holmberg, G., and Thesleff, S.: Succinylcholine iodide as a muscle relaxant in electro—shock treatment. Nordisk Med. 4621567, 19SL‘Abst. in J.A.M.A. 14821064, 1952. Dardel, 0.37., and Thesleﬁ, 8.: Clinical results with succinylcholine iodide, a new muscle relaxant. Nordisk Med.‘46:1308. 1951. Thesleﬁ‘, 5., and Dardel, O.V.:'Clinical report on succinylcholine iodide. Presented at 26th International Congress of Anaesthetists, London, September 3—7, 1951. Abstracted in J. Am. MJWom. Assn. 7:58, 1952. " 3. 4. 5. 6. 7. 8. 9.' 10. 11. : 12. 13. . - , ‘ 14. 15. ‘ 16. ~ ' �I7. Mayrhofer, 0., and Hassfurter, M.: Surgical risks in patients with cardiac and vascular disorder. Wien. klin. Wchnschr. 63:88.5, 1951. 18. Holzer, 1-1.: Wien. med. Wchnschr. 102:112, 1952. 19. {IggerfgIséKd Prolonged respiratory paralysis after succinylcholine. Correspondence. Brit. MJ. 20. Love, S.H.S.: Prolonged apnea following scoline. Correspondence. Anesthesia (London) 7:113, 1952. 21. Gould, R.B.: Succinylcholine. Correspondence. Brit. MJ. 1:440, 1952. 22. Bovet, D., Bovet—Nitti, E, Guarino, S., Longo, V.G., and Fusco, R.: Investigations on synthetic 23. 24. 25. 26. 27. 28. 29. 30. 31. curarizing drugs. III. Succinylcholine and its aliphatic derivatives. Arch. int. Pharmacodyn. and Therapy 88:1, 1951. Poulsen, H. and Hougs, W.: Letters to the Editor, Lancet 2:199, 1952. Foldes, F.F.: Letters to the Editor, Lancet 2:245, 1952. Kay, H.T.: Letters to the Editor, Lancet 2:200, 1952. Evans, F.T., Gray, P.W.S., Lehmann, 1-1., and Silk, E.: Sensitivity to Succinylcholine in Relation to Serum-cholinesterase, Lancet 1:17.29, 1952. Bourne, J.G., Collier, H.O.J., and Somers, G.E-:ASuccinyIchoIine (Succinoylcholine)—MuscIe »S[« Relaxant of Short Action, Lancet 1'§2.£5, 1952. Lehmann, 1-1.: Letters to the Editor, Lancet 2:199, 1952. Hampton, L.J.: Personal communication. .L . ,r .:l Diacétiyilchdlihe I" and Little. M., Jr , Hampton, L.]., Grosskreutz, D.C.'. (Succin’yIcIroIine): A Controllable Mu'scIe Rel’axant. Presented before the Twenty-seventh Annual Cpnzress of Anes‘ ” ‘h thetistSyVirginia Beach, Virginia, Septemher 22-15,..1952. " " ‘1 ' Lincoff, H.A., Ellis, C.H., DeVoe, A.G., de Beer, E.J., Impastato, D._I., Berg, 5., Orkin, L., and Magda, 1-1.: The EEect of Succinylcholine on Intraocular Pressure. Am. J. Opth. 40:501,1955. — PREPARATION FOR IMMEDIATE INJECTION OF SINGLE DOSES FOR SHORT PROCEDURES ‘ANECTINE’ CH LORIDE mo SUCCINYLCHOLINE CHLORIDE INJECTION 20 mg. in each cc. multiple-dose vial: of IO cc. For intravenous i'nieetion V Also available: FOR PREPARATION OF INTRAVENOUS DRIP SOLUTIONS ONLY ‘ANE CTINE ’ C H LO R I D E m SUCCINYLCHOLINE CHLORIDE STERILE SOLUTION 50 mg. in each cc. IO cc. ampuls (Total contents 500 mg. Succinylcholine Chlorlde) To be diluted before using FOR PREPARATION OF INTRAVENOUS DRIP SOLUTIONS ONLY HIGH POTENCY ‘A N E C T I N E ’0 CHLORIDE SUCCINYLCHOLINE CHLORIDE STERILE SOLUTION 100 mg. in each cc. 10 cc. ampuls (Total contents I Gm. SuccinyIchoIine Chloride) To be diluted before using ‘Aneetine’ Injection is supplied in the form of a sterile isotonic aqueous .rolution. ImtoniCity 15' achieved by the addition of a :uitable quantity of sodium chloride. \\ .” p,“ BURROUGHS WELLCOME & CO. (U.S.A.) INC.,TUCKAHOE, N.Y. Associated Houses: LONDON BOMBAY by 731 MONTREAL BUENOS AIRES Printed in u.s.A. SYDNEY CAIRO JOHANNESBURG DUBLIN AUCKLAND 41 I o o 6 �Poloni, A.: L'Acetilcolina nel liquor dei malati di mente. Hancenze di effetto curarosimile del liquor di echizophrenici sul mnecolo acetilcolina e en dorsale dell: saga, I1 Gervello g1: 81-1oh, 1951. Translation of EEEEEEE‘ author, using the method of Tower for the conservation of acetylcholine in spinal fluid, and the dorsal muscle of the leech for the test, has made the fol» lowing observations in several trials, making use of the spinal fluid of 10 normal subjects and 110 mental patients, of whom 50 were schizophrenics, 10 progressive paralytica and 50 subjects with other forms of mental disease: The (1) That the spinal fluid of normalaubjects cistains acetylcholine in a to 1:1G' concentration varying from 1:1 (2) That the spinal fluid or schiaophrenice in 9h$ of the case: does not contain ecetyloholine bet a substance which produces an action antagoMstic to acetglgholine, 7; weble to that of ”curare", in a concentration of 1:1 to 1:1' .... (3) In the spinal fluid‘of the progressive paralytic: one encounters the some curare-like subetance nut in a lower concentration than in that of schizophrenics. (h) The spinal fluid of persons affected with other forms of mental sick— ness, as well as that of normal subjects, did not contain the curerelike substance in a discernible quantity, but only acetylchcline, which was found in greater concentration in the hystericale and epileptice, in lower concentration in senile psychotics and alcoholics. This emphasizes the pathologic vale of the report obtained from the spinal fluid of schizophrenics and progressive parelytics and suggests the hypothesis that the curare-like substance is trimethylamine, product of the excessive catabol~ ion of choline, of which the author has found an abnormal urinary excretion in schizophrenics; (In the some paper, in a footnote, the author eliminates trimethylamine, since does not have aurora-like properties.) it �CHOLINERGIC ASPECTS OF CONVULSIVE THERAPY Max Fink, M'.D. �\ From ‘ the Department of Psychiatry, Washington University School of Medicine and the Department of Psychiatry at the Missouri Institute of Psychiatry, University of Missouri School of Medicine, SUOO Arsenal St., St. Louis, Missouri 63139. MH-072u9 and MH—2715, MH—927, grants part, IVE-11380; and the Psychiatric Research Fomdation of Missouri. Aided, in IX: 65-8 2-25-66 by USPHS Revised for the Jowmal. 06 vaouA and Manta! Disease. �CHOLINERGIC ASPECTS OF CONVULSIVE THERAPY While the mode of action of convulsive therapies remains enigmatic, one theory holds that the early development and persistence of changes in brain function are requisite to changes in behavior.“3’21,22 useful index of neurophysiological change is the appearance of high voltage electroencephalographic slow wave activity.22 '23 While the biochemistry of this activity is A poorly understood, demonstrations that it is inhibited by anticholinergic corrxpoundsl9920’3""56 suggest that cholinergic systems may play an active part. The EEG patterns and the response to anticholinergic drugs in convulsive therapy are similar to experimental and clinical head trauma and to a lesser extent, to spontaneous seizures. impulses has been extensively studied since the early descriptions by Dale12 and Loewi.38 A constituent of nervous tissue in a acetylcroline is liberated during the excitation process. It is rapidly hydrolyzed through the mediation of aoetylcholinesterase and is rapidly reconstituted by the bound form, �choline—acetylase system.‘+5 Free acetylcholine has not been measurable in normal cerebrospinal fluid despite the rapid breakdom of bound acetylcholine during periods of activity and excitement.63 But the normal have measurable cholinesterase cerebrospinal fluid does activity.“1 ChoLéneILgic Mme/ta 06 CILanLoce/Lebm mena. Free acetylcholine was found in the cerebrospinal fluid of cats within a few minutes after experimental head trauma and persisted for varying periods up to 1+8 hours. The quantity of free acetylcholine varied between 2.7 and 9.0 gamma/ 100cc and the amount was related to the degree of induced trauma.6 Concurrent electroencephalogram first demonstrated high voltage fast activity, interpreted as evidence of an intense neuronal discharge, which was succeeded by-a short period of flattening of all recorded electrical activity. These phases were followed by prolonged periods of high amplitude sharp waves in the delta frequencies. The behavioral changes related to the degree of induced trauma and to the amount of measured free acetylcholine. With higher levels of acetylcholine, Bornstein reported greater degrees of EEG abnormality and greater changes in consciousness. Spontaneous post-traumatic seizures were also amount related to the of free acetylcholine measured in the cerebrospinal fluid. �Bornstein applied acetylcholine to exposed cat cerebral cortex. When the concentration of acetylcholine was or less, high amplitude sharp the electroencephalogram. to 2 waves When of low frequency appeared in the concentration gamma/100cc, the electroencephalogram parallel to the post-traumatic records. Investigations in neurological patients McEachern demonstrated 1 gamma/10000 was increased flattened in a fashion by Tower and free acetylcholine in the cerebro- spinal fluid only in patients with recent head trauma, recent grand—Hal seizures or after electroconvulsive therapy.63 Free acetylcholine varied from 0.2 to 100 gamma/ 100cc. In assaying spinal fluid cholinesterase activity, they noted a sharp rise in the butyrylcholinesterase fraction and a fall in the acetylcholinesterase fraction in patients with head trauma and following convulsive therapy. however, the cerebrospinal although it ' After spontaneous seizures, fluid did not exhibit such inversion contained free acetylcholine. They concluded that the level of free acetylcholine varied directly with the degree of cerebral damage and that reversal of cholinesterase fractions was a more sensitive indicator of cerebral damage. Electroencephalograms taken at varying intervals following trauma also indicated a relation between the degree of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal fluid. �Increased acetylcholine in rat brain after traumatic shock was also reported by Kbvach, at a£.35 This acetylcholine activity vitae. was inhibited by the administration of atropine tn electrographic, behavioral and neurologic signs of head trauma were blocked by the parenteral administration of The atropine, as were similar clinical changes occurring after the intracisternal addition of acetylcholine.6 0.5—1.0 mg/kg applied these observations to the treatnent of closed head injuries. In 20 patients with varying degrees of trauma, he administered atropine subcutaneously in doses of 0 .1 mg/kg, Ward noting clinical improvement in some and electrographic effects in others.67 a reversal of the The same changes in the' .*-‘_ post-traumatic electroencephalogram were reported by Jenkner and Lechner in a study of diethazine, another anticholinergic single intravenous dose in forty patients resulted in nornalizing the abnormal electroencephalogram in twenty—two drug. A and marked improvement in six others.33 Similarly, in experiments of post—traumatic shock and cerebral edema in animals, Denisenko reported a blocking of the clinical changes by such anticholinergic compounds as methylbenactyzine and adiphenine (Trasentin).13 ThuA, the amount 06 Mae acetytchloune may tamed/52 éptnat ﬂuid 60110“)th cmtnocuebaat mama and the tn the, amount 06 - ‘ -A,‘r �ghee acety£cho£ine, the degnee and type 05 e£ecthoencepha£nghaphie in carded/C behavion abnolzmablty, and changed phenomena, which may be deduced by appear/L aA the adminibtnation Lute/mutated anti- 06 chounugie daugb. Bluuln acetylchoﬂéne and antéehounugic dhugb. The effects of the direct application of acetylcholine to the central nervous system may also be blocked by anticholinergic drugs. The administration of the cholinesterase inhibitor di—isopropyl fluorophysphate (DFP) elicited high amplitude rapid frequency patterns similar to status epilepticus and some posttraumatic states.2'*’31a32a68 These EEG effects were blocked by small doses of parenteral atropine and scopolamine. The' EEG geat increase in acetylcholine after tetraethyl (TEPP) was measured and pyrophosphate related to the toxic effects and the induced convulsions .29 ’59 Chatfield and Dempsey prepared exposed animal cortex with prestigmine and evoked electroencephalographic spike activity. prior administration of atropine blocked the appearance of spiking, or if present, this electrical activity could be The eliminated by atropine.9 In contrast to these findings, Brenner and Merritt applied topical acetylcholine in concentrations of 2—1/2 to 1096 to the exposed cortex of cats and noted no effect. on the electro— encephalographic changes after intravenous atropine (1 mg/kg) .7 �The concentrations of acetylcholine in these experdnents, however, were higher than the topical applications (1-H gamma/1000c) and the intracisternal (0.2-10 gamma/10000) injections of Bornstein.6 Brenner and Merritt also noted electroencephalographic effects similar to acetylcholine after methacholine (Mecholyl) and carbamylcholine (Doryl) in concentrations much lower than the acetylcholine concentrations. They ascribed the increased effectiveness of these cholinergic drugs to their lack of sensitivity to cerebral cholinesterases. 6mm Atady a necuAa/Lg Ceaebao¢pina£ Fluid Acetyﬁchoﬁine and Seizuneb. One view Thug data M9, conﬁuwxg and to quaiiﬁy thié iAAue. of acetylcholine metabolism finds it in nervous tissues in an inactive and bound form. During periods of activity, acetylcholine is liberated at the cell membrane where it is rapidly deactivated by cholinesterases. The amount of bound acetylcholine is the resultant of the continuous processes of synthesis, liberation 'u and breakdown.15 It has been postulated that the level rises falls during waking activity.15’29’“5’6° at al. reported increased free and total acetylcholine during sleep and Tbbias after chlorofornland pentobarbital anesthesia in rat and frog brain but no changes after strychnine or picrotoxin convulsions.5° �(microacetylcholine of level the neasured Richter and Crossland in and rat sleep anesthesia during tissue) brain gamma per mg. brain to be 300% The difference levels. post—seizure than higher rate resynthesis the as however, transient, in tissue levels is gamma/gm/minute).“5 (7 high is brain in rat for acetylcholine Crossland a£.16 and at Elliott confirmed by These observations were and Merrick.11 Giarman and Pepeu reported the increase in be roughly to various depressants following acetylcholine nervous central the of of depression the degree proportional to Buck, and Maynert activity.29 motor in system and the reduction sedation during levels acetylcholine brain however, studying elevated with associated were sedatives concluded that some existed.39 relationships rigorous brain acetylcholine but that no of. observations In part, this may be related to the earlier in measured synthesis acetylcholine McLennan and Elliott that narcotic of low dosages by accelerated rat brain slices is dosages.”° by-high inhibited but drugs, in fluid the in spinal Free acetylcholine was reported an patients, epileptic patients with epilepsy.1°’63 5.0 0.02 to of in quantities demonstrated free acetylcholine Of 56 Acetylcholine gamma/100cc. 1.0 of with an average gamma/100cc extent the seizures, of the frequency to related levels were since time the and to abnormality, of electroencephalographic �the last seizure but bore no relation to medication, type of epilepsy or level of cholinesterase activity. Elliott at al. also noted free acetylcholine in the spinal fluid in concentrations up to 3 gamma/100cc after pentylenetetrazol (Metrazol) convulsions.16 Tower and McEachern viewed the increased acetylcholine as a by—product of the seizure and not causal.63 Studying the hypothesis that seizures were induced by the accumulation of acetylcholine, Tbrda neasured the level of acetylcholine in brain tissue after pentylenetetrazol convulsions. She noted a rise in the acetylcholine content of brain before and a fall during the convulsion. Below certain levels of acetylcholine, convulsions failed to occur. She suggested that the fall in . tissue acetylcholine during a convulsion was due to the inhibition of acetylcholine synthesis by increased concentra-’ tions of metabolites such as annenium ions.51:62 Giarnen and Pepeu also measured changes in central nervous system acetylcholine following various stimulants.29 Only after nethacholine and 3, 5—dimethylbutylethyl-barbiturate was there a significant change in the acetylcholine level. They noted a decrease in association with induced convulsions. With other drugs which they classified as stimulants (LSD, iproniazid, iproniazid + hydroxytryptophan, and iproniazid were no changes in the acetylcholine level. + DOPA) there They concluded that �despite intense excitation produced by these compounds, there were no changes in acetylcholine levels unless these were accompanied by convulsions. (The between these observers and Cone may be differences in observations at at. related to the differences in measurenents, fOr the latter and Tower and McEachern methods measured changes of biochemical reflecting free acetylcholine only, while Giarman and Pepeu measured total acetylcholine including bound and free forns of acetylcholine.“°). Thane btudieb Auggebt that aae accompanied by an tncteaee tibeaated 6aom tté Apontaneoub on tnduced 4etzune¢ tn tnteaeettutaa ﬁnee aeetytchottne bound ﬁonm whtch may be aeﬁteeted tn the Aptnat staid. Ceaebnat activity and eetzuneé enhance aeetytehottne deatAuction, toweatng txnbue teveZA 06 aeetytehottne, white eteep and anebthebta augment aeetytehatine paoduetion ineaeaetng ttbbue tavetb. ' Centaat Menuoue SyAtem Cholineeteaaeee. Tower and McBachern also measured spinal fluid cholinesterase activity.63’5“’65 By reporting cholinesterase activity as a ratio of the rate of hydrolysis with two substrates compared to an acetylcholine substrate, acetylcholinesterase/acetylcholine and butyrylcholinesterase/ acetylcholine ratios are derived. Normal cerebrospinal fluid contains these esterases in the ratio of 33:17. �-10In patients with head trauma, Tower and MCEachern reported an inversion of the cholinesterases with an increase in the butyrylcholinesterase of the spinal fluid and a decrease in acetylcholinesterase activity. The extent of the cholinesterase related to the severity of trauma and to the degree abnormality. A similar reversal was observed in patients reversal of EEG was undergoing convulsive therapy. In patients with elevated spinal fluid acetylcholine spontaneous seizures, however, no change in the after ratio of cholinesterases or total cholinesterase activity was found. Changes in cholinesterase activity may be related to changes in cell membrane permeability. Acetylcholinesterase is found in highest concentration in the central nervous system while butyrylcholinesterase predominates in other tissues, especially blood serum. With increased cerebral acetylcholine, vasodilation predicted, with vascular fluid transudation varying with the extent and duration of the vasodilation.35 Spiegel, Spiegel—Adolf, and their and increased cellular perneability may be co-workers demonstrated such perneability changes and increased conductivity of the tissues associated with the appearance of various ions (as potassium and phosphate) in the spinal fluid following electrically induced convulsions.5"'58 electrolytes as nucleic-acid splitting enzymes Such non- also increased. �-11- Changes in cellular permeability may be the basis for the high concentrations of acetylcholine and increased concentrations of butyrylcholinesterase after induced seizures or head trauma.65 That changes in cholinesterases may be large and measurable is suggested tte recent demonstrations that neural stimulation by and learning produces changes in brain weight and acetylcholinesterase reports, Pryor and Otis studied the effects of repeated induced seizures in Wistar rats.“3 After Following these activity.37’“9 as little as u weeks they observed increases in brain weight and in acetylcholinesterase activity which was related to decrements in behavioral perfornance. persistance of acetylcholine in spinal fluid after head trauma and after seizures despite increased cholinesterase The activity may be acetylcholine— the of the related to sensitivity acetylcholinesterase system to concentration relationships.8’“1’55 At "physiologic" concentrations, hydrolysis of acetylcholine is rapid (3—H ndcmoseconds) but at higher and lower concentrations, the activity falls off quickly. In contrast, the butyryldholinesterase~acetylcholine relationship is non—specific rate of hydrolysis increases with increased concentration. These relationships relate to theories of the induction of seizures. While the usual concentrations of acetylcholine at and the cell membranes are destroyed by the specific activity of acetylcholinesterase in a few microseconds, an excessive concentration following excitation may exceed its rate of �-12- hydrolysis. The seizure threshold induced, with the seizure itself may be reached and a seizure adding to the amount of free acetylcholine. Increased acetylcholine affects vascular and cellular perneability altering the concentrations of various ions, including butyrylcholinesterase in tissues and in the cerebrospinal fluid. Through the activity of this esterase, though of low efficiency and depending on concentration acetylcholine is reduced in tissues to levels for the action of acetylcholinesterase. ChoZanAzcnaAeA appcanb in the Apina£ 6£uid kinetics. more direct a4 a ncﬁﬂcction 06 theta incncaAc in inzcnchZuzan gluidb ac6u£xing diam changcb in cc££ mcmbnanc pcnmcabizity accompanying incncabcd EEG Hypcnbynchnony and Induced Convu£5ion4. of high voltage EEG slow wave The acctchhoanc. significance activity for the convulsive therapy process has been repeatedly described."’?-’23’50,51 In the usual course of convulsive therapy, interhtreatment electroencephalograms record progressive increases in amplitude and in theta activity and a reduction in beta activity. As treatment continues, delta activity appears in bursts and eventually is the dominant activity in all leads. These changes are directly related to the number and rate of induced convulsions, and is not specific for a method of induction. While some relationships to type of electrical current has been observed, all seizure inducing methods —- electrical, intravenous chemical or inhalant -— exhibit the same type of EEG pattern changes.21’22a23:3° �-13The early appearance of high degree hypersynchrony and its persistence throughout a treatment course has been found to be prerequisite to improvement. Both the electrographic and the behavioral changes of induced convulsions are transiently reversed by the acute administration of experimental anticholinergic compounds.19’2° The intravenoue injection of diethazine, bonactvzine, the piperidylbenzilates JB—318, JB—336 and JB—329 (Ditren), and subjects. WIN-2299 induced EEG These EEG desynchronization in psychiatric changes were associated with behavioral alerting, anxiety, tremors, illusions and hallucinations. In patients who had recently received electroconvulsive therapy there was a reduction in slow wave activity and a reversal of euphoria, denial and confusion. Atropine, in low doses, was also associated with EEG desynchronization accompanied by tachycardia, nervousness and tension. At higher dosages, hypersynchronous slow waves followed by lower voltage, poorly organized delta activity with superimposed beta activity was accompanied by progressive confusion and disorientation. effect of anticholinergic drugs on the slow wave activity of convulsive therapy was also assessed by the chronic administration of atropine (5 mgm per day) and scopolamine (1-3 The during the weeks of treatment. The amount of EEG slowing was significantly less than in a control group.66 The samples were too small for a clinical correlation but the data is consistent mg) �-1uwith blocking of the clinical effects of electroconvulsive therapy. Marked improvement was reported in treated, none of scopolamine-treated and in 5 controls receiving unmodified replicated ECT. of 2 1+ 7 atropine— of the 6 This study was not by the authors who suggest or population changes may have results in a second study.“ that dosage factors contributed to the different - AA tn cueblcat tJLauma, the demographic changes induced convuutoms may be modiﬁed by the 06 antichounugtc dlLugb Auggebting 06 Want/cation that tncneeued amounts acetytchoune on tncneated chounugtc aecepttvity ts amounted with the htgh voltage Atow wave activity. 06 Acetytchoune and Induced Convutbtont . Despite a constant application of treatments, however, there is great variability in the time of appearance, the duration, anount, and sensitivity to modification by alerting, hyperventilation and barbiturates of the electrographic slow activity in psychiatric populations.30 These differences relate to differences in central cholinergic activity. The failure of certain patients to develop hypersynchrony may be associated with the absence of free acetylcholine and with minimal changes in cerebral function, wave �-15thus precluding a clinical response to induced convulsions. Tower and McEachern in their study of craniocerebral trauma, included observations of six psychiatric patients undergoing convulsive therapy.63 Studying the patients ments they reported free spinal after 3-7 fluid acetylcholine in treattwo patients; and an increase in butyrylcholinesterase and a decrease in acetylcholinesterase with a reversal of the ratio of cholinesterases in five of the six patients. Concerning the one patient in the series who failed to show either free acetylcholine or a cholinesterase ratio reversal in the spinal fluid, the authors stated; "It is interesting that this patient was the only one of the six to show no response to treatment." From these observations they concluded that the spinal fluid' <3; changes in induced convulsions were more like those of 4 ‘4‘ craniocerebral trauma than those of spontaneous epilepsy. «3-.3‘ Other evidence of alterations in the perneability barrier may be seen in the demonstrations of an increaSed concentration of cocaine in brain tissues three days after a series of induced convulsions.1 The change 12 in concentration of this large molecule, ordinarily absent in brain tissue, was associated with the appearance of hypersynclu'ony (delta bursts) in the electroencephalogram, �1 -.,,-_..._. -15Fhom theae oboehvationb we would conclude that induced convuibioni, like chaniocehebhai thauma and Apontaneoui Aeizuheb, ane aAAociated with an incheaie in ghee acetyichoiine in inten- cebtuiah 6iuidA, attuing cuebhai pumeabifity and enhancing the appeahance is maintained Lb . one 05 cholinebteJLaAeA. The Level 06 ghee by hepeated induced Aeizunei . heﬁiection ieveu 06 aLCULed aitehed pehmeabiiity 06 06 EEG acetyichoiine hypmynchlwny acetyichoiine and the eiecthoiyteb and otheh Aubitanceé, inciuding choiineAtULaAeAs. The changeé in intuceuuiah elect/w- .oi.m_m_._._.. _ ..l.__a u.- iyteé, inciuding aeetuichoiine phovide the biochendcai AubAthate 601:. the pelwibtent behaviouai changed and EEG hypwynchnony ﬁoaowing induced convuibianb. An ww...-._.~__.-m~ 06 application the phedietion o6 06 these conciuiioni is been in the btudieb the convuiAive thehapy heéponbe and the ctaiiisication as psychoaei. ~--....-_ Choiineétehabei and the Ciaibiﬂicatian 06 PAychOAeb. ._‘ 4» .. V Punkenstein at at. reported a relationship between the blood pressure response to methacholine and the clinical response to convulsive therepy.25'27 Immediately after the injection the blood pressure falls, usually returning to the baseline within 5-20 minutes. A return within 5 minutes Of methacholine places the patients in Groups after- 20 minutes \‘ \e I, II or III; places'the patient in while a return Groups VI and VII. �-17Group I and Group II-III respectively, while and 97% have a 9% and a 35% Gkoup VI and Group VII recovery rate, subjects have 89% recovery rates to induced convulsions.27 Group I to III reactors may be looked upon as patients in whom is rapidly hydrolyzed; while Groups VI and VII have a slow hydrolysis rate. (The response to injected epinephrine was suggested as a second criteria in the classification, but is of limited discriminating value.”8) methacholine While we have no biochemical explanation fbr the differences in the metabolism of methacholine in these psychiatric groups, it is possible that the blood and tissue cholinesterase activity levels of Groups I—III is high while that of Groups VI-VII is The low compared to general psychiatric populations. differences in blood cholinesterase levels in normal and mentally ill subjects have been extensively studied. Despite differences in nethods,“’5 elevated cholinesterase levels compared to normal populations have been reported for depressive subjects,"""’5"‘7952 schizophrenic subjectslh’28’53 and a mixed psychiatric populations .“2 Alpern reported lowered cholinesterase levels in schizophrenic subjects.2 While these studies appear inconclusive, they provide data that the variations in blood cholinesterase levels are generally greater and frequently elevated in the mentally ill. Negative reports include the failure by Ellman and Callaway” to confirm Rubin's study; and Altschule's review of the data suggesting �-13no abnornality ' of cholinesterase levels in the mentally ill.3 that cholineAth play These Atudteb AuggeAt meaAuAeA may a signiﬁcant note. in the thuapeutéc aupome to canvutatve the/mpg and in the pathoggnebta 06 paychobu. �-19; CONCLUSIONS This review summarizes some of the available data suggesting that cholinergic mechanisms may be central to the convulsive therapy process. Induced convulsions are associated with cerebral vasodilaticn and increased cellular permeability, followed by the appearance of increased amounts of enzymes and electrolytes in intercellular and cerebrospinal fluids . The increase in acetylcholine, vasodilation and increased permeability appear as interrelated phenomena associated with ' trauma, seizures and induced convulsions. These biochemical changes acconpany increased hypersynchrony which is recorded as EEG slow wave electrical activity in scalp electrodes and which can be nodified by the acute and ' chronic administration of anticholinergic drugs as atropine, benactyzine, diethazine, procyclidine and various piperidyl— benzilates . In these regards, induced convulsions are more similar to cerebral trauma than to spontaneous seizures. in cerebral biochemistry alter cellular activity sufficiently to affect consciousness and the behavior of subjects . Failure to induce persistent biochemical changes, including the The changes concentration of acetylcholine, results in failure to produce behavioral change. �-20There is, as yet, no consistent evidence for differences in the sensitivity or dependence of populations on cholinergic mechanisms. Differences in the rate of development of cerebral changes to the sane number and frequency of induced convulsions classifications of the nentally ill based on the blood pressure response to methacholine suggest, however, that such differences may be significant in the pathogenesis of different and .._..__...V ___,‘~,‘....____... ' «uAW—‘wﬂﬂw ,1“ psychoses . �REFERENCES 1. Aim, B., Strait, R. L. A., Pace, J. W., Hnenoff, M. K. and Neumphysiological effects of electrically Bowditch, S. C. indnced convulsions. Arch. Neurol. Psychiat., 75: 371-378, 1956. 2. Alpern, D. O. i kholinergicheskaya Aktivnost kholinesterasy reaktsiya kmvi pri shizofrenii. 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Rascova, Phamnacologicat York, 1965. F., Hemphill, R. E., Reiss, M. and Brunmel, E. Investigations into cholinesterase levels in serum and cerebroepinal fluid of psychotic patients. Biochem. J. , Early, D. 45: 552-556, 19u9. 15. Bccles, J. C. The Phyuozogy 06 Synapbu, Press, New York, 196“. 316 pp- Academic �16. Elliott, K. A. C., Swank, R. L. and Henderson, N. Effects of anesthetics and convulsants on acetylcholine content of brain. Amer. J. Physiol., .162: neg-um, 1950. 17. Ellman, G. L. and Callaway, E. Erythrocyte cholinesterase—levels in mental patients. Nature (London), 18. Pink, M. A J. Hillside 19. 192: 1216, 1961. unified theory of the action of physiodynamic therapies. Hosp. (Glen Oaks), 6: 197-206, 1957. Effect of anticholinergic agent, diethazine, on EEG and behavior: significance for theory of convulsiVe therapy. Pink, M. Arch. Neurol. Psychiat., 80: 380-387, 1958. 20. Pink, M. Effect of anticholinergic compounds on post convulsive electroencephalogram and behavior of psychiatric patients. Electroenceph. Clin. Neurophysiol., 21. 22. 12 (2): 359-369, 1960. of action of convulsive therapy: the neurophysiologicadaptive view. J. Neumpsyclﬁat. , 3: 231-233, Pink, Pink,- M. M. The mode 1962. and Kahn, R. L. Quantitative studies of slow wave activity following electroshock. Electroenceph. Clin. Neurophysiol. , s: 153, 1956. 23. Alan, B, and beﬂcowits, H. J. Inhalant-induced convulsions. Arch. Gen. Psychiat. (Chicago), 4: 259-266, 1961. �2“. Freedman, A. M., Bales, P. D., Experimental production of Amer. 25. J. Physiol., mstem’ Do Ho Willis, electrical major convulsiVe patterns. 156: 117-1214, 19%. . Gr‘eenblatt, J. New. mnto Dis. , [08: mnkenstein, changes J. 27. D. Rmkenstein, D. nervous system Autonomc shock treatment. M. and Solomon, H. C. in mentally Autonomic ill patients. 114: 1-18, 1951. H., Greenblatt, M. and Solomon, H. C. Autonomic test of prognostic significance in relation to electroshocktreatment. 28. electric psyChOIOgic changes Dis., Nerv. Ment. 301011011, H. C. HOQ-HZZ, 19.48. H., Greenblatt, paralleling and Mn nervous system changes following 26. A. and Hinwich, H. E. Psychosom. Med., 14: 3147-362, 1952. Cholinesterase activity of whole blood from healthy and schizophrenic individuals. Nature (London), 198: 1118-1119, Gal, E. M. . 1963. 29. Giannan, M. J. acetylcholine. 30. and Pepeu, G. Drug-induced changes Brit. J. Pharmacol., in brain 19: 226-2314, 1962. Significance of individual variability in EEG response to electroshock. J. Hillside Hosp. (Glen Oaks), Green, M. A. 6: 229-2H0, 1957. 31. Hampson, J. L., Essig, C. F., McCauley, A. and Himwich, H. E. Effects of di-isopropyl flnomphosphate (DFP) on electroencephalogram and cholinesterase activity. Electroenceph. Clin. Neurophysiol. , 2: ui-us, 1950. �32. E., Essig, Hinwich, H. Freedman, A. M. F., C. Hampson, J. L., Bales, P. D. and Effect of trimethadione (Tridione) and other drugs on convulsions caused by di-isopropyl fluorophosphate (DFPj . Amer. 33. J. Psychiat., 106: 816-820, 1950. effect of Diparool on the electroencephalogram in the normal subject and in those with Jenkner, F. L. and Lechner, H. The cerebral trauma. Eleotroenoeph. Clin. Neurophysiol., 7: 303-305, 1955. 3M. Johnson, L. c., Ulett, A., Johnson, M., Smith, G. K. and Sines, J. o. ElectroconvulsiVe therapy (with and without atropine); effect on electronically analyzed electroencephalogram. Arch. (Chicago), 2: 35. Gen. Psychiat. 32u—336, 1960. Kabat, E. A. , Glusman, of the albumin and and Knaub, V. M. ganma Quantitative estimation globulin in normal and pathologic cerebmspinal fluid by inmunochemioal methods. Amer. J. Med. , 4: 653—662, 1948. 36. Kovach, A. G. 3., Fonyo, A. and Halmagyi, M. Acetylcholine content of the brain in tratmatic shock. Acta Physiol. Acad. SCio Hung., 37. '3: 1-“, 1957. Krech, D., Rosenzweig, M. R. and Bennett, E. L. Effects of envirormental complexity and training on brain chemistry. J. 38. Carp. Physiol. Psychol., 53: 509-519, 1960. Loewi, 0. ﬁber hmmrale Ubertragbarkeit der Hemmemdirkxmg. Arch. Ges. Physiol., 1898 239-2‘J2, 1921. �39. Maynert, E. on H0. W. Effects of C.N.S. depressants and Buck, E. G. brain acetylcholine. Phamtacologist, 6: 191, McLennan, H. and Elliott, 196M. Effects of convulsant and K. A. C. narcotic drugs on acetylcholine synthesis. J. Pharmacol. Exp. “1. Ther., 103: 35-u3, 1951. Nachmansohn, D. and Rothenberg, on Specificity of enzymes M. A. Studies on cholinesterase: in nerve tissue. J. Biol. Chem., 158: 653-666, lSHS. M2. Plum, C. M. Study of cholinesterase mental disorders. #3. Pryor, T. and G. nervous and in activity Clin. Chem” 6: 332-3H0, 1960. Otis, Effects of chronic administration L. S. of electroconvulsive shock on behavior, brain weight and brain Presented chemistry. at the American Association for the Advanoenent of Science, Berkeley, 1965. an. Ravin, H. A. and Altschule, M. D. Serum cholinesterase activity in mental disease. Arch. Neurol. Psychiat., M5. Richter, D. and 58: 6‘45-650, 1952. Grassland, J. Variation in acetylcholine content of the brain with physiological state. Amer. J. Physiol., M6. 159: 2u7-255, 19u9. Richter, D. J. Sci... 88: I‘28-‘43“, Ment. and Lee, M. Serum choline esterase and anxiety. 19M2. �H7. “8. #9. Richter, D. J. Sci., Ment. and Lee, M. Serum 88: 1135-439, 19H2. Rose, J. Acta Psychiat. Scand., 38: T. Rosenzweig, The Funkenstein M. choline esterase and depression. test - a review of the literature. 12H—153, 1962. R., Krech, D., Bennett, E. L. and Diamond, M. C. Effects of environmental complexity and training on brain chemistry and anatomy: a replication and extension. J. Comp. Physiol. Psychol., 55: l4294437, 1962. 50. Roth, M. Changes in the EEG under barbiturate anaesthesia produced by electro-convulsive treatment and for the theory of ECI‘ their significance action. Electroenceph. Clin. Neurophysiol. , 3: 261—280, 1951. 51. Roth, M., Kay, D. W. K., Shaw, J. and Green, J. Prognosis and Pentothal induced electroencephalographic changes in electro-convulsive treatment. Electroenceph. Clin. Neurophysiol. , 9: 225—237, 1957. 52. Rowntree, D. W., Nevin, S. and Wilson, A. The effects of diisopropylflmrophosphonate in schizophrenia and manic depressive psychosis. J. Neurol. Neurosurg. Psychiat., 13: 53. 167-62, 1950. Rubin, L. S. Acetylcholine hydrolysis in psychiatric patients. Science, 128: 2510-255, 1958. . -1 �5Q. Spiegel, E. A. and Spiegel-Adolf, Permeability changes in M. the brain induced by Metrazol and insulin convulsions. J. New. Ment. 55. Dis., 93: 750-755, Spiegel, E. A. 191*1. and Spiegel—Adolf, Physicochemical effects M. of electrically induced convulsions (cerebrospinal fluid studies). W5. 56. A880, 70: 130-132, 19“”. AHEI‘. NeUI‘Ol. Spiegel, E. A. and SpiegeléAdolf, Physiological and M. physicochemical mechanisms in electroshock treatment. COnfin. Neum1., 13: 38-63, 1953. 57. 58. Spiegel, A., Spiegel—Adolf, E. and Henry, G. .M. Physicochemical changes in the brain accompanying electrically induced convulsive discharges. Trans. Ass., 68: Amer. Neurol. Spiegel-Adolf, M., Wilcox, P. H. and 171+, 19'42. Spiegel, E. A. Cerebrospinal ﬂuid changes in electroshock treatment of 59. psychoses. Amer. J. Psychiat., Stone, role of acetylcholine in brain metabolism W. E. The and function. 60. Amer. J. 'IbbiaS, Jo Ml. Lipton, 104: 697-705, 19%. Phys. Med., 36: 222-255, 1957. Mo A. and Iepinat, A. A. Effect Of anesthetics and convulsants on brain acetylcholine content. Proc- $Co Exp. 61. Torda, C. B11010 Mdo, 6': 51'5“, 19145. Effect of convulsion inducing agents on the acetylcholine content of the brain. 173: 179-183, 1953. Amer. J. Physiol. , �62. Torda, Effects of single injection of corticotropin C. on ammonium ion and acetylcholine content 63. Tower, D. B. and McEachern, D. of brain. (ACTH) Amer. J. Acetylcholine and neuronal activity. I. Cholinesterase patterns and acetylcholine in the cerebrcspinal fluids of patients with craniocerebral tram. 616. Canad. Jo Researdl, Sect. E, 27: 105-119, lgugo \ Tower, D. B. and McBachern, D. of cholinesterases in human The content and characterization cerebrospinal fluids. Canad. J. Research, Sect. E, 27: 132-145. 1949. 65. Tower, D. B. and McEachern, D. II. Acetylcholine and neuronal activity. Acetylcholine and cholinesterase activity in the cerebmspinal fluids of patients with epilepsy. Canad. J. Research, Sect. 66. Ulett, G. A. E, 27: 120—131, 19u9. and Johnson, M. W. Effect of atropine and sc0polamine upon electroencephalographic changes induced by electro—convulsive therapy. Electmenceph. Clin. Neurophysiol., 9: 217-22u, 1957. 67. Ward, A. A... Jr. Atropine in the treatment of closed head injury. J. Neurosurg., 68. Wescoe, w. The 0., 7: 398-402, 1950. Green, R. E., McNamara, B. P. and Krop, S. influence of atropine and scopolamine on the central effects of DFP. J. Pharmacol. Exp. Then, 92: 63-72, 191.8. �for Ihe Bio Sciences Informgﬁon Exchange. . . . . NoI' for publlgnhon pubhcahon or Prepared j DEPARTMENT OF HEALTH, EDUCATION. AND WELFARE ——1 m”: PUBLIC HEALTH SERVICE NATIONAL INSTITUTES OF HEALTH "one: or ; . s SUBMITTED TO! ‘Public Hoalth Service. NeIionaI lnr+i+u+es of 'n-r OF Paganini “mmame ‘ and Give names. department. and ofﬁcial Win ‘l'ifles RESEARCH Hulfh. ' ‘ ' rnoJEcIr;”.-\ Div. of Research Grants. Bofhesda l4. Md. ' , in Spinal Fluid § 7 a—sm. (022 , ' , PROJECT NO. (Do no? use this space) and. U lemme} l Read" Injuries“ ' , I of PRINCIPAL INVESTIGATORS and ALL OTHER PROFESSIONAL PERSONNEL engaged on the proiecf. 11.9., Rmsurgem, mums: Gluing Instructor in NeuroIn. surgery. Dartmouth Radical School Smutﬁadgs. i. . John P. Wilson, Ph.D., Assistant meensor 1n the Physiological Sciences, Dartmouth Medical School I NAME AND ADDRESS OF APPLICANT INSTITUTION: ' Hitchcock Fomdation Hanover , New Hampshire SUMMARY OF PROPOSED WORK — (200 words or less —- Omlf Conﬁdential data.) In In Bio Sciences lnforrnaﬁon Exchange summer!“ of work In progrcss are exchanged wlﬂn qovernmonf and privan agencies supporﬁng research In modiul and rant-d ﬁelds and an forward“ to invosﬂqaton such informnﬁon. Your summary Is to be usod for rhese purposes. vbnqm study of in. neq'tylnholine MW: of spinal fluid mama“ in hudinjxaﬁu, utilizing the biéh'nsa'y author! am! Young; Mariana, has A, bun Wt“ tale .mn. In! study Indiana the presence put of «cannon», smtonin.‘ and one. unidentified in the period following head injury. mezpmponod “any: is an extension of this Mainly ml: u.m1n tissue as will as tpifail fluid. and ~11; aging. in addition chain: 'analysis for these one 3mm” (spectrephntnnuomter). during tha We“ f.‘ Silbmitted beginning SIGNATURE OF PRINCIPA INVESTIGATOR for periOd I. September 1956 A , ldenfify fhe Professional SchooI (medical, dental; public healfh. graduafe. or ofher) wifh which this proiecf should b idenfiﬁed: mm, INVESTIGATOR —— mm Romanian .. Do NOT um:- Ti—u: :nnn'n- I 11 ed. �12/17/56 smmc comm wanes WW3 rwml :5an or ~ may mam Acrmr! IN BLOOD ml mm... m) mma: )5.“th for the at mum of t papa-1m mutation mod for): Gil-13:1 mm th Mien, in Matt“, Mm mum Samar, Brooklyn, «.2... Pom-my 15, 1957. A with. m mom-mm nth-ad in ”portal for tho «5mm; a! W My W m W tar um» 91' m «mu-cm» Minty. Though of W31. “14 «mm-nan (2.39) and on m thalliutan» in min-.1 fluid. the mum. in nanny applaud. to the may.“ of and and «11:, um mm, m. on» biological num. Only 0.3 um, :1. of 13311:]. fluid at 0.001 I1. at m mu «um: knyltuooblno 10 why-d a lmdng incubation, m um is nquirod for a in dnmtion. W but”, pa 8. 1! “Situated by am“ 51 tol- trickle”— mm into a calorimeter tube. notummm¢1smwwnmmrm~wmmm «.1331. uotio acid, cum-1mm, ind daunting m thus Whom. Thu than that map mu :m an: m mt: with ”Miami” to product Absorption mm a. 510 tho a. ma to format ton, color with an New”. want, m m M. or new in. y. an be both may.» mum the cam in not by Adding *Mn 1397" u in spin]. ﬂuid, um sham-mu 1: n «1mm Wu: mum-m), (lawnmmmwmmm dot-ruin“ 0! W “machinist-mu. mm of mm in various Mansion. fluids at. amounts-nod and coup-rd to tho ﬁndings in pun-nu with mm dim». Th. nor-:1 W “01ka Yb Ind!!! W10»). alto mu .ployd to “My «batman. that action, no): u LSD, which is a mum inhibitar of 10 �WW. Wham” mtahmtortothnmnmwwwcm hr this mu the awyummm - hm“: - WOJn1¢romoerquythu¢ummmmmtof tm»mmlibcatdhyumc lauwrkmwamwmawmmmnmm mum at m mm, 9.3. mm mu m... 3 601m, 3., m4 Gold-abut, m, a. 3mm. My», 1, 21.6 (1956). �we «mwmman. m: 31.3mm, wmmmc cmmms, m 1'3ch W W, W W. 'm .m no Magnum - Lon; Inland for of a n.‘., 3661“,, 1) m ”may, not M1» on an. ”WW- mm» harm), and for tho Illa; than 111:“ mu u spam. mum mum“ of and and ”both“!— mum.» 1mm in fan madman. a: aninitiou 1: Mm a. "mm m mm and tin-Sr to u» » W in mu W. W]! ma ‘ wat u Wtimﬂu York Mm, 11.0%ch cm 15, 19,7! “W nautical mm: m mm. mu that: m s: muons; mm; (nmalm, mom. mm of atypical alkaloid- m- mm», mthmuumbounafmuc mp: mkummcut 1n thiamine, and Wow. I'm: sum in : Mia «fat mm, 2) awn-s in ”WM 111le 20mm rm- the 91‘ m from macros! M Marina. municidanﬂmdtmmdwmﬁkh wish alkaloid! W I” be much. duration at diam-ranting nut-win 1:: tbs who «Wu. to We 03:10:13.1" I couple“ uh“ for henna; m6. mutating than and hack «mm ma mum-1a, «man. um, mad tmtm into a. null value at cthylm mum“. Tho aim a truncated m M Wu to dryness, thin upon-d out on mt» pupa. Separates: of tho 1: want either by handing cur-anaemia an; Mme).- 1anmmppmu1n mmmnarmmuostmtmamm mum. at mun, ms. mu. am.» 3min. m �“ cam mum «an an a! mt thomh with H» (521:1), or by in 1n 1:: m3. m- petition :5me“ W (m bola). At oommdm mum m «a «a: 1m puma). um ﬂax-1p: , the. club“ with 1106M, tht «ma by mpontm in «11ﬁlth ﬂaking. mud tub», than mm. arms. and Wm mama. m this point than W WI m MinnaﬁyotwlwtomdbthnMaunm«maintain-momma mummuawxomumqmmutmmmu W. M Mal-Inﬂux com-mm; 1m «mum at out amen my be gland mm, thmhthMmWw5uw, mat. mad ”imam, mmtmu, WWI» W mama. W W bah structural {mm at th- '13., and to! 16 drug: tar in pasture m dam-trusting the with ml: w. metric Rub dag mhmtmthmmmoﬁhmcamwath WWIMtMO. Amioutm of tin mm to ﬂu arm. a! “Mum“ prior to m {allowing 4mg than” will I» mean“. �(Effect a! In a Was Mona an 3% Theory of convulsion for amriigmﬂme report to this society we noted the relational” between the degree of induced delta eetidw during the course or therapy and the behavioral response to electroshock. Thane patients, in when big: éegreee of delta nativity were induced early, and were sustained, miteeted the greatest. degree: at helmvieral change, as well as a significantly greater percentage of inprovemrt. and recovery than these patients in when only law degree: a: delta activity were We (Fm: m: m. 1957). In the past few years, a variety of reports relating changes in £me( 1‘) leetylchoum and oholineeternae in the spiral fluids of patients (Subs, Herd) 1rd minis 0 (Bernstein, Teller and HeEnohern) following head the obsem’cime that cholixm'wbic agents may by trauma (32mm, Bard, Jemmr) alter the EEG m; putterne induced and by electreeheck (Inuit), led us to investigate the role of autylcholine-eholinestemee metabolism in acctroeheck therapy. In 1956 Ulett reported that atropine or schpclmne, when administered row! the clock schedule blocked the appurme of the delta activity on a. we hm com to mandate with electroshock therapy. meet. noted, however, �that his patients nurtured numerous madcaiubla aide effecta during these mutations. (19%) had Previously, mm (1950 ramming the suggestion of Bernstein new that atmpine mama bath the EEG patterns and the mumlogm signs induced in an by head trauma. Here, too, the side effects wen marked. In 1953. W:- md Lechmr ropertad that mum-a1 effects similar to atropine mm intend in patients with 610W 11-. in tram, head on also reported the effect at normal subjects. the EEG hypothesis of the we of nation lanthanum is a soluble We: Wr “was: dry with. at“ comlaiva mama» aethnsm the bmdyoardia, «11m: moment neumplvuiolagicnqdapﬂva than”. coupow with Wologic to atropine. In maximum animals. hymns 335; Media 1.1m. and 111mm: of patients ﬂaring electroshock Warsaw; and to relate than them findings to the ham and whim by Maine min- we purpose of this repwt to describe the effects of is dicthuine um; Thcy EEG blocks slowing of the heart; Wasp-m, «ﬂatten. induced by ucatylcholme, main ugal uni hypotenaion. m ma fasciculation e and pilocarpmﬁ and induces �~3- m: shock ﬁreﬂy-two paymttric patients, in-vurioua stages of electron- treatmnt in an studied. the EEG these 351 upon-ward. voltm’ury purchiatric hospital have been WW Follow laboratory. Wtemd intmmny at a routino amtration, 4mm” both the were 25 mm the habtwioral m per minute, for a total errata. Prior and a to the W Mahatma, period were upeonaordad. Running 'dmg record again tested in recording, diamante unstmtured historical intervicw regarding, and meordeﬁ EEG EEG an BEG at the rate or 290 to 250 nan, depending upcn drug maximum, aubjoots Imam periods were mntinued until mummm Wanna patterns on visual \. inspe ction. m m: (a) Neal: follwed by n fooling of Q. 11!. subject; manifested spontaneous gouging initially; dryness of the mouth and, a thickmsa of speech. They nohd heaimde and makneu of the increased mathsmou and difficulty in W were Psychiatnc/cleaﬂy mnifoctad in between 13 and 30 mm attaining mm am noon rammed by eyelid closure. subjects. In the not. pound titer drug mutation, ax subjects spontan- �.3. 0011333” med fouling: of «mm mums mm amnion illusions, about than" 111mm, the setting of the «auras or our icientity. by the um: and Myrtle Such and m: pm- patterns were transient and had diaappuamd‘ of the expat-meat, usually vitiun three hours. In um subjects, mesing august-loan and panic led to, a «mum at an wrung. amt Hero, too, mummm at minimisation War was mum: tune hours. (b) In previous studies, we had noted the intimate rolaﬁommP hem ehangan in syntactic language 1:3th with mmm induced by allotmm. changes diothaaino inﬂamed In In subjects alteration in mm prior to abatmshook, in syntactic pattern at an “lurking” musty. 3&3er with tielta activity, We}: clinical amnesia {anthems of an ”alteration in cerebral function, diathaninu induced a appearance or animation of amt: languaga ambnl patterns. indicative tmient. dis- The pct-5.06 01' ohms” in language in mum-rent with 63mm in eloetmmephalom. (a) Patterns: In all words, than dosymhmiaaum or fmqmneics. Them m. M 15 in 3. MW in wltage and a decrease in pruinamo at In patients without. delta activity (magmas), �.5. me «mum ‘ppannoa or small by the T123543 5.- W8 of 198 voltage 6-? cps uctivity. are Monstmtcé in Slidoa 1, not. appear slower to be alterad. 0131.2. The basic alpha rate does Mishap in voltags and appaamnoe of The fmuweies with mwmtmtion in blockad. In patients with vu'ying ”thaw waiting voltages: W 1m voltage m and burst «halite. in 3 is a decrease ntdxitw diuppoun; and 31m and am Wotan hem This change It wants times {bits or Maud high voltage dean from convulsive urea-am, them are now: in Sudan ham. «W «mm Manny and voltage 1m, 15mm. mm Ghana's Ind h. mm: is West in all 6100mm imam. during drag mumum, and persists far one Concurrent with electroencephalogram changes, uillon}. and language patterns at the pm-dnjoatioa language in 313% m putter”, Nauru: awn uppured. ciascxﬁbed. With the to three as the ho- mum the para-injection behavioral and �as w: ﬁtness obaorntions confirm the report of Jeanne: and Manner of tho affects af diethaaim altars moot-d: subjects. in’*uonm1" we also note that diam II‘ with mammal: induced delta activity in a fuhion dearth“ similar ta atropine and ocopolnmine, l5 ty- Ulett. Memo". Shea patterns are similar to the affect of these anti-showman conpaw-ads in records 1'0le head tram. In the» subjects, intmvma ammo caused immediate changes bath in the we and in behavior. It is appsrmt, Wafers, and that. it; its: duration of activity is most mum). for the @0an mm. mutual: aim audits by mmus obumra at new man attracts of head ﬁrm point to an inﬂate of muralagie dyst‘motion, the :2» mwlohonm 1n the the madly affects the centre). nervous when, basis fer the owned EEG alteration; and the 1m). at spinal fluid. the effmt at ttmpine both an mm a» continuum tin-tho: support to ﬂu chm: of relationship batman the dome an mm» m wbjoets with heaé mm mm Wim Em putt-rams. of mmm. In those studies of Wain. and u the patterns and has nutylcholmo chatmahook, the intimate relationship 13¢qu EEG bonnie: �.7. m trauma... m ﬂuid m mama. beam On We the bases note the parallel to we observations» in head of, these observatim, as wall as studies at spinal chanmmmu lavela, would magi-st that [the (Tower and mwem, Mammal substrate in similar to that. of head tram. Fink and W22), of the electmshack promos: Electroshock my be Ionized upon as a continua-d mothod of inducing cerebral dysfwc’oian for its bazaviaml “Tact. Purim pmidas 13m atudiaa have (1th that. alteration in cerebral mm: pbyuiologic basis for the behavioral changes in electmahock (Fink and Kahn, 1957). Such altamtion in embm mum pmidol m milieu for a change in the eat-mum's adaptation to his environment. aspects a? behavior, in pemaptim, mum lama, mood, recall, memory, m affect, the basis for the therapist's ovalmtim ate. Margo mange, and of immanent. studies of ﬁiathudm amplify this neumplvnolegia mm“ The hypothesis of electroshock by suggesting the type of Minute mat. Marlins both the Wuhan biennium and the beluvioral chm. �m: Dicbhaam, a patent mﬁwohcainergic unwound, 1:1th was upemmntnny intuwnmsly in wyuhiatric subjects in various sages at commlaive thanpy. mectmmcephalogma minimum theme in voltggs, a. and observatmm or éeaynchronixatim of fmquencioa, hyperventilation Manson in mean}: mmmt print dnlta activity. accords with delta activity sham! ammu- changes with mama‘s-anus of delta burst activity. Gmmt pat-amass with the ahetrogmﬁxic effects, behavioral and language indicative of a reversal of the electroshock affoct. were charred. It is maelndod that: (a) Disthuine is a patent anti—cholimrgia amount! that readily enters the antral not—mus system upon intmmm ministration. (b) The Modalities}. butts ras- Fm changes in electroshock is to this of head trams; and (s) therapy The may biocheniml lie in buis of the mode of action or m cmﬂsive the acetylchounoocholmatemu system. ��(glum‘ﬁrzr Wﬂ «/¢V7/‘ “W“W WMWW— #MZ ; _WMQ!4¢W MM ‘ é; 7% WM/ 64331” .461 ha— @fﬁ/If/y EEQaQ/JW gag/M1114. ﬂ 64x7 ��14.3.,“ , / -4I/ . .. M... �é“; sessé c W ﬁg? ngz/ & W‘Za- MWX m ’55 2 “a! gégil Mara. 461/ 4. .4“) ¢ MM: Wu W Jeni #M“ K/m 1» 14:44::____ ��/Z¢, Aﬁfﬁgg L££A4AIZI~ mWMmQ ("43 2% 2 . @a M 3" ��/ / 'v-—-9:' wpw'.” v -' MIG/’4 4trsmg+¢zi9 - ._ ~‘ ~ . " . Dr ��10/ M‘ £77. ~———-—-—-————-——__ / 1 w W? WW M tr M WM mu 5 m; Mar fir WM ltra in x1“! EEQ. 32 ' #2 Cf; .- .20 _ Wa MAX—«l 4.4.!” . #34“... 4'“ ‘7 AIM xcreq cwé‘.’ :4. ('3) M44. Min-A- ��“0011/ /;4a+ a” ._—————-9 ,4¢,,‘“‘“':_:=, l/aw M #u/t. 410/ ﬁ’é‘fu’” S“ v MM ��[f7 x, W/ r{ /¢C// A"! wax / (31) I) 2 %%l -———-> MIL. ”cw / ) ��ﬂew- �O EST —_WU. ”WXW IK. Bag 11“» “~ f ‘ 4W Iy .NQ W .CW ‘e’ Iaéas/uue' ‘ MM? c) jivfeaﬂﬁuﬁp 041.. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Files: Acetylcholine and Cholinesterase, 1956-1966 (folder title 1/4). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-003-0-001 Date A point or period of time associated with an event in the lifecycle of the resource 1956-1966 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/9528d68ea90232ebce57ade28fbef74f.pdf 93461c25c5f8ae971bd4c1aadc2a1278 PDF Text Text I; I Mnémc . ' Recent studies changes in the 7&4 ’demonstrated that a necessary change in behaviort was the development of early mg sistent signs of altered cerebral function of slomgga ”a was a “f7 in these laboratories re-evaluating the role of cerebral mechanism of electroshock pie-requisite for ?. [ours Wt (Fm/IL indeay and per- which electroencep/alographic and/(ah , r:f.:'6) any. mes may of this observation remained unclear until the recent reports of Ulett describing the ability of premedication with high doses of atropine to pre- We wt}; (WMI‘Collowing 5 vent the appearance of the EEG suggestion of this report, we delta abnormality a . nth the investigated the roles of acetylcholine and cholinesterase in electroshock therapy. The data amply demonstrates a close relationship between the degree? and persistence of the ele ctroencephalographt‘cr abnomality and the appearance of measurable quantities of free acetylcholine in the m ‘ mm“ as“ as well {:5mm of. to ﬁcholyl-cholinesterase, The I q ”'2 ('7’de } Loewi u W? normal ratios of” cholinesterase WW of the ‘ p $.00» . 1 f .— p. role of acetylcholine in the transmission of nervous impulses has been a subject Edi} W x 072/) Q). for study since the first description of The arguments as «If theWeﬁ‘ects 4 (ﬁes r’ to whether actylcholine is the main or only �agent in the transmission of the nervous impulse are not of primary concern It is sufficient to here. of nervous tissue; that note that acetylcholine it excitation process; that exists in a it is bound form and a normal constituent is librated during the a is rapidly hydrﬁlyzed through the specific action S of cholinesterase; and as rapidly reconstituted by the choline-acetyléueg fluid iﬁ: Richter Crossland - 1916). Furthemore, normal cerebrospinal I‘M? Mariam ”‘?¢‘94) 4.94mi m‘t‘uﬁv contains no free acetylcholine deSpite the rapid breakdown of system ( & a, bound acetylcholine during periods of activity and excitement. The cerebra- spinal fluid normally has a definite level of cholinesterase activity, which is principally of the "true" or mecholyl hydrolyzing type{ IVMﬂM/“V 4“} "Romsuetkg. any). .111 the absence of free acetylcholineﬁand under the ”normal" conditions described! ﬁe electroencephalograms fail to (a) Effect of Cranlocerebral Trauma: variables was lationship of described by show any . The consistent abnormality. earliest changes in these 0 glmstein (l9h6) in a classical study of the re- changes, degree of experimental head trauma, and levels of cad/w»?!grew oft! cats free acetylcholine in the 09!. stu subjected to varying degrees EEG 0 a of head trauma, B/mstein first showed that free acetylcholine appeared in {Yaszwm the CSF ‘ céE. within a few minutes; and persisted for varying periods up to M hours. There was a positive relation between the degree of 17am and the quantity �-3gamma 9 per cent. cu- electroencephalograms demonstrated patterned changes. Initially, the of free acet’lcholtne which w Eg-rwﬁﬁal varied-khan 2.7 and 9.0 Ocn Com-raw records were filled with high voltage .fast activity, 516 int'preted as an intense neuronal discharge; only to be followed by a short period of flattening of all #01 recorded electrical activity. These periods were "followed by prolonged periods of high amplitude sharp waves in the delta frequencies. Mt 0 Ulth thes/e'zlectroencephalographic changes, Bﬁrnstein fur- ther noted that behavioral manifestations w{ he werencorrelated with degree of the of as as free level well acetylcholine traumal/ ”in; highest levels of acetyleholine; he noted the greatest degree of abnormality as well as the greater severity ””77? M u/ the of WW t'anges a the appearance ofAseizures. _ W, diva EEG alteration in consciousness, 7393!. rnnumnrm further substantiate these observations, B/grnstein applied acetylE Y 105553 choline to the cat cerebral cortex. When the concentration of acetylTo and choline was 1 gamma per cent or less, he observed high amplitude \sharp waves of low frequency in the electroencephalogram. creased to .7lmaém WAC/c! the concentration was in- he ~Wana Mada per-cent, the electroencephalogram we. fad-w 2 gamma 74: When Tower and McEachern (1919 a) flattened,‘ m repeated thﬁe studies in human cases: w �cere‘rospinal in the fluid only in patients following head trauma, recent grandmal seizures and electroshock therapy. to 100 gamma In cent. addition, per terase activity of the. ific cholinesterase spinal fluid. (benzoylcholine Specific cholinesterase ( mecholyl The free acetylcholine varied from 0.2 Tower and Mc Eachem assayed the choles- They noted a sharp - splitting)fraction rise in the nonspecand a drop in the - splitting) fraction in the patients head trauma and those following electroshock therapy. No with such inversion was demonstrated in the fluids containing free acetylcholine following spontaneous seizures. These authors also conclude that the level of free acety- lcholine varies directly with the degree of cerebral damage; adding, however, that the degree of reversal of the cholinesterase fraction is an even sensitive indicatbr of cerebral more damage. In most of these subjects electroencepéhlograms were taken at varying intervals following trauma. Here, too, as in Bernstein's experimental study, there Was a direct correlation of the extent of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal Thus, we may conclude that craniocerebral fluid. trauma results in the appear» �-5. in the spinal fluid; and that a ance of increased amounts of acetylcholine direct {KN rJ relation “between the amount of acetylcholine, the degree and type of electroencep‘llographic abnomality and clinical behavior. (b) Effect of Atropine on post-tramuatic EEG and Behavior: In his studies, Bernstein, administering 0.5 0 atropine, demonstrated a reversal or a blféking of the EEG - 1.0 mg/kg. effects of trauma, depending on the relation of the dose to the trauma. Atropine also modified W the behavioral and neurologic signs of trauma. In the experimental condition of [Mrﬁﬁc/UEPNM acetylcholine, which induced EEG and clinical ﬂanges similar +1.14 to head trauma, Bornstein also demonstrated the blocking and reversing effect of atropine. Ward ( 1950) applied these ideas to the treatment of human cases of closed head injury. In 20 patients with varying degree‘ of trauma, he admin- istered atropine subcutaneously in doses of 0.1 mg/kg.. In selected cases he noted dramatic clinical improvement which action. He \ .traum.we. also noted, alographic effects of IA) lg. m M ATTRI Ben-5;} to he atropine selected instances, reversal of the electroenceph. In the study of another anti- �To“) f \DIW I cholinergé' drug, "DIPARCOL" ‘6' (diethazine), Jelkner and Lechner( 1955) re- port significant alterations in the post-traumatic electroencepbdogramio A single intravenous dose in no instances of abnormal electroencephalogram re- sulted in nomalizing in More 22 instances and marked improvement in six others, recently, Ulett and Johnson (1956) demonstrated the of peripheral atropine IL’ .0 to block the same effect occurrence of slow wave activity follow- ing electroshock therapy. This study suggests the possibility that the same biochemical condition underlies the electroencephalographic abnormalities in head trauma and One in electroshock. report stands out in contrast to these findings. the§5 In ex- periments Brenner and Merritt (19h2), applying topical acetylcholine in con- centrations of to 232‘ intravenous atropine to the exposed cortex of cats, noted no effect of 10% ng/kg) on the electroencepahalographic changes. It is important to note however, that the concentrations of acetylcholine in these experiments was significantly higher than the topical applications “a, 0.: ML andnmtra-steruc (0.2 Merritt, however, make - 10 gamma) (1-34 g7ama%) injections of Bomstein (19h6). Brenner aha-4.1L note of electroencephalographic effects similar to ace- 0 tycholine from mecholyl (acetylbetamethylcholine) and d’iryl (carbamylcholine) , ‘ each in concentrations much lower than the acetylcholine concentrations. �-7. They ascribed the increased effectiveness of these cholinergic drugs to their lack of sensitivity to cerebral cholinesterases. A - variety of experiments utilizing DFP (di-isopropyl fluorophosphate) a compound with irreversible anti-cholinesterase effects - demonstrate‘ the developnent of high amplitude rapid frequency waves similar to status epileptic“;s as well as lesser degrees of abnormality noted in post-tramnatic states _ wich et a1, 1950; Frefdman _e_t_ a}, 1929; and Hampson gt a}, 1950.) A! .. (Hit In these studies, too, the electroencepahalographic effects were blocked by small doses of atropine. In another laboratory study, Qhatfield and posed animal cortex with activity. The Me PR0 ST! Dempsey (l9h2) prepared ex- NW and evoked electroencephalographic Spike admestratgﬁof prior atropine blocked this spiking, or if present, the alnormality could be eliminated by atropine. Thus, from a clude variety of experimental and clinical studies, that electroencephalographic activity as a result of trauma, To PM; AL ‘5“ we may con- induced by acetylcholine, either application or interference with normal cerebral metabolism, can be blocked or eliminated by atropine. �-8(c) Role of CembraSpinal Fluid Acetylcholine in Seizures Acetylcholine is normally present in nervous tissue in a bound, in- active form. During periods of activity, the free acetylcholine is liberated at the cell ”I; The membrane, where it is rapidly deactivated by cholinesterasmﬁ- level of central nervous system a acetylcholine is this ant of the processes of synthesis, liberation and breakdown. It the result- may be post- ulated, there/jars, that the level will rise during sleep and fall during act- ivity. this hypothesis is tge That (1949) and Elliott, , was demonstrated by Swank and Henderson (1950) liquid air quick-freezing methods, Etc.“ ter ANIM in “8.1 experments. was 300% higher than ' micrograxmna the post seizure level. tissue levels is transoi'ent, however, as the 7 in rat brain is high (1 gr: . and Crossland demonstrated anesthesia and sleep level of acetylcholine (measured as brain tissue) Richter and Grassland ’R’tSW ”thesis The By using that the per mg ' difference in rate for acetylcholine J Elliott 33 a; confirmed thez'e (I950) gaxmna/gm/minute). observations. In addition, they noted that after metrﬂzole convulsions Jﬁi FK’EE acetylcholine was always demonstrable in the spinal fluid in concentrations up to 3 gamma per cent. In spinal fluid studies in Tower and Me man, Cone, Tower and Me Eachern (19h8) and Eachern (19h9 B) also demonstrated significant quantities of free �.9acetylcholine in patients with epilepsy. 0f 56 epileptic patients, meaSurable demonstrated/free acetylcholine in quantities of 0.92 to 5.0 with an average of 1.0 gamma per cent. gamma “¢¢ ‘7.) ()7 per cent, acetylcholine level was directly The related to the frequency of seizuresf/ the extent of electroencephalographic abnormality, and the relation of time of / n01 ., M sampling l 14¢, tonlast seiZure. It bore I relation to medication, type of epilepsy or level of cholinesterase act- ivity. As to whether the acetylcholine appeared in the spinal fluid is a by- product of the a M V“ ' s I o n / conclusion; or whether C the increase in acetylocholine was a is problematical. a, increased cause of the seizure, lieve that the Tower and [{cetylcholine liberation itself but related Me Eachem (19h9 B) be- is not due to the seizure to the basic process causing the seizure. I In a study of thfhypothesis that the accmuulation of acetylcholine is basic to the seizure process, Torda (1953), induced convulsions in animals by met zole. She determined the level of acetylcholine in brain fore and during convulsions. She W tissue be1' ' . noted that convulsions are preceded by a rise in the acetylcholine content of tissue; that the content gradually $118 during the convulsion; and that * 5423..) occur. Furthermore, she postulated convulsions u WAS 8. certain levels, convulsions failed to can?» send 3 factor} which in physostigmine probably acetylcholine, but in electroshock seizures was not. �Shendllu concluded was due that the fall in tissue acetylcholine during a convulsion to inhibition of acetylcholine synthesis by increased concentration?- Sec” of metabolitesnas ammonium ions. While considerable argﬁihent waxes about the significance of acety- lécholine in the mechanism of seizures, it is apparent that free acetylcholine appears in the Spinal fluid following seizures; that activity and seizures enhanceﬁiacetylcholine; dfstruction/lowering tissue levels of acetylcholine; while sleep and anesthesia Aﬁgment acetylcholine production increasing tissue levels. �W!"— " WM—w-"ﬁ ' TNT <- Mm; E Aest‘ I. / I w- . , » urr u ' , M 0' - ,,._ -m—~ I 4,4 " 6Z7 v - ,1 5 M 1,;“414, m. -w—.‘ —V<.._—. .Avv»/— up ~~r .-———:v mm” M: . ~ . w.,-- ”v7 /’ W“, .. -v. .. . . . wﬂnm .,,_.V,r, _.._ .<‘._,._r_.__.=_,,m,_qw ' -. ‘ EE < ,. ’ I I: l -7' ['4imzzm4m-‘ean-,g-gﬁc ‘ ~ — ‘ , / -~—...:.;_.-f.._ Mg; ((244.4'4/pv A , , ,.. / /' l . ’ / 3 ‘ j Z e" . ��-« ”tum-35$: 434.. \2 as: {525% mthhw ‘3‘ M . {3%. «3%. Ma g. 7 \i‘xw _. , n ﬁwkﬁkxﬁhﬁ \.m§\. 5n Q“ W; ‘53 h}. 41“; 7 53.3% _ x w x ”‘1; (“VM , «$ka ��the level of free acetylcholine and should follow a decay rate equal to the EEG WWI-£6 rate of in desthtion. Since previous studies demonstrated that Ron hypersynchuy was a necessary pre-requisite to clinical response to electroshock therapy, it may be stated that the absence of free acetyl- choline precludes changes in cerebral function and thus precludes a ical response to electroshock. Certain assumptions 61M (1/ .WQS in \mﬁxam em . may be made regarding M‘ W£%,ML 4W; Cholinesterase I is found in clin- WM“; all 4 {a ;ﬁb€,¢.¢£ £0»£u64* ' ' highest concentration in the central W, W nervous system; while cholinesterase II is predominant inAblood serum. With the increase W! M/mx.dv£[7 in acetylcholine levels, in the intercellular fluids M Wftoaow M 6i mm ‘5‘”; vs odilation and increased cellular permeability degree of transudation of vascular fluids may be I: into the dependent on the extent and duration of the / predicted, with a intercellular spaces tasodilation, (Kabat gt 3;.) 19118); ration changesggﬁztlt high ncentrations of 15?; , enzymet, th 4/ rate of hydrolysis idndecreased, ' achnﬁnson and Rothenberg, �@ Tit/4M ﬁgﬂﬂﬁ W05! M. r ' ”1“." I (m0 4» w- ar A » W M L’ M.%u 7 . WW1 ’53), do W MW; - ’ . - W I44"! %_ /o¢ /ZM"‘ �2% Mwaﬂ.‘ éﬁ 7M/Cc 42 d a >/~7‘$[ 6a 56) iwwwh‘ 4M 444W ' 'wZ/zé 9“. ﬂ A—ﬁr7:9%__~_ ��__ _%j%i%% __M __~__ Meg/Eran!» , , M W/ 8&9- afﬂt ‘9 _4€§./_""f. ' 1% ﬁﬂwjg; W M; ___-#__ ��F:+r§¥¥33~%¢;*‘ '77 , "“37 ' \. *Q W~~ -~’ vM—w7ﬂx-«7A 77.7.«7-«7 . .ﬁW-M 1'} f MW~ §' \»M ‘ \ ﬂ r \- j "39% \~§\-&3~ .uxawk , 7 - 7 «.77; 7 777 , 77.7—7— ...-< w... 7- W - 7 7 7 7 77 77.3, 777 a Q7 M353; --:-..___7—a.7..7 ' 77.7.7 1377-3 ~&\ 71;;7.}7c§?§37\7:s7 sw C\ hﬂa§»3~§~3~ 77-.. 7.7.77 ‘ 7- 7., 7 x 77 5g .v‘wz\ if»; ~ \ f ��I: she/ﬂ ammunummmmmmmmemw at our.Mating um 'mmsmmmmaozmmmmmmumu Meat 11: than Inherited“ ﬂu 1-01. mmpn—mquuiuformmhmurnammtot mhwpmtsim ddﬁndocobulmuondmam Wcummawmmm(mmmv$6h topmtmawotthamdalhtmutw(mttmdm 1956). rationing the Inseam at this report, In investigated the , of acetylcholm Ind cholinoatome in diam-tutu n clone of w’ My. «f ﬁfe? ":9- ‘ therapy. as. data amply the dean. and persistm of the ham 1".th 010W 113109 mm 75:, role: “humility math- I'm acetﬂdwlim in :ppm of measurable quat- the cerebmpinal fluid as wall as an in- moralenrucetvlchdjnohthotmumornemmpnmm Mamamrormsmmtmtmumotmwxm affects by Dale M1 (1911s) Ind/(1921). ' rho W: n to another «1th 4 ' �“wwwmmmtu‘mdmammmm of M 0mm hon. It in affluent to who that mtyldmnm 1| nmmlmtitmtofmmmmy mtnmmmabmtmaaa is liberated as. an mum normal cut-Ironing]. 1.913%) than“ th- or activity and that m ﬂuid contains an hm saga-mt. no true of bdund 1?. iallnpidly mtylchoum (faster and McEachorn new periods The comma-121ml dummy; nomliy has ﬂuid lenl of Munster-nae activity, Men is principally of the mM W was; a: Manning and .- mam mmtitutod mun (mm-a 6mm - 19M). Funk-awn, «citation W through by during thy W (W n “two" deﬁnitm- and Rothanborg: 1935). hmmdfmmtylchonmmdwwrthc'mml"condium (a) fact. :10 mmbrd Tm: th- mliast chug» in than Wmaomumwaommmwmuauummdm vngaumpdEmm,mdoxpommhudtm,mdm otrmumymwminthoembmpamnm. human-numbMtedtonqingdogmluthomtrm,homu1nnruahamdthattm �v r A—w— WWW—«WW. W-_-m_w..__quw$ mtmmmwnmcsruuunarummmmm per-1m for varying poriodl up to Mm. that m a. pain» mum ‘mmmmammmmwnttnomwmma mamaandsammmh human; mum, W was rm activity{ inmlytohtoﬁmdbyawm tbs records won filled with high voltam urpntodalunmﬁeuo neuranldiachatgoy period of mtumd We. {humus of :11 room-dud Glacial-191 activity. Thou period: ~mwwwmm—n -M." mthntoﬂmndbypnlowmothighwnwbshammmh fw. summogmmc . tbs delta. than With that behavioral as wen u . i changel, - Barnum 11mm:- new Nautical! an duo 00th with dogma of tum, with the 15931 of tree mtylclmline. with highest levels a: mmmmwmmuudagmotmmnmwumuum the in alteratim in seventy gm‘bar ma the 1'0 Wmu.» o: apontanam farms:- ahounotothnupoud mam, change! Wanna: animus. those chain-mum, in m. Bantam applied acetyl- «teen-balsam. Unauthomntntimot amylmmlgmporom.arm,hooblemdhighmpntudu �Mmsdloufnqumyintheauctmmoplhlom. manommutation an increased to 2 gun pen-cont, the ﬂattened; in a tnhiun pal-Inn}. to the Tatar,“ kaW mammpmlogm pout-twat“ a) repeated mm. § rum. mm mum-um otnxwingtmofwmandoﬂm»wm¢nsordem. 13112 mmmmmmmrmmmmmnmwm mummmwzm,mmiummmm therapy. murmmtyloholimuxﬁsdhuOJwMgmmrmt. In muQMrmm-aemmdmmmmmiuwatmm ﬂuid. Mm:MmmmmpMcmmmM(m wmmntm) - (tn-chem fondling dug: in the lpociric chainsaw emitting) fraction in the pntiantl with head trams mm W. tho fluids outlining mean faction m a lo s'ugh hint-310nm and We Wadi: rm antyloholim tanning mutations mum. more also conclude ﬂat the Laval a: nu agctymm uric. Wummmotumbmmgm,mr. than: Mmdnﬁmldmmnmmmtnmummmw sitiw indiutor of mm m. �Inn-tatuaumjomwmrmunmnmh— iamla tanning. m. Hun, too, an in Bernstein's W cm, Mmammwmumamumtdmmwwum adenwmmmaﬁWMd. mmmmmludnmtmmnmmnmunthaw ”ammuarmmmmmmnudgmum adfmtrahﬁondmhomﬂnmtofmwlm,ﬂum mmdwogmowwmmhémmﬁ Banners gm Am 9&th of (12) In u.- on BEG and mms, Barnum, maturing 0.5 - 1.0 lag/kg. um, mumudamdor&umdmm¢hm¢tmb Mam'unumorunmmmm; Atmpimdsomdm tho Word and usablogic aim of tum. In tho maximum eon-.- .wmgm mmmwmm,mmaumnwmm dmm of mmcistam induced Km and clinical m: rmrsing arrest. or «3mm. m<m>mmmmmmmathmm¢ WWW. mmpumummmotmhmintend atropin- aubomunly in data «(0.1 W0. In about! an! �.__.. _“_«, _._.__,,....<.,.___,. W7. w _. mmwmmummmmmmnmwam actim. ”waww", .. __._ 7 bmmnmmma,mrmafﬂualectw 'exmpmpmpmo effaahl .w M” wwwmmwv—WWWWWV.W_ 0239113301110 «um. hmsmammu- am, Inn-mm (mm). mwmuﬁﬂ mmamwmmwmmnm.” AWWMHMMWOIWW mmmmmmammwwmmomn: IMW,Mtandemm(1956)Wthume£fm -A——.~-T.v _ ofpoﬁpheglatnﬁminﬂocﬂngthemmotdmmwacﬁuw following unattached: the sm Wen]. mm. 00:811th mm saw mggom tbs Minty any mm. the mmmmmmum WWW mu- MWMdsmmnmmnmmgﬂndi-nga. Inmates- 3m: W mmmm in Wmmdzimloﬂwtmmedmnaotmu,wbudmdfm parjnants and Hewitt (1913); topical .ofinWatnﬂmﬂM/kﬂmthooloatmmmm xtumrwmmmhmr, thatthecmnmumofmamwm mmmnmamswmwmmmmmmappuuuéu (Mm$)mmmmmm(o.2emm)mmatnom �thin (W). 3m: and ”.11“. of hm“, mar, WW]:- ognplun affects 81:11” to noetycholino (WW), chonu) and duty]. than th- mmm mmm. 1mm at that. cholinorgic drugs mums. IA - n van-Low ma at expert-ants nah in commutation! Inch lover my mum ﬂu 1mm attach thou-lack.“ to um with incur-11:10 2m mmm (awwmﬂ- DFP muutytomhnl (div-1W}. Imam“) cumin-stoma. strum - mum- thadaubmtnthighmpnmdonmdfuqmymvelmumm mnpueusuuuumm dugmoxabmmutymmnmt-W mm 919;. (Es-non. museum, too, 1950; mag, 192m and Ema-ca mmmmmnphicoftoctImnWby Inn dot» at am. In W as. 1950). mama-y mm, tantrum and 3-way (191:!) pm mud dwtmmphdomplﬁc m1 mmuw. ﬁnpriarWtimotnmpimelm, expand cox-u: with procugdno md ovum, mmmntyoomuonmmmbyatm. m.rmanneworupommae1mmam.mmm and. tint datum-MW activity induced by mtyldzoune, um �tuna, uI combs-alum unbeblocbdoralmmmbyatmm. topical tpplmuen or interference with mum. of am run. may. mummpnmtmnemuamuam, mmmotacuuty.mrmmmunhenuumw maxi-,1Ihonit1lnpiﬂym1nudbycholmmnu. thunder Wmmauwlm ilyﬁnnﬂaruulhntd’ﬁbpmm at manna, ulnar-1510:: and mmmuuuu - this mm is true um It N ha mm, Wm. dudngnlupmdhﬂdnﬂngmiﬂw. nut m Maud by aches:- and 02-083de (1919) NW§.mmﬂdeM'(19SO)mmupemu. 11mm: on quash-trauma methods, Riches: and cm wining dam-mad um (many-dam mwmmmxamwm prn.mmm)ulwmmmmtmm an wmmmmnmymnummm rats. for Micheline 1n nth-11:1 18 high (1 gulp/mu). Elliott ggmmjmmunu'obsemum. 111mm, thqmtndthat snot-mm mmmrmmwmmmmmn �_...—_——___w wv—wwrvnvr—ﬁwwv—wvw th‘smmnmmmtmﬂmuptoJEtmmm Intpdmlﬂuidotﬂiuinnn,“m,Tmrundﬂon(19hﬂ)md mwhmmm alumnae-ad mimt managed rmmmmupumuumomm. 0t56wihpthpt1mﬂ.hh (1919 B) (Wmmmnmmmwmnm'mmuuudoawa mmoem,umqmndeJMWM. magnetism:- mmmnmpdmmmotmymmot WWw,wmnuumor‘motmm¢ “Whitman“. Itbonmnhﬂmtomdicgﬁm,typadepﬂsply armaehammnuacuuv. hummumtymwmmmamuam mammumrmmmmamwmma _munofthaac1mn,1apobmm rmrlhdmmm (19193)» mmmwmmnumumtmuwm iwmmnudhthohsdcmumth-mum. ht’ahwdmlwmmmdmdmw lib-intact): «13m process, rm (1953).1ndnoodoauvu1d.min mwmtruoh. Sheatoxudmdtholmlofmtyldxolim 13an - �”memcm. mmmtommmmm,addbytmommmmmmmmtdusmj anthem” Mfmsdumgwmmgwdmtmmmmh,m Wmn,mmudtmtm, .MhWWumpmmyaummm,bﬂh mmmmtmrmnmm WWWM. maimhiladtoopw. Wmammmmmummumotmtymmm that: by increased mam-cums ﬂ ”tam“. such a min in. M13 mm nrgunent mm the significance of newb- ‘Wmﬂnmcmdms, niaappumtﬂmttmmwh mwmmmmdrmmm; thitmvityuﬂ mummammamum, «mm; mm sloop mug-mm, M W mammal-19701.net tum @tyldzonm product“ mm with than muse: 80m omimumdchmgummmm,2mrmdncm(mwhw (a) , Walnut! ”1:413:de «shun-ammo activity. «Wmaammmrmmmmmm Twin.- Minster». �"w ——_<__~___..——ww—m_mw—.wrw “—vwr , wwwv I (”ta-m“, .. ”apedtic',: for Mahlﬂgdw mid: he a ma: Spain-o{r 21w for WW; and «shaman-a II ('psendo", ﬁes-Specific,“ a!" WW Warsaw-MW). m have 6133mm ram «Wrormmawmmmoum. differential a..—vnv—_——-_ nu cholimteme activity an mm he» 083 Bach/Ann and mm 1133a, This qualitative dintlnctim. W Rpm-ting the 138111158 substratu’to mtylchonnc, but a ratio of the activity mtylcholm mum-nu, an Wm (mu Wm - me). autumnal m the zonal as: consist: a; mm necholyl and haul- m nuns are found: In mch ntiol non-1 of 33:17 for lack/10h to sub/Ash. manor “pawn" amt-Suez- with a mi]. ‘ non-speciﬁc eaten“ emporium. In patients with hand .‘IZ chainsaw” activity. tram, I'm and kitchen report a sweat may, manu- mum. the county of mammmm eorrdnﬁm between ﬂu extent at tho th- dagm of Wu. tuna and usert. that. there in a definit- mend both with �r,_._W__,__.___._... Inpuumvith mmmmammuvmru: unatotopmmuiznm,hmr,mm1nthonuodobd139mm or total audits-Item activity“: round. Imrandlhmm (191:? g), in than study érudounbnl at tram, n- W‘mmmtmmtmmmw. 3m» &pm WW, zuwnzmmmnmmmgmmmmmw ﬁmw decram c‘Wmﬂthnmerulofth Wotan“, amr 3-? am Mupomd rm mtylchanm m..1? ratio at abolition-M7411 ﬁve pt tho :1: patient.“ Fro-than ohm» nmmwmmtmmtmwmmmmm nor: 1113 than. of crunooerehnl um than that: found in opium. kmtmmpmmmmmmmmmwum Momtmwaweamna ratio reversal,- fb-ymwﬂn ummmmtmnpcmntmaaamlymotmmumwm to want." W �mrmmyaahmmmu. Alia, fmmcwdmrmﬂ pungent m ot’l'mrmdgcﬁcehcémb), mtthctcguths fwdtoMspimlncid WWW thalamus tomcat-ant, penuts us to considor the yummy basic to the anaemia of the um:- that such hm 9:.th pmceu. Ghana‘s: .g. . ocmlusians Certain further deauctiom and agaafalectric m mmmgmmma mum. The pmscuce intcmnnhr ﬂuids Mean alcctmcn Maximum; The pen-- mduccaachangeinccn— ﬂax-activitywith‘anmmu when acetylcholina induce; to gradual pastime. tom: “trim ofﬁo mtylchaum inﬁll WW, nﬂwted in tb nudomeofhwanmmncmtelymﬂm �»;y- mmarmmwmmmwwrmamnuoqmmw an at new destruction. 31m. pm” IMO? Mutated tint lmonnnnmmmnmausaxnmumuypnhunmxuwintnhumnxmqmmnijhmbmahock thonpy, it my be stated that the absence a! {mo acetylchcnne pm- cludu chmgu 1n eczema]. {motion and thus pracludu n clinical aspen-e to electroshock. ‘hﬁhhnummmummsnybomwbrqpnnmgdumpainaﬂluuwmmepmb usability at! explaining the increald 1n Ghanaian-Ame activiw. I is round in highaat cannuntrttian in the central narvoun estemse Quintet-rue aystaum while n is pram in other games, especially blood serum. choline- With the increase in mtylchoum levels in the inter-cellular ﬂuid: as a result. of stimulation and convulsion, “sodium and increased cellular pemeability may bawm¢mum,muhacbgmouttnmmmmmaaatwumnurﬂmuh1Mmibuhﬂmm celluhr spaces dependent on the extent and duration of the ﬂuctuation, (but �r_"__. m,_m into tbs spin-1 fluid; and that thus the electrolytes increased, than siwmsnt increase in changes . mm in permsbmty of calls may ﬂms such u nusledc‘soid Splitting was s amps“. pmids the basis for the sppomncs of high concentrations of scstylchouns and for increase concentrations of Cholinutsrus II, (Tatar sad With the increase HcEschom 19h? in cholinss’oerssa activity, should not the free sooty. lchouns be rapidly destroysd? ﬂuid after trams a). To what melanin cam it's persistence and seizure be «embed? An explanation is available in the for this discrepancy observations 0: Hush-am and Rothsabsrg (191:5). continue! by Tower and Ks ﬁschsm (191396) and Burgaa and the Intosh (1955), tylchouas - shonnsstersse I system “humanips. At ”physiologic” extremely rapid (3-4.1 1vity in spinal is cmcsntrations, mdrolysis microseconds) but falls of! very ﬂuidly extremely sensitive to (Haldane at higher and lower of, ill-t the sea- montrstion acetylchonne is consentmtims, set.- tbs Cholinesusrass II cum). In contrast, acetylchonns uhtionship 1s non-specific, and the rats at hy€re1ysis incmsss with concentrsum. 0011 mums, insstarase this I, in the 11:53 acetyai‘shonm functional with nouns]. st. 1m_ls o: soatylsholins is dsstmysd by the specific. oMsr 0! milliseconds. Where wvity of chol- the excitaﬂea is such as to - �1nd. to an of “casein mm by concentration of sootyloholino in nervous tissue, the rots momma. ‘aooodoo. choline mounts, the ssisuro threshold dissociation in sootyloholino - unt vaaouur ad As is ruched the oonoontntion o: oootyiand c soisuro occurs. 1h. _ cholinostorsse I motionﬂzip vaults in s per- sistonoe of acetylcholine. rho «ism-o, In. acotylchouns. ‘ itself, perhaps adds to the Ian]. at inc'mmd mtylaholino airing.” rapidly. with result- 1'1» permeability connineffects and the appearance of increased names») mmoimnuooohomonom II. Itumoouvuyorwo onlym, though of lot sfﬂciomy, roduoos tho sootyicholins ~«mum of cholinostonso and 69th on concentration aworim, 1on1, InAhours to kinetics that - to levels for the plvsiologic I. Altontionintlnbloodbnin pewbmty humorbyths cantimingsutim omo observed in pout-electroshock oioctmooophnogrm. 1: evident in the mount apart no Aird 33 g (1956) Such s possibility- «annotating a significant increase in tho concentration or odd-inc in bmin tissuo 3-day: utter s ashes of 12 elects-om. an on. shows #olooulo, ordinarily obsent in brain tho clung. tism, in omcantntion of this mg. to b. con-eluted with the spposmoo �, w— _, N‘erm—. #179 WW ducal unu, however, the 1:: mt subjects. the ma 1tuntoa 311 com awumum of trout- «‘WW AM» 7 ms extent; miuuw to «- Despite a Maﬁa: nry may in the of high dogs-ea hypersymhmy, m: by Alerting, mule the duratiamdﬁ' hypnrvmtmum populating. me and wly appearance m persist-mo Wont the tmtamt cont-u, has been described In a neceﬁnry pu-requinita for imprwmmt following shook( nuke: Kuhn. 1956). Batman certain patients to dovdop 137”“an aholine Ind Manama: Assuming my be um mechanism Perhaps and gloom- of.macs-mug the failure them staring of acetyl- nﬁud. is. that a gnnd m1 leisure indicative of the developmnt of tissue 1min or free acetylchonm in mass at the I; hub- at. at hydrolysis by Mae-unl- that the electroencephalographic Wrenchrany in a reflection of tbs persistence of this almond. concentration of acatylcholineg than tho diffemnco in paint: who maintain hypermchrm and those in when it rapidly (tumour-O Ida] disappem, 15 a nﬂactim of the theta.“ of the wonmatemmcetyldmum hydrolysi- Byataa. Persistent. Mommy "cults non decreased "to of �rw‘“. a“ + V ‘. , “m---“vmw hydrolysis of acetylcholim. .Ismbmmmmmdm'oomct, dWrmorbothof the following postulates m opantin an patient: with persist-mt hyper”:— chm. 1) Western” spread batman the the tiam. opt“ ammunition, so that than in a great Imam.- substrate concentration and those present in with high gootylchaline) Ind/[Y 2) Gunmetal-nu m I~1a in 108 1113.1”, lo that the cmntntian kenotion a: this mm opemtim, thong) at a slow decay rate. Conversely, in patients with short ed lampemymhm, cholineatomaelandnintismandspimlﬂuidm Anthem, at” the appunnce of high oomentratiom of acetylcholine stuns!» the production or tissue cholinestemse I in the central Frau tho lucid studies of ”am-noun (195$), a stated in depnasive psych” induced mtylchonne my pncnorbid m1. (1 nervous system. dim rahtionahip batman cm— Mutton of tum cholinestcmse‘ I and level . /) luv-750.. of nervous nativity can be mmpnuul depression) , than the choc:4 . g.» alumni“ I to production a maul. Waters” amt. m �g; hmmmmmwmmumummm _atummuv1ty. Wuﬂaweiwtnmwmmmd WWNWPGW. Itilmww mmmxmmbymmmxx. rhpbhodpmmnotnb mrmcmwmohdmmumbéomuam matm.g.g.nntommzomm. hummus-Wm” mmumuimmsmwmmmducmx,n,mmm Mgmwmmsmuﬁamwmm tomato: Wumumdmmum. mmxnﬁmmaﬁw mtnuuummmmmamnumw;sssmnm �4t). awn-mwmm. the l «tutor cautnlnorvm ”Input Immuoimumm” 1, human tn: of our): and sustained ma levels of :cotylnhouno m Khan, the Wencﬂlhareaaidhrpndicumnm data Wmnohm and 910nm spinal ﬂuid mum to a slow 1nd of chainsaw” activiw. at peripheral “mat-.1431 w chained: neat: 1| thn hypotheti- roaming central nervous syntax nictivity to “rte elect—reducer. �thmmphmdem, 1) mammmamnmmmnud. It'snhuato 3) Whmdduudbwhmcuaoﬂurmmﬂmﬁxm ﬁn" memm—Wrww. «swim 1nd... W tht ‘3) a) shamans activity and patterns ethical norm all at up blame mm a m” a) ‘) 1’) at. of W at M “1 frequency at emu-mu (patina-1) mung; Momummy. mm 1 .7 �NEW» J? I i . , \J Danae ReleefAeetylchenne / bu]. ' E ”Km m Mm at i E Wvulsulﬂ 45% (”<— thenpyﬁdmtnted thet/ Gen-change in behevie 6 wee the development or slowing up he"? as f Wheat oheervetion W - we. index (Finkw and ﬁlm, mined unclear until the «out report! J’ the than; at Mention with high deeee of atropine s f1. E «‘1 E {E ""1? ijmtmg Week WWM”) ﬁcdw- View. describing "‘" hum-tomemﬁemmenw E)W” “M" “ W131- '7: the role of care- Wrelrequeite , ?:- Conan/.hve in the melanin o: WW0 E F amazes - 7'3""‘ early and persistent eight of altered cerebral Mention 2 E 15:7 umrmwwww22". 'W‘m~" "M" m-dbe’prevent the appeennce of the EEG delta abnormality (meet um John-on, name“) 1d; 1956). Following the mggomm at this report, we role/ Convu' | £09 of eeetylchame and cholineetereee in therepy. The data up]:- m E W ”‘35“: e m clue relationship ehetreeneephalogrephic S‘ounvxﬁ ities of free eeetylchonne 1n Wane ~> between the degree and persistence of the led the appeuenee of measurable quant- the eerebreepinel fluid as wall as an inn. vereim of the annual ratios of bensoycholmemlinemme to monomehenmetereee . W he role. of ecetylehenne 1n the bum tea! study since the Loud tnnuﬁdan first eﬂeﬁe—by m1. (1911:) and/(1921). the 3 description of We. W of nervous impel-ea he: as to whether gmmm "’ �lawmanaalyﬁgentmthomaiuionofmuwmmmmmt cf pm", man: here. It in mnmnt a normal constituent of nervous is liberated m it mm in n baund torn and tiuuo; that during the excitation process; that through the specific notion of that mtyldzonm 1: Minute” 11'. in rapidly hydrolysed aid as rapidly raconttitutod by tho Wtyhu‘ Bysm (Righter h mainland - new]. «3&0;me ﬂuid 191m) damn W W contain- no 1910).. in» mtylcholim (Tower and 1493116th mo rapid breakdown o: bound acetylcholine during periods of activiﬁy and excitement. cerebroapiml fluid manually has The chain-stance activity, principauy ”ohm hydrolysing typo (Warm and of the ducribed, eloobmemelﬁdlogma Effect. :3 crab fail to 'tm‘ or w condition- Wm Show Tram: W Bothenborg. 1915). In tbs shame of fmo «Mammalia- and under the (3.) Fummm, any conailtant abnormality. 506-) ﬁﬁMU Jeotad to varying degree: of had tram, Bomtainﬂﬁut abated that (I 4 In. �‘1'. acetylchmne uppeu'ed in the 08? within a _ few aw” minutee etterhtnme and Wm up“: Wﬂoeitiwhnktm persisted for verying periods up to he hams. hw_¢,_e./ ”MK“ at tame/:1 ﬁe quantity of tree W... W”-~Nu '{L versed heaven 2.? and 9.0 pm per cent, Mi 'Wgne 7__ ‘ , “MM . Wu} Mm amount-m. electroencepﬂlogrm 1111:1113, the Vracorde were mud filled with all patterned changes. high voltage recorded electrical fut Witty. 1n:1 short mm in immune. my!» mum F. - activity. mane periods then Inﬂated by prolonged perloﬁe a! high amplitude sharp the delta “V, z.- terpreted as an intense neuron-J. discharge; only to he followed by m “I. were 0.190 correlated with degree of tame, WW mtylcmhemthegmteetdegneotmmmntylmthe M seventy-M WM. as well all with the level of tree mtylcholine. with highest levels W MA. 5(- in containment-change- in greatef and '20 J gamma“-/' ‘ period of ﬂattening of Iﬁ‘J‘ eponteneoue of. name, poet~tremt1c eeimree/ 0/1/24. Wow furtmr substantiate these abstention, Bemetein applied ecet choline to the apoeed cat oerehrel cortex. acetylcholine use 1 gm When the concentration of per cent or lose, he observed high mutude �W“ sharp ms at low frequency castration m immune! to mum . m (£2, patimto therapy. gm pan-09111.; Eu mount "(19349 a.) :1me mpeutud was found Wham the can. the electmcaphalogm in a fashion pummel to the poototnmtic Tower and @ 2 in the electroencepmom. ”com. by}; WI W ”arm. thou studios in in up «rebroapiml ﬂuid only 13' '7 adtmm,moentgmm«1uuure3}nd’m that :m neotylchguna varied IMOA to .100 gm per ant. In ”1 addition. Inner and Mencken-n assayed the cholkutenu activity at the spinal “Maternal M (W ﬂatwf/ m. W W fluid. They noted a sharp rise in the mamaiﬂc oholinesterase (berm. Molina-splitting) .WW” with”. taunting thanpy._ Ho such inversion m dmmstrated 1n the fluids containing tree acatylohonm following Spontaneous seizures. than: authors oL ‘ do. concludcﬁt the m1 of tree acetyloholm varies directly with the degree of cerebral W P. .._ ‘ 3% dam; Mr, rover-:1 of tho ohalinenterue slum inﬂate:- nt con-bra dunno. adding, tau a, that the traction/tram non m �W -5- want-)Ww an m at (g m of those i P 5 tervala tanning MA mm, direct cox-“hum of the _of Em Mommy m appearance of true uoo‘ylgaolmo in the nnbmspzlml Tf (-l [I m. I' that. eminent-b211, traum- WM ﬂ” W/ m I 1" m?! mes-d a in- the ﬂuid. . min-11mm- ofﬂaoctyldmnno in tho Imus]. ﬂuid; and, that the” bemoan mum the dim: degree pthmtylcholiﬁ, aim wt at and type ()3) {“49— . ‘ varying 1 . lA~ mammognphic nbnomlity/ an!" clinical War. am Am g. mtg-swan at EEG and Behaiorz ﬁw‘x mu Mud- W u“ /w mama-d {munching at mam attests/Mb— . W j—h‘ “1.31m °£ 3th. 6‘“ W ”ﬁshnet-n1 a and neurolcgic {.1336 of W *h tum. trams. 4;; W ”1.574; Mn“ 2 “:86 awn/9 Men of 'mtncistorml acetylchoune, which induaod Em and clinical . W effect of utmpdm. closed head In 20 clung” 11:11:: to had Ward (1950) tum, Bgmatoin applied axons 1331117. 1m: 06 31.10414. _ Water! ibis—W to the trentmt of 0... human pttienuuith varying agree of iatarad atropine subcutaneously in dam o: 0.1 when In cues 9f m, , be achin- M can! �r WWWmmmm—W’mmww E aux. mmmmmmlmm'mmm rmml at tho electro- ,_ .W. . A E. enceprmlognphclc effects . W ~vm1Wv—wr E m. cholinergic drug, a! alterations in the report 31mm Inﬁm study of author anuJaguar and Loom (1955) 915::th We Ammumtmnmmhommammmmm E E «(At a_ 833”“me r A-..“ ‘ m . __V W tu: 9.11.4447 M W mudmmmnmgmzzmmmmmdwmmcmm of atropino in blocking the following the 010% and Johnna (1956) WW w W and I in m Wm of that wave activiw therapy. this study suggest; an biodmictl in head mm.- Mutated the smith“ ﬂat uﬁdeﬂ; th- chctmnoepkﬂommic \ I \\ E I ‘ _ manpoz'tstandaoutinconmsttothuennmngarlnﬁwhm_ ' \ pennants Brenner and Merritt. (19M), applying topical aoéﬁyldzoline 1n concentratiomctﬁtomitoWWcomdmu,Wmdfm i or intmenma atropin- (1 E E It is important to not. the r ‘ 1r E nag/lag) on hmr, oloctraomphnlom that the concentrations of “Mabel!” in thésa expemnta ma signiﬂmﬂy higher than the topim¥ upplioationl . r E . L E «hang». (1-1; game. S) and than intncistamn1(o.2 . - 10 N , Born.of gum)1njecti%a 1 .:/\_ .\ �mm Banner and (19115). ognphic affect: 01101130) and than tbs imu hunt, annu- to doryl hunter, m not. of 0100th :cetyuholina from mecholyl (nootylhetmthylo (Micheline), not: in mneontrations 193$).de concentration. mh 1m:- Thq ascribed the manned effect- at those abolinergic drug: to their lack of maitivity to cerebral mums. mm high «11 u n epileptic”, mm In (W, ﬂan at 913;, am. In author 1950; degrees a! abnomlity noted in mhtmmtie boom 339,, 1919; and Emma 23$.19So). m1 if present, ﬂu», mentor} The tho in: warn W by ‘ study, Ghntﬂald and aorta with prosuwm 39m activity. or 1075531; studios, too, the olectmneoﬂnlognphie effects .1111 date! exposed W «puma. npid fnquencykw similar, to status Dempsey (19152) and «oh-d pnpmd eloctmemoptnlomma prior aduiniatntim of ntropinn blocked this spiking, Ibnomlity could be 15leth by atropine. a variety of upexdmntul and clinical elude that eloctroenuphnlogmphic nativity induced by studiu, u- my con- uctyldmuno, nth»! �w .—-——\W- W.. 'WM as e result at Btu-Lug tram, topical application or interference with nee-all period! of aetiviﬁy, 3% free acetylcholhe in liberated W, mm, when it in rapidly Mum by 01103111081283”. {mu—ML WAammchmne 115M101: at ma We, hm. that the than the Th9 10701 mint, of remnant of the processes It may be postulated. therefore, m1 mm rise during aleep and run mmiﬂw. this methane is true and is at the cell That we: denountrehd by Richter and Cree-land (19h?) Swank and Render-eon (1950) in animal uporlmntn. m using liquid air quick-freezing methods, Edema: and Greenland denomtrated that. mm the anesthesia and sleep 1M1 at wetylehonne (manned ea per a. brain tissue) was 300% difference in ﬂame level: rate for acetyleholme in 21g f” (1950) Maw, “ _ Vﬂ ' *~-~r-—.._ (ﬁtter mtmole camﬂei brain is however, an the meynﬂxeeia high (7 W‘“ observation» The game/alum“). Elliott W‘mey H“ , 0,94» A noted that ”W «J'N'n‘ﬁ' a free mtylohnline was always demmatrabh WW”, x. is tme’imt, at 6611th these higher than the poet eeiaure level. in - �-7 w» mmmwmm_—-— '“ " ' - : qumm unmadﬂﬁdmmcmquptoBmwmt. m, In ’lpin-J. ﬂuid audio. in fear and Kahuna!!! (191:9 B) Illa Geno, Tan:- and He Enohem (191:8) and mmm woman!) in patients with opuspay. free (77%) mud lignuieant quantum: at Of 56 OpilOPtic W mammal.- rm miyloholine directly ranted to the momma to the last minute. W ‘in quantities of 0.02 to 5.0 at cultures, the extent It hon no mention to mansion, cm emulsion, orwhetharthe «nun, that. the 3pm ﬂuidisabyb mummammoamumd-s is prom-untied. Tm: and When: hem-ad mtylchoum liberation in not itself m‘mntod to the mic is buie to the scum process due mung ﬂu ”inure.” process, Torch (1953)/ induced» animals by metruole. She dctomined mm; type of epilepsy mm.“ line ot‘ I “ﬂammumymmmauzymm or the mo-ammm af-f;m abnormality, ml the mung»: of or lavai of choljnaatemne activiw. product of the M; J gum per cent, with In may at 1.0 gum per cent. 16791 ﬂuent“, tin level 01' (191:9- B) to up be. “ism § mm Won: 1:: mammalian in bran �Mam berm nadduring W Wm. mm¢me convulsions rise in mintymmum Mutant of tissue; that tho by a my» mum Mfﬂndudngﬂwcmnlﬁm3umﬂutbomcemm15,m whim failed to occur, )hrﬁzem/de a - \\\_~_,_.H_. than” K.’ as during u convulsion We»; H111» duo V‘; to inhibition at aoetylchenno mama; martial. argument” about. the MWWM’ZMMM choline the W Mum mﬁummum Inch 3: ram-m; ' mtylchaum; while sleep and W . mtautivity tum 1m].- nf and - 15min. WW magma: mem- mum 0.th mtylchoum produnﬁan abut-ration: of change: in mtylchonm, armor and of of W»! Gmtlnt War/wed...“ 03m. Mun 1m. W Mb... in clam ﬂuid Jan-L, dostmcum, lowering mowing J.» —_‘_..~... . ,‘_‘ manned concentration- at by tum, /" prob-Lb acatylohouna, but in m msm"ﬁot¢&nmumtthofmmmmw in mm poetuhud /,:v’ . ‘ whim: z” with When: (1916),..— min-1 fluid cholinemmu activity. are normally fwd 1n the spinal fluid: than Two W Minuteman-I �\ } 0m”, - ~apec1nc',§ or ity for wetylcholine; and hm mxéming)mm Bath W W Wyn for Mom and differential rite pend” qualitative distinction... cholirmstame activity a, memo. has a high cholimtarwo 'II (.“psaﬁdo', 'nm—apecitio,' or Mam-manning). dittemnt. rates a! madam—1 1 .éetymxoam, but Mandamus. By Thin ‘ ”porting the M ratio of the activity ”errand and prf W(mﬂ1M/Aah Wk”: bent. oylcholiué swam—ates to an aoetylcholim substrate, m_ meio- are round: WMw-‘C/WLW M osr contains antenna in an _ Thus, normal 68! consists ntio - /1,u?l’zjdua.2 mo)‘ In such 0133:17 for n“ non-specific ester-nae component. In institute with hand tram, Tour and Warn report ‘5 dwinzfTr W the dog-reset mmtyg ﬁzz-J2 65.x; tram and‘tho “Av-o: ”” mu it" ,g 3 nAsimﬂmt correlation batman the extent of the chalkenamc reversal “in with ' 1 WW a)”; M minly of imposing" octane“ with a . no I , the oWncomalogmphin 33 3 Jr”? �In patients with 130de mu ﬂuid hétylcholm activity a I result of Ipcntenoouc seizures, hammer, no change in the ratio of chol- inestemea or total cholineeternae activity an Wm Manx:- Tower and a their study of creaioocrehral (19w 3), in ‘:A six portede psychiatric phtienta mapping in: * ﬁle rm. W); W patients utter 3.7 troatmntc, theymported {1; m M decrease cholimntame, a “I. tram, re- therapy. ﬁtm- rm ioetylohonne act- a: cholinectemco with a revered of the 5 W We: W ratio of chcnneetoru? in five of the six patiente. Fro: tho/e oblont “time more (V they concludejthnt the apinﬂ. ﬂuid Wax: are- “Du—4 ' in lib those of cmniooemhrel tum than then found in opucpcy. haul-ding the one patient in the series who {tiled to show either 1“ﬁeyW“ tat "It {mnwetylcholim or a cholincaterace ntio reversal, 0 u mum-ting that this patient was the only om o: the six to chow no recponce to treatment .' �Ducunm m , but than variant obnomtiom, In my comma that therapy induces spinal ﬂuid changes mm otrmrandwchem (191:9 rum to maps»). ﬂuid b), ﬂu W 111m cerebral tram amt. that onlytho gamma, railed ta show a response to peanuts us to consider the pwnibmty that such biochemical “t, basic to the machinist o: the W at alas-uric current through brain ular activity with an .inemaae to inﬂuee a grand mal'acisun. in m. Thu tmtnant, We m process. cnmlusiom certain further deduction: and ‘ago than than. an mamas poasibla. the pun-- manna: a change in cell- mtylnhnuno to level: uranium. presence at! free :1lech in tho �enema—II in Mt in other tam, W blood anew man. With a. 1mm in acetylcholino levels in the inter-canning fluids an a result of . mum amm'umnmdtmundmmmmmmmm annular ms dupendantm ma ottoman duration or themuon, (mm. ngm)vltmwpmwmwmbmmsmmmmw 81:6.me in mm mom (19M. "s2. W» M. '53). Thu I!!! convulsion, 3111:9301 and modihﬁna and nomad annular pemahility my �throws mumm;mmtmbmehmmud, luxuriant mmmmmmumw-m splitting m. 4 mummramtydmmmmmﬁomtormtw _ wwmumamwmmwtermmmtma ﬂmmm ’n. (rmr w mm 1916 B). mammmincholmMmae activity. mummfmmwb 1mm replay be ﬂuid nth-r m doatroyud? and re whet We. ”ism I» «edited? :1: can . . it’- pal-datum in in amplmtim for this (1180mm ammuntheobumtmormmmmm.mm" tyrower and He Enchun (1919c) and Bax-gen me monoun- At ”physiologic“ mantmtione, m «2% (m rapid (3-15 dam) mtnﬂm. mm: but at. higher and fans acetylnhoum nation-hip 1: with (195$). thet the 33.6w sensitive - chonmteme-I cyst. is mtienehipe. 1v1ty he Intonh cm). Wu, mg. with hem-1 ne- to concentrationor. acetymhenne 1s Mr concentmtiona, set- In contrast. the [hasten-e411 and the mm rd: of hydrants 11mm levels of acetylohnnna et eettutyoreheaamteytheepune «name-nu, theseemohenne inseam-I, 1n the order or nimucom. . more 3% annotation W - �loaf» In main menu-luau or mwlaxolm in mm tissue, at hydrolysis Mascara-2‘1: by ehouneumtn, my As tha rah an mutation at acetyl- thaimnthrydzouu mammalian”. occurs. In. dissociation inpootylcboum - Ghanaian-a I whammy results in a par-- mm,1tu1f,par}upalddstothtlmlof unﬁt-#61:. with munnu mom-ea untmoeofaoetylchonne. nu ﬁtym. mm gym: pemmuw grim .W 1mm muesnmnummmmnmumﬂ.'1t1umauuwottua ant. vascular and 0mm, aid the or mummcm,mmmmnmmmmmt, ypuulbi uduoeathnm‘ylcholmm, action at ' mmudm,umrermmo1agu muons-I mm,muhasentumm,ubccomnmummw �all?» . ! I W dwwm{mubm)nmmmmm hmumnamwaotmmmmmmuu Wuhnecmﬂmdmmpnvmmmmtmmm due” mu, )2pr m, extent) its in lost abducts. Ila-pelt. n m up at uppunnoa mum: m vuy greatly in of mg: dogma WW. nut.- daumua: m 2171 to modiﬁcation by ﬂex-ting, ituntosa- has bean W applicatiu: of b mmmﬁan and hub-- w psyuhntzic popﬁhtion. me and 1t! any appearance courts, trait“: Want yum the 63mm u n uncanny pn-mquuiu for Mt following 01.0m— m( ampmumwmm'z Pcmmiomudwm. M&Km,1956). ButmtutbcmhmiumucﬂnngtheMnno! dialing and Mentor-Ion m be nut-d. Assuming that a grand Ill is. seizure indicative of the MW of tism le'nlloffmo mmmnm-«mnudwwwmm-I/ ’md ehctmphdognmc hyperqnchmil a reflection at u: um. the per-31m of thin abnoml commutation a! Micheline; than the difference upmummnmmmmmmmman W(Mhouni Wm, 13 a nﬂactian of tho mm m W «we. d tho dammsuwtymm Persimt types-3mm units m- M nt- of �.vp—v—vW—yw—qw—nw « W ‘13mzmmmmmmm.dummorwd WWW. of ! ﬁn {ma-mg postulates are opontiiu k £3 menu with pom-tons E chm; l E W . Westerns-i 18 in low cWﬁﬁ;u tint 12W in a great 1) . spread tho hm tho amigo]. mum- aubatmh Mutation and at Wanna-II 131m. no that tho concentration 135mm. of chum on oporatiw, [and hi. W1: a lion docq nu. Camel-loin in patients with short hypersy'mhm, Whoomrnae-I and-II in tissue mm and spinal a. ”7 fluid am we produotion of tissua cholimsteaé-a-ao-I 1n the oentml nervous syntax. W mm WW ame-I my“ aim-rm tho lucid studio! o: (1955’), mutation of Mam? cholimateroao-J ﬂ ‘ 35 4‘— high. \Purmemon, the appeal-once or nigh concentration of acetyldxouno am in I new with high mummy 2) and those pmsent and a direct mum}: between on» level of aetiuty can deMa’o be ‘ do... 91»th 1M Manon» my stunts chainsaw-1 pmduotion to o m zoom. stated 1:: Massive psycho-3 (fungus-.1 60pm). than tho Wu! mu. Eﬁofji 1 �‘ .53.- In moth-r cutout, those studies of outcome reactivity. “Eadie: _ In have opplioation imp-W by to the woman Watch an! other: havo damn-tram a mhtiomhip between the blood pressure reopen-o of patients to inject“! mohohl and ahock. Namely]. Ward“, is ﬂair mama). naponaivity to alcoho- a potent oholinugio agent which induces sweating; and vuadﬂation, momod peristalsis. It is rapidly cholimutoma-I and slowly by cholinostam-ﬂ. Tho W 15'de w pressure of sub- mu an: arm- mused menoml and Muml to the baguun. 1n n variablo length of tin, 3.3. the to natal-unto ' 20.119112“. more than Patients whoa- blood pressure “mummswmmomieduaroupl, II, QMIII no notions; those whose blood pressure “has 20 or more 11mm to rotum to o MWImotonhwooﬁm WM M”! mt ntouitthdthonupII-vmructomaﬁimute. hmmmmnmtonmoMmmmwpﬂIn9ﬁmmxy buoﬂmueroupvlmdmmcum. , g" Wilt-v rats. (momma at, 1952.) ' hmmmzummuummupumumm-mmA Wmédmlylio a lion npiﬂyhydmlyudy than the W81. nu. V. may Gmumm potiontahan m» predict. Hanson, that tho tholinoutenu ‘ uuuwmnmdwxammuldbohighyuhuoﬂmmuvﬁy \va x �a. dwnamwum. Homnhnrcaamrpnmnm mmurwmmmmdemM4,mumuu mammmmwmmmnmmmm mammmmﬁarhmammmmmum mmaudpwmmwmmmumpmu mwnmmuammmmuwumm. �Wmmamnﬁanummotmm-oraammmm W emmwmuummamyummtmwmm l quire #11: veriﬂmtim. 1mm For this purpose mutionahipo ho WM Wash-at 1) it in anaemia. ' murmumaammmmmnm. typo, OllQWﬂogrlI patterns. m and magnum at suggest-d that an mam. 1‘4an A1», the “mum 2)Rohumdmchmty1choumuvohtothomnicalmd patina“. 3) mung» 1:: indie” or mama brain nmcuon othorthnn mama: such mtylrhmao 10701:. h) mums; of cholinoatenae actimy and patterns or blood spinal ﬂuid to: 41)le b) We!“ a) ram otdwoloznant of 3m , d) amber and frequency of tmtnentl a) antennae (perimnl) mativity f) 60mm]. meti‘rityo 14 .& 7’ 5. Wm n... WWWM? éIJMW~ 4* , um and �111: 7-3-6A (I: on rue ROLE or AcsrrtCHOLrue ' ' 'vh .d) AND CHOLINESTERASE 'IN'OONVULSIVE THERAPY -« IStudies evaluating the role of cerebral changes in the mechanism of cenvulsive therapy have demonstrsted that the develogpent of early and persistent signs of altered cerebral. function are prerequisite to changes in behavior (Pink and » t A ~A. . at ': n . ' .c. ‘ I: ‘c .' V A s ', <:-~t ‘ Kahn,‘l956), In these studies, electroencephalographic slowing was the nest significant.index This ohzrvation remained un-v clear until the reports of Ulett describing the effects of pre- medication with high doses of appearance in the atropine preventing of the EEG delta abnonnslity (Ulett and Johnson, 1956). Following reniewed the suggestion of the we report. role dt acetylthis cholinestersse in-‘convulsiva' therapy. ‘he data suggests a close relationship between the degree and persis of the electroencephalographic slowing end the appea ence of and choline measurable quantities of free acetylchnline in theygnrebrnspinal / influid as well as an inVersian of the aerial ratios of benenycholine. . 'cholinesterase to lecholylcholinesterase. that: The role of acetylcholine in transmission of nervous the impulses has been studied since the first descriptions of Dale (1915) ..snd Loewi (1921). The srgunenta as to whether actylcholine' is the main or only agent in the trans-ﬁssion of the nervous, impulse are not of primary concern here. .It is sufficient that acetylcholine is a normal constituent of nervous tissue; that it exists in a bound torn and is liberated during the excitation is that process; it rapidly hydrolyzed through the specific'action~ - A ‘ " . A .1 F .v «an ‘ -< _- : .V. l antes-.3 var-I‘m.- ,, . “be”: wMYJ/I'" 44:: gauges-5mm �. .1 of cholineeteraae and as rapidly reconstituted by the choline- I ' acetylaee system (Richter &.Crossland, 1969). Furthermore, normal cerebrospinal fluid containe _ free acetylcholine despite the rapid breakdown of (Tower and HcEechern, l9b9a) bound no acetylcholine during periods of activity and excitement. 'The cerebrospinal fluid normally has measureeble cholin- esterase activity, principally of the "true" or mecholyl ’ hydrolyzin3 type (Nachmeneon and Rothenberg, 1965); ' In the absence of free acetylcholine and under the conditions described, electroencephalograme_fail to consistent show any ‘ I abnormality; .. ‘ i (a) Effect of gregiggerghggl . 3 Exagggz .1n n study of cats subjected to varying degrees of head trauma, Borenetein (1946) reported that free ecetyltholine appeared in the CSF within a few udnutes after experimental head trauma and persisted for varying houret acetylcholine quantity of periods up to £8 free _The varied between 2.7 and.9.0 gamma percent, and-the amount weeV poeitively related to degree of trauma...‘ Conconntant electroencephalo3raes demonatrated patterned chan3ee. Initially, the records were high , filled with n fast activity, interpreted as voltage intenee neuronal discharge; only to be followed by a short period of flattenin3 of ell recorded dectrical activity. These periods were then followed by prolonged periods of. hi3h amplitude sharp waves in the delta frequencies. The . behavioral chan3es were also correlated with degree of trauma, as well as with the level of tree acetylcholine, with ,higheet levels of-acetylcholine. Bernstein reported the greatest _‘-_... �_, ‘ 1 , _ ,. .3 w. a yawn-mun?” lift!“ .1»? . .. my vmr in?! 0...“, yr,“ y». my -1,“ 'V'W'FM' cream-ls“. . _ . .~ > I -3degree of m abhor-slit” the greatest. and thence; in consumes ' furthermre. spontaneous post-Ftrat-oticseisures livers also related to the of tree aco'tylcholino- appearing iii the apical fluid. 1 “t l..,‘_.‘.__.. l... V A t ‘ ’ further substation ,theae‘ohsarvations, Bonstsin applied .acetylcholine to the eiposed cat cerebral cortex.' "h. the concentration of sutylcholine use percent or less. he To , ‘ . . ' EI - . line ‘ observed high amlituda sharp waves of low froqmncy in tho electroencephalogram. When/the concentration ‘ves increased to 2 3—: perceot,’ the electroencephalogr- flattened in. afashion parallel l to the post-trematic records. ‘ . Tower and HcIIchem(l9lo9a)'-Iropa_ated neurological pstients. thssa studies in Irse acotylcholins ass 112 foond in the cerebrospinal fluid only in the patients with. rocoot hood trams, ~recent grand-ml seizures or convulsive therapy.- The free acetylcholine varied from 0.2 to lOO' 3‘s perceot. lnladdition, Tower end lichchern assayed the cholinesterasa activity of the spinal fluid; They noted ashsrp rite in the “nonspecific cholinesters'se ‘ fraction '(hensc'ﬁiholine-splittiog) and a drug in the specific choliioesterasefractiou (escholyl-splittioc); in the patients ‘ with head trams and those'follwiu in Mlsive thereby. no ~ - such inversion was ’d-oustrstod it: the fluids containing tree acetylcholins fondling spontuooos soisores; These authors concluded that the level of tree acetyleholino varies directly} the degree of cerebral dance; «nesting, haever. that with. the reversal of the oholinostersse' frantic: cos ‘a sore sensitive indicator ot-esrshral donate-V ,' I. ' _ ' ’ �7-1-2 intorvalo following varying at cm in loot of theoe anhjeeto. .‘lhe nthore reported a direct Electroencephalocrnooere trano - m and the appearnce of the of ahnorn'lity degree correlation oerobroopinal fluid. in the of free acetylcholine _ two Theoe ' increeoe the etudiea indicate. that crnioeerehral tron-a nay nomt of free acetylcholino in the opinal fluid; ’wt of froo that a direct relation eniota between tho acetylcholine, the degree and type of eioctroondphalouraphic and abnormality. and changeo in clinical behavior. ' Bornotein adainiot'ered O.5-l.0 tog/its atropine after hood traumawae tho induced anddennatrated blocking of mifeot no effecto. Following the experitrana.~ induced intreciotornal which ecotyldlouno. addition of jof and neurologi'c eigno behavioral nntal 2 clinical change. oililar to head trouno.'lornatoinohoerved 1 blocking effect or atropino. zoo and , Vardf1950) applied theoe idoaa to tho treatnont caeeo. .. of hulah ' of closed head injury. .In 20 patiento with varying degree of trau'oa.‘ he adminioterod atropine outmoly dooea of in 0.1 tog/kg. In one eaoao'henot'ed'clini'éel ignorant. and in tho of electroencephalographic of the 1 othero, revoroal effocto am: ntioholinargic of 'otndy a another dm. tragna. In Lechnar (1955) reported oinificant altoretiona in the poet- and » tranatic electroencephalogrn. inota‘nceo ' in 22 of A. oingle iatrovonooo dooe in abnornal electroenoeph'aloorno reoulted in inatoncea and unto-a iaprovooont 1. eix othoro. ‘ 1.0 nor-dieing ! o , �. 3 Iv. . . p 5 u ' .. ' ‘ , . V“ U - 'F ‘ ‘ ' r ‘‘ Ulctt and Johnson (1956) donoootntd tho I... ’oﬂoct'ot Antroptno 1n blocung tho oppnronco of no: 111601” couwlo1n. oct1v1ty vi. than". an' mood: tho study oouuto tho that 0.- Motbdcal .chauo. oloctMuphoch on... 13 hood ; m... cod 1: ,.- i . “owl-1o...1:: oootrut t6 thou 11.11:. In an: out undo noon 0. mod-onto Broom: .d Hordtt _(1m).__m1y1og top1c‘11'ocoty1f161111.11 ,' - 1 ’ thou. of tom! 1o concoctrouooo o1-2-1l2 «to; noted no offoct of clocttooocoohologuohu that tho mtntw. no “unfunny atom an... 11: to tho otrop1. of oootylohou. 1o than tho tinted lad-or tho .rooot) ,m :5 ~ ' I m2. W at onoophalogtophic otfocto won Modal by . ‘_- A #ﬁ.1w-_ ‘ moot“. . -V . in ﬁ...___‘..-% 1.,mr-4gmv4._.ﬂ 41V W to 6.1;.an about:- ‘Wq 1950) 11.. 1950).. Inothou 3 . 1 «duty of 1.011qu nth choumtoruo' 1nh1b1tor on (614.9:ny (Imam-photo) Mutton 1113b qutodo 1‘.“ (Money pot... “-11“ to out. 1n opuoptmoo. u -11 u 1.3.: «lop-o. of no.6 .' 1969; and v _ tho potont post-truth: . _' . ototuﬂlltnttcmuot 11., - on tho h w ‘ motion. to. thutlod o1 logo1t1v1ty A . _ . tut1oom1hoyucﬂbold01Wdfott1Mﬂthou- at"... ‘ 1"...“ § (mutants). I _. '34; (oatylutuothylcho1bl a“ by: -chol'yl 111 commutati.oh 1.» ti.” on. .otylobu. concou“ch ennui-31c. drugs to w...h- hM-—mbvwmmr wWe... am (OJ-IQ ‘ A quuuuu'u (1-1 3-1 oloctroooooohologrqluc oflocto 011111: to 4 ﬁlls) to ooto. '- ‘ (1 1-..... earth: Mt tho. Wu 1; atria-tuna 'o’z Wain (1946). mm: .11 smut. potent) at] ow w. m new”. at .1... too, tho “cotto- 0.11 dam of otrop1oo. �- 6.In another_laboretpry study, Chetfleld and Dempsey (1942) 'ptepered exposed animal cortex with proatlgnlne and evoked electroedcephalographic spike actlvlty. The prier.edu1nlstratlon of V . _ ‘ 'atroplne blqcked’thls spiking, er if present, the abnormality could be elimlnated-by ettopineuv Thus. from a _ variety of experimental end cllnlcnl studles; __ we A may conclude that.eletttoencephaldgtaphic aetlvlty_1nduced by ‘ acetylchallne. either as a result of trauma, topical applleation qr [ntefitxcnce with cerebral metabolism, can be blocked gr ellmﬁnated 5y atrnpxne (a) ‘Role of Cerebtnaplnal Fluid W...‘ " Acetyicholtne normally appears to be present-1n nervbus tissue in bound. inactive farm. 'chollne 15 activated thus the During periods of liberated at the cell by Ac cholinesterese. activity, free acetyl- membrane, where The it is rapidly de- level of-bqund acetylchcllne ls resultant of the processes of sinthesis. liberation breekdpunw It may be and postulated, therefore, that-the level wlll rise during sleep and fall daring ectlvity. ‘That this hypothesis '15 true was demonstrated by thhtet and Crosslend (19a9) and Elllatt. Swank-and Henderson (1950) in anlmal experiments. By using ltquld-alr‘qule-freezlug methods. Rlcﬁter_and‘Croaslapd demonstteted that the anesthesia and sleep level of acetylchollne {measuted as microgtemﬁe per mg: brain tiesue) was JCCZ higher- poet thaﬁ the seizure level“ ‘The d1£fetence_1n tissee levels is trapslent. however. as the tesyntheels rete for acetylchollhe 1p rat brain is high (7 gimme/gm/mlnute). lﬁlllett‘et a1. (19$0l; a �- 7 _ AIter metrezole convulsions, confirmed these observations [they also noted that free acetyl~ was choline ttatione always demonstrable in the spinal fluid in concen. up to 3 V . l genus per cent.> ln spinsl.£luid studies in and and Tower (1948) Cone, Tower and Menschern men, Mcéechern.(l949h)-slso denonstrsted significsnt of free eoetylcholine in pstients with quantititCe 56 enileptic patients. 49 epilepsyl"0f (77X)'demonstrsted’messursble free acetyl— chuline in Quantities of 0;02'to 5;O genus oer cent. with an average per.cent. lhe acetylcholine level was directly reletedl extent eelzures; of electraencephslogrephic the to the frequency of ebnormslity..snd the telation.of the time of coupling to the last of.l.0 gamma seizure. It hare no relation'to indication, type of epilepsy or“ .Ievel of cholinestetese sctivity.ll ' . , Whether the acetylcholine appesttng in the ~ '. A 3 g. spinal fluid is a by-broduct of the convulsion, or whether the incress} in acetyl- I]choline is'n cause of the seisure, is problematitel. McEachern (l949b) Tower and believe that the increased scetylcholine libetstion' ls not due to the seizure itself but related to the basic procees' causing the seizure; In a s“dy of the hypothesih that the accumulation of scetylcholine is basic to the seizure process, Terds'(1§53) induced Canvaeions'in animals by nettezoles She_determined the level of scetylcholine in brsin tissue before and during convulsions. .She noted that convulsions ere preceded by s " rise in the scetylcholine content of tissue; that the coucanc‘grueuaiiy fells'durins the convulsion; and that below certain levels, convulsions failed to ‘occur.v She suggesteﬂ that the fell in tissue scetylcholine during convulsion use due to inhibition of see.tyleholine synthesis by concentrstious of metabolites such so smunnium ions. increased a ' �While ebout erguneut the role of acetylthere.ls considerable choline in the mechanism of seizures. it is probable the: free acetylcholine ie increased during seizure. and appears in the cerebral spinal fluid; that activity and eeizures enhance acetylcholine destruction; lowering tissue level. of acetylcholine;‘ WW while sleep and enestheeie.eugmeot acetylcholine production, . increasing tissoe levels. 7 l. . rd) Concomitant with their observations of changes in acetycﬁbline. Toqer and Mczechern (1949) oeaeured spinal fluid cholineetereee activity. ‘rwb types of cholinii lesteresea are normally found in too ebinel fluid: .cholioeeteraee-I ("c-me". "specific" or-necholy'l hydrolyzinﬁ), which has a high: ' nod specificity far eeetylcholioe; cholineeterdIo-II ("peeudo"." epecific". or beozoylcholine-hydrolyzine). -Both coupounds hydrolyze' - ‘ ecetylchollne, but have different rates of hydrolyeie ftr mecholyl "and beoZOylcholine. -Thioldifferehtiel rate permit! duelitetive' distinctionse of the .By repertins the cholioeetereoe ectivityJee e ratio. activity with uncholyl and benroylcholine substrates to on retidio ere found: cholinesterene-l/ choline-tereue-II[acetylchbline.(with Ash/Ash - 100). acetylcholioe substrate, acetylcholine and ln-such ratios normal CS? two contain: eatereeee in the ratio of 33:17 ‘ior choliuentereee-I to cholioeetereee-II. Thus; noruel CS? consistedllllllli with of "epe¢i£ic” utterance a euell non~apecific eetereoe component. mainly ' i In patients udth heed tron-I. Toner end Holechern reportm m inverting of the eniupte of dbollniptirg‘le with d lignIIiCInt meg. mime unionist-nan meme decreaue in choline-cerebe-I ectivity.- betweenthe current or the cltolihbotereee of mm fluid and e They eleogreQOrted a Mﬂel correlation with the severity �of cm... W the of electroencepheloirmhic and with the degree I II I abnormality; '- . ,I" In patients with increeeed result of spanteneoue eeieurne. of. 1 e 395-1221: r" , eoihel'tluid ,ecetylchoiine howewet. no cerebral ad Tower tum, ee e thmge'ingthe ratio. cholineste'raseslor total" cholineetereee ectivity‘ w _ wee found. nonethern (194090. in their etudy of crazie- reported obeervetione in eix peythietrit petiente undergoing convulsive there", \Studyiegthe patients otter 3-? treatments; they. reported tree ecetylcholtne activity in the Iepinel fluid in two petiente; end en increeee in cholineetereee-II and e decreeee' in aoli‘neeteree'e-I with e revel-eel of the retio of cholineetereeee in five 6! the eie petiente. In: the,” Nobeervetione, they - like thoee of ctmiooen‘hrel tron-e epilepe'y. petient in the Veeriee who foiled to ehow. free eoetyltholine or e cholineetereee retio either Mani-in _ Regarding the one the eoihel fluid. they Petient wee wtou:_"1t.ieinteteetlnsthet thie no" one-of. theeie tee-me. to only. to a... the tree'tneut". .. . I 1 ' I DISCU§§ION . Fran theee verioue met-yetioneQwe hey contlode thet canvuleive therepy iodueee epiunl fluid like cerebrel sore ehmgee emtw thn than of maintained. we chpredtet trans” , epilehey. If the perhllel ie‘ ot the degree ehhtitn new electroencephalogrmhic ebnouelity, the acetylcholine, end e— , thaaee the thetfluid epinel in cootlmd induced céwuleione were sure thihkthoee found in . “arena of free revered of cholineetereee ectivity retioe �-.10 _ the splnal field and the nunber and frequency of lnduced cone vtlslons., Also, item the observntlans of Tower end McEachern 1n (1949b), the cemment thst ohly the patient who failed to shew. -§pinal fluid changes-talled'to show a response to treatment, ptrmits us tu consider the possibility that such biochemical bas1c therapy of the the chmges are to ccnvulelve medical“ process. cpnClualonsiare pnsslhls'. ad The hasssge of electric current: through breln sw‘stencesilnduces in change sctlvlcy with an increase 121 free a deductions Certain further mm“ . acetyl-. choline to levela'suffictenti‘to1nduce a grand nsl seizure. The . presence of ' ' free acetylchollne 1n the intercellulsr fluids electrical hyperaynchronyr‘renscted lathe .386 as delta? slwlng-r The degree of hyperaynchrow sc'mrate-ly reflect} the, decay acetylchollne of should fonds! free a ad rate equal level S1nce studiesthe purines of deatrhctlon. acetylchollne rate to demonstrated. that EEG hypersﬁchtony use: a, necessary ﬁrvrequlsite induces. ' . ' ' to the cllnlcsl respome 1n central‘slvsthﬁapy. it my be stated .mu'mm chances that the dunes of free aestylchollne in cerebral fulcrum ad thus prilud'es s clinical rem the 1ndueed convulsions. tn Certain eat-muons nay be ends regardles changes In cell embrace permeability as emlal’nlng the incresse in theme-:- .estetasd activity; Chollnesterase-l ls feud m htgheat concen- ' tratlran . 15 ~- 1n the centre} nervms system; predominant in other tlesues. especihlly the increase in eoetylchollne ‘ anus chounfcsmrsse-II Innis blid serum With 1h the 1ntercel§lulsr cerebral fluids as a result of stlmletlon and cmwlslhn, vasodilation and increased cellular permshillty be Pradicted’;’ my ' D E .MLr-JM: 4‘ . ‘ . M. -. . t a ‘- . �~11} thﬁ inch:vasculdglfluids'tnto with a degree of ggancudatian of dnrittan of thg'. and ch. on dlpcndcnt spaces nxtcnt cellulnr vnddtlptlio-n _do occur numétous wag (um 0:11., 19m, anpiy.dcnonstrstcd ‘Ihnt ouch ”manna chm ' SﬁlejiIFAdolf 8910331 1n and by répofti (1961; '62, 'bb,"£§;.'53)é - . . denunstrat§d They cdnductivity cbhvulsldnn e1.c:r1c.11y_iuaucgd tacguased.che that Idikqgo pot-saint as ﬁargous of ions. 1n n cf the clouue; resultud thh lldid§ el§ctgolyths the while phbiphatQ, that and ipingl into and nan-cltcirolytés nngsnittcant 1n .tncraalcd. incrpaso 1h Gunﬁght prﬁibiliﬁy nucleic-acid abutting 'enzyus. of £011; may'thtu prﬁvida thé basil for-thudappoarahco of high ‘w-u 'contgntrati§u§ of a¢§tylch611ns and for lqcrcnand cancantgattons' of cholineaterasefll (Tower 1nd1HcBIéhern.19b9c)." _ . within. 1n;glil%;1n‘ch011héytct‘ne‘acglgitz; free act-tylﬁtoiiné _rnp1d1y> b0 dutioyoih? T.“ wit ohoﬁﬂd not tﬂe $phdnsn can ind uéttbed? agitate-ht. sbtml' fluid. arm: ugh; m panache-e. in. 1‘ qbuertitiann. EB. thin‘diactcpcdcf nvnillbla in An éxplanattqn.for ' Sy :kuurgxl (19.005). Nachuntoh of Mun-ad and__loth¢nber3 . McEdchcm (1969c) .ind poison and HuprtoIh (1955),.{thaf the acetylcholinc-cholthél'brabe-I'uyatﬁu is vary aanptttvi~co:¢on¢aq4 itdtibn relpttonshlpq; At "physiqlogic" éoncentrdtlons, hydtolysis , - and, buc'd: 1i higher of ncntylcholigi tdpid‘(3—6’nucranecoudn) qu1c¥1§itiL}dqno off cutv,). activity £111: lower cqngcptrgtionl. rtiatiénﬁhip to chbltneutaraac-Il-acutylchollno In conraac. the rafd with egocenttaiian. hydrolyita-tncfgases of the and non-specific. i . 'um. nor-.1 um. {mama mu- n: «manna. a cell ' Qéttvity' chi geocylchbltnn ipqctftc by thidgntioﬁjd npnbr-neny tho f ;_1 ‘jt �.i. V-“ wry...” m.“ r'rr'l r . v: _, r“'\7ﬁ"x.:r'7m¢rm., _ ’0"; 3 Of cholineaterase4l ithhe order of niliiseconds. . _Where - . . 'l excitation 3 A a , lead% to an'excesaive‘concentration of acetylcholine in nervous tissua the :nté othydtnlysia I by cholinesterase-I is F 4A A 'A’Q": exec-eded. thu con:enrration of acetylcholine mounts, the seizure threshold is reached and a seirure cccurs. The dissociation in ncetyichoiine- A3 m}! 1 “+4—ow cholinestern5u—Z zclationahip chnlinn The neiznrej liree acetylcholineul itself, The results in a perniatcnce of acetyl— pernapa adds to the level of “gt“..i. increased acetylcholine diffuses rapidly,» with resultant vascular-and cellular_permeability effects and the iPPEﬁvahcé cf inzréaaed ions in CéF; ﬁnd also etficiencf, increased cholin- r LAM; astsrawemii. 4 Aﬂnmnmm. It 15 the activity of this enzyme}.th0ugh'cf lqw- 3 and dependent on concentration kinetics that rdduceﬁ’ the acetylcholine leval;yaperiod I . j ' , of houra to days. tb levels - .__\._-xw-:‘.mz...' for the p‘Eaiologic action of cholinesterase-I 1“ Alteratian in the blood brain permeability barrier by the f ~continuing action of acety-lchoiin e may be the biochemical aub'5trntc {or the hvpcrsynchrony so often obServed in past~electro~ «nu—“\me'mut maﬁw—«A .hnck-electraencephalogramst Such a possibility is evident in the' I 'i ' ' report by.Aird et all (1956) demondtrating a significant increasn in the concentration of cocaine in brain tissue 3 days after a' 'seriea'of 12 induced convulsions. ‘ g of concentration tiisued to he His data about the change in i, . 1M . ' - ' In ..—.u..‘,~«.r.n.v.— 9-1.4.L — .1. “F... thi a large molecule, ordinarily absent in brain torrelatcd with the appearance of bypersynchrony ’ I (delta.bursta) in the elecnroencapnalogran. In our studiea of thc appearanca cf clactroencepnalographic he, have confirmed tire many changes with acmvulaimi .previous reports tnat convulsive thctapy induces hyparsynchrony in most subjectst Despite a constant application of treatments, ‘ a �«.13-‘ electro- however. the time-of'appeatancé. duration and extent of the graphic slow ' 1' A . 'ventiiation it; its sensitivity barbiturates - all QAV$f and populations. and - The to wodification by aierting,'hypervary greatly in psychiatric appearance degree of hypersynchrony, high early beeﬁ has the course; tieatmeﬁt persistencv throughoﬁt described as a necessagy prerequisite for improvement following Electroshock(Pink and Kahﬁ..1956). But what is thé~mec§anism" "undcrlying the failure of certain patients_to deielcb hyperaynahrony?_ Perhaps-thgse studies of aceryléhollne and cholinEstﬁraﬁes may be rélated. ‘Assumiug that a grand mal seizure is indicative of the at‘ttssue levels 9f free acetylchnline In eicess of "' ﬁhu fate of ﬁydzoiysis by cholinesterase~I;-and_thét the electroencephalographiC.hypatéyuchrony.13 a reflection of the'peraiatenCe, development ' of this.abncrmél concentration of acetylcholihe; than the differencé 1h pugzehts who maintain.hyperaynchrony"ind those lh'vhom it ‘rnpidly (fgv hears) disappears. is a reflection 0f the kinetics of the ch01tngsterase-acegylnhollne h§dtofysis systeﬁg Persistént.. hypersynchrbnj Insult; from dccteiqéd rate of hydrdlyeﬁs of ’cboline.v ¢ ‘arahstn-nﬂ acttyl- ,. _If the hypothclla~prevtouely'deducgd are cattact; nithér-ane» ‘ . . V ' . , f u-ww-xa..yrmwméw.w}v-JH‘ or both bf the felLowlng postﬁlateg‘are operative in patients with 99 tslsteﬁnt hypersy nebr‘ony: (1) is a ‘ . Chaitaeﬁteraseél is in low great.spread betweén the apt! thosé preéent '_and 1n cancentratton, an that théte' trace concentration the ttésue with high acctyicﬁolxne;vandlor' '(2) Chalinesregage-Ii is a1 enzym¢~aub low, so that the concentration Ltwetzks cf chis‘system are opcratxve, though at a slow decay .. .13...- ...,.__..J rate“ �‘ _ fonversoiy. :u patientc with short-lived hyper:yuchruny. Cholin- cetetaee-I and -II in tissue and spinal fiuid may be unusually - Furthermore, the‘appeatﬁnce at high concentrations of acetyl-~ Ichcline stimulates the production of tissue chclinesterdse-i in the(antral nerVDus.system.- From the lucid studies of Nechmanaon (1955). a direct relatzonship bétwéen concentration of“tiesue cholin-- estethee~1 and level of nervous activity can be deduced. It 109' ievels of cholinestereaeél can be dull- demonstrated in depressive 'psythoseé (? menonaueal deptession), then the electrcshock_induced _acetylcholine may stimulate cholineetetaee-I production to a mare normal. pre~morbid leverm , cantext, these studies 1n_enqrher problem of autonomic reactivity. may have application to the. ‘Rncent qtndies by Funkenltein and others have demonstrated a relationship between the blood presents of patients .respbhsefto injected mecholyl and their event-n1 reopensiyity to ' :i' ” ' - 'Hecholyl which a induces“ cholinetgic potent is agent electsaShack. ' “ ~2i: tachycatdia, ic?‘ perietaISist sweating. incteaeed and vagadilation. chnlin~e hy hydraitzed cholinestetaseél and slowly by ls rapidly estetaee—II. 5;.. atter injected fails vatinb'le length of time, blood pressure of subjects return. to the baseline in a five to more than 20ninutee. Patients rthalyi i The and presiﬁre'l whose blood 5 the minutes are classified as Group I. baseline in to returns those whose blood pressure takes 20 or more '21! ':an reactions; minutes II to return to‘a baselineg‘es Group The Gtoup 1 reactors have a 92 improvement ' VI and VII reactions. 'IlllI-I-I - rate with canvuisive {1- - H; i ~ therapy. and the Group II, II-III reectorl : 352 rueovery rate In a i contrast, the Gto up VI reactors have a 892 and the Group US;da~9§1~agent-uzeaauuzyq:ate.£runktntto&n-otqe3~y¥$953-- I ; 1 �“ VII a 97! recovery as patients in 2W4"??-:'£€i§:?fjw*ja 15 _ Groupu_ I to may llI may be looked ubon the injedted mecholyl is hydrolyzed; rapidly while the Group V! and VII patients have We a slow hydrolysis rate. predict, therefore, that the blood cholinestereee ectivlty.-' levels of Grouce l-III would be high; while the activity of Groups Vl-Vll would be low we recall here a similar prediction cholinthe date central for of nervous levels item Iy regarding esterese~l, in which the develovuent df early and sustained EEG hypersyhchrony and elevated epinel fluid levels of acetylchdline related to low level of cholineeterase activity. _Thus, the date of peripherelystlmulatiou by cholinergic agents is A ,was congruent to the hypothesiq regerding central nervous‘system‘reP activity to electrcahock. cammsmus: This survey of the literature of the roles of acetylchollne of cholinesterase in convulsive therapy hue led to a number speculetione which require yeriflcetlan. 'For this purboee, it and 3 is ‘ suggested that en-investigetion of the following relationships, 'be undertaken. (1) Level of free_ecetylchollne iu the epiqal fluid. 1‘3. type; cbnvulalye frequeucy. to number and therapy relation Also. the essociated electroencephalogram'patterns; Reletidn of such ecctylcholine levels to the clinicel (2) behavior of patients. (3) than z‘ 3;“:Ww’gwwm‘us rate (Funkenetein $5321" 1952); ;Patients in Funkeaetein whom .24; EEG in indicec of altered brein function other with such ecetylcholine levels. Changes ’ , .7 ., _ �{4); Reiéttoh chalineate'fﬁe gétivify of blpbd scrim andpspinu fluid to: (I) ﬁattémﬁ of and ‘ age, , (b) alméta (c) rate bf deveiwopt'zent of‘ EEG (d). numbg: ,md fréqqencyof . f ‘ treamhts . (e) ,aﬁtbn'omc (heriphgnli reactivity -(.f)',cerébu1 reacthﬂty‘ ‘ ‘ , 3 . gpexfsonauty Run: ofatroptne“. physos‘tiglnlne'admini‘attatian on (’8‘) (5) hypersyhchrony ‘qliﬁical behavtdr. , _- ‘ ~‘ E36,“, j 4 �III: 7-3-6A ‘r (1:, ﬂab-(i) ‘ ON THE ROLE OF ACETYLCHOLINE AND CHOLINESTERASE IN CONVULSIVE THERAPY Studies evaluating the role of cerebral changes in the mechanism of convulsive therapy have demonstrated that the development of early and tunct persistent signs of altered cerebral are prerequisite to changes in behavior (Pink and on Kain, 1956) - was the most In these studies, electroencephalographic slowing s significant index. This obhrvation remained un- clear until the reports of Ulett describing the effects of pre~ meo11ation with high doses of atropine in preventing the appearance of the EEC delta abnormalitv (Ulect and Johnson, 1956). ’Followlng the suggestion of this report. - we Eg 5: reniewed the role of acetyl— choline and cholinesterase in convulsive therapy” {é to data The lg; ve x close relationship between the degree and persistence? of the electroencephalographic slowing and the appearance of Suggests a T: .¥ measurable quantities of free acetylcholine in the cerebrospinal {g fluid E; as well as an inversion of the normal ratios of benzoycholine- cholinesterase to mncholylcholinestersse. I h:§ . . Ihe role of acetylcholine in the transudssion of nervous impulses has been studied since the (1914) and Loevi (1921). first descriptions The arguments as d of Dale to whether actylcholine is the main or only agent in the transmission of the nervous impulse are not of primary concern here. .It is sufficient that acetylcholine is a normal constituent of nervous tissue; thst exists in a bound form and is liberated during the excitation process; that it is rapidly it hydrolyzed through the specific action g) �oi cholinesterase and as rapidly reconstituted by the choline— acetylase system (Richter normal cerebrospinal a Crossland, 1949). Furthermore, fluid contains (Tower and McEachern, 1949a) no free acetylcholine despite the rapid breakdown of bound The acetylcholine during periods of activity and excitement, cerebrcspinal fluid normally has measureable cholin- esterase activity, principally of the "true" or mecholyl hydrolyzing type (Nachmanson and Rothenberg, 1945); In the absence of free acetylcholine and the conditions under described, electroencephalograms fail to show any consistent . abnormality. Effect of Craniocerebral Trauma: .In a study of cats subjected to varying degrees of head trauma, Borenatein (1946) (al reported that free acetlehcline appeared in the CSF within a few minutes after experimental head trauma and persisted for varying periods up to 48 hours. The quantity of free acetylcholine varied between 2.7 and.9.0 gamma and the amount wasl percent, positively related to degree of trauma. Concommtant changes. electroencephalograms demonstrated patterned Initially, the records were filled with high voltage fast activity, interpreted as an intense neuronal discharge; only to be followed by a short period of flattening of all recordedeaectrical activity. These periods were then followed delta frequencies. behavioral changes were also correlated with degree of‘ trauma, as well as with the level of free acetylcholine. with highest levels of acetylcholine, Bornstein reported the greatest The m �consciousness in change the greatest degree of EEG abnormality, also seizures uere and furthermore, spontaneous post-traunatic the in appearing related to the amount of free acatylcholine spinal fluid. applied' Bernstein observations. these To further substantiate when the cortex. cerebral exposed cat scetylcholine to the he gamma 1 less. or acetylcholine percent was concentration of waves of low frequency in the electrosharp observed high amplitude encephalogram. When the concentration'vas increased to 2 gamma parallel fashion in-a flattened percent, the electroencephalogram to the post-traumatic records. A 112 in studies these Tower and McEachern(l969a) repeated the found in was Free acetylcholine patients. pneurological head trauma, with recent the in patients only cerebrospinal fluid The free acetyltherapy. convulsive ‘recent grand--nal seizures or from 0.2 to varied choline lGO gamma percent. In addition, Tower spinal the of and HcEachern assayed the cholinesterase activity cholinesterase the nonspecific in rise fluid; They noted a sharp fraction (benzcyhholine-splitting) and a drop in the specific the in patients (mecholyl-splitting), fraction cholinesterase therapy. No those convulsive following with head trauma and in free containing the in demonstrated fluids such inversion was acetylcholine follouing spontaneous seizures. These authors directly acetylcholine varies concluded that the level of free that however, damage; cerebral of with the degree suggesting, sensitive more a was fraction cholinesterase of the the reversal indicator of cerebral damage._ -' �- 4-following intervals varying taken at were Electroencephalograma direct a reported The authors most of these subjects. trauma in of the of degree correlation EEG abnormality and the appearance cerebrospinal fluid. the in of free acetylcholine trauma craniocerebral indicate that These two studies may fluid; spinal in acatylcholine the of free amount the increase free of the between amount and that a direct relation exists electroencephalographic of type and acetylcholine, the degree behavior. and changes in clinical abnormality, (b) Effect of Atropine on Bernstein administered 0.5-1.0 pggt-grggggtig mg/kg EEG 5&4 thgviog; atropine after head trauma- EEG effects, manifest of the blocking demonstrated and induced was the experiFollowing of trauma. behavioral and neurologic signs mental addition of intracisternal induced which acetylcholine, trauma,“Bornstein' head to similar EEG and clinical changes observed a blocking effect of atropine. human of treatment the Wardflgﬁo) applied these ideas to degree with varying 20 In patients head injury. closed of cases of doses in subcutaneously of trauma, he administered atropine and in improvement, clinical noted he some cases In mg/kg. 0.1 the of effects electroencephalographic the of others, a reversal Jenkner anticholinergic drug, trauma. In a study of another the in putreported.simificantl'alterations (1955) Lechner and 40 in dose intravenous traumatic electroencephalogram. Asingle normalizing‘ in instances of abnormal electroencephalograms resulted others. in 22 instances and marked improvement in six _ �- 5 - atropine effectwof Ulett and Johnson (1956) demonstrated the sane conVulsive‘v illoﬁing slow wave of activity the in blocking appearance biochemical‘nechanisnl same the therapy. This_stndy suggests that ’ . V ' under£:5the electroencephalographic changes in head cranes and in . *-',._—s Mov ~...,_..-—~ in contrast to these findings}: In their i _. M. . experiments Brenner and.Herritt (1962), applying topical scetyle in concentrations of 2-1/2 to choline 102 ‘ to the exposed cortex of cats, noted no effect of intravenous atropine (l nglkg) on the electroencephalographic changes. lt_is iaportant to note, however, that the concentrations of acetylcholine in these experiments than significantly the topical applicetions (1-4. was higher 3“. I percent) and the intracistsrnal (0.2-10 galls percent) injections Bornsteind(1946). Brenner and Merritt. houever5'slks_note of of electroencephalographic effects similar to acetycholine free mecholyl (acstylbetanethylcholine) and doryl (carbanylcholine), each in concentrations Inch lover than the acetylcholine concen- effectiveness of these incteessd the ascribed trstions. lack drugs cholincerebral of to sensitivity to cholinergic their They ‘ estereses. A I variety of experiments with the potent cholinestarsse' inhibitor DFP . .31. induced convulsions. due report stands out a.m- fluorophosphate) demonstrated high (di-isopropyl amplitude rapid frequency 885 patterns similar to status epilepticus, as well as lesser degrees of abnormality noted in post-traumatic stete!!(ainnich, et el., 1950) Freedman et a1., electrohempson the 1949; and et al.. 1950). In these studies, too, encephalogrephic effects were blocked by snail doses of atropine. -——.‘ Cs- �In rustle? labcratbry study. Chétfield and Dempsey (1942) evoked and anxmai prestigmlne :ortcx expasud ytch prepared r9103hdlU.YJDF1C Spiﬂe autlwtzy. electro- prior.admznzs:ration of The 'uzrcane biotk\d this 5:1 1:5. a: if present, the abnormality v?u.d be viim‘:1th by atrepir~ 7C 1 trtn 'hu.. a variety of experimental clznlcal scudzcs, and 'har eie-ttnuvcethIographic acti;1cr ._:ti;:hrr;:¢. irhc: -T;t'!‘!". ‘th as 3 wﬁ tnd¢¢¢d bv reswlt of trauma. topical appl;astict or :rrvzral m;:a‘clzﬁn, can be blscked ur elzmztated ltz'tln|k‘ -. (r) ‘3}.: 'x '.;re:.cwg:n31 ~ a:e:yL.n;1;1¢ ﬁcrtully appnars :; “Jqu, ;v¢;ttae iczm. It trcaxd;un {L58 Ln 4 The level of spund acetyichclinc is v c: the pro: I! 3325 cf synLEcsig. liberation an; may be Lcscuiat is true :45 npmanstratpd 1W: -. nex.{;3;. pr-Sen: 1: vezvous 11554t a I u . therefore, that the level bill during «lead and fall duslng activity {111352. 9v'xn a“ ‘T ac:1;i:;, r:ce acatvicell membrane. where it is rapidl; de- Activated ty challnestarase. c::.:an; bv . Du::n3 pazxud$ of :hu;in# is liberated at the ;h;. the .,‘.‘.:l Au€£.luld.;‘£- "‘ r.u.J 2 by thhte: Pyzdur$;n (1950? and La That this hypothesis Crosaiand {19u9b and aagzyz uxanrimun;s Sy Richter and Grassland qu1ck-freézing methods. asxrg liquid air deﬁoﬂSLYdtzd that the anesthesia ard sleep level of acetylchoiin‘ .Lgustcd mi:ragra:13 per 25 :Fdn fn» Ln»? uvi;urc lcvc; Itdnxieﬁt .. ?. .5 (D N mg. The brain fiSbUd} was 3092 hich? difteteECe in tinauc levels 13 .5 the resynthesis rate for azetyluhclihe in m rat braxn is high (7 gammaigm/clnute). 'Elliott er a1. (1930} :. par-- �After metraeole convulsions, free noted that also XIhey acetylobservaticne, these “K ;3r?ic~‘i n ; chul;ne :ws always demunstzable in the spinal fluid in concen- tratians to up In spinal 3 gamma per cent. man, Cone, Tower and HtEechern fleid studies in ahd Thuer and McEathern (1949b) ‘1348) ti quantititls 86 also demonstrated significant free acetylcholine in patients with epilepsy‘ 'Of patiehts. epileptic Lhuiine in quanti'iea 49 (7723 demonstrated 0:02 tc of SP0 gamma naeeurable free acetyl- per cent. ith an average was related level directly acetylcholine pu:.cent. Ih: (L the frequeﬁcy cf seizures; the extent of electroencephalzgraphic t6 the last of relation of time the sampling and the abnormality, cf 2 O gamma It bore seizure. no relation ta medication. type of epilepsy or level at cholinestetase activity. Whether the ', a . a the in fluid is spinal appearing acetylcholihe ty—prcdcct of the canvulsion. or whether the increase in 9 - catae of the Seizure, is prshlenlticela acetyl- Tower and chachern (1949b) believ that the increased e;e:ylchcline liberation (T; itself but related is not due to the seizure caaeing the seizure. A“ In a to the basic preceee s“dy ef the hypOthesls that the accumulation acetyleheline is basic to the seizure process. Torda (1953? indured convdsxcrs in animals by metzazcle She determined the level of acetylcholine in brain tissee before and during convulsions.» convulsichs byla She noted that preceded are rise in the acetyicholine content of t:ssue; the: the content gradually falls during the convulsion; and that below certain levels, convulsions failed to occur. 3 She ccnvulsioc suggesteﬂ that the was due fell in tissue acetylcholine during to inhibitien of acetylcholine synthesis by incrcdeed reagentratiacs of mezabclites such as ammonium ions. �While there is considerable orgumcnt about the role of the machanism of seizures. choline in it is acetyl- probable thot free atetyltholice is increased during seizures and appears in the spinal fluid; that cerebral activity and seizures enhance acetyl:hcline destruction. lowering tissue levels of_acetylcholine;while sleep and anesthesia augment acetylcholine production, V inLrGaSXSg (d) tissue levels. Svstoo Nervous Centrai Cholinestegase: Concomitant with their observations of changes in acetycholine, measured spinal fluid choliuesteraee activity. Tower and Hcﬁachern Two (l9é9) types of cholinii esterases are normally found in the spinal fluid: cholihesteraso-I i"true". "specific". or metholyl hydrolyzing), - which has a high specificity for acetylcholioe; and cholinesteraBe-II ("pseudo","nonspecific”, or beozoylaholine—hydrclyzine). Both compounds hydrolyze acetylchcline. but have different ratio of hydrolysis for mecholyl and beozoylcholite. distinctions of the .By This diffexehtial rate permits qualitative reporting the cholioesteraso activity as 5 ratio activaty with mecholyl acetyicholine substrate, two and benioyloholine rati$ are found: substtates to an cholinesterasevl/ acetylcholine and cholinesteraoe-II/acetylcholine (with Ash/Ash - 100). in such ratios manual CSF contains esterasea in tho ratio of 33:17 for cholinasterase-I to cholineateraee-Il. Thus, normal ‘ CSF consists- inly of "specific" eaterases with a small nonhSpeciiic esterane component. traoma, with head Toner and Kcﬁachotn report an patients inversion of the amounts of cholineoteraies with a significant In increoae in the cholinei‘trase-II fractiOn of spinal fluid and a decrease in cholineatorase-l activity. They also reported a correlation between [la extent of the cholinesterasc rcvérsal with the senority �the electroencephalographic of trauma and with the degree of ‘ abnormality. scetylcholine a as patients With spinal‘fluid increesed .In however, the ratio in change no sponteneous of seizures, result found. actitity was cf :holinesterases or total cholinestereee (e) Effect of ﬁle trnehock on at A Tower and McEachern’(l9493), esterases: it oline and Ch in- in their study of cranio- psychiatric trauma. in patients six reported observations cerebral Studying 3-7 after the patients convulsive therapy. undergoing the they.reported in activity free acetylcholine treatments, . ’spinsl fluid in increase in cholinsstersse-II patients; and a decreaee in cholinestarase-I vith a reversal of the rstio llron'thess Of the six patients. of cholinestersees in five and an two in changes fluid the concluded spinal that they observations, cdnvuleions trauma craniocerebral those like more were at induced than those found in * epilepsy. Regarding the one patient in the series who failed to show cholinestsraee in ratio reversal or s free scetylcholine either the spinal fluid, they wrote: "It is interesting that this response shun to no of to the six one the was only patient treataen.." . DISCUSSION From these various observations, vnlsive therapy induces spinal fluid we may conclude changes more that con- like cerebral is. 'trauma than those of spontaneous epilepsy. If the parhllel of. the degree maintained. we can predict a relation between of abnormality, the appearance free electroencephalographic qcetylcholi1e. 3nd ; ra"97331 of cholinestcrane activity ratios ' �‘“ the L-L Fpl'd: fizid and the number and frequency of induced-con; xtisisrs. Alsu. irsm the Observatians of raver (1959b), 1hr ccmnent that cnly the patient suing? ELUiJ ;hangua us in ptrmits :hnngcs are filled who and McEacharn failed to Show to show a response to treatment, cozsider the pcssibility that such biochemical basi: to the :cchanism of the achuleive therapy process. Certain further deductions and conclusions are possible. rhé brnin subrtances of induces through electric current passage change a in cellular activity with an increase in free acetylchclinc to levels sufficient‘to induce a grand mal seizure.i The preaence 3f free acetyltholinc_in the intercellhlnr fluids electrical hypersynchrony.ref1ecced in the induces , slaving The degree of hyperaynchroqracturately reflecth the level of free acetylcholine and should follow to the rate of acctylcholine destruction. demonstrated that 1c the as delta EEG a decay rate equal Since previous studies hypersynchtony was n_neccssary pre-requisitc EEG clinical responsc in coavulsive thcrapy, it may be stated that the absence of free acetylcholine suggests minimal changes in cerebral function and thus pracludes a clinical reapanse to the induced convulsions, bc made regarding changes in Certain assumption: may membrane cell permeability as explaining the increase in cholinf esterasd activity“ Cholinesterase-I is found'in highest concen- trarian in the :entral nerQOus system; while cholinﬂesteruse-li is predominant in other tissues, especially bloba sdrum. ~With the increase in acctylcholine levels in the intercellulur terebral ilwids as a ‘ xesult'of stimulation .-J.-;'..L ..i ;w::tjs;; and convnleibn,‘ :uliuau: gartelhllzty may be predicted, �.. 11.. interthe fluids into of vascular with a degree of transudstion of and the duration the on extent dependent cellular spaces vssodilstisn (Rabat et all. 1948). 'Ihst _do such permeability changes in and Spiegel-Adolf by Spiegal demonstrated amply occur was ; . demonstrated They '53). 'é8, '6h, '42, (lQél, numercus reports cenductivity the increased that electrically induced convulsions cf the tissue; resulted in a leakage of various ions, as potassium and phosphate, into the spinal fluid; md that while the electrolytes iignificsnt increase in non-electrolytes permeebility in Charges nucleic-acid splitting enzymes. i .creased. there was a Wes of cells may this provide the basis for the appearance of high :ﬁccentrations of acetylchdline and for increased concentrations - oi chalinesterase-Il wt ch~he (T owe: and Mczachern l9h9c) incevihy in cholinesterase activity, shculd not the free acetylcholine be rapidly destroyed? To what Mechanism can seizure be ascribed} its persistenze in spinal fluid after An explanaticn for this descrepancy is available id the ebsersetidns trauma and cf Nachmsnson and Rothenberg (l9é5), hy confirmed McEachetn (1949c) end Bergen and Macintosh lever and ' (l955),lthet the scary!:hcline-chclineglerssc-I system is very sensitive to concen- tration relaticnships. of acetylcholine At is rapid "physiologic" concentrations, hydrolysis (3~4 microseconds) but at higher and quichly_(hsldene off curve). lower concentrations, activity falls relationship is In conrast. the chdlinesterase-Il-acetylcholine nGt'EpCCllli, and the rate of hydrolysis increases with csncentration. Thus, with normal functional levels of scetylcholine membranes, the scetylcholine is destroyed by the at cell specific activity �where'exzxtJZLcn -:41 in the Urdu: of "111;3dC9ﬂdi '!;U&uLVc '1..‘q;. :rL:.:1"-"wf cchaevtratton of acatylcholisu in “Bfiohs is Hytirwﬁxw ‘; ‘b: ‘*::e:tr3:icn f :lr311rﬁ:ster.19a—I t.s ex;cc:J¢d_ Ev: {Htéskrld the seizure uf acatvlzholivc mount:, The :2 I tree acetylahoiine t"r‘1"; -~'.' *1 I: ~~II .r‘;c1nn;y. The “erhaps adds to the level of rapkdly,« diffuses ucstylcholtne increased a; the actlvtzi cf thia enzyae. Jun LCgﬁﬁduﬁt ad Lu CUCLUDCYaCXCn A ‘Lc acetylcholice level’ f): fke shwcx persistence of azwtyl- a the and pctmrubility effects vaatulax-ind cellular £53; cholxn~ Inzteased 413: and .v‘retued inn. 1n 1" t.~':t"’ '¢ ’.vnshiv rzeults in nex:;ra. itself. The Etna 'W' disscnlation in acet/isholtné~ a tﬁOugh c1 low klnolizs that lchls period of heurs to days. to p cholineatetaRP-I. of action /w;alcgic (lottrtcnvcphgiagraMs Suuh a posstblllty xs ev.5c:t in the' I Tcpﬂ$2 by Axrd e: 1n 1n-.e;ae a democdttating (1936) sxgniticact 1;. erin gdcszte in of cuvuent::;103 the ‘ 12 L9LC€RTT¢L10a itisund Cedutuw ’v‘ tiesue is data induced convulsionq. 3 da,; af e' shows the change in brain in absent tﬁis ordinarily nnlecule. large ct of wﬁtﬁ hypersynchrvnv the ;nTT91aLcJ Appearance ta be eleCtroancephaiogram‘ the in (deitu bursts} electroencephalographi: of of the appearance In 0d: stLdica nuwbuni' the many confirmed have we changes nuth hypersynchtony induces therapy convulsive previoug reparas that of treataents. application constant a Deepitc in maqt Suh‘c~(w ' #cmwnlsiozs, _ �FLHCLICof the Jnd 54r3:1cn extra: ILmv of Appearance, (it “VlﬁVﬁf, ‘rT'XXATXOH 315 *"ri‘::w“" . ‘ {v hyperaler21u1. c;d1‘i:1L1‘" tc senaazxvzty its Qaca graph;; 5ch I herb:tgrates all cgrly appearrnce TLQ vary greatly in géyzhiatric of?.igh degree hvpe: vnchrany. bwaa has tzcatmunt the ::.r:‘~‘ 1:* ::§ 33:1IHEE'CV (Lfvgghiji 31¢;Yihﬁﬂ as a nuccaaary E'sctrgﬁﬁ”( t-tr': 'quh:iwlrr 2H: and Kihn. 1956). Bu: what 1: ch; meghanism' imitate of caftain pﬂttents_zo deveiop n3persy1.Lrauy be and acccyléhriine may chottneqterases of <tgiiee - L%ewﬁ 9:;L4y3 greraqgtsira to: inprrvcmeu: folluwing \s-uﬂ.' .la "Z¢piwﬁx seizuze ls :ndznattnc o: thy *EA: 4 armnd m;. ; {13:uc KQIHL; 2f {tee a»:'{2.chv'LHv in ‘HH and ghnlznugcaraae-i; by ," -«;c *nd~a;;z‘s n. erlag'-.5;; hypetsyncnrcnv La 1 iKSQ$E a! that the alertrc— ref\r\::LLn cf the pvrstazunce the ditfctence then 3f acetylcholinu; c~rven‘:¢;2cn Phﬁ”':d1 ‘32: 9‘ u. :rﬂ-tr:: -in ra:a;¢1r ry;c:e,n :n:;r.v in- at in whom it Persistent .frizzc=2-r3we-QLPn;l;bol{we hydrolysln system. {La 3 Lh of ace:"Lhvnral of atu I decreased fr3a rate I h5“a7annchtnn", resulcs K . . V s-prrvlousiy deduced are correct, ezther one 'J 9" 0' LI V 1 rv- in .A 0‘ t r9 n ’ I‘ ‘1 ,— P" patients with (a as are operatlva pcstula: suing .cr'xst.uz hyﬁvrzy nebrbny: (" 1% :‘i attrast-I IS in law s: rte er: in LF: tisSue t2) h‘ Yh<‘ 2 Cb'litugrpzata—II is :oﬁc=n£r3££nu , «12L h1gh Kev, so %: that thc:e a;¢:ylchclzne; and/3r that the noncancraziou at though are 02e241122. g; 5. suqtyt 'h:..- 1 slaw decay rash o �I ‘, f)‘:W-‘rvrs. t“: " st: gfztzl Ira in» ‘.-* “2:- 1" 2 ~ 3 :: "ca proqz tlcn <th .L . Fran Chv a:v:yl- nzgh cgnawnLratiors or :"l':us:eraae—I stuchn suuid . attivit" cad be (;Q55!. . of Wacnmunsan ill-n If can be deduzcd“ 13w demorstracad in dapre:?£ve yzr~xe5 g‘ acnopausal depr¢sszct), then the electroshock induced ' $:L:V1-‘QIIUL 1¢v-:rimula:2 ;%;l;ne {grasp-I graduation to a more usn“ku: Eu ,4 -\ \ v 1‘! :g: - - cgﬁu"'crac#3 c r .t “.CE Ha4.3: xu“ « chhriy. 2 z: ‘“"gi;ia:: r, tzarv122d;3, an r31): l éﬁn y‘;rra L) txue to more than -;‘.c;- upnli:ation cm Rucent szudius by Funkeaatein and. rglarlcsshlp Fatwaer the blond p:e>3ure a "aren* L!(11FP:51~ ‘gegt whicb iﬂduces swancpag, and in;:¢n.cd peristalris. 20 minutes. 5 minutés are :lauSLfied as Gtaup 1. .1, 20 or were c ‘JYI .3. 'daczsrs have h.'..~¢‘ax:u.-, ax a 92 Improvemant C’W‘Tiht, the Group ‘,~.. , .._..- V1 sir-.1 GK'C‘J-P charapv, and the Group II—III reactors a 'IIIII-III I: Patients whcsa bleed preséﬁre 'na.r1:#e: zhcsa vF‘ue blaod presecrc zukej 92:13:: 2:. (ha :1: b43313: in.a varlnc;e {ength of time. t;ﬁh.ﬁ$ to [J3 baseline in xrd .L‘ :1J11e3_may hive untrrgvi: [EdQLIUity ‘Ezm 01 '\ Iiﬁ.~it. tigsc 4 if tiaaué ;nclltester85&—E in the ogzuac‘ ctaLentrat on 0‘ chxuu 'hcixn— aid snvgi cf rer"ccs 3t _ _‘ c..". x‘ _ "\c_r..e— ‘ ’P?‘ é ratu with Louvulsive 35% recovery rate reactor: have MW. -......»n.a.cac textzmw a 892 and the Group I‘*'Hal-*mHO‘vw-Iy9ﬁ-’ ' In ,- �ﬁll a: 31., 1952). :e:c"crﬂ rate (Funkensteln 9—“ -Pa7;ean in Fuzkensteln Grcups l to Ill may be looked 972 a ;: Ew;l;ui- :1 "him ET n 'J' m C‘. '1 de Ch: 1716 and VI; V1 upon tad weuhalyl is r2p;dly hYJrolyzed; patients have a-slow hydrolysis rate. predict, therefore, that the blood cholinesterase activity. levels of Grorps I~III w0uld be high; while the activity of Je may Grazps Vl-Vll would be low We recall here a siuular prediction rega:ding the ds:a fur central nervous system levels of cholin-A 11 which u‘rergse~l, the development of early and sustained EEC hyperaynchran) and elevated spinal fluid levels of acetylchclinc relatvd to was a law level of cholinestarase activity, 1. 43"¢ cf 9:11pﬁnral ‘u: V \ u \ . azngtuast 0y 8 cbslincrgic agcntz is the hypotheeib'regarding central nervous sysrvm re? :5 aztivitv :2 :zzm‘;atl>n Thus. a ., ”w“ “a ~c:r.shuix. a A,~‘ ,.-."..( 'c-~ :AJ'L H—-—.- as... ThLG survey of the litarature of the rJlos acetylzholin (f "V .o. :hclinestarase in ccnvﬁlslve therapy has led to a aﬁd speculations which require verification. For number of this purbose. ‘t L Rdgglilhd that an-investlgarion of the ftlivwing relationships :elztlon :c :3Evulslve therapy - type, ,0 J I v o 9 L." I in 14" number and fttquency. .ociated oleczrcencephalogram'partarns. h Relsclcn of such a;eryl:hollne levels to the clinical behavior oi patients. (2) (3) Llaé BE“ Changes in lndices of altered braih function other with Such acetylchcline levels �(L) 'Relaciou of :holinesherase accivity 1:03 serum and splnal and patterns of fluid to: (a) age (b) diagncsis (c) rate at development cf (d) number and frequency of EEG hypersynzhrocy t:eatmehts reactivity (e) autcacmlc (peripheral) reactiﬁity [csrebral (i) if») «g; _pe:sona11ty Rut at" :nLrIL Eshxvic: atropine. 'physcgstigmine adrainistmticn on ’ EC,“ � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Files: Acetylcholine and Cholinesterase, 1956-1966 (folder title 2/4). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-003-0-002 Date A point or period of time associated with an event in the lifecycle of the resource 1956-1967 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/22ce0e2ce2b39aba2aae8d5d1394cc60.pdf 2c9db7ac17279fda4146fb703f39bab1 PDF Text Text ' """ "r ' " WWO WW WW3. IN Max Rink, -*-' '"I’W v“ ”kw "FWHWOMV'.’ v.3. "m qr min...“ .7... W 14.1). mthofPoydmiatry of School Missouri Meir» , of MRI-nit}; Psychiatry, at the Nissan Institute of 63139. Macaw}. St. Innis, Annual Street, and Vii—072w, bin—927, m—zns, usms in part, by gums Missouri. of Formation :3 Iii-11380; ltd the Psychiatri 5WD W. VII: 7—25—65 Ram ��Wm, lQNQe) . The activity md emitement (Tracer and oembmepiml fluid does have measurable cholinestemse activity, however, principally of the ”true” or maholyl hydrolyzing type (Madmen and Rothenberg, 19%). In the absence of free acetyldroline and mder the cmditims described, electmenoephalogrm fail to (e) Show almorulity. mummy: Meta of Crmiooembml Trauma: Free mtylcholim was found in the cembmepiml fluid within a few minutes after experismntel head trauma in cats and persisted for varying periods up to #8 m9 (Bernstein, 19%). The quantity of free mtyldmline varied between 2.7 and 9.0 gamma percent, and the was related to the degree of induced trauma. wt electmemeptulogmm demstmted patterned Carma-rent charges. The records were first filled with high voltage fest activity, interpreted as evidence of an intense neuronal discharge, com to he succeeded by a short period of ﬂattening of all recorded electrical activity. These phases were then followed by prolonged periods of high amplitude sharp waves in the delta . freqmncies. The behavioral changes related both to the degree of trauma wt of mtylcholine, md the of measured free acetyleholim. With higher Bernstein reported greater degrees of abnormality and greater charges in omecioumess. poet-tnunetic seizures were levels EEG Spmtmeoue also related to the ammt of free mtylcholine warring in the spinal fluid. �Bernstein applied amtylcholine to exposed cat cerebral cortex. men the concentration of acetyldroline was or less, high wlitude shup the electromoephalogrm. waves When of 1 gm percent low frequency appeared in the concentration was increased tOngmepemnt, theelectmencephalogmflattmdina fashim parallel to the post—tramtic records. Investigatims in neurological patients by Tower and HcEadrem (1909a) damnatmted free acetylclwline in the cerebmepinal fluid only in patients with recent head recem grind-mu seizures or after electmvulaive Free acetyldxolhe varied from 0.2 to 100 gm tram, therapy. percent. In assaying spinal fluid dnlineetemae activity, they noted a sharp rise in the nonspecific dmlimsterase fraction (bmwyldwlineaplitting) sad a drop in the specific dwlinesteraee fraction (mdmlyl-eplitting) in patients with head trauma and following convulsive therapy. The cerebmapinal fluid did not exhibit such inversion, although it contained free acetylcholine, after spontmeous seizures. They cmcluded that the level of free aoetylcholine varied directly with the degree of cerebral dmage and that reversal of the cholimvterase W was a m sensitive indicator of cerebral (image. Electroencephalogrm, taken at varying intervals following EEG of between the degree relation indicated a tram, also abnormality and the appeamce of free acetylcholine in the cerehmeﬁinal fluid. �. r -; o-Tn- "W wu-rm- V“ 7 ~ MNIWWF‘. «wwwnmw' . ”3-.— :Nr‘ ‘mw— l‘.«nmw~.—WMM v-y »".\—- (max .9 w— , r‘ "murmur 1 Wm" q‘ 4;. These observations were recently oonfimd by Kovaoh, wounded increased aoetjldxoline in o: 1.1;. rat brain after traumatic shock, and an inhibiﬁn of this activity by the ministration of atropine to the muscle preparation. Tim the «want 05 {no aootgtchoune may ammo in tho who Aptaol staid {cunning WWW mum and the. mount 05 (no acugwwune, the dean.“ and typo cg mmmcapmogwuc «bloom/aim and «Maya in clinical bohavion appeal: cu Wound phenomena. (b) Antioholinegﬂo m and tram: oleotmgr'aphic, The bohavioml and neurologio signs of head trauma were blocked by the parenteral achinistmtion of 0.5~1.0 m/kg atropine (Bomtein, 19%), as were similar clinical changes: oomrring after the intmciutornal addition of acetylcrnlino. Ward (1950) applied these observations to tho treatmm: of closed head injuries. In 20 pttiants with varying dogmas of tram, he amtiniotomd atropine subcutanowsly in doses of O .1 mg/kg, noting clinical in soon and a reversal of the oleotmgraphic effects in others. Similar alterations in the poat-trmnnatic electroimprovement encephalogram were reported by Jenkner and Igdmer (1955) in a rtudy of diethaxino; amthor antidxolinergic drug. A single introvomm dose in forty patients maultod in normalizing the ' abnormal electroencephalogram in six othom. in twentyi-tm and marked ingrovemt .mr—‘xv �T-W‘vw 'h'mivu‘ -.-. ~.w—w.y‘~ WVMMW'Wn-uvw‘w—W 1."'"q'( v -— m7 "In“? - "mmwuﬁwuwmw‘vu “m""vw -WW’-xm -~ wr: TW'f..‘-|‘.Yr 1m Sinilar oboewatiam have been reported with mthylbezuctyzine md in minal exporimnts of post-trumutic shock and man 03mm}. Odom: (mm, affect of atropine Thu 1&5). assessed in the convulsive therapy was process by Ulott and Johnson (1957). With the administration of mnpordaydvmtngmwoeksthepatimts moeivnd oleotxoshodc therapy, the of slow wave activity atropinewto mt oigxificmtly lass than in a omtrol grow who had not monivod tho atropine adhinistmtion. (In a later study these was authors failed to replicate this study, suggesting that dosage factors or popllatim ohms-m multo [Johnson 93; &, may haw contributed to diffemnt 1960]). Similar affects mm obacmd with experimental antioholixnrgio was diothaxim, banaotyiim, the pipaddylbenzilates (Pink, 1958, 1960). The intruvonms injection of and JB-329 (Ditm), lid WIN-2299 JB-318. JB~336 111de ES damchrmizatim in psychiatric subjects. Those EEG ohmgos were associated with bahaviml alerting, anxiety, tram, illusions, and hallucina— tions. In patients the than had recently received eloctmomvulsive a reductim in slow wave activity md a manual of euphoria, denial md oonmsim. Atropine in low thumpy, dam, was was associated with tadnvoardia, mass E88 desyndumization acoarpmiod and Maxim. by At higher dosages, hypcnyndum slow wows, followad by lower voltage , poorly omitted delta activity with super-imposed beta activity wm associated with progressive confusion and disorientation. ”I..- —w m hwy”.-- �.erw—spmﬂlwtvnvamnw." w— r..«wwruun-x...—..,«».w..i. in combat Both Wguphtc mm"._., w-uvw-m .7..-7._~.-—v-—wwww..— um ~— ._.‘...,W wan rvw—Hw. ;W.——»—.- w—u w "r - , -— wwv—ku.“ and induced convulsions, the. ehahgu my be modiﬁed by the. WWMOR antichottuugte MA, Auggutbig that tamed manta 96 acetytehaane on. chawvigtc unpuvttg 4'4 undated with the. high vauaga Alon) wave activity. 05 Wed (0) Brain Similar EEG mﬂlcholim and mtfahnlimggzc ahmgaa and similar blocking by my mticblinergic drugs has been obserwd following the direct application of amtyldmoline to the central nervous cystem. The achinistmtim of a cholimtemse inhibitor Df'P (di-isagpmpyl fluoroplvsphate) elicited high unplitudn rapid frequency EEG patterns similar to of poststatus epileptiws, as wall as changes similar to M stma (Madam £314, 19‘69, Samson gt 9;” 1950, mid Hindi-m 333b, 1950, and Weasel 93.31;, 19%). These EEG traumatic effects were blodmd by small. dose: of parenteral atropine and in amtylcholim after awpolmim. The mat tetmthyl pyrophosphate (TEPP) was masumd and related to the toxic misfostatims and cmwlsims induced (Sim and inm Pepcu, 1952; Stone, 1957). Chatfield and W (1M2) prepared exposed miml cortex with pmstiminn and cvdcud oluhmnoephalogmphic spike activity. Thu spiking, or prior mismtim of atmpim blocked this if present, thc «mutuality could be eliminated by atropine. In contrast to that: findings, Bmmor and Merritt (19%) applied tepical acetylduolim in concentrations of 2~1/ 2 to to the exposed cortex of cats, and noted no effect on the 10% w- «ﬂu-xwa—VVlwu- ��“mun-ny- rw-WV‘VKwnZw'w—w "1W:wmwvtwwav 1W”'_<1>vwnv.<_wum,vwwv ]- ‘_ VFW, .. .- w n - ~-....Vr.ﬂ.--“ “W,- ..‘,_.,‘......_,.,.‘ -.v—--Y‘. ,-. -3- Elliot gt. 5}; (1950) md Crosslmd lid Herridc (195“). 61mm and Popou (1962) fomd the increm in aoetyldnlm following various dapmssants to bc proportional to the degree of depmssim of the central nervous system and the mduction in motor md Buck (196:4), turnover, studying 13min activity. My W lavas and sedation omeludod that some ”dating agents are associated with devoted brain aoetylomline, but that no dawns mlatimxshipo existed. In part, this may be mlated acetyld'xolina to the earlier obsorvatims of Wu: Elliott (1951) that acetylcholine synthesis unsound in mt brain slices, is accelerated by low dosages of mootic drugs, but inhibited by and him dosages. Pme autylcholim patimts with epilepsy was mported in the spinal fluid in (Cone, Tower and Wm, 19%; Tower an (7‘3 epileptic patients, Mom, domtmted free aoetylcholine in qumtities of 0.02 to 5.0 percent with an average of 1.0 gm percent. Acetylcholine and 191mb). 0f 56 gm lawla Hem related to the fmquonoﬁ of seizures, the extent of electmmplulogmphio abnomality, and to the time since the lam: soizum, but bore no relation to mdication, type of epilepsy or lawl of cholinesteme activity. Elliott at al. also noted that :1: fm acetyldmoline was dennnstmble in the spinal fluid in cmoentmtims up to 3 gm permnt after mmzoln convulsions. 7 .w .. "urn“... �.7.~w.. V. - V ,, “my",w 1...,"— 4~.vn,w—._._.m~,m raw-w": '— 0.. ”75v.. .— _‘ . ‘wwm‘ ,van... ..__.,.Wry.~.~ m-Zwm-V'I—r‘wn W.W ”-mw-w.w.mwr~m - n—r.~~—. >¢r:'l.irmv --"‘v-w-V‘MVSWVP -9Tower and McEachem (19'4933) viewed mm the increased acetylcholine of the seizure, and not causal. Studying the hypothesis that the acmlatim of acetylcholixm induced seizures, Tom (1953) masumd the level of acetyldxoline in brain tissue after mtmnolc convulsions. She noted a rise in the as a aoetyloholim content of bmin, before a soizum and a fall during the convulsion. Below certain levela of acetylcholine, cotwulsiona failed to occmr. that the fall in tissue aoctyldaolim during a convulsion was due to inhibition She suggested of aoatylcholim synthesis by increased concentmtims of metabolites such as mimn ions. Gianna!) and Pepeu also measured chmges in cantml nervous system acetylcholine follwing various stinmlanta. moholyl and 3, S—dimthylbutylcthylobarbiturate Chly was after them a significant chmgc in the amtylmolim level. may noted a decmase in association with induced convulsions. With other drug: which they classified as stimlmts iprmiazid 1: (LSD, hydroxytmyptophan and iprmiaxid a ipmniazid, DOPA) tum war: no changes in acetylcholine level. may omcluded that despite intense excitatim produced an by these coupomds, them in acetylomline levels unless trace mm by convulsims. (The differences in obscrvatims no changes Wand between these MomdemcgggléandTmranndEaduem muted to the differences in mthoda of biochemical monuments, for the latter measured chmges in spinal fluid my be mflocting the free acetyloholim. while Gimmn and Pepeu «way—.- —-—.\. �T- - w;—----w~~~.~ .7 um . r - xu ‘ r v,m__.mwa,mﬂmuwwr~pw m~'mvv'v—rﬂr vav-u—w. ---—w ~ ,~ .ﬁﬁr'A—HIwmmrrw‘(Wr-1Inr’mwmr"W'mv-w’ total acetyloholim reflecting band and free fame and Elliott, 1951]). of amtyloholim. The“ mom augguz that Apart/tango“ an. induced su'zwtu by moanpmécd in intercom 6n: mag/Maine an m abound 6m La bound {own which my be inﬂected in the (Laid. Cmbm activity and Auzwtu enhance magma” «lawman, awaiting wine Levels 05 Mots/Moan, Mule “up and muthuia my augment acetytchoune paoduotéan inc/away about mm. measured the [mm We W ’ (:3) Central Nervous sttem Cholinostemes: Tower and Worn (19%) also measured spinal fluid molinesterase activity. The typos of cholimatemnos are nomally found in the spinal fluid: mimestemoe-I (“tm,“ "opecifio," or macholyl—hydrolyzing), whim haaaa high specificity for aoetyldaoline; and cholinestemse—II ("psexido," "non-Specific," or banzoyloholine~hydrolyzing) . momds Both hydrolyze aoetyloholim but have different rates of hydrolysis for monolyl and benzoyldzoline . 'mis differential rate permits qualitative distinctions. By reporting the cholinestemsc activity as a ratio of the activity with a moholyl substrate and with a benzoyldioline substrate compared to a substrate of acetylcholim; two mtios are found: crolinestemse-L/aoetyldlolim and clnlimntemoolllaoetyldiolim. In such mtios normal oembmspinal fluid contains astemsea in the ratio of 33:17 for molimstome—I to dialinestcme‘ll . _ In patimts with head trauma, Twer and Mcanhom reported an inversion of tho cholinestemsea with an increase in the VHF-"147 �».———w ~. r... >qu . 'v—vv—W n» “W...“ mm xwwu-w_~ WY— . “-7 mrmm wnwW—u—mr- w...” maum—w—w—y w «W . unv'r“! "31A“ man-.wvvmw "w” w~:- -11.. dtolimtum—II fraction of the spinal fluid and a decrease in cholinesteme-I activity. Tho extent of the dualinssterass reversal was related to the severity of trauma and to the dogma of the electrocnccphalogmphic abnormality. In patients with elevated spinal fluid acetylchclins after $1)th seizures, however, no change in the ckmlimstomscs or total armlinestemse activty woof was found. in cholinestcms activity may be undamtood in relatim to ohmgcs in cell neutron: permsability. C'holixnsteme—I is fmmd in highest cmmntratim in the The charge cmtral mmus system whilc d'xolinsstemse-II pmdaninatss in othcr tissues, especially blood serum. With an incmm in acetylcmnnc levels in cerebral intcmellular fluids, vasodilatim md incmased cellular permeability may be predicted, with a dsgme of tmsudaticn of vascular fluids into the intemsllular spaces varying with the extent and duration of the vasodilatim and their (W g, 31:. 19%). Spiegsl, Spiegel-Adolf, oo-woﬂcem (19“1, 19M, 19““, 19148, 1953) demonstrated and: pemeability changes and inmassd conductivity of the titauos associated with the appearance of various ions (as pctassim and phosphate) in the Spinal fluid following electrically induced convulsims . Such nm~clcctrolytes as nucleic-acid splitting cellular psmability enzymes may also increased. in Changes thus provide the basis for the high concentrations of metylchclim and the increased concentmtims of duclinesteme-II in induced seizures or head trmma (Tcww V 4nd HcEcchem 19n9c). . persistence of acetylcmlim in spinal fluid after head dmlimstencsc dcspdte and trauma «fur seizma The imam . vmr Var" .muw ��rw ~—.r< —-._..'—v-w__ ‘- ,m Am w—w— WW 7- v nan—1"“ w—u-n w v mm mug; '- wmn—uw—v W v mm -- ,mmmm‘u—n w a"... mm -13- «mum m mm 5M nuvocu Mama 0‘ mbmu nmuimy «a WWW at «may. (a) Aceﬂldaolino, EEG 13mmmd‘wmy and Induced Oonvulsims: Alteration in the blood—brain permeability barrier by the cmtinuing action of acatylcholine may be a biochemical substrate for the postwlectmshoa hypemynchrmy of the electroencephalogram Sud: a possibility is evident in the damnation of an inmm in the mmtmtim of cocaine in brain tissues thme days after a series of 12 induced cmwlsims (Aird We g: .1332., 1956). The in emcentmtim of this large molecule, ordinarily absent in brain tissue, was associated with the appearance of syndimny delta bursts) in the electroencephalogm. We hove oonfimd the many hyper— pmvious reports that convulsive therapy induces electrogmphio hypersynchrmy (Pink and Karin, g 53;, 1961) . Despite a constant applicatim of treatments them is a great Variability in the time of appeanmce, 1956:, Pink the duration and the extent of the electrcgraphic slow wave activity as well as the sensitivity to modificatim by alerting, hyperventilation and barbiturates in pcytidaﬂxic populations. The early appearancn of dagroo hypersynchrony and high persistence thmugzout a prerequisite to mamnt cause has its been described as improvement following electmshodc (Roth, 1951; Roth, §£_g£;, 1957; Pink and Kahn, 1958). the differences in the dogma of induced It is EEG possible that hypersyndurmy mlated to differences in central clmlimrgic activity. The failure of certain patients to develop hypersynchrony may be associated with the absmce of fame aoetyldroline being related may be to him). changes in cumbml function and thus producing .a » “V.lvf"——Iw vu.- "a'v �WW. _. 7: .my- "“ .~..v.,W ”" . , . “V WW 7*MW--—- ‘-u :u wr—u ‘V-U-lw‘-um- WWWW‘,”._¢.~K—.wvﬂﬂ m”. ~"m--'~w , e ~ * .7 _,.,. , v ,7, , (lawn), in their study at” cmniocambml tmmna, included observations of six psychiatric patients undergoing cmvulsive trumpy. Studying the patients aftar 3~7 tmatmnts they reported free spinal fluid acetyldmline in two patients; and an increase in cholimstemse-II and a decrease in dwlinestemsesl with a reversal of the ratio of dialinestemses in five of the six patients. hm those obscrvatims they concluded that the spinal fluid changes in induced convulsions were more like those of amniocembml trump. than those of spmtmeous epilepsy. described the one patient in the series failed to show either fme mtylcmline or a dmlixnsterase ratio reversal in the. spinal fluid as: "It is interesting that this patient was the only one of the six to shrew no response to treatment." They If olectrogmphie hypersynchmny who is a mflectim of increased fme mtyldxolim, subjects who maintain hypersynchmny and those in whom it disappears rapidly may be exhibiting diffemnaes in the kinetics of the dwlinestamsawoatyldmoline hydrolysis systcns . Persistent hypemyndumy may result from a decreased rate of hyd‘olysis of wetylcholine , associated with low mntmtims of either- cholinestarase-I or cholinestemse—II . (Conversely, in patients with short-lived hypemymdurony, dmlimstnmse-I md -II in tissue md spinal fluid may be unusually high) . Fm thug chuwacéoM we would conclude demon; m mediated M an Mme in in W, mm enhancing 2th: MW“ that induczd {we acetyichouue Mg Momma. naming mutual 06 The and Lava as ﬁne 1:; . ru- » m. “mmvw-w' - , v- �"w aw-"m, wrrwnw“—5— mmrwmwm._ . mallow 426 Wad m wm—w—w w. "mm-v m-u—v—v— nw—wuw- gwmy"w_mw u- m. -55.. by muted induud autumn. EEG hwynchlwny a one. Reﬂection 05 abtmed {even 05 Managua and muted 05 01h“ momtym. It 11A pubabtz that that chaugu in movide the mam mngw mm“ pwibtwt 4mm: Mochwécaﬁ 50mm 56!: {nomad the bohemian“ changes mm“ . (f) malimstezm md the Classification of Psychoses: mesa studies have application to tho problem of autonomic reactivity and tho classificatim of the psychoses . Manstein, 91:. 31;. (19%, 1951, 1952) have demtmted a relationship betwaon the blood pmaaum maponse to injected mthacmoline (Macholyl) and the clinioal response of spydtiatric patients to convulsive therapy. is a potent cholimrgic agent which induces vasodilation, tamycardia, mating; and increased peristalsis . 11:53 rapidly Phﬂmacholinc hydmlyled by ermlimstemse-I and slowly by duelinesterase-II . mo blood pronouns of subjects falls after injected macholyl and returns to the baseline within five to whose blood pressure 20 Grow VI and VII have a 9 and a am recovery and Group VII mactom 1133;” 1952). patients in 20 89% to nﬁnutes. Patients 5 those whose blood Wine, Group II—III rate, respectively, while and 97% minutes have recovery mtes as reactors Group VI (Wotan GmupItoIII mactommybelohkeduponas whom while Grows v1 I, II, or III reactors; ormm minutes to motors. Group I and 35% than returns to the baseline within how classified as Gmup pronoun takes more the injected mdwlyl is rapidly hydrolyzed; ‘and VII have a slow hydrolysis rate. It is probable, themfom, that the blood and tissue oholimstemse activity levels of Grows I-III is high; while that of Groups - unr �.- n. .— . VI .wr-. .,m-w.w-,,. ..- - VII in low. A mwkwmr “or a mum: mviow, similar analysis systom levels of "'"ww—ﬁi-m may in mud: r—nmﬁm.mn-‘mrmrp.’ "nu—mu“wl'r-_'In. m Rose, 1962.] mgarding central nervous dwlimammo-I in the dcvelqmnt of EEG hypmyndnmy and spinal fluid levels of acetyldxoline, providing the built for a hypoﬂuais mgarding contra}. nervous cyst-m periptnral mt Inactivity to induocd convulsions and to momma agate. Arm �. ”V7“ :vn-r— www- 7.". New“- mu..~ “Av ‘:~vv-'me~'v xwmm~m.__en.sw—_. mm _.m immv—rmc "cw. .ww-‘rwwm-u-ﬁ—Wrw—_ml -17- see significant in the convulsive therapy ptccess. The published data indicates thlt induced convulsions ame.associated with an inczease in intercollulsr scetylcholinc to levels greater than can be destroyed by cholinsstensse—I activity. Vascdilstion and increased cellular permeability are fblloued by increased amounts cf cholineetersse—II electrolytes in inter» and other enzymes and cellular fluids. These changes are hypersynchwcny which reflected in the increased electrical is recorded as EEG slow wave activity in scalp electrodes, and which can be modified by a wide variety of enticholinerzic drugs. In these reasrds, induced convulsions are more similar to cerebral trance, than to spontaneous seizures. The changes in the onrebmel biochemical milieu alter cellular activities sufficiently to be associated with altered behavior of subjects. Failure to induce high and persistent concentrations of ecotylcholine and Illiuwe to induce concomitant fbilume to produce behavioral electrolyte changes results in a ‘ change. Difﬁerences in the rate of development of cerebral changes reflect differences in the dependence of subjects on cholinergic mechanisms or in their sensitivity to changes in acetylcholine 1mm. mm differences provide the basic for the classification of the mentally The the mode ill by Funkenstein and by Pink and Kahn (1961). observations provide a rational biochemical basis for of action of induced convulsions in altering the �m" 'A "VI-v Ww—vv—n—u—m—«rrm mum-mam mm with tho mm «truer mmmmwrmawm -13.. of pomtie subjactn. 'nnu mm view mwopmsiologie—adapﬂm (Fink, 1957, 1962). an mistmt wavy expressed �_.,. m...“ ... .4. .. .ﬁ-a v “3-..."- w..——_ww «av—m... ”VWFI-WquwLH-‘M‘AW‘K' w-v'lw . . "m." Inn—www-Iw‘m v. "uvw -wu v rays-y‘— :—.- me‘n—I'“m 32mm Aird, R. B... Strait, L. A., Pact, J. 91., muncff, H. K. and Witch, 8. C. Neurophysiologic effects of electrically indwed convulsims. M’ch. Newt. rum. scum, 1956, 75: 371-373. Pram and actim cf acatylchclinch experimntal Bomstuin, NJ). trauma. 1. Nuanpkyuatu 19166, 9: sue-355. min Horritt, H. B. Effect of certain choline dcrivatim clactrionl activity of the cortex. Auk. “want. (6%.). on Runner, C. and mm. Human, A. S. V. and NacIntosh, P. C. The physiOIOgical significant of acctylcholim. In K. A. C. Elliot, I. H. Page and J. H. Qustcl C. C. Thoma, Springficld, 111., 1955: 37I4~375. (Editors), uwmmuw. mtfield, on Dewy, cortical potentials. Mu. Cam, W. “Viv P. O. and Tm, in epil’psy. V., Worn, Jo‘oquo. 1&3, 73: D. B. Grassland, J. 1950, 162: “SQ—MW. E. w. Effects of prostimine md acetylcholine J. Pkg/«20L, 19142, 135: 633~6u0. and D. I. Acotylchcline and mammal 59.639 effect of anaesthesia on the matylchclim commit of the brain. J. Phydob, 195%, 125: 56~66. Dale, R. H. Th action of certain «tau and ether: of choline. and their relation to maxim, J. Plummet. Exp. Thu., 1913, 6: 1'47. Elliott, R. A. (3., Swank, R. L. and Henchman, N. Effects of mﬂmtics and cmvuhmts on acctylcholixn content of brain. W. J. Phgual... Pink, H. A and Merrick, A. Tm unified meaty of the cctim of psychodynmic therapies. Pink, H. Effect of anticholimrgic agent, diethazine, cn EEG and behavior: Iimificm for theory of convulsiva therapy. Mch. Newt. (cued, 1958, 80: 380-4587. was “ch. Fink, H. Effect of mticholinomic on pcat—cmvulsiw electromccplaogm md behavior of psychiatric patients. can. Humming 1%0, 12 (2): 359—369. Emeh. ’ Pink, view. m. of action of cmvulaivu therapy: the mm'ophysiolosic-adaptivc J. Nwaoplgcuazu 3: 231-233. M. Pbdo Pink, H. and Kahn, R. L. thtintive studies of slow wave activity following cloctmstnck. Bactuzuccph. can. "wuphyuotn 1956, 8: 158. Pink, 14., mm, R. I... Karp, 2., Pollack, M., Gm, H. A., Alan, B. and Lafkcwita, H. J. Inhalantuinducad convulsions. ma. Gen. mama, 1961, In 259-356. mm, A. PL, Bales, P. D., Willis, md Himwich, H. 8. Experimental pmdwtim of electrical major convulsive patterns. Amen. J. PhyuloL, 1&9, 1H6: 117—1218. Mkenstuin, D. H., Gmmblatt, H. and A. new Mutt. 0.3., 801mm, H. C. Autmmdc chins“ ramming electric shock Mutant. mm 19%, 108: #094122. J. New. �.- “ 'E'mr u-men... Mountain, wumW,mu“... 1~w‘mww.w“~-mmmern“—"~—IJ...- mm, amnesia H., paralleling peyoholoﬁo 1951, 11”: 1‘18. D. qvp- —..,. WW me‘w ”Va-WV“..— mwmmwmvmuww W3 mantally ill paﬂlnts. 1. How. m. 01.6., H. and Solomon, H. C. Autonoiuio Menuhin, D. it, emenbhtt, M. and 301m, H. C. Autammio nervous system out of prognostic simfioanoe in mlation to alactmskndc treatment. P‘ymm. Mo, 1952. 1“: 3“?“3620 Gianna, N. J. and Pepeu, G. Drug-induced charm in bmin aoetylcholim. W. J. Fitment” 1962, 1% W233. A. and Hiwich, H. E. Effects of Mam, J., 33313, C. P., Manley, di-iaopmpyl flmmptmplmto (DEF) on alectmanoephalogm and cholinastarase activity. ,Eumamcph. can. “Mphysutu 1950, 2: Mil—ha. Basis, C. F... C. F. Hampson, J. L. Balsa, P. D. and Effect of trimthadima (Tridima) and other drugs on Madam, oonwlaions caused by di-isqwmpyl flmmplmphata (OFF). Ame-A. J. mum. Himioh, H. 23., A. H. 1950, 106: 816-820. Jonkner, P. 1.. no ladmer, H. The effect of Dipamol on the olectmmoopmlogrm in tho normal subject and in time with canme tmuna. EWmuph. can. ”meto' 1955, 73 303’3050 6., Ulett, G. A., Johnson, H., Sﬂth, K. and Sines, J. 0. Eleotmomwlsive thrapy (with and without atmpim); affect on Johnsm, I... analyzed ahctmanoophalogmm. chemically 2: 32u-336. 1960, Melt. Gan. Paychiot” alum, M. and Knaub, V. Quantitative estimatim of the Kabat, E. A., albmin and gamma globulin in actual and paﬂmlogic oembmspinal fluid by nomads. MM. 1. Mad" 193:8, *3 (5): 653-662. Wm Kovada, A. G. 3., meo, A. and Halmagyi, M. hm Hamid"Wit Aoetyldiolina‘omtmt of the brain in traumatic smdc. Aotc Phyaiozaglca (HungJ, 13: fiber Lou-vi, 0. Meir. £. 4. gas. 14. our Hemmnwﬁkmg. 1921, 189: 239-»2u2. Haymrt, E. W. and Buck, E. 6. Effects of C.N.S. Dapmsmts on Brain Aoatyloholim. 19M, 6: 191. Wtagut, Heisman, H. and Elliott, K. A. C. Effects on omvulsmt and narcotic drug on aootyldxolim aynﬂnus. 1. PM. I Expat. Thump" 19513103: 35. mam. Wm, specificity of We in mm D. and Studies on cholimtama: on tissue. 1. Biol. (than, 191:5, 158: 653—666. M. A. Ridxtor, 1). mad Crossland, J. Variation in acetyloholim’oontmt of the brain with physiological stata. J. Phyatolu 19%, 159: 2h7-255. W. Rosa, J. '1'. 'me We; Menuhin hat in the ~ A mview of the literature. Add mdor barhitmte anaesthesia produced by twain-mt mad their simificmoa for the theory of M clam-awake actim. Enougmuph. can. Managua" 1951, 3: 261480. Roth, )4. EEG �Both, 15., Kay, D. W. K., Show, J. end (keen, J. Prognosis and pentothel induced electmnmplulogmphic changes in electm—omvuleive treatment. summaph. can. Nemphy‘iol” 1951, 9: 225-237. Spiegel, E. A. and Spiegel-Adolf, H. Permebility chmgee in the brain induced by tamed and insulin cannﬂaions. J. Nuv. Max. 91.5., 19‘31, 93: 750—3755. Spiegel, E. A. and Spiegel~AwlL H. mysiooodieuionl effects of electrimlly inclined cmvulsime (mmbmepinal fluid studies). Tum. Mu. mm. 1455., 19%, '70: 130-132. Spieaal, E. A. and Spinal-Adolf, H. Physiological and phyuicodwmicel mechanism in electroshock treatment. Conan. Newt” 1953, 13: 38-53. Spieael, E. A., Spinal-Adolf, H. and Hem'y, G. mysiooodxdical changes in the brain electrically induced convulsive discharges. marina Tm. m. Newt. Au" 19M, 68: 17h. Spinal-Adolf, M., Wilcox. P. H. and Spiegal, E. in electrmhodc treatment of psydxoees. Mae 19.48, 10“: 697-406. Stem, We Tom, H. E. 1. Pk”. The mole Me, A. Cerebmspiml fluid m. J. mama, of acetyldwbline in brain mtebolism and fmctim 1957, 36: 222'255. Effect of omwlsion inducing agents in the amtylcholine content of the brain. J. Phyeutn 1953, 173: 179—183. (2. m. Effects of single injection of corticotmpin (ACTH) on We, ion and emtyldxolim ambmt of bmin. Ana. 1. Miguel” mnim 1953, 173: 1764.78. C. Wm, and patterns wetyldmline in the oemhmspinal fluich 0011th a. Aoetylclmline ma neumml activity. I. ﬂower, D. B. and of patients with maimmbml mm. CW. 1. Quench, Tatar, Wehem, 27 lQuQa, (Seat. E): 105-119. D. B. and dnlimstemes in hm 1949b, 27 (Seat. 13): mutant and characterization of mmbmspiml fluids. Canad. J. Rum, D. 'Ihe 132-1'45. Acetyleholine and neuronal activity. Worn, II . Acetylmolim and dwlima‘hmsa activity in the Tuner, D. B. and D. fluids of patient: with epilepsy. szm'. J. (Sm. E): 120‘1310 Ulett, G. A. and mbmspiml RPAWA’?, 27 1mm, datum, M. W. Effect of atropine and soopolanﬁne upon eleetmenceplulogmphic charges induced by electm-oonvulsive therapy. Euwameph. can. Namaphguot" 1957, I: 2174224. Ward. A. A. Atropine in the treatment of closed head injury. J. Newsag” 1950, '7: 398-402. Ueeeoe, H. C., Green, R. Wm, of atropm md aoopolauim on the 3., B. P... and Kmp, S. central effects of DFP. Wt. The J. inﬂuence �DEPARTMENTAL CORRESPONDENCE DATE Julx 29z I965 SUBJECT Cholinergic Mechanisms in Convulsive Therapy To.“ Max Fink FROM George A, Ulettz MODo A most interesting paper, well put together and documented and with which I MoDo DEP'T DEP'T am in the main in agreemento There is one minor typographical error on page l2. GAUzlz �CFDLINBMC W315 WV!) IN Max W Fink, PM). mmmpmmotpmmnmmsmmmma Paydaiatzy, (immunity of Iii-semi. Sdml of Medicine SHOO Arsenal Street, St. Innis, Missouri. 63139. , Aided, in part, by usms grants ”44.921, 114-2715, ail-mus, md Iii-11380; ad the Psydiiatric March Fomdntion of Missouri. �VI: 7-17-65 WCWHWIVEW Despite mm application and study, the nod: of action ofﬂnccnwhivethmpmmnminsuﬁmic. Matudy mmmdtomumphysiological( paydwlogical( social ). clinical ( ), ( and aspects, elucidating me pmaent nam— ) phyaiological-«laptiw ). View of the process ). ( 'lha amply dnvalcpmnt and persimmon of signs of altered cerebral fmctiun mm mpomd to be requisite to (Pink md Kahn, 1956), with mess in behavior 0100*:ch slow wave activity as the mat significant index of altered brain function. Thu this Mien slow um that pmddcatim with ampina inhibited ‘Jormcn, 1957) and the report activity (Ulett and that antidxolimrgic a mm nursed these clinical ahatmgmphic alarms (Fink, 1958) 311mm that .me biodmnical basis for the convulsive therapy process the clnlimraic m as wall may be in of the central nervous system. This raviaw discusses the available data agarding acatylcholim ﬂ �and the dwlimstemes in the convulsive therapy process. Acetylcmline has been extermively studied m an active agent in the transmission of dowdptiom of Dale mm impulses since the It is (191A) and Loewi (1921). first a comtitmmt of mmm tissue, existing in a bound form which is liberated during the excitation process. It is rapidly hydmlyud thrwgh the specific action of duclinestarase and in rapidly momstituted by the ohcline~aoety1ase system (Rid'ater and Crosslmd, 19W) . In noml cembmspinal fluid, free acotylchclim is not present despite the mpid bound and breakdown of acetylomline during periom of activity and excitement (Tower Wm, 19u9a). The cambmspinal fluid does have measurable dwlinesteme activity, havever, principally of the "two" or mdwlyl hytvlyzing type (Madam and mm, 19%). In the absence of free aoetyldxomle and mdar the conditions described, electroencephalom fail to show abnormality. �(a) Grahame ﬂats of sootylcholim was found Crmiooembml Tram: Prue in the osmbrospinal fluid within a few minim after sxpsrimtsl Mad trauma in cats md persisted for varying periods up to “8 hours (Bomstein, 19%). The quantity of ﬂu the amtyldmlim varied W1: was (:th between 2.7 and 9.0 gm pennant, and related to the degree of induced mum. shotmsnoephalogmms amazes. me mooxds were demtmted pattmd first filled with activity, immuted as svidsnoo of high voltage fast an intense neuronal distant-3e. soon to be sumedsd by a short period of flattening of all recorded electrical activity. These phases wen then followed by pmlongod periods of high mlitude sharp waves- in ttwdcltafmqusnciss. 'msbehaviomlohmgsswsmmlatsdboﬂitothsdsgmsof mmmd to tho want of mmd fme amtyld‘nline. Vth highcr lovels of amtyldlolim, Bomstsin reported greater dogmas of EEG Why and water changes in consciousness. �31>th wt post-traumatic seizures ware also related to the of fme acetyldwlim appearing in the Spinal fluid. Bomstein applied amtylctnline to exposod cat cambml cortex. When the concentration of amtyldxolim percent or lass, higx amplitude slurp waves appomd in the electxmmaphalom. When was W6 t0 2 gm percent. was 1 gm of low frequency the concentration 01.0meth the 1000160 fashion the patetzmnatic flatumed in a parallal to Parallel investigatima in neurological patients by and Wm (mm dumtmtad free Tower acetylcholine in the cerebmspiml fluid only in patients with meant head tmuna, meant wand-ml seizures or after alectmcmvulsiye therapy. M0 amtychlim varied fluid spinal assaying from 0.2 to 0310111103001”: 100 gm peasant. In activity, they noted a sharp rise in the nonspecific dwlinesteme fraction (Mmoylcholim-splitting) and a dmp in the specific cholinesteme fzmtian (mohaiyl—eplitting) in patients with had tmma and sanguine convulsiva therapy. The cambmspinal fluid did not �exhibit such invemion, although after it contained free acetyldxolim, spontaneous seizums . They concluded fr“ mtyldzoline varied directly with the damage and that the level of degree of cerebral that reversal of the dualimeteraae fmetims was a mm sensitive indicator of cerebral dmgc. Electmencephalogrmna, taken at arming intervals fellowing minim between the dagme of tram, also indicated a EEG-Wt); md the appoamm of free amtylcmline in the cerebmspiml fluid. mm Wkwwm Tim «the, 4;me We! mm 0‘ due magma-u. may tame in the (cumming {m autgtchouu, abnombbty, and WW «the. Mg“ W“ W. «tam and the want chalk.“ and type 0‘ 4'.» 05 demomuphalogmpuc dialed mm); «ppm «6 �Antietam} (b) bahavioml and mutual m and trauma: mmlogio signs of mum The m electrogmphic, blocked by tbs awninistmtion of 0.5-1.0 Wkg ntmpim (Bernstein. I 1986). as was similar inmcistml clinical change” mowing after the additim of aestylchcline. Ward (1950) applied injtmida. those oboemtima to tbs tmatmnt of closed head In 20 of patients with varying dean-e3 trauma, ha administamd mopim WW1); immt in some and in doses of 0.1 m/kg, noting clinidal a mml effects in others. In a study of diethnxine. Jonkner and the W at the W forty patients with anticholimgic drug, altemtiaw in (1955) mportad post-mmtic aloctmcmophnlnm. dose in electroencephalographic W A sinﬂe intmvamus electroencepmlogrmm resulted in normalizing in twanty-tm and marked inpromnt in six otham. Similar observations have been Imported by Denisamco (1965) using mthyl‘bamctyzim and poat-atrmmtic mmtin in animal that and 03li em. ewinmta of �Truss obssmtims were assasssd in the convulsive therapy process by Ulstt and Jornsm (1957). These workers administersd dosages of atropine w to the patients waived that the mt: mm slsctmsm of slow wave per day during the weeks therapy. They downstmtsd activity prodmsd in those patisnts ms significantly less than tbs control group who had not received the atropine ministration. (In a 141th study these authors fdlsd to mplicats this study, suggssting that dosage factors or population changes have contributed to different msults [Jormsm These observations provided the basis g}. 31., 1960]). for studies with othsr imam anticholinsrgic mounds (Fink. 1958, 1960). hummus JB—336 arid Wins. the pipsridylbsnxilntss JB-329 (131mm). and WIN-.2299 induced dssmhrmiutim in psychiatric subjscts. These Hum The injection of smrimntally active anticmlinsrgic camels as disthssim. JB-ala, may EEG EEG changes associated with barnvioml darting, anxiety, tramm, illusions and hallucinatima. In patients also had mently - �mind elootmoonvcnsivs the achsinistmtion of throw, these Imomds was associated with a mduotion in slow awn, mm wave and 'eonnnion. activity and reversal of Aunpim was also examined in low doses, and in these administmtims, EEG dosynctumizstion ms obsomd nervousness sod tension. At highnr dosages, hypersynchrmous slow waves, followod by lower activity with menisci by tachycardia. mimosa wings. poorly organized delta bots activity melamine: by pmmssivo confusion and disorientation. Both in oleotrogmphic annual tum and indwed convulsions, the 0W8 may be mdified by the commont (hogs, administratioh of mticholinargio thus suggcoting that immaud smarts of aootylohlim or inorusod oholimrgic receptivity is sssoointod with the high voltage slow wave activity. (a) min and iomlino anticholimm gm m: SimilanEGorangesandtublookingthmmnobumd following the dinct application of mm systm. sootyloholixu to the mm]. �The aministmtim of a omlineeteme inhibitor- DP? (di-isopmpyl fluoroxmospheta) elicited high amplitude rapid frequency We 19mm, EEG patterns similar to status epileptious, as well as similm to those of post—hmtio states (Freeman 33 11., Hanson Egg, effects were blod<ed 1959; and Himioh by small doses 339;, 1950). These EEG of parenteral atropine. 'me great increase in aoetylcmoline after tetmtthyl pyrophosphete was (TBPP) manned and related to the toxic misfestetims and omvulaims induced (mm and u: thfield and Dempsey 1952; Stone, 1957;) (19%) prepared exposed animal cortex with pmstigmim md evoked electroencephalographic spike activity. The prior mistmtion of atropine blocked thio spiking, the almomality oould be eliminated present, by or if atropine. In contrast to those finding, Emma!" and Merritt (19%) applied topical aoetyldxolim in concentrutima of 2-412 to to the exposed cortex of cats, and noted no effect on 10% the electroencephalographic changes after intmwnous atropine (1 mg/kg.) 'lhe concentrations of acetyldtoline in these experiments, �10 however, were higher than the and the gm topical applications (l-‘t intrusistemal (0.2-10 gm percent) percent) injections of Bernstein (19%).. Burner and Merritt also made note of elem- encephalogmphic effects similar to acetylcholine from motion/1 (emtylhetmthylcmline) much lower than the and cloud (oerbanyldlolinﬂin mtyloholim concentrations. They cmoentmtims ascribed the increased effectivems of these diolinergic drugs to their lack of sensitivity to cerebral almlimstemses. These data are conflicting and further study is museum to qualify this issue . (c) Oembxnsgiml fluid Amtxlcholine and Seizures: of aoetyldiolim metabolism indicates that it is One View fomd in nervous tissues in an inactive band fem. hiring periods of activity, amtylcholim is liberated at the cell dsectivated rapidly by mm, dwlinestemse. The where wt it is of bum asetyldmolim is the resultmt of the continuous processes of synthesis, liberation and bredcdmm. It has been postulated that the level rises during sleep and falls during activity. (Richter and Cmssland, 19%; Elliott, Swank and Hendersm, 1950; Giaruun �Pepeu. 1962). By using liquid air quick freezing methods. Richter and Grassland measured the level of acetylcholine (micro- gem per brain tissue) during anaesthesia and sleep to be mg. 300‘ higher than post-“12m levels. The difference in tissue levels is tnansient. however, as the resynthesis rate for acetylcmline in net brain in high (1950) confirmed m1. the” owemtiom, also Pepeu (1962) fomd an increase 3 noting that after gm per cent. Gimmn md in wetylcholine named by a central nervous mum depressants to be roughly reduction in and no mm activity. acetyloholim we reported in the spinal fluid in patients withepllepey (Cone, and PbEeahem. 19149 1)). 0f 55 'Ibwer and mascara, 19%; epileptic patients. demetmted free acetylcholim in quantities of 5.0 M proportiml to the degree of depression of the central nervous system m :3in convulaims free wetylcholine me demustmble in the spinal fluid in concentrations w to 1;! gm/gm/minute). Elliot (7 with 1.0 of an cent average per gem gamma Tower an (77%) 0.02 to per cent. �12 Acetylchclim levels were related to the frequency of seizures, ﬂnextentofelectnnncemelogmphicmmlity,mdtothe the since the lat seizum, but bore no relation to medication, type of epilepsy or level of clnlinestense eotivity. Tower and Maﬁa-hem (1904912) vimd the increased acetyldwlim a by‘prodmt of the seiem, Studying the hypothesis that the and not camel . emetim of ecstylchcline indmed minutes, 'l‘orde (1953) measured the level of ecstylclwline in brain tissue netmmle convulsims. .‘ She noted a rise in the ,_ V V ecetylcholine content of brain, before a seizure and a the cmvuleion. Below fall (bring certain levels of ecstylcholine, convulsims failed to comm. Stu suggested that the fall in tissue acetylmolim during a oonvulsim was due to imibition of ecstylcholine synthesis by increased concentrations of metabolites such as mnium ions. Wmmmmumdohmgesmmmmm system acetyldmolim following various stimulmts . Only after �13 unholy]. and 3, S-dimthylbutylcthyl-barbitmte significant chmge in the acetylcholim level. damn. was They noted a in associatim with induced convulsions. drugs which ﬁrearm as stimlants Md mmmdumainmtyldmlim + other With 133mm, (LSD, hymoxytmyptaphm and iEprmiazid level. there a + DOPA) them WWW daspito inﬂame excitation produced by these commie. them wan no dung» in mtylcholim level unless than were accompanied by convulsions. (The differences in observations botmmmuwerkmmdmggglmdmmrmdﬂcﬁadmm my be in diffemnaas the to related mummnts, for thc latter methods of biochemical wand changes in spinal fluid w 61m and Pepeu mﬂecting the fun acctyldxolim,‘while 12; bound and reflecting acetyldwlim mumdntatal true form of aoetyldzoline.) Thu: Atuau wages: that on: Wed by an sputum Lame. in an. induced 1mm law 5n: awtytchaunc �”mm—“hr“ V» 3- ‘ v w» . m w 1-: “r. 0... ~ W "n , nr-r-w, ..-.p:..u<ﬂv.»rrw-¢.M “av—w. . .,. 4. ....“.,_. w... ,, 'zs-sznr-W"“air‘quvww'ﬁ'qmti'd‘u. w. » ,‘rv —.».‘ wm‘ , w - 1n abound 4m in bound (on which my wind. (Laid. Cmbm nativity Micheline dalmatian, manna. Lemming mum 15qu in #1: enhauu tame (cum 9‘ Me blew and Mama auguwut mallow: madam“ 42mm aunt (d) Comm]. Nervous Wm and be mm . Sgt” ('holinostemes: (19%) also uncured spinal Tower and ﬂuid cholimsturase activity. No types of dnlimstemes are normally found in the spinal fluid: dwolimstemad ”true," "Specific," or Molyl-hydmlyzing) . whim has a high specificity for acetylcholim; and dxolimtemacu-II ("pseudo," or bonmyld'uolim-hydmlyzing) . "mpacificﬂ Both oompomds hydrolyze acetylcholim but have diffmnt rates of hydrolysis for mcholyl and bonzoyloholine . 'mis differmtial mta permits qualitative diatimtiom. By reporting the cholinostemse activity as a ratio of the activity with a mocholyl substrate and with a homoyldmoline substrate compared to a substrate of acetyldmlim, two ratios are fomd: dzolimsteme-I/wetyldzoline . --- v r v , -- ‘ ~- a"; . ��rmw, 16 vasodilation and increased with a degree of cellular permeability may be pmdicted. amudetion of vascular fluids into the inter. the of duration md with extent the varying cellular spaces g: vaaodilxtutim (Rabat mad their comma pomability such 51;, 19%) . Spiegel, Spiegel-Arblf, (19%, 19W, 19%, 19%, 1953) chm demtmted and increased oonchwtivity of the ions (as various of with the associated appearance tissues potassium and phosphate) in the spinal ﬂuid following electrically indwed convulsions . Such non-electrolytes , as nucleic-edit: splitting mama , also increased. Ganges in cellular permeability @6011th may thus provide the basis for the high of aoetyldzoline and the increased concentratiom of aholimstemse-II in induced animus or head and We!“ The head 1989c.) . persistence of acetyldxolim in spinal fluid after tram activity tram (Taver- and may be after seizm'es despite increased cholinesteme related to the sensitivity of the acetyldxoline- dxolimsteme-I system to meantmim relationships (Nadmm W. , ~1— ~- A” .—,.- �17 and Wu, 1935; Tower and Wm, muse; Burger: and McIntosh, 1955) . At "physiologic" comantmticrns, hydrolysis of mtylcmlim is rapid (3-4 lunar com—um, MW) but at higher and the activity falls off quickly . In contrast, the dialinastemaun acutylchclim relatimship is map-cite and the rats of hydrolysis incimma with increased: ammunition. 0m view of these mktimhips suggests that while the usual concentrations of mtyldmolim a cell dostmyod by the specific activity of few Wounds, my «and the seizum are dnlimstomeJ in a m excessive concentration following excitation the mate of hydrolysis by coir-m Mahala mnbms may be itself cholimstcmeJ. m reached and a seizure inclined, with adding to the mum: of free amtylcholim. The immune! acctylcholine diffuses rapidly, affecting vascular and annular pumability and imam; the mntmticns of various iom and dmlinentemmn in the of molimateme-II , though of low 031". The activity efficiency and depending on ��in brain tissue, associated with the appearmoo of hyper- (delta bursts) in tho electroencephalogram. syndmrony We was have oonﬂmd the many pmvim reports that convulsive thumps: induces elootmgmphio hypomyndarony (Pink and Kahn, m 1956; 93. 93;, 1981) . mutants than is mom. slow by m Despite a constmt application of a great variability in the the W103! and the exam of the alcotmgmphio mitivity activity as well as the alerting. hypeantilatim synchrony and in psychiatric dew hyper- its persistence thmmlmt a treatmt has boon described as pmmquiaite to It is to mdifioatim and barbitumtes populations . 'lhe early appearance of high Week tins of (Roth, 1951; Both 93.2%, mm 19531;th possible that the £15.fome in EEG-hypemynduw my be of central oholimrgio following and @,1956) . induood the dogma of muted to differences in the activity ”Wm . patients to develop hypomyndmmy pnoluding a clinical me name me failure of certain may thus be associated to Wood convulsions. Tower �.. 7.7. wrunvx—u— 20 and Will“ (lauea), in ﬂair study of mommbml tram, included obaawations of six paydziatrio patients mdergoing convulsive therapy. Studying the patimts aftor 3.7 momenta aootyldaoline in two patients; may mpootod free spinal fluid and an imam in (momma—II mumstomod with and a demase in a reversal of tho mti-o of mono-stoma: in five of the six patients. hm those observations they minded that the spinal ﬂuid dmges in induced convulsions mmmliketmmofcmimmbmltrmmanﬂmoof spontaneous epilepsy. Boarding the one pttient in the series failed to who show either true wotyldmlim or a duolimoocmse ratio reversal in the spinal fluid, they wrote: patimt was Mt." "It is interesting that this the only one of the six to show no rospouso If electmgmphio hypemyndxrmy is of inommd {me acetylcholim , subjects whammy and those in whom it who to a reﬂection maintain hyperh disappears rapidly may be exhibiting diffemnoes in the kinetics of the d1011nestemse~ wm. w,- Nx‘vrpl .1 �-\ “ --~w an» .7 r'v-vww-‘ 1". -.r Ti'prp"-ﬂ-=Au‘n “-6.“..- ~-‘ ‘31 . W W . , “‘7.dvzw‘". V... mu. metw'w—mwmlv‘lu":.e.vrlvn—“Atm-‘mWW w-xm “m.- Y‘a""' 21 acutylctwlim hydrolysis system. 'Fhmistant hypemyndumy result dsmd {mm a may rate of hydrolysis of acetylemline, associated with low mnemtmtions of either molimatemsea-I with shortin patients '(Oonwmly, dlolimutcmc-II . or lived hypemynduw, dxommteme—I md -II in tissue and spinal fluid PM: be mmually him) . may that: anomalous was 0&0:va «wanted “W‘m, «shaming the We. an: WWW a EEG 51prwa 1.5 a; Lgtu at WWW paovtde We in We mwmum.‘ wumtuuu. Mad one WW W pubable that saw! an that induced Wag embmcpweabuétym and It a on would coucmde aw by The Level. 05 upcmd Mad .5qu . mama of pmabuéty Mud Law 05 exhale. ﬂzuc changes in 05 «anaemia. mm deem- m mama: 4mm (an m pmumx chugu foaming induced 0.0qu . w ..—-.w-w~.-w... �K. i [ ‘ v. ,7 W .. f m .l . V, ». V, ,,,,_V -. .o “:2 ....V ﬂu, ”w...“ - w-wﬂl’m'." ”no”. .7 ..n “w... amp-“mm- "...v'vmm. ._, f.v-w—«-—v~—— v0?" m—v‘ wkumu. , 3‘“ .7 a run ,. . -- 22 (6) Gaolimtemes Thus studies may and the Classifimtim of Paw: also have applicatim to the problem of ‘ automic Inactivity mum and the clansiﬁcatim of the psychoses . and athora ( a «Miami-nip between ) true blood haw ”castrated pmssum response to injected madmlyl an! the clinical mponae of psychiatric patients to ammlsiw whim ﬁlmy. lel is a potent cholimrgio agent mm, mama vasodilation, tadxyoardia, peristalsis. It is rapidly hydrolysed by and W6 diolinesteme-el and :11me by dzolimstemse-II . Tbs blood pronoun of subjects fall: after injected mohalyl within five to more than 20 md mtums to the basolina minutes. Patients whose blood E l I i plum returns to the baseline within classified as Group panama takes 20 Group VI and VII 5 minutes have boon I. II, or III mentors; those whose blood armors minutes to mtum to baseline, as rumors. Group I md Grow; IIoIII motors �23 have a 9 and a 35% recovery rota, respectively, while Group and Group VII reactors 9:92;, 1952). Group patients in whom 89% and 97% recovery rates I to III reactors may be VI (Menorah looked upon as the injected morolyl is rapidly hydrolyzed; while Groups VI and VII have a slow hydrolysis rate. We may predict, therefore, that the blood cholinestamsa activity levels of Groups I-III would be high; while the activity of Groups VI A - VII would be low. similar analysis may be made mgarding central nervous uysten levels of cholineatemmel in the development of Em hypersynolumy and spinal fluid levels of acetyloholim, providing a basis for a oongment hypothesis mgarding central nervous system reactivity to induced convulsions dmolimngio agents. and to peripheral �. ..— .—\..‘ .. .—Vw-~'. 7...... "any.” “.7 lmr.r"vv,~ .. ...~ y.. . _,_,‘ , ~~,.. m. .WWV mm. rm. ~ v-y ‘ WV W H .wa-ﬂq 2'4 CONCLUSION : Central oholinergic Insomniac: appear nah- W in!» in the convulsive therapy process. ‘ significant The published data [that induced convulsions are indicate associated with an increase: in interoelluler acetyloholme to levels greater thm can be destroyed activity.“ Veeodiletim and increased are followed by increased other enzymes and by cholinestemse-I cellular permeability wants of cholinesterese—II and electrolytes in intercellulsr ﬂuids. These chmges are reflected in the increased hypereynchrmy which can be modified by is electrical recorded in scalp electrodes, and which mticrnlimrgc drugs as atropine, benactyzine, and diethazine. The changes in the cerebral biochemical milieu alter cellular activities sufficiently to be associated with altered behavior of subjects. Failure to induce high and persistent cmcentrttions of acetylcholim and failure to induce concomitant electrolyte changes results in a failure to produce behavioral change. 4'u-L...» 1.x. —~- -- 7 �2S Diffcmnoos in the mates of development of reflect diffemnoea in mbml that ‘0me of subjects on ohangas cholinergic ruthenium or in their sensitivity to changos in aoetyloholixm levels. Then diffemoes provide the basis for the classifica‘ tion of the mntally “most: the mode ill by Pmkonstein and by Fink and Kahn (1961). observations pmvidu a rational biodnmical basis for of action of induced mnvulsicns in altering the buhavior of psychotic subjects. These views are consistent with the mom general neurophysiologio—adaptive theory expressed earlier (Fink , 1957) . �REFERENCES M, R. Bo, Stmit’ L. A0, PM, do We, “muff, Mo K. ma Bowditch, S . C. Nemphysiologic effects of electrically induced ccnvuleicm. Melt. Peyehiet. 1956, 75: 371-378. ”Wt. 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"15161.0(" 1950. 162: ass-hm. PM. M. A unified theory of the action of paydzodynmic therapies. J. Hill‘idl H06p., 1957, 6: 197-206. Pink, M. Effect of mtichclinergic agent, diethezine , on behavior: simﬂcance for theory of convulsive therapy. Adah. Mental. Paychiat. {Ch£c.). 1958, 80: 380‘387. EEG and Fink, H. Effect of mticholinergic compom$ on poet—convulsive olectmencephelogxm and berminr of psychiatric patients. Eummuph. cu... Nauphyuot" 1960, 12 (2): 359-369. Pink, H. and Kuhn, R. L. Qumtitati-ve studies of slow wave activity following electroshock. Eucmemph. can. ”canophyaiat” 1956, 8:158. Fisk, M... Kahn, R. 1..., Ken), 2., Pollack, H., Green, M. A.. Alan, and Iefhowits, H. J. Inhalmtoinduc-d convulsions. Mch. Gen. 1961, “:259-266. mm, ' m, Bales, P. p., Willis, A. md Hinwich, H. B. Experimtel production of electrical major convulsive patterns . W. A. J. ”twin-L" 1%9. 1%: 117.12“- B. hymn ��an'V-WI' -3Spicgol, E. A. and Spinal—Adolf, M. Physicochemical effects of electrically inclined convulsims (cambmspinal fluid studias) . Tm. MM. Newt. AAA” 19%, 70: 130-132. Spicgel, E. A. and Spinal-Adolf, H. Physiological and mysicochomical Marxism in tmatmnt. Conga. NewwL, 1953, 13: 38-63. 013::th Spiegol, E. A., Wm Spicgclmlf, changes in the brain H. and Benny, G. Physiococl'xcmical electrically induced convulsive discharges. Tum. ML. Haunt. MA... 19%, 68: 17a. Spinal—Adolf, 14., Wilcox, P. H. and Spiegel, E. A. Cembmspinal fluid menses in electroshock treatmnt of paydzoces. Mu. J. mm” Stone, H. E. The role of acatyldmolim in brain metabolism and “mm. Tom, m. J. M0 M9, Effect of convulsim content of the brain. Man. J. C. 1957, 36: 222“255c inning agents much, on the acetylcholim 1953, 173: 179.183. Tonia, C. Effects of single injection of corticotmpin (ACIH) on manium ion and acetylcholine (intent of bmin. MM. 1 . Myuol" 1953, 173: 176-178. Acctylcmline and murmal activity. I. Warm, Gnumtomso pattcrm and acutyldwlim in the cembmpinal fluids Tower, D. B. and D. of pationts with armiommbml trauma. 27 (seat. E): 105“].190 I cm. 1. Rucauh, 19u9a, cmtent and dmmcteriatim of cambmspiml fluids. Canad. J. Rumch, Tow-r. D. B. and McEachcm, D. The hm 27 (Sect. E): 132-1u5. dwiimatcmes in Rush, w Tower, D. B. and HcEaclnm, D. Amtylcholino and neurmal activity. II . Acetylcholim and cholinestcme activity in the cembmspinal fluids of patients with cpilnpay. Can“. J. Image, 27 (Seat. E): 120~131. Mum. “We Ulott, upon Rum, Effect of atropine md scopolminc changes indumd by electm—conwlsive G. A. and Johnson, H. w. can. MthyAioL., therapy. Ward, A. A. 1957, 9: 217-22u. Atropine in the treatment of closed head injuzy, J. Nwww., 1950, 7: 3984402. �cmLINElEIC WIﬂiS, AND BEHAVIOR CONWLSIVE TIERAPY Max hm tha Pink, M.D. Wt m1 of Psychiatry at the Miami. Institute of Psychiatry, University of Hisawm'. School of Hedicim, suoo Stmet, St. Louis, Missouri. 63139. Aided, in part, by USHiS grunts $1.009”, I‘m-2715, ”ii-07239, and Mil-11380; and thc Psychiatric Recent-h Poundaticn of Missmri. 'mismportispartofﬂnstudypmmminhmctimand Behavior" undertaken New York. Hillside at Hospital in �n -.v-..ww.nmipv~.. NJ, mi V: CHOLINERGIC MECHANISMS, CONVULSIVE THERAPY, AND BEHAVIOR Studies of induced convulsions have m that the early develommt and persistence of aims of altered colonel function are prerequisite to chmgee in behavior (Pink and Kenn, 1956). Electmemptmlogmphic slow new activity was found to be a significant index of altered bmin ftmction, and the dmnonetm- ticn that premdiceticn with atropine inhibited this slow activity (Ulett and Johnem, 195$) suggested a wave relation to cholimmio melamine. In the following review the mle of acetylcl'olixn and the axolineetemeee in convulsive therapy is diamond. Aoetylcholine he: been extensively studied as an active agent in the transmission of nervous iwulses since the descriptions of Dale (1911;) and loud. (1921). It is first a constituent of nervous tissue, existing in a bomd form mich is liberated during the excitation process. It is rapidly hydrolyzed through the specific ectim o rapidly reconstituted by gelimetemee and is the cholimﬂeoetyleee system (Richter s V 6~28~65 , �Croeslmd, 1909). In normal cerebroepinal fluid {me eoetylcholim is not present despite the rapid breekdom of bound ecetylcholine during periods of activity and excitement (Tour and HoEecMm, lease). The cerebrospinal fluid does have neasmble ctnlineetemee activity, beaver, principally of the "true" or mctwlyl hydrolyzing type (New and ibthenberg, m5). In the absence of free acetylcholine and under the conditions described, electroencephalogram fail to show abnormality. (e) Effect of ﬁrmiocerebral was Item: Free eoetylclnline fomd in the cembroepinal fluid within a few minutes after- experimntal heed periods up to '58 tram in cats and persisted for varying hours (Bernstein, 19“). The quantity of free ecetylcholim varied between 2.7 and 9.0 game percent, and the mount me related to the degree of induced Concurrent electmmoephelogrm The records were first filled he followed by e demetreted patterned changes. with high voltage fest interpreted as evidence of an intense to tram. nemel activity, discharge, only short period of flattening of all recorded �alactriaal activity. periods of high 'Iha These phases were than followed by prolonged mlituda sharp wam in the delta fmqmncies. behaviml chmgea wan nlatad both to the dame of amt of masmd trams and higher haul: of acatylcholine, of amornality and EEG to tha addition, spmtmaous to ﬂu matar With Bernstein uportad snatcr degrees (mange: poet-Me aunt of free fm aoatylcholim. in consciomnass. In aaixums «am also ralatad amtyldlolina app-axing in tha spinal ﬂuid. Bomatain also applied acatyld'zolim to exposed oat cambml cortex. ”Mt When 01‘ tho omeantmtion of mtg/lanolin. 1808. fraqmncy in the was inmasad to ht EX: vaporized high amplitude sharp waves electmphalogm. “man ’7 2 was 1 gm pamt, wam by Towar- and HoEaeham of law the oonoantratim the alactmonoaphalogrm flattened in a fashion parallel to the Pamllal studies ' post-Mic ram. can'iad out in mlogioal patients (19%”. Pm: acatylcholina was fomd in 7 1 {wéli 14?”! [6cm �«1—. . ;_.... 7,. rm. . ‘ 4‘1"“.7 .. run-- «m w, raw-"aw ~~.w.:-v-w—.--lam—www—nv-rwww - the cambmopinal fluid only in patients withmoent Mad wv .r'. r tram mount pond-m1 seizures or aftor convulsive trunpy. Free ...;—--°-"“' " aootyldioline varied from 0.2 to 100 gm __ ~ peroent. _,,./ Tour ~ v. m3...» Mom also assayed spinal fluid oholimtome activity, rating a sharp rise in the nonspecific cholinestemse fmctim (benzoylclwlimqmitting) and a drop in the specific oholinestemse the oeubmopiml fluid did not exhibit such invasion, although it “dined fm mtyloholim. of They concluded fm mtylcl'nlim varied directly with the damage huge. taken at varying intervals following Kantian batman the dome of {m EEG was a mo Electmmoephuomm, tram, also indicated a abnormlity and the appeazmoa aootylcholine in the umbmspinal fluid. Thu, ﬂu spinal dogma of oombml andhat reversal of the dwlinesteme fraction sensitive indicator of cerebral of that the level want as 549.: Micheline. my {mug in the (Mdéaltmiugmuocmbwmmmdmmuntaé Wt / W“ _4___._.._..-' follavdng oonvulaivo mommy. Pollovim spontaneous soizums 01W, 4a.: \ and fraction (mohalyl-splitting) in patients with had 12mm and , �.5and the degue acotylchoune, (no Wenuphdogmﬁic «type 06 abnambbty, and changu in clinical bellow»! my be {Wad phenom. (b) antioholm Am1m, o behavioral and neurologic aims of pamtenl m mm and The EEG were blocked by the Mimic»: of 0.5.1.0 lag/kg atropine (Bomtein, as were similar clinical charges counting addition of mtyloholim . to the tram: W1: Ward (1950) after the intmistenul applied these observations of closed head injuries. In varying dogmas of tame, he 20 patients ’with ministered atropine subcutmly indousof0.lnglkg,notingclinioelimrovmntinsommda Md reversal of the eloctxmoephalogmphic effects in others, In a study 09m, mower uﬁtmolinergio Inchner (1955) reported altemticns in the moephalogm. W A p‘tvtremtio electro- single intravenous dose in forty patients with aleotmpmlom resulted in normalizing in twenty- ), �F i H4 ~37». .V v . “WW. awn" V l -.—.p..r \':v';"'r~~ gw~-_.....—m .— ...r 1"" “v: n n‘ , , , m. ,- two and marked , . , .- ,,_ _ , , __.,,_3._.7,,_,._ “,1”, ‘4‘._,V , an- a www-ruymumrm-e ,, ., .F ‘7...arm'Hﬂ ,_ ya,V. a“W. .. ﬁauawﬂl.‘ .w-qﬂw’ uvwwwrvw-1': -r~)\w‘nw . . . I 5.1119th in six others. In subjects following convulsive therapy the (feet of atropine inblockingtheappeamceofelwwaveectbdtywaemported (mm 139 :Iohnsm, and 1956). (In a later study these authors failed replicate this study, suggesting that dosage factors or population changes [Johmcn gel“, “niece may have mntributed to different results 1980]). observations provided the basis for studies with other loom mticmolimrgic canpcunth (Pink, 1968, 1960). The intravenous injection of experimentally potent antidwolimrgic momds as dietlmine. bemctyzine, the piperidylbenzilates JB-Bls, and .— JB—329 (Ditm), Wution. VIN-2299 and pmcyclidine induced The EEG chmgea were alerting, anxiety, trauma. illusions and JB—336 EEG associated with behavioral hallucinaticna in peyduietric subjects . In patients with recent induced conwlsims these «awards resulted in a reduction in 31m useciated with a reversal of euphoria, denial wave and activity cmfmion. .3 “‘11 i a 5161,! . ﬁg?“ �“Rpm, .,,,,..( ,“_.,. ,.. , N" .37.. 7”,. v Atropine was also Md, . ”a“, N mined in y:~.uf..~r\v.“r - o—r- .. n «v low doses, maniac] by todnyouwdia, “any "n www-mur - voltage, poor-1y organized delta activity with activity was Mum.” ._..-t m... who .er ixﬂu’Joitor, I)?!” elicited high anplitude rapid 935;, post-tmmtic states 1950; andHiwidx 5.3;. m as (mm 1950). These 3: 2.1.2. m; offoats won block-d by small doses of parenteral atropine . Qutficld Tho - “law‘vpm-x- superimed beta patterns similar to atatm epileptious, as charges similar to those of with .-- slow waves . followed by lower mumatarau (di—isopmpyl flmmphooptute) Hanson .,.,, associated with pmgnssive confusion and disorientation. mo administmtimoof a 191:9; , nervousness and tension. At hyporsynolm £1qu ...,,.,..;. dosynohmnizatim was BEG higher dosages, BBC V and Dupscy (19“!) pmpamd exposed animal cortex prostim and evoked eleotmenoaphalogmphic spike prior aministmtion of otmpinc Hacked this spiking, or present, the abnormality could be olimiratcd In contrast to those findings, Mr activity. by and if atmpim. Darrin (19%), applied topical aoetylobolino in concentrations of 2~ll2 to to the exposed cortex of oats, and notedno effect on the 10% «- �ehatrmnaphlomxic The damages after intravenous atropine (1 mg/kg) . concantmtims of acetylcholim in those encperimants, however, were higher than the and thc topical gpplioatims (1-4 intraeistemal (0.2-10 gm gm pement) percent) injections of Bomstoin (19%) . Bmmmr and Merritt, also made note of electro- enceplnlognphic affects similar to aoetyldxolim from nacholyl (mtylbetmt‘m‘lmoline) much and doryl (carbmldlolim) in concentrations lower than the amtyldtolim concentrations . may ascribed the increased effectiveness of these dnlimrgic drugs to their lack of sensitivity to cambml dzolincsterases . 11qu nativity Mamie The“. W and war. 0‘ man, mama induced by autgzehaune 46 can be. backed out maﬁa, mama“, of mtyloholim antebellum indicates that an oak“ as Wed a imctiw bound by anti.- etc. (a) Cambrmghnl Fluid Anglcholine and tissue in that!» topical application, M lintuéowm. with chum-Amt activity 49M studio» tuggeat that it is 34513112.: Ono View fomdv in nervous fem. Wing periods of activity, mtyldxolinc is liberated at the cell membrane, where it is �.v. .mTr,--m.,—,w..‘_-w.. ”“51“,”, wwryw , . "a". 7.,“ -\‘-yuv;-vv—n—-,17'zr'~.m"--r mm.-- .ﬂ‘vv—‘r- - MW‘VW'v'bn-‘Imwx‘y ,. ..,,..‘v-_.v..—-u.-~, ,- -10.. rapidly deactivated by molmesteme. acetylcholim is the remnant of oontinm lihemtion and brim. rises dining sleep was amputee! and mmt The and It processes of synthsis, has been postulated that the level falls during activity. This hypothesis in miml experiments Elliott, Sunk of bomd by Richter and Crosslmd (19%) and Hmdemm (1950). By using liquid air quickffnezing methods, Richter and Grassland observed the level of aoetyldmolim during metathesis and sleep (unsound as W per levels. mg. The basin tissue) to be 300$ micro— higher thm post-seizure difference in tissue levels is tmsiont. however, as the msynthssis nuts for aoetyldaoline in net brain is high (7 gum/Walnuts). Elliott 939;, (1950) confirmed these observetims. After utmsole convulsions they also noted that free aoetyldaolim in concentrations m always demnstmble in the spinal fluid up to 3 gm per cent. In spine]. fluid studies in mm, Cme, Tower and (19%) and Tower and HcEsctnm (19am) reported Wm simificant �quantities of free eoetyldwline in patients with epilepsy. or 56 epileptic patients, an (77%) in quantities of 0.02 to 5.0 gm per cent. The gm mmted free acetyldxolixu per cent with at average of 1.0 eeetyldroline level was related to the frequency of seizures, the extent of electroenceplulogephic ehmlity,endtothetiusinoethelutseizm. Itboreno relation to mdioetian, type of epilepsy or level of dmlimstemse activity. Mather tr: ecetylcholine appearing in the spinal ﬂuid is e by~prudmt of the oonvuleim or Mather the increase in acetyl- cholim is e eeuee of the seizure is pmblemeticel. HeEeehem (19%») suggested Tower and that increased acetyleholine liberation ismtdutotheseizureitselfbuttothepmoese causingthe eeimre. In e study of the hypatrueis that the mmlation of mtyldtolim is causal for seizures. in urinals by mmzole m (1953) induced convulsion and determined the level of acetylcholine in brain tissue before and during convulsions. cmwleime are preceded by She noted that a rise in the acetylcholine content of �M- iv“... “.0". ,_ v Hr. “7 a.“ rm . . ~.— ,VT .m", ...,. ‘mr—v-,~7..‘..v.».. . , ..,_ 1mm- ’77.. ., w.‘ .5, 1. .w, 'TVV'WHP-‘ ‘(n'ry Humannnruu .. . ww'" v-vm ‘r‘ ~ , 1-v.‘.r—~-.- r---v um”... mam-awn” -12- tissuc, abut the content fills during the convulsion, below and that curtain Invals of acetylcholinn,‘eonvulsions failed to occur. She sugspstod that the fall in tissun aeotyldholine during a canvulsion was due to inhibition of acutylcholine oonc¥ntration incroaéed synthnsia by the of mutaholitns/ such as ammonium ions. Seizunzb nan aceompanizd by an lacke¢4¢ {act aettytchclluc libeaatld {Ann (:3 in inteacnllutan bound £03m, Amucmybeumuedinmwud (Md; and’liit this Mammal nativity and Atizultb cnhanct acatyteholluc debthuction, lawtning 125£u¢ (cvelt as aettytchalilc; ukilc Attcp W and ancsthetla acaywwm wanton Alumnus tune. mm . (d) Cuntral Nervous SystaEKCholinestcnanas: Oanoamitant with their~obaervarions of changpa in aestylcholine, waor and HhEaahorn (19kg) neasunod Tho spinal fluid cholinnstcraso activity. types of cholinnatexuscs are normally found in the spinal ,, -~a 1 Wm "F-Ir «rm-“r Tau—w �fluid: cholimter-ase-I which has a high Wm," ”specific,” or mdnlyl-hydrolyzing) , specificity for acetyldzolme; and cholinesteme-II ”punch," "um-specific," or bemoyldiolim—hydmlyzing). Bath mama-uh hydrolyze wetylclnlim but have different rates of » hymolysil form‘mdiolyl and hmmyldxolim . This differential rate permits qualitative distimticns . By reporting the cholinestemse activity In a ratio of the activity with a maholyl substrate with two on Walnut» substrate mated and to substrate of wetylcholim, ratios are found: dwlimstemso~1Iacetylcrwlim and oralinesteme-II/metyldaolim (with WM'IOO) . In Inch ratios noml cambmepinel fluid contains estemes in the ratio 33:17 of for dwlimtemee-I to eholimtemedl . In patients with head tram Tower md Wan reported an inversion of the cholimstemee, with an increase in the dxolimstemeI fraction of the spinal fluid and a decrease in cholinesteme-IL. (ctivity. me extent of the duelinestemee reversal was related ��u. wc- 15": w“: w—qggywww—mqw 'vwﬂvw‘r' w'w. ;~m«w usedatcd with the plum“) . we “c- ,‘ rm-“ ,n, mvmr "W_.,“-..‘w .ﬂ. appear-am: of variws isms (as potassium and in the spinal ﬂuid follwing electrically comm. than was electrolytes u cellular an. ._- ~———~> also a significant increase in such nan- music-acid splitting mama . Minty may aluminum-41 in md madam ‘13:. with the and the induced mixtures or hand km may be in cholimstem activity should of true mtyldxoline. be associated The persistence L a“? M man md after commas: relationships 1945; Tamar and Wm, mummtiom, microseconds) but Men (Nadmnsm and ”MA n5 and laser matmﬁms, contmt, the dzolimstemo-II— 5e 5 5744 (K biz k 4% 4: Mute-h, hydrolysis of mtyleholim at higher the activity falls off quidtly. In 19169; . é'dééﬂloéj“(.1 related to the sensitivity of me mtylahomu-v 1955) . At ”physiologic" (3—43 (Tamr- 54’2“” [w mid damnation Murmurs, is rapid than muse). dmlimstcmsed system to and in incmmd concentrations of mtyldaolim in spinal fluid after hand mum‘s Oranges thus provide the basis for th- high cone-stations of matyldxolim of inctuoed �. “N-r —~ n. 7., VFW..-” W _ a. .. vw—w-‘w— 7..- .—-..~,-— :7 tm'w“‘n‘.mm"\ "Va-"er-rwswrwnh‘ Inwr'n'ra'" ., "mu-wmu» m y'WWW—m. w~~vw-'VI"-’wr11‘xn—n‘ ~ .x v . .. ”rip-“73“‘miwl‘wuw1vv'1‘y; NV”; —,—-.-r~.. .nr w "WWW,— «.v “ «mu—v..."- ‘ . .15acctybholino rulaticnship is non-specific and the rate of hydrolysis inexact-a with cone-ntratian. Mi 1‘“ ; Aum£-‘£o’%}4i 4;; ‘T f? dnatrcyud by tho spocific activity of cholinnsteraseol in faw lasso-.aondn, an excessive concentration fallowing excitation may canned tho by cholinesterase-I. The L¢¢1¢4 A¢M4 ‘ acixurn thrushold nay be reached and a noifnnu indueen, with thc stizumi f i rats of hydrolysis Thu itself adding to the amount of free acetyldholine. innrnanod acutylcholins diffnoos rapidly, affecting vascular i and cnllulnr poxlnability and increasing the concentrations of various ions and cholinnstnrusc~11 in CSP. The activity of dholinnstoraao-II, though of law efficiency and depending th- mmmm kinetics, Mass on the mtylcholim in the tissuns in hours to days to lavels for tho physiologic action of cholinnatonuae.1. 422;“ 42351“ �‘vr , wwvw—M. . ‘ «ruuuv <t—V'1vwv “—w—ww wwwmwrwwnw. raw—em: un.mnv:.-.Wm "WW—.1» yrmlmx-N ltd-www'ﬁa'wmw'guw‘I‘v ~ 1.. —_ '~V"(—m'v M.Wr>‘\'m‘ .17- Choumtmu «ppm in nu mind We! as a acumen 05 their. 41mm: in Lu ceu. The mm: gammy ma m swam 6;;th (e) 5mm», muting 5m mentioned by changes 1,2:qu Midtown. momma; m pout of the eybmetéc mechanum awn-(muting the 604 Ante/Lem Me 05 «mama»: at was mainland: mu‘uy WW9. Mainline EEG! and Induced Ccmvulsiam: . Almmtion in the blood~brain pemability barrier by the cmtiming team of amtyldaolim may be the biodwmical substrate for the post-ehetmshod: hypcmyndmmy of the alectxmnmphalogrmn. Such a possibility is avid-at in the report by Aird «mutating an increase W 23; 3141955) in‘the concentration of cocaine in brain . tissues thme days after a series of 12 induced omvulsiom. His data Show the change in mnemtmtion of this large animals, ominarily abaerrgu: inbrain tissue to be mociated with the appeamnoa of hypnrsyndzmy (delta bursts) in the electm~ W. , �. inn-ha -'!SA‘-’-"—'r-.“ viva... ..».-~=v—-nn , wan-.wp» ‘ wn “-1....er ﬂ.” .7,» :w .r x» In studies of induced convuleime, many ﬂaw-u. we WW“ -; ‘v w "M”,Vrmm “ w... -wA.we--wﬁm~mvav" . _ ‘1 dump-.— have confirmed the pmvioue reports that convulsive therapy induces electmgraphic hypersyndxmny (Fiﬁ: and Kahn, 1956) . Despite a constant applica- tion of mutants, the time of appeamsoe, the dlmatim and the extent of the electromphic slow sensitivity to modificatim by wave activity as well as its alerting, hypemntilatim barbiturates vary greatly in paydxiatrk: populations . appear-awe of high degree hypereyndumy and Too and early its persistence through- out the txeatmnt name has been described as prerequisite to iapmvemnt following electmehodc (Fink md Kahn, 1956). The failm of certain patients to develop hypemyndmmny may be related to differences in the activity of central aeetylcholine and dwlineetemeee. with the absence of free acetyld'xolim beingmlatedtoninimalehangesincembmlfmctimmdﬂnm precluding a clinical response to induced convuleime. Tower and HeEaehem (mum, in their study of Madembml trmma, included observations of six peydmiatric patients mdergoing mleive therapy. Studying the patients after 3—7 treatments "- mpg-w“... �.ww pwzwrn . 7 .19... thay reported free two 41lede patients; and an 1mm activity in the spinal fluid in in duelimstemae-II md a dome in dummtomee-I with a mammal of the ratio of dwolixnstemes in five of thn six patients. ms that the spinal fluid like those of From mica-tubal these observations they concluded in induced convulsions m Ragar'dim the mo patient were mom than those found in epilepsy. in the series who failed to show cithcr me mtylaholim or a cholimstomc ratio reversal in the spinal fluid, thcy wmte: "It is interesting that this paticnt an the only can of the six to show no msponse It a pawn that induce! mama» £6 mmuu i/ t:”PM/1AA ﬂy ff-WLL AW by 1.6 3 0‘ JA mm, sums. Law 96 me EEG Fm «commune hypwyueMony mama“ and 1.6 mm on: mm ascenumcngm. uuuueehuguzazmouummm- AMM‘W was that plowidc ﬂu. biochemical. 60.be (on the pmaaut V WW) mamnt." mm mm pmabuuy m Mug the. mam a; mumamu. W W Wilma mm “#19” ( in Wt to bchaviom changes {allowing inland canmuiau. w;- �(f) Choline-tomes moss studies may and th- Classification of chosos: also have spplicatim to the problem of catatonic reactivity and the clmificntim of the psychoses . Mkonstoinsndotlwrs( )havsdsmxstmtedamlatiom ug ship botwun tin blood possum response to injectedﬂm) (dd‘é’ﬂﬂ and the clinical mpomo of psychiatric patients to convulsive W. lbchclyl is a potent molimrgic agont which induces vasoﬁmion, tachycardia, mating, It is and harassed peristalsis. mpidly hydrolyud by mournstoms-I and slowly by clmlinutcmc-II . M, injoctod m m blood pmssum of subjects falls aftor udulyl and 2‘th to the five to m bssclinc than 20 minutes. Patients Mobloodpmsmmtxmtothbaulimwiﬂﬁnsmutos are classificd as Groups blood possum takos 2O I, II, or III auctions; arm aszprIdeIImctims. imprcvomnt mactors a minutes to mum to baseline, mexoupIrssctorshawa9% rats with conwlsivs therapy, 35% those whose and the Group II—III memory mtc. In contrast, the Group VI �_.__.. ”(ya-v —— . h\'~rvhl."ll'F reactoreheveasstm'themupvnasﬂ recoveryme (human-1n 35;. Patients in an patiente in 1952). “main Groups I to III may be looked upon whm the injected maholyl is rapidly hydrolyzed; VI and VII patients heve the a slow hydrolysis rate. 41121311. 65‘ Weny predict, themfoze, that an blood ahalimateme activity levels of I-III would be high; while the activity of WV” y ’ ,-. u... V,._V.......,m--.-n—nw ’0 ﬂy” 6/” W W hypersynchxuny and spinal In studies of EEG fluid levels of acetylcholim. ahengee {uncaring induced omvuleicne subjects were identified in when e few seixme resulted in e greet of elm wave activity; mile other subjects exhibited mat few changes to my and to frequent seizures (Pink and Kuhn, 1956). If electmgrephic hyper-gum in e reflection of incremd (Conversely, in patients with short-lived hypereyndxrmy, dwiineetense-I be unusually and high). -II in tissue Thue and spinal ﬂuid these epeauletime provide may �-22a basis fcr a congruent hypothesis regarding central nervous system reactivity to clactroshock, and to peripheral éholinergic CONCLUSION: Ccntral dholincrzic nadhanismsqmpoar to be a significant flycﬂu«’g factor in the convulsive therapy process. ”Inc published data {unrinriznlmymnandhto indialté;that induced convulsions are associated with an incruasa in intarcallular acetylcholinn tn 4L¢¢4Eygd4£5414¢¢¢délAbiﬂ— lnvels greater than can be dustxoyed by choiéanoturuneéE— nativity. Vascdilatian follouod and and innnuasud callular'permnabilitylin«a4wc. 71L‘5@ﬁ¢.4;«xu> g aibcgérﬁyxapglugu‘542;;wmatvi byﬂincrnascd amounts of~ehoiinnaﬂcuuao~¥l~ other'enzymas clactrolytas in inturunllular fluids. ��n, w~. «v— ‘w—rr‘Y .r uy-nmvv—mwum-mn "vv'. rwzm—r w—uw-v-mw-wztwvm... a ~II'-v-'<w-:'W.\1v;w'rku'svmv‘mv'nvﬂwv wwww CEDLIWC WV}: mm. MD mum Max w;— .n»;_...v W... "on." ,vurw»; M Pink, H.D. W at th- Pﬂnmi Initiate of -Pmthanapmntof Psychiatry, admity of Miami School of Midas, 5800 Annual St. Louis, Missouri. 63139. attest, W, W mm. Wmismofthnwm"hinhnatimm York. Hillside Hospital in Ethnic!” at mm in part, 2:57 aunts iii-00927, iii-2715, W72“, md $11380; and the Paydaiatric- Renard! Fantastic: 0! New - - w—n mu, mung—.w an �CHOLINEMIC W, AND V: CONVUISIVE BHWIIOR 11W, StudiuofinMdmwldmhnwmmmuﬂy dwalopnntmdpmittmofsiguofutomdmwmmm mpnmquiaitetoahmguinbahavinr (Maximum, 1956). Wesleyanwmivitymfommm: aimificmtinduxoflltondbxuinfmctim,andﬂndemmticn that Mention activity (015th album-sic and Jdmm, W. mtylcmum and with atropine inhihimd tho 196’) this slow wave muted a minim to In the following review the dwlimmruas in mole of Waive ﬁnnpy is discussed. Mutyldnlimmwcmivelystudiedummive amtintrnmmuimofmmusimluusimsmﬂm It is a dcnmiptions of Dale (191k) and Load. (1921). mtitxmrtofmtium,uistinginaboundfommida illibnmtcdmmwiutimmm. )J and is action of culimmme specific hydrolyud m Itiarupidly W rapidly matitutcd by the cholimmtylau cystem (Richter 8 sum-55 �wan-r”... Grassland, 19%). In actual autumnal fluid has mtylclnlim Emmanpitemupidmmofmmmm (Town-mm, Magmaoaofactivitymdcmitmt 19%;). The activity. ”Mimi mm, fluid does but Inﬁnmoffm 19%). matylahonm md undnr the conditions than cholimatcraso principally of tho “tan” or medulla wdmlyzing typemmsmwibﬁmbcrg. fail to gamble Whoa, cleatrunmpimhgrm Witty. (a) Effcct of m Mint}: W hm: hm acetylctnlim mun-951151 ﬂuidwiﬁﬁnafwninuua after demmmtsmdpmiuedforvmina periods 2.» m as hours (Win, 1”). The qumtity of fun gm mtmmumdmthdumeofimmtrm. mtylcholim vanhd between 2.? did 9.0 The W accord. chcmewaphalogzu um first filled with percent. and th- mutated patterned W. high voltage fast activity, intorpmtad as alderman of an intern. mm). diam, only tobfoﬂmdbyadmtpexiodofﬂmingofmmcomod ﬂuv - v > .. �-- .vwru V.—.Ym'> electrical activity. Thou phuu wen then followed - 'u-uwuﬂxm n. ww- by pmlmgod mamamummmmmmmmms. mwmsmnmwmthtothedameof mmmmmtafmmdhumtyldnﬂm. highs:- levuln of mtyldnlim. Romania 911‘th "Modulator dew ofmcmntymdmmrctmpsinmcimu. In addiﬂm, apcntmn post-We aim wan also muted totbmmtoffmmtylebomnapparingintmspiml fluid. Wain also :13le acntyldxolim to expound out 03:11me W. Mthommmimofmtyldmlimmlgm pamtorhu,hnpwtodhighm11tudoshupwmoflm fmmncyinthocloctmmmplulogﬁm. mmmnoentmtim mimmdtoZmpcmt,ﬂnchctm-naplulogm Whafuhionpqﬂhlmﬂnpon—tmicm. Parallel studios m wr carried out in analogical patients byrmmunsmnumw. Pmautyldnnmmfmxdin - r-w» ' 'c . ' -' ' �- the Main]. mount grand-ml mtyldwlim 7...» 7w wn>wwv 'v'vcv’ ku- w. VII-"I'M‘WW ﬂuiﬂ mly in patients withncmt head 1""!t-W'J" \‘vv- "ram-V" tram 301nm or afar convulsive trnmpy. Fun vadedmeﬁtolOOgmpcmt. Tomrmd Wm also assayed spinal fluid cholimstcme activity, noting a map rise in the mpocific cholimtcme factim (WW-cpnttim) and a drop in the specific mailman” fmtim (metnlyl-splitting) in paticnts with had mm and following minim W. Followhu sputum calm the cornucopia-l fluid did not exhibit such it comma {no mtyldmlixn. inwaim, Thay cmcluded 11W that the lavel of {no mtylcmnm varied d1mct1y with the dame of comm}. Manama: mnnlofﬂnedlolimctem fmﬂmmam with» indicator of Gambia]. m. madam, talcmatvuyingintorvalsfonowingmm, mimic-med: mhtionbctmcntkmdcmeofﬁmmntymdtheappem of In: mtylcholim Thu. due in the annbmspinal fluid. want 0‘ We autylchounc my (me. in the ‘mmgoummwwmmmmmog ' 'v "F “'4‘“ �, 'V'lvw—‘U‘ w‘ war.- —',~3 nan—- u ,w--y_.n..-. u. ‘ ., .- ww,———w~.wm_w—w-q ‘1‘ wwm “- v-~.-W . a..“.~,~.-u . q. . WW -..' .m “Fwy-Fumwyv,‘ “15;.” .w, , .7 “mm .-.» 7w.v--m»w~uu-——. .3... 51m. “Wotan, abunuty, MW. (2)) «the «glue and type mmmmgupuc a; mmummmmamumw m, WWMO m and m: The EEG aim ofmmnmmodadhyﬂu behaviomlmdmmlogic (Bnmstein, pun-nun). examination of 0.5-1.0 ug/kg atropine mmmmcunimmmmmmmmum addition of mmmu. Ward (1950) applied mmmdmmmm. We m, Wand of varying ho m'obumum In20patiantswith ntmpim 3W1)? hduudOJq/kynothmdhﬁmliqmtinmmda mutual of the 013:!ch effects in om. In a smdw.muﬁamwm¢Jmm Loam (1955) meoph-‘logrn. m1 W am A single 5.an WW in the pit-atrmmatic ghetto— dose in forty patients with resulted in normalizing in twenty- ), was” w, �two and marked Wm: In subjects in 35.): mm. £011ng conwlsive therapy the affect of atropine inbloddmmappemotslmwmuﬁdtymmmd (um and Jdmsm, 1956). (In a Later smdy these mﬁm failed maplicmﬁxiastudy,suggastinsmatdouge facumuw popnlldmdwgauyhmmtdhumdtodiffemntmulta [Jemima $5, 1960]). Moumatimpmvidedtmmformwithm hum “idioms: Wad: (Pink, 1958, 1960). me hummus injection of Wm, and Wm “WW. durum, may, We mamas mum-yum. thn piperldylbmzilnm JB-318, (Dim), JB—329 pan-m: mticholinergic VIN-2299 and an JB-336 3% 1mm mendim MMWmm ammﬂﬁabduvioml truism, illusion whim. and mlminttims in In patients with mount induaad mnvulsium Mqultodinamdueﬁminslwm activity Wuiﬂzamdofmplmia,dmidmdommsim. ��-. _«.w...-.——~.m. w, .u . . r” v ﬂaw-v v "'wA“"‘f'N‘" . wrv-r-P electmncepiulogmphic The concentrations of were higher than Win W arbor _.. w-av. rwa-mvnw—wvm- v-.-~ TWZ'Awyvq-u'n‘Vtvmw‘T“ "Ann—w- 1::th th- topiml appliantims (1-4 (19%). atmpim (1 Myldlolim in these oxpeﬂmts, imiatnml and the , (—7.“ ~;—v—u~.~~.—.u—pv.—.—~nn:,+-ra.-w—u w... (0.2-3.0 gm pennant) gm '-‘a nag/kg) . however, parent) injectim of Exam md thud“, also made note of chat-.m- axmptulngmphic effects similar to amtyldwlim ﬁrm mcholyl mtmtiom (WWW) (mtylhetmﬂxxlmonne) ascribed mmh Mrthm tho amtyldnomn M Wm. in and duty). Wimqffmimwmwmmcmmm lack of mitivity to rumba]. duality-sums . ThuewmmmmmsuggutmuumWWWWWbyMWu/tmua man 9‘ aqua, tam Won, imam on. with WW¢Mmbebum¢ueummdbgma~ WWHMAn-gmnmmdmw «new (c) a mm, mm. etc. Onoviw «mlmuWMwa-smnnfomdiamm Winnimatiwbmfom. Wyﬁnchofactivity, WWhnmmdatthno-ummm.m1tia r umnnmv~wv yr.- -~ �“Hwy-v .7 m. » ._v .W”...w.— —...‘..r,.u...,...._...,-, Hm..."- va,unlum‘w‘hi‘wv'mvmwv;'QX.‘""“ W ~n-- v “w a”... ‘ ,7 ,v W---w mw_.-r—... Wt “‘1': run”... -- - ww» v" ‘7. "‘ ww.-,-_p.w.~.wmw. midlyduwtimdbydwlknmo. mamtofbomd mm is the resultant of continuum 1122mm lad mm. promotes of synthuis, It has bun pastuhtad that the rdmduuingslmmfnummuctivity. level Thishypaﬂmil mwmmwwmrmmammum) mm,mmmm(1asm. Byusing liquidair qumumm.mmmmmmmmm ofamtyldwlimdndngmﬂmiamdalup<mamdumim www.mmm)mhaocthigturthmpoum hurls. nudiffminmmmlaiatmsimt,hmm, uthnmthaismforamtyldacliminmbminism (7 gums/gallium). Elliott 539;, (1950) mnfimd than obsorvntima. Afﬁrm}. mum-ism Malacnated that {no mtyldxolim am always «washable in the spinal fluid mmwmagmparmnt. Insphulﬂuidstuﬁuinm,ﬂam,lbwnrmdmm (use) md fear and Wm (19m) “perm dwicam: ��m.uﬁumtfansmgﬁumnmdm,mdm balmeevuin lawn of mm, convulsions failed to om. Stunumudﬁntﬁnfanintium Winona: Wamwhimmdummiﬂmofmtﬂdmnm m‘md mm byst- anemia“. We! sud: mtabolim, Bummwwnmeumm mmmmwwwmmwm Wmuumam¢mm MW mmm;mmmuuyzmuummmn,zmmg rmumumzmum W MW WW madam» (d) §xg~ an MAMMWthuLa W (new: tutu. Lena. Cmocnitam: wimﬂnirohamtiam ofchmm inuntyldaolim, Wm (1939) Tutor-mt! name! spinal fluid dolimtcrm activity. Mtymofdnumemmmmnyfminﬁmspiml �» ‘am-V ”II-"Iv ."V'a. ~,.1- . u -;— V’V~-¥'U'~‘v‘<~u Tam—xv... mw—uL-ww-"wv Wanna-I ﬂuid: mich .V m ("pocudoﬁ W as nu-mq-wnwh-..“ .,.,ﬂ_. .. Um," sﬁociﬂcity for him "rm-amiﬂc,” ow two .,. ,... .. n. ..~-. - . ..- ’r .,.,_H. .\..v7,..,,..~—V.TM ,wv, .,.,.< V . a a ‘ , , v.“ .w: _v_ ”specific," or manlyl—hydmlyzing) , Micheline; and “museum-II WWHMWIM) . Both for udzolyl and bemoylduolim. This diffomtial me panda qualitatiw dintimtims . with 3 ”a.“ hydmlyu amtylcmmn but have diffmnt arm: of mm activity ,. By I: a ratio of the activity with MW!» ratios an found: sub-mu mind mpovting the dwlimstumsc a maholyl substrate and to mm of amtylcholim, mumm—I/amtyldxolim and Wm-II/mtylcmnm (with Adi/@8100). In much nudes 'mlm‘bmupimlﬂuidmuimuminttumioofﬂzu for Grantham-J to aluminum-II . mpnﬁmwimmmmmﬂcﬁadmmdm invasion of th- daolimumu, with an We in the cholimammac-II fmtim of tho spiral fluid and a dam in circumstance-I. iathity. m mam: of the WW maul was related �we: --r"vr— mr ww- ~r-r—vrm...‘ v .—-1«w‘ms¢—ae.—r ”"7.“ mgr-nus, r, mm, a." 'W nve- “w, -~. w n r...“ mwv “van" e w.— ‘1‘“ m‘r‘nvwvﬂﬁ‘l'v—vV-v ”Wuwx—m‘me - vuvax wmmrityofmmmdmmawofﬁuem- WWOWW. Inpatim with eleveudspimlﬂuid acetyldxolim other WW,Wr,mminmmioof dulimetemesortommlimtem wdvitymfomd. ‘meimmindxsmnetemeactivitymbemdentood mnmmmmmnmpemmmty. mW-Ihfmmhimmtmﬁminﬁn mud nervous system while duelineweme-II pram inwartiam,upooianyb1mdsem. Hiﬂamimas fin atyldnnne m1: in intemelluler mum fluia stimledm, communion: or hm, modiletim oellulmpemeabilitymybepmdiotod, Wﬁm and We! withedewof of wonder flunk into the inter-0011M spaces vuyingwdmthemmddm'etimofthevasodimion g g, 19:0). Spiml pun-Ability following W 1953). may cheer-val no Spinal-Molt in mm (Rabat m mm reports (19%, 19%. 19W, 19%. memo mndactivity of the tissm , ~~y-..‘.--~_~~.m-mm-v, �av“ y."— ww_"v-w.w . w «mum...»- a. 4 W cm van—n: . Wwmwum u wI-ww—t'h wmw—wmew-mw ..-,m.— w --u-- mumps—m mum-PV- Hw'ms a: w :w-n r- "rm usociatadwithﬂaappemofvuiwsm (apotmiummd W) in the spiral fluid follwing chemically inducad mm. Mmdmasimiﬁmthmminsmhm- electrolytes as madam-acid splitting cums. Chang-s in alluhrWilitywthmpmviwﬁabasisformhm demmmmmmmm ofdnumumeIinirmmdmoermmﬂw MWIMQGJ. mmmmmwuwmammm with the mid «instruction of hue mtyldxolim. me punctuation rammummspimnudmwmmm aims any be minted to the dxolixastuaso-J syntax m and Wm, 19%; mitivity of the mtyldzolinc- Widen mummy (um Tm adﬁcﬁadam, 19%; Burger: and martian, is rapid (3-H mama) but at high» and lunar 1955) . At ”physiologic” helm-h, hyckolyais of amtyldxonm the activity falls off quidcly. In contrast, the mm, chainsaw-II- �«.18.. “mum nhtimMpismn—spociﬁcmdﬁumof mmmwiﬁzmmim. mmammmsummmmm WWWOfac-tyldmmnnmnmm We hy the spadfin activity of him, an massiv- WW4 mﬁm in few billowing excitation mmmmdmmlmwmum-I. The uhmuthruhuldmhomadndnﬂamimindxmd,with mmimuwngmﬂnmtoffnomtyldnﬁm. n» and W murmur: durum 'mpidly, cellular pambﬂity and humming tho vmmmdwlimm-Ilmw. alum-II, W affecting vaswlar mmtim of 'nnactivityof of lowcfﬁcisxwy mt! chpcnding m ﬂammﬂgmkhnua.mmm1mmm dominhammdlyatohwhforﬁnphysiohgmmﬁm of <21»me . �“.1. -. _. n "w' .~. -»~ uv- r—r-wu. szﬂ‘”R—vu'w.vw w-W-wt mm- W-w—mwwswwmwwrrwmxmm’mv-mwmmun-m zmwm-Wm “W A. A. V. AW mmmuWuM¢mmuaumm _\_A_._V_-__‘__.__~V.A,__ ‘-_,__,A__________ 05mmc&W.W, Wad “WWWW m put“ ma Wm“ waning smut-Maya by The {named the waywam. Wade. madam-u ammmoguagmumauumw WW ‘MMWMAmMWW. (a) mymm. HE‘S MWintbblmd—bnin mm permeability and Induced 000mm: bmiwbytheconﬁmm actimofmtymnmmybaﬁlebiodmimmtmfwﬁn chphuogm. _m.mmwuommmmmbymgggy(ms} pout-electroshod: hypemymsm of 13m Wmmmmmumormmmm tummaysamrambfnmdmmm. mmmmmmimufthismmhm, ordinarilyabsmtinbnintissmtobemociamdwimm W orhyponyndm (delta bursts) in W. the electro- at: . �- Inmofﬁmmhm,whmcmﬁmdﬂn mpmimnpmﬂthﬂmwhiwwmchcmmuc Imp-W (Maxim, 1956). myimamtmt applica- www.mmaw,mmmm Wtdﬂunhmmdcslmmaadvityuwnuim sensitivity to mdiﬂwtim by muting. tamer-ventilation whim‘ vary my in manta: Wow. The and only memwmmmiupu‘ismmghmumthmmasMupmmmium W 1‘0le «loam-rm (Fink mm, 1955). m «land in diam {dimofamainptdmtodnvolaphymymhmxymybo Nahum. 1n th- activity of annual mtyldxonm withﬁnmoffmemtyldmlim mmmmeWMmmm mamammmemnmmmm. W (19‘8“), inmiz‘ttudyofcz‘iimbml Tmrmd trauma. imlududobumtimofdxpsyctﬂatricpaﬁm underpins mad“ W. Ming the patimts afar 3~7 mam-ms u I'vv: WW7 ~,-- a'ﬁr‘f �mwmmtymummutymmspmunudm mmmsmdmimmmmm-Hmdams in “11:33th with a mammal of the ratio of WW3 infiveofﬂnuixpatm. mmmWaﬂamﬂnyomclmed wmspimlﬂuiddminhumdmhimsmm mmwmmnbmmmmrmmcmy. wmmpatimtinmududnfdhdmm dmmmldnnmwacholimummmmalin thespimlfluid,ﬁuymz“1tisinmtingﬁutﬂﬁa WmmmlymnofﬂuaixtoﬂIwmmpm-emtm." Itammwzmwmuuuzm¢m mamgm,mmmm mmmWoammu. 1%...qu umbyupuudAumu. EEGhyme/uom umo‘mmwumgzmmmmmwxy at Mumwuqm. Radian muammmmmWMWWWWM‘MMMAM 6:!wa Mu 60W Mad «WM. ��-21- WanamaeﬂmtthmaSﬂmmrym 1952). 93a]. (Wain Patimtsinhmuinmltonlmybclmdupm when the in is injected rapidly hydmlyxed; putientl mdmlyl u uhiln ﬁn Groups VI and VII pctimts but a slow hydrolysis rate. V. my pndiat, theni‘on, that tha bleed dulimatem activity huhofWI-lemﬂdbohiﬂu mihﬂnaotivityof WAdlihrunlysiouyboudumaxdingmtnlm VI - VII walla be 1m. mmmhofdwmmm-Iinﬁummtofm Wynclumy and spinal ﬂuid hwls of amtyldnlim. Instadiosofﬁﬁﬂdumgu followingixducudmnvulsim subject-wan idlntifiodinmmafwsoimmultedin a mat mat of now an. activity; while othox- subjacts mind mammmymmMu-Muim (Pinkmdm, 1956). IfWWionntbctimofmd Inbjommuintainhypcnynm in: mm, inwmitdiupp-m them did mpidlynybccadﬁbitingdiffgmnccs in th- kimtim of the dwiimntm-mtylmolim hydrolysis mm. Panhtcnthypcnyndmyuymultfmamd Mcofhydmlysinotmtyldwlim. mociatcdwithlow I mutation of cithcr choline-tumult or mummy-II . (W13, in aheﬁrutcm-I In many paints and «II high). with m—livod hypnmyndmmny. in tissue and spinal fluid any Thus thou mutations provide �. ..‘-.,—r >17 ,...v v“ » , may .1 ~w ~ v....<~u-.~,nz‘y«.r.-~, w‘wrr' ,. ~_»w—-w-y- ash-:1" ~ want »-.1N" vmn www-z-‘w BMW-“‘1‘;- n ~wm~wvv qu-w-m-w- wrumrwS—V-‘a W-xmp‘rvww .22... amumamhmnmmmmm reactivity to W syntax: em, and to poripmm dwlimrgic WON: mmmmmmawmt _1’minﬁn mmiwﬁmupypmu. 1119me whimdmiﬂmomtimdmmmm Wummmmmmnmmmw MhWMmbodntmyodbydmlimmI nativity. Vuodilatimaﬂimuodmllulupmbﬂityis follmdbyimuodmxtsof diam-II, strut-am and electrolytes in int-”114mm ﬂuids. - "r' :1 Wyn-mu wr “unawa- "I“ �mwmminmmdumm mmmnmamswom.mwmm Mmeiduﬁuminbiodmicalnﬂiwwhidz alters cerebral «11.qu activities sufficient to Alter the 1m behavior of subjects. Failure to mountmim electrolyte dim. of acetylebalimi lid W, high md pmismm: {aim to 1m tht results in a failun to produce behavioral ”mummuofdowlmntofmw reflect differences in th- 63ch of subjects «1 dour-remit: admin”, or in their sensitivity to changes in acetylemlinc lawn. tim of M tho diffcmm ﬁnally in W by Mountain These observations provide a the mode the Win for the classificaand by Pink and Kuhn (1960). rational biochemical basis for of action of induced convulsions in altering the behavior of psychotic subjects. These views are consistent with the more general neurophysiologic—adaptive theory expressed earlier (Fink, 1957). �IFn->"'v'—-'—vnu—w— w—r—v-r—u ”ﬁt—W‘- ".9. ‘- -. u » V . WWII-.11“: CI-DUINEIBIC . , nv— rm mw- WIN, WWOR Wmvw—qmvmmpwmw'm x.xm~.;w~ww-ww mum—w". CONWLSIVB AND 13%”, Stalin of cerebral changes accounted with (Pink and Kain, 1956). convulsive trump}! In these studies, electroencephalographic slowing was the most siyzificant index of altered brain function. The dematmticn that premedicetim with prevented the appearmce of slow 1956) suggested a wave high doses of atropine activity (Ulett relatim to ctnlimrgic meﬁiims. and Johnson, The role of acetylcholine and the dmlineatemaes in convulsive therapy is mlified in the following review which summizes the published am. The role of acetylcmline in the tmsmissicn of nervous imulsea has been studied extensively since the first descriptions of Dale (1914) and Loewi (1921). Acetylcholine is a normal which form bamd is in a tissue existing of neurons cmstituent �.,, ~21- ' - "~va ":murmmrnur-v— «m . Ernie-'4 ‘ ,. v “War W'r’W-erd - 4wr‘; Wr' .w-nv 1'5“”uH-I'J. .1m- ,.w;uwv‘.m,w.‘. liberated mixing the excitation process. It is “m ...Y.,_.,. F“. -v-v—.ﬂ, ,. . t .. 7 m" ,..,nvrv.w._,,m_1w V,.w.,‘.,.,.,,v rapidly hydrolyzed thrmgh the specific action of eholinestemee and as rapidly reconstituted by the momﬁiaeetylase system (Richter 19“ 9) . No a Croeslmd, free ac}tylctoline has been reported in normal mmbnospinal fwd despite ﬂu rapid bmakdom of bound acetyl— eholine during perioa of activity and excitement (Tower and McEechem, 19u9e). The oembmpinal fluid normally has measurable cholinesterese activity, however, principally of the "true" or mcholyl hydmlyzing type (Neelmensm and Rothenberg, 19115). In the absence of free acetylcholine and under the conditions described, electroenceprnlogxms fail te show any consistent ehxornality. (a) Effect of Cranioeerebml Them: Free acetyleholine was found in the cambroepinel fluid within a few minutes after experimental head trauma in cats and persisted for varying periods up to #8 hours (Bomstein 19%). The quantity of free aeetylcholine varied between 2.7 and 9.0 gamma related to degree of induced percent, md the ammt was tram. N" ._., , . V.‘ ,.. . �F‘s—“ﬂ 4 w .iv-IJ'n-urr'wlv'i- \I'-w-v|n"r" ».v 21‘.- .IN w— rh- W Th! records were u. . - ~~w~mvww. a?“ : aux-rum W...“ m“- - ‘vv‘ w—a—E.ww~r_~w um... g‘vi- wn-rv-w mun» r: 1- K—‘Irw' «a...» ,. w... w” ‘quw u,- 1,- \w electroencephalogms demonstrated pattern-d changes. first filled with high an voltage fast activity, intense neuronal discharge, only to all short period of flattening of electrical activity. mesa recorded phases were men followed by prolonged periods of high amplitude sharp waves in the delta frequencies. The to the behavioral wt mrﬁzlated 13%:ng of clmges trauma and of seasoned free eoetylcholine. With higher levels of eontyloholine, Bernstein reported greater degrees of abnormality and greater charges in cmscicusmss. spmtanecus . -3- interpreted as evidence of be followed by a -~ post-tmmtic seizms were also EEG In additim. related to the want of free acetylcholine appearing in the spinal fluid. Bernstein $31- applied aoetylcholine to exposed cat cerebral cortex. men the concentration of acetyloholixm was or less, he observed high mlitude sharp the electroencephalogram. When waves 1 gm percent of low frequency in the concentration was increased to �-- <vw'x' >1:- 2 '.‘W',WWV\Wmm/'FP a». an gm . W v- .n ‘n'uv 7 ~m—w-w..». v m... .vvc'wTV-t or v'.‘.wwuwxnn_r'~u—l’v»wy wrv-suw‘ mw~wwn~w~mnpmmm .- »— -nnmmw—rr-muwawu nvre --u w percent, the electmenoephalogm flattened in a fashion parallel to the post-tramtic meant. 11.1% stndies wemWin neurological patients by Tour and Hohdmm (19am). Free aoatyloholine the oumbmspinal fluid only in mam, The 1.: patients was found in with recent head mount grand-ml seizures or after omvulsive therapy. free acetyloholinc varied from 0.2 to Tower and HoEachem of the spinal fluid. 100 gm percent. also assayed the molimsterase activity They noted a sharp rise in the nonspecific cholinesterase fraction (benzoyloholine-splitting) and a drop in the specific cholinesteme fmtim both in patients with head .trmma convulsive therapy. amd 'me oembroSpinal (moholyl—splitting) in those following fluid following spontaneous seizures containing free aoetylcholine did not exhibit such inversion. 3-2:. and-II: concluded that the level of free aoetylcholino varies directly with the dogma of cerebral damage - �that the reversal of the cholinestemse fraction sensitive indicator of cerebral (image. and was a more Electroencephalogrem, taken at varying intervals following mum in most of these subjects, indicated a degree of EEG relation between the abnormality and the appearance of free acetylcholine in the cerebrospinal fluid. ‘hecstmﬁu Watt. an to. mom 0‘ (no. aaetzﬂdwdne m1 incuae in #:24me {Md 4011ng Macadam tum and me a «wad: lactation my mwowa, duomug, (b) «in. degm and dumgo Effect of anathema“ ﬁe and type as in Am mount 05 ﬁne demamcmuagmic dialed bdrawloa. on ﬁb-traunatic EEG and Behavior: Bernstein aministered 0.5-1.0 lag/kg atropine parentually after head tram and denmstmted bloating of the EEG, behavioral and homologies signs of clinical tram. changes occurring Similar EEG and after the experimental addition of intruciaternal aoetylcholine were also blocked by atropine. �w. --r.-~r-v—~--ww- w-Im-vmm 'mm' "-W‘mmv'm" Ward (1980) 'memnmw applied tmse observations to the hum cases of closed dogmas of tram, head injury. In tremnt of patients with varying 20 he aaninistamd atropine subcutmzsly in doses immt in of 0.1 rug/kg. In saw‘oam he noted clinical and others a reversal of the eloctromoephalogmphic effects of the tmma. In a study of .1er and War diethﬁf’ mother mtidmlimrgic drug, (1955) reported sigmificmt alterations in the post-tmmtic elactmmoephalogm. dose in 1&0 patients with in normalizing in The same slow wave 22 A single 1:1th ahmal electroencephalogram subjects land marked «act of atropine in inmt msul’cad in six others. blocking the appearance of activity wm reported in subjects follwing convulsive therapy (Ulett and Johnson, 1956).. (In a later study thé‘authors failed to mplicate this study, suggesting that dosage factors or population mass” may have omtributed to the different results [Jdmm 559;, 19603). M... �8: These obeervatiom provided the basis for a series of studies with other Imam mtidlolinemic ooepomde (Pink, 1958, 1960). The intuvenom injection of experimental patent antidmolinergic «mantis es diethezim. (Dim). Maine, the pipeddylbemiletes, Jana, J8336, and pmoyclidine were shown to induce EEG illusions deeynotmiutim and behavioral alerting, mxiety. J8329 WIN 2299 end md helluoinetiom in nm—ehotmehodc subjects; and e reduction in allow new ectivity associated with e mvemal of the Wm; euphoria, dmiel ma omfmion in these with prior meant induced omvﬂsiom. In these studies, atropine was also emineddn low doses, EEG desynohrmizetion was observed, eoooepmied by considerable peripheral tachycardia, mmaenese and tension. At higher dosages, oonfmion and disorientation min! hypemyndzmm slow a mduction waves and of-hmmiutiea their replacement by lower voltage. poorly organized delta activity with superimposed beta activity. . �~. . a" ~~_,—vn~m«~p.-~W» A q ”We," W. _ ,_. 1..“ ., ,. w." .-—...n-r.. t ,, . u ,t. .( m...w-,V -—..~— _\|=V-\w:w.~a ~FVJH-ﬁ'u—p‘muwt »‘wb‘wﬂ- 7.;r._‘,.,v,wr _ﬁuv;a_n.‘--,,.p‘m .w-wunw... \ .,.—_,.....~ variety of experiments with a potent duolinesteme inhibitor, D}? (di—isopmpyl frequency EEG fluorophosphate) denmstmted high amplitude rapid patterns similar to status epilepticus, as well as lesser degrees of abnormality similar to that noted in post-tnunatic states (Munich 333;, 1950). 1950; Pmdman 3331., 19:49; md Hampson 93.51,. These electroencephalographic doses of effects were blocked pumteml atropine. Chetfield md Dempsey by small (19%) prepared exposed mimal cortex with pmtigmine and evoked electroencephalo- graphic spike activity. 'lha prior blocked this spiking, or ministration of atropine if present, the abnomality could be eliminated by atropine. In contmt to these findings, Brenner md Merritt (19%), applied topical aoatylcholine in cmcmtmtiom of 2-1/2 to to the exposed cortex of cats, and noted no 10% effect after intravenous atropine (1 rig/kg) on the electmmcephelogmphic changes. The montratims of acetylcholine in these experinmts , hmever, was significmtly higher than the topical applicatims (1-4 game percent) new v” rm— ‘7“ .wv-u- �and the intmcisteml (0.2-10 gamma percent) injections of Bernstein (191.6). Bmmer and hmzitt, also made note of electroencephalogmphio effects similar to soatylduoline from macholyl (aoetylbetmthuldsolinefmd Meryl (wbaxyldloline) in oonosntmtims moh lower thm the aoetylcholine cmomtmtims. inmd They ascribed the effectiveness of those oholinergic drug to their lack of sensitivity to oembml dualinsstemses. FM a waist; conduct: that and MAW“ Wencapdz Logaaﬁtic activity Mu a a “nu mu! upwwtaz 06 as deans tome. Manama agent induced by acwjzdwu'm, appuc'mon'og Mam, topical be. backed can it was; a (Lt/topaz, we may on. Magma Wand by humans, as. (c) Carebmsginal Fluid Amylcholine md Seizures: Aostyld'xolino bomd form. is nomally present in mrvous tissues in an inactive wring periods of activity, free acetylcholine is �. ; .m, . .. ..., , m .. .ﬂzwuwﬂurww—w 1.... y ..‘ , v ".4 .4 .. J, vV—I-N‘r W. . . ._... dwlimstorase. The v—- "’W\‘,a(')~\ro" >m»":qnaArv-n3l.!' 'r ~w.'vu.* '4.-:--wr~vr g~u~wr~a~~u~w> www.1-v-u mm it is libemted at the cell madame, by K." w- level of “mum rapidly deactivated bound aoetyloholine is thus the resultant of the prooosses of synthesis, liberation and It breakdom. may be rise during shop and pootulatod, therafom, that the level will fall during activity. lhis hypothesis was support“ in animal emunants and Elliott, by Richter md Cmasland (19%) Swank and Henderson (1950). By using liquid air quick-frosting mthods, Richter and Crosslmd observed the mtl'nsia and sleep gm per levels. mg. The level of aoatylcholim (masumd as brain tissua) to be 300$ higher than poet seizure difference in tissue levels is transient, however, as the “synthesis rate for aootyloholinc in (7 mimo— mulmlﬁnute). Elliott gt 5;, mt brain is high (1950) omfimnd these oheowatims. After- mtmzole oonwlsiom, they also noted that free mtylcholine was always fluid in concentrations up to 3 domtmble in the spinal gm per cent. v -.~~v~ , . .- �- .... nut, v-wwgg—w mauw-Vr‘ u-~0'iv-a—. n... mg. ._, -:Jpag-.'~vw1 4mv..l.‘N'-rv-~Vr‘-\ ﬁrm—um r“ nmww-r w WM- "— w—rw" .“ - -wmv~—-w--m.. -v.‘ F»; "-v-q .~ www-rwt:.v—.m.-v .10In spinal fluid studies in man, Cbne, waer and (lSMB) and waer and McEachern (laugh) reported McEanhern significant quantities of fro. acntyldholine in patients with epilepsy. 0f 56 apilnptic patients, an (77%) dnmnnstrated measurable acetylcholins in quantities of 0.02 to 5.0 «warns» of 1.0 gamma per cunt. The gamma free per cent with an acntylcholine level was directly related to the frequancy of seizures, the extent of olnctronnccphalogruphic abnonunlity, and the relation of the time of sampling to the last seizure. It home no relation to mndicatian, type of epilepsy or level of cholinesteruse activity. Whethcr>tho acutyldholino appearing in the spinal fluid is a byiproduet of the convulsion or whother the increase in acetyldholine is a Wu!!! cause is of the seizure prublamatical. (1939b) suggested Tower and that the increased wetyloholine liberation in not due to the seizura itself but is related to the procnss causing the seizuma. In a study of the hypothesis that �11 the acommlstim of acetylcholine is basic to the seizure process, Tonia (1953) induced convulsions in animals by mtmzolc and dotsmined the level of acatyloholine in brain tissue before and during comulsions. She noted that convulsions are pmcsded a rise in the acetyldmolim contsnt of tissue; Wily falls during the cmvulsion; levels, cmvulsims failed to occur. and an that the content that bolas curtain She suggested in tissue acotylctmline during a omwlsicn by was due that the fall to inhibition of aootyloholins synthesis by increase! concentrations of metabolites such as In. mim Likely ions. #:215de m mmwbg mm {m mam; ohm «:3;qu an wanted (m it inmate in bound tat t3 isms my be inﬂected in sum 5%; ands wanes «wanna: do 5m, and that cumbmt auction, taming and Leap nhuu an to in augment Minoan; tin no. touch as “mum“ pmduoaon imam ing “A as touch . �v......,.,.w.,. ., 7.“..- www. min-w: .~-.Twr-r.~a y: m nvmw-m ...v 'Nwwmu‘agnar' "n T“.1.,1~V;’§mm- ,M m..., . .u..." .“WWFV . m: or..‘m--.w-,.-W,‘_..< WW. m.ﬁwl... .V w‘~...oww»..wm-_v m_w,ﬁ WWW-A“ .12. central nervous slaten Cholineetoraaeez Concomitant with their observations or change: in ooetyioholine, Tower (d) fluid oholinoateraae end noanhern (1949) mnaeured epinel activity. Two types or oholinoetorenoe ere normally found in the epinnl fluid: oholinoetereee—I ('true," "specific,” or neoholyl hydrolysing), whioh has e high specificity for aoetyloholine: til oholineetereee—II ('peeudo.””non~epeoitio,” or bensoylcholineohydrolyging). Both compounds hydrolyze eoetyioholine but have dirforont rate: of hydrolyeie for This meoholyi and tensoyoholine. qualitative dietinotione. activity as a By differential rate permit: reporting the oholinootoraee ratio of the nativity with meohdvl end with bonzoyioholine outstrnten compared to an noetyloholine lubetrete two ratios are round: oholineeteresoai/aoetyicholine and cholineoterooo-II/aootyioholine (with retﬂoa Initials! norMul 08F th/th: 100). In such contains eeteroeeo in the ratio of 53.17 for oholineatoreno-I to oholineotoroee-II. Thus. normal 08? consist: , ,»-.- .- �_.w.W—-« “mu-wow. arr-u- ﬁmwmmm "WW?“ me-‘Ww‘wmvjrimwmmrm )5 s: mainly of "specific" estomes with a small mn~specific ostemse want. In patients with head tram Tower and McEnchem report and inversim of the dualinestsmos with a simificant increase in tbs daolhnsts'mse-II fraction of the spinal ﬂuid dualimstems-I activity. They and a «mass in also observed a relation batman the extant of the momentous” manual with the severity of trans and with the dogma of the olcctmmceprmlompie In patients with 5.an spinal fluid acetyldzoline as a result of spmtmom saizms. howswr. of cholincstsmss or total Why. no change in the ratio duelinsstss-ase activity was found. Certain usunptions my be mad. mgmding changes in cell mm psmability as explaining the humans in duelinsstcmse contamination in found in highest is Gaolinsstcmse-I activity. the antral mm systm mile molinestemse-II in atlas:- tissues, especially blood sewn. pmdminates With an increase in �,7. ,.~.n_..._..‘..,.q—. 7. v . ...,~ “NW... . «g..- Wv-slv'n-nrrh w-rw-muwwwmmmwwvaWmn-mmmmmv‘wvwrvhmv w -w~'r v- acutyloholim levels in interoellular cerebral fluids following stimulation, convulsions or trauma, vaaodilatim md increased cellular pomability may be pmdiotad, with a degree of transudatim of vascular fluids into the inter cellular Spaces dependant on the extent and duration of tha vmodilation (Kabat 33:. 9;, 19%). Spiegal and SpiogebAdolf dummtmted such pamability ohmgas in nmorma "ports 1953). Thay reported inmmd (19141. 19%, 198%, 19148, oomhzctivity of the tissues associated with tho appearance of various ions as potassium and phosphate in the spinal fluid following convulsions. more was also a significant as nucleic-acid nm-clactmlytes cellular pamability mtmims electrically inmoed may imam in such splitting mzyms. Chases in thus provide the basis for the high of acetyldxolino and the managed omoantmtions of dwlinostorasaJIﬂTmr and Hoanhem muse) . '5 �— m‘ w «'7'- M-mrwrvva-mmmw.mw m The increase in ammnstcme activity should be associated with the rapid «stamina of free mtylcholim. Its persistence in spinal fluid afar tram ad 931m related to the sensitivity may be mtmim of the amtyldwlim—dmﬂmstm-I system to ships 5mm (mam md Rathmbarg, and lowar Midtown Mauritius, ad mo mnemtmtims, tha nativity falls off quickly. In contact, of hydrolysis mm minimip «sciatica mm who in few isdestroyedbythe udlliuomds. where bmoentmtim of mtyldwlim in tiasun. tbs mm of hydrolysis by dwlixnstome-I is W. com. m WWW—I to an is nut—specific with concentration. Thus, the mlhwnbfmtyldxonmatmnmbm specific activity of Wm, 19kg; is mpid (3-3 mimeoonds) but at higher th- dnlimanmc—II-m‘tylcholino the m and At "physiologc" and HacIntoah, 1955). hydrolysis of 19445; mktim~ mmmMMMmybemadndmdaseizm me disaoaiatim in ship nouns in a pemiatm amtylmoummﬁneamml relationof mldwline. The seizure may �16 itself in add wt to the of free acetyloholine. 'lhe increased mtylctnlim diffuses rapidly, affecting vascular and cellular permeability and increasing the cmocntmticns of various ions and dmolincstemse—II (SF. activity of cholinsstemsc—II, though of The on the concentration runs to days to efficiency and dependant kinetics, reduces the acetylcholine in the tissues in in! levels mm” 1c»: for the physiologic action of cholinescemse-I. #:1st am Manuela manta 5M, «may 5m «ppm in {Add dowsmaa someway in. «was {on mm 05 ma past a a gestation dzangm “mad Mwouﬂne. Mme. madman; om «toned by (named in 06 «he :1ij (ﬂ 05 in cut 'hc mechanism mun-um at sou moms nausea; system sanctioning. (c) Agglchclinc a EEG WNW and Induced Convulsicns: Altamtion in the blood brain permeability barrier by the continuing action of acotyloholine may be the biochemical substrate for the post- olectmsbock hypemynchrmy of the electroencephalogram. Such a possibility is oviduct in the upon an increase days by Aird 93 9_1_, 1956, W denmstmting in the cmocntmtion of cocaine in brain tissues three afar a series of 12 induood convulsions. His data shows the change in �-17concentration of this large molecule, ordinarily absent in brein tissue to be seeocieted with the eppearence of hypereynchrony (delts'burets) in the electroencephalogren. In studies of induced convulsions. we have confirmed the neny previous reports that convulsive therapy induces electrcgrephic hypersynchrony (Pink and a constant Kuhn, 1956). Despite time the or however, or treetncnts. epplicetion slow the and of extent electrosrsphic duration eppearence. wave activity; its sensitivity to modification by alerting, hyperventilation and barbiturates psychiatric populations. degree hypersynchrcny. end The - s11 vary greatly in early appearsnce of high its persistence throughout the treatment course, hes been described as prerequisite to improvement following electroshock (Pink and Kuhn, 1956). The failure of certain patients to develcp hypersynchrony may be relatedto differences in activity of central seetylehcline and cholineeteraees. may reflect The degree of hypereynchrcny the level of tree ecetylchcline and should follow s decay rate eqael to the rate of ccetylcholine destruction. �vuzvnc—v-w: —. Since previous studies demonstrated thnt ens prerequisite to the it may be EEG hypersynchrony clinical response in convulsive therapy, suggested that the absence of free soetylcholine suggests minimal changes in cerebral function and thus precludes s clinicsl response to induced convulsions.Touer snd their study of creniocerebrsl trauma, hoEedhern (1949s), in included observstions of six psychistric pstients undergoing convulsive therspy. Studying the pstients after 3.7 trestu meats. they reported free soetylcholine activity in the spinal fluid in ten pstients; and en increase in cholinestersse-II and a decrease in cholinestersse~l with a reversal of the ratio or cholinestersses in five of the six patients. From these observations they concluded that the spinsl fluid changes in induced convulsions were more like those of creniooerebral trsume than those found Regsrding the one show in. ilepsyu pstient in the series who thiled to either free ocetylcholine or e cholinesterese ratio reverssl in the spinal fluid, they wrote: that this patient was the only one "It is interesting of the six to show no _.,. �7‘ response to treatment." It is I probably that induced convulsions increase free acetylcholine and enhancing cerebral perniability altering fluids. in intereellular the appearance of cholinesterases. Free acetylcholine by JMAco repeated seizures. EEG hypersynchrony is one is maintained reflection of altered of other electrolytes. and altered permiebility of acetylcholine levels It is these changes in intercellulor electrolytes that provide behavioral changes the for substrate biochemical persistent the following induced convulsions. L/ (f) Cholineatersaes and the Classification of Pezchoses: These studies may also have autonomic reactivity and the Funkenstein and others ( application to the problem of classification of the psychoses. ) have demonstrated a relationship between the blood pressure response of patients -“.:')l\w - w—w - Fry-w M7.“ �rm, w.» v—v-v- ya—_ -7. -. v'*a‘ 1——.r an ad“): , v-u n.7,. y ~. 7' V .. - r—*yx:'\r‘~'7—‘ —..vwr rhw- revues—WWI: a-m-x) v aw. 'IIMIN'.WP1L _,.. wr—Mrn 'w .n-u- u ...- nun-mun—u-wwwsrx— I‘d 'fllr-nr-F-qlf r".:'m~ — - —» ~ to injected meoholyl and their clinical response to convulsive therapy. which induce! Neoholyl is e potent oholinergie agent Vlsodiletion, tachycardia, sweating, and It is inoreesed peristelsis. rapidly hydrolysed by cholinesterese-I and slowly by eholinestsrese-II. blood pressure or subjects tells etter injected The meeholyl end returns to the baseline in a variable length of time, 2‘2;, five to pressure returns to the hgaeline in as Groups Pstients more than an minutes. I. II, or III reactions: 5 whose blood minutes ere olessitied those whose blood pressure takes so or more minutes to return to baseline, as Group and VIII reactions. The Group I reactors here s 9% improvement reactors s rate with convulsive therepy, and the 35% recovery rate. In contrast, the reactors heve s 89% (Punkenstein 35 3;, 1952). petients In whom IInIII Group VI and the Group VII 3 9'71 recovery Patients in Funkenstein Groups I to III upon as Group VI may be rate looked the injected meeholyl 1s rqpidly ~ �. . ”(Inni- rwlv‘v -. v -hr ~r. ‘r Wﬂm‘r;vz.z ~~w~ ‘ vmvrmm-mwvnvmwurr . . . . -.n- . ~v-cv rwwmvrrw-r ’Hm . , . warm-n'ku-w—w-vwvu-r‘mwm ’W'I-W‘WW . , ., . ‘23.. Groups VII v1 and the while hydrolyzed; slow hydrolysis rste. we may patients have a. the therefore. that predict, would 1.1!! Groups of blood oholinestersse nativity levels be high; while the setivity of Groups A VI-u-VII would be low. central odds nervous be rsgsrding similsr analysis msy devsIOpeent of the in system levels or oholinsstersse~l EEG of soetyloholine. levels and fluid spinal hypersyndhrony In studies of EEG changes following indueed eonvulsions resolted in seizures subjects were identified in whom a few a great amount or slow save activity; while other subjects (Pink seizures and to frequent exhibited few changes to many and Kuhn. 1956). If electrogrsphio hypersynehrony is s that probable is refleetion of inoressed tree soetyloholine, it subjeets who rapidly (the usintain hypersynehrony end those in whom it differences be exhibiting hours) disappears nsy hydrolysis oholinestsrsseoseetyloholine the of in the kinetics systems. Persistent hypersynehreny may be seen to result from associated of soetyloholins. s decreased rate of hydrolysis with low or oholinestersse-I either oonomntrstions of z - w mv as ‘— e �nw—w—uurw—u-A ~ «wv-u . "Hp; v-r w: w-ws-u—mxw —» al’im'rw‘imﬂl'wnnmmﬁ.rww-‘wmm' cholinesterasemII. Conversely, in patients with hyperaynchrony. cholinestoruaoul and fluid may be a basin fbr :yutom 1110111 : unusually high). wwwvvnwa >vv'wwa-uww «VII-MWI—w-W short~IIth .1: in tissue and spinal Thus these speculations providn congruent hypothesis rognrdlng central norvnua ruaativity to electroshock, and parephoral ahelinergio 09‘. �‘‘ r— v» -v «'1: -w:. . ~v~wr 1.». —.vn.~n—u nvw .w is w,“ . V m .,._v you-um: v...“ .uw m...” w. i. (“Hwy . , . V . v—wr\wl~;r‘-V‘va"vwg . 7-..,emu.,_,._c w‘,_pwmi,,”.w.'w.ww rtr‘ ., 1”,.“ M y OOHGLUSIONI be to e neehsnisns appear Gentrel eholinergie The convulsive the therspy process. dignifiesnt teeter in induced that to indioste be date interpreted any published Leonvulsione ere ssseeisted with en increase in intereelluler be by destroyed than esn to levels greeter seetyleholine eholinestersseal activity. Vhsodilstion and increased oellulsr pernisbility is relieved by increased amounts of eholineetsreeeoII, other and electrolytes in inter- celluler fluids. It is these changes that ere reflected in the increased electrical hypersynehreny which is recorded in scalp electrodes, and which esn be modified by sntieholinergie drugs. as stropine, beneotysine, dietheeine, proeyelidine, etc. It in these changes. else. thst provide the change in biochemical milieu which to slter alters cellular ectivities eufﬂ.eient the behsvior of subjects. Fhilure to induce high and failure of aoetyicholine, concentrations and persistent ( . . 'W—vnww �- —-——--p~rm- ,v-vln’ .-. ‘w-m-w --v< w u-wv «m ”uru-ewmmw‘ vat—rm,“ W'WV -. - . wwwm mmnmnuw—wm "wrrm,w— "-1. Wm, chengpe, concomitant results in a failure to induce electrolyte to produce behavioral change. Difference: in the rate 0! development of cerebral chengee may on reflect differences in subjects in their reliance cholinergic mechaniene, or in their sensitivity to changes in acetylcholine levele. These differences provide the basic fer the claeeificcticn cf the menilly by my: and Kuhn (1960). 111 by Funkenetein and �.4 w . .._u~mv — \w"wxww ~ wlxmw-mwmmwwrlmmrrw IV: 6-6-65 CI‘DIINEmIC WISE, CWVULSIVE AND BBMVIOR W, Studies of cerebral changes associated with convulsive therapy have indicated that the development of early and persistent signs of altered coronal fmctim are prerequisite to oranges in behavior (Pink and Kern, 1956). In these studies, electroencephalographic slowing was the most sigmificent index of altered brain function. Th demonstratim that premedication with high doses of atropine and Johnson, (Ulett slow of mve the activity prevented appearance 1956) suggested a relation to cholinergio nechnisms. The role of eoetylcholine and ﬂu cholinestemses in convulsive therapy is amplified in the following review which smrizes the published data. The mle of acetylcholine in the tmsmis sion of nervous impulses has been studies extensively since the of Dale (19136) and Loewi (1921). Acetylcholine constituent of nervous tissue existing in a first descriptions is bound .21 normal fans which is �. -~»-.- cwlwx—Wm.m~mn mmmvwvx 'w'w-m‘ w'dnuev—Wn —-'-v.":'-v-yvl~<-wmv -‘-w'-W"’mnrm"u'm’mmp '«ai-lu'vwv'w»; umpnw-so w-wm'n It is liberated driving the excitatim process. W the specific action of ctnlimstemse and as rapidly recmstituted 19:59). mpidly hydrolyzed by the dwlimacetylase system (Richter 8 Welland, free ac etylcmline has been reported in normal No cemhmspinal ﬂuid despite the rapid breakdom of bound acetyl— choline during pariah of activity and excitement (Tower and HcEechem, muse). The cembmspinel fluid normlly has resemble chclinesteme activity, homver, principally of the "true" or mechclyl hydrolyzing type (Nectmensm and Rcthmberg, 19u5). In the absence of free acetyldxoline and under the cmditims described, electroencephalogram fail to shm: any mietent abmmelity. (1:) was fmmd Effect of Wiccambml Mm: Pme acetyldioline in the cerebrmpirml fluid within a experimtel heed tram varied between 2.7 and 9.0 dew after in cats and persisted for varying periods (Bernstein 19%). an hours to m related to few minutes gamma The qumtity of free acetylchclim percent, and the amount was of induced trmrne. -n way-a ---1-m'— «mu-w v;- �v ‘ .v-vuwv—‘uwuwaI—r'm mm ‘lh'une‘ “an”, . - 1W um van-mar ammw— mmmx($—‘Wv~ ~-;Www Ww-v' .wma a..- ‘nv‘w I'u Commitmt electmemephalogme Th records were first filhd with mmted patterned dwxges. high voltage fast activity, interpreted as evidmoe of m intense manual disclmze, mly to befollmdbyasrwrtperiodofﬂettmingofallmcomed electrical activity. 'Ihese planes were then followed by pmlmged periods of high amplitude sharp waves in the delta frequencies. The to the beheviml enemas were mutant of measured fme related to degree of acetylcmlim. tram and With higmer greater of acetylcholine, Bernstein reported degrees of abnormality and greater- changes in moiwmss. levels EEG In addition, spmtaneous poct~tmunatic seizures were also related to the mt of free eontylcholine appearing in the spinal fluid. aoetylcholine Bunstein later applied to expomd out cerebral cortex. mm the cmmtmtim of acetyldaoline was 1 gm pement orless, Mowemdhimmlitude sharpwavesoflwfmquencyin the electmenoephalm. When the concentration was inmd to w... wal‘r-vunu .,.. u ��min-u .41. - v... and :— » -1~—— “Va-x v,m..,».«n—n ww'Al'wr‘w'nx‘xa'r .. ”-p- vwrn 'iwrylvv.-ws“ «ﬁrm-mu». tr'r'r—I‘lumm$1~I'm’w-VWW-Iv‘rn'wwu .~ that the reversal of the dwlinestemse fractim sensitive indicator of cerebral BMW tram Jag-Anny... ”a.“ r‘np‘woyppﬂ" v—y- x w— v—w-1,msw»: v. was a more damage. were takan at varying intervals following in most of these subjects. me authors reported the relation homunmofﬁmahmmntymdtheappeammoffrm mtyldwlim in the w‘bmspinal fluid. Thu: AW my We and that a «the mount 05 (m acdytcholxiuc 5mm summing Weenebmdtﬂawm batman the mount 05 mayuuz Won W Memory, main wind In the Micheline, (1)) M indicate m dcgm and changes Effect of and typc 05 in AM mm on unﬁnisnmd 0.5-1.0 awomuphatogmmc bchawéoa. at-«mmtic nag/kg (an. atropine EEG and Behavior: pmtually after mmummdmmmmdbmmofmeme. behaviomland anatomic aims of tmuna. Atropine also blocked the clinical changes similar to head mum EEG md seen following the experi— mtal additim of intracisterml aoetyldnline. n-w �.r .nwm-nuw v m, 1‘ x—~.wwrv-—um—mw“n-«WW«-Waqm v Ward (1950) . mm dawn c." m xwwuv— m ‘- um ,r—m—xw applied thase observations to the treatment of hmm cases of closed head injury. In of a: patients with varying be administered atropine subcutaneously in doses tram, of 0.1 mg/kg. In 20 some cam he noted clinical immanent and in others a reversal of the electmphalogruphic effects of the tram. In a study of dietlmint. another antidmolimrgic dmg, Janknor and “dancer (1958) reported significant alterations in the post~trmmntic olectmenoephalogzm. dose in #0 slow single intravenom patients with ahmml electroencephalogram resulted in normalizing in The A 22 subjects and marked immvemnt in six others. sum elect of atropine in blocking the appearance of um activity convulsive following in subjects reported was 1956); (In a therapy (Ulett md Johnson, later study then authors failed to mplioate this study, suggesting that or population changes may have [Johnson 93.51., 1960]). dosage factors cmtributed to the different results .u-wmwm �"rm—W .7, . .\.—.~ v‘ u. w wr— w' w --=»—-.--«-v- 'w' nu.- "I 1- nun.“ mm-‘Ivm’lwuu‘twr "uvmq-WIWVWW. “HM-:rv‘lwr." 1— x—A 'i‘w'wwuvuwrwwn uvvmw": «rung-w unmoun- . aw awn:v-v—nnJ—m variety of experimta with a potent dzolinestomo inhibitor, A DI? (di—iaopmpyl ﬂmmophosphatc) fmqumcy EEG mutated hiya mpﬂttxde rapid éimilar pat-hams to status epilepticus. as well as dam status (Md: 5331.. of abnormality similar to that noted in pmt—trmtic looser m 1950). doses of mad 1950; W ﬁg, 19139; aid Won 95%, eleotmonoeptulomphic effects were blocked by small pmteral atropine. Chatﬂald md miml com»: with proatignine Way (19142) pmpamd and evoked electmmoamalo- graphic spike activity. The prior uninistmtion of atmpim blodmd this spiking, 'cuminatod by wif mat, the abnomlity could be mine. what to these findings, Banner md Harri.“ (19152), applied topical mimome in Momma of 2-1/2 to In 10% to tho awed cortex of cats, and noted no effect after intravmous WClm/kg)mﬂne1¢otmumphalommicdmges. 'Iho mtmtims of acetyldnlim in those experimts , mm, was significantly higher than the topical application: (1—1; gm meant) m "nm‘lV‘I-"WPX' mm» �.9— intmiﬁuml and the Bormtdn (19%). (0.2—1.0 W gm percent) injections of and Pbrz'itt, also made mate of elmwuhgrmic effects similar to aoetydxolim from ucholyl 1n (mummyldwline) commenting: dam. '33); m and dozyl (carbmayldloline) later than the acutyldnlim concentrau ”W th- inmmd offeetivomss of these momma. drum to their mitivity to animal lack of durum. FmavWa‘WandWaMu my I mama that Waupiwgwm «may mm by «wane, uau we. on a a mutt 0‘ mm. Magnum: with chaunutume blocked M (:3) We): Waxed bg We. Role mm away applied.- can be ‘ of Oanbmsgg ﬂuid @951me in Saizums: Amtyldzolim is normally present in mrvous tissm in an inactive bound fem. Daring periods of activity, free amtyld'aoline is ��. N...- ~mv nun-7‘ «mamwmw-nrwu-W-ww-m—mmw Yum—U" v2»: 'lwwvv Wx-uwww- vv'r‘wr-I w-ww ‘t‘I—L :\ mean-v1- avast-Lo— nary-row: .10... Inspimlﬂuidstudiesinm, (19%) and Tower md Warn Cone. TmrmndEadnm (mush) reported significant qumtitios of fun mtyldwlim in patients with epilepsy. 0f 56 cpilaptic patients, an (77%) demastmted ﬂammable free Michelin in quantities of 0.02 mm of 1.0 gm to 5.0 gm per cent with m per cunt. The acetylcholine 11.3ch. was dinctlymlaudmﬂmfmqmcyofaeizm, theemntof 0W0 dun-normality, and the minim oflthe It‘bom lagt seizure. tha to angling tingof no mmim to of Ila-dictum. type epilepsy or lewd of dwlimtemse activity. WW a W 61011110 Michelin: appearinginﬁn of the awn. is a (mm of the Madam arlwhetha-r the aim fluid is spinal W is pmblmtical. (mush) suggested that the in acety1~ Tower md' inmd acetyldwline mlat§d liberation is not due to the seizum itself but is to the process casing the seizum. In a study of the hypothesis that v w. �' “W "m’ W“"‘W*P"W‘ TW""-'“'M'rmz‘m-ww' : ~<I w'l-w' uzm-w-wwnw-rmr wrmnsa-mmrw “my; —nwu—n-»mrw—u-—r w-w w n—w- wan-m .mmw- n- -_w.—..——,aw—. mw'hmmrmw m «w -11. the accumulation of acctylcholine is basic to the seizure process, and animals metrazole convulsions induced in (1953) by Tcrda dctcrnined the level of aoetyldmlinc in bmin tissue befom and during convulsions. She noted that convulsions are pmocoded by tissue; of content that the content in the acotylcholinc a rise gradually falls during the convulsion; and that below certain lcvols, convulsions foilod to occur. fall in tissue acctyldholinc She suggested that the during a convulsion was due to inhibition of acctylcholinc synthesis by increased concentrations of notabolitcs such as alumniumicns. Tho passagp of electric current through brain substances induces a change in callular activity with an increase in free aoatylcholinc to lnvcls sufficient to induce a grand mal soizumc. Tho prosenco of free aoctylcholinc in the interocllular fluids is associated with electrical hyperoynchrcny, reflected the EEG as dolta slowing. (d) Effcct of Electroahock on Acctxlcholinc and Cholin~ saturates: Tower and McEachern (lShQa), in their study of cnanioocrcbnnl trauma, includcd obscrvations of six psychiatrin �, .— “7 hin""'-"""""’n w—xwwr‘W'wv-Wsmuwvw ”‘1.meer!. ., . A a .m "Jaw-«v 7 wmr- mm- vmm:wwwq~mw‘m¢7~w 1"‘3-0! w ~12-- patients attu- 3-7 Linda-going mmrulsive therapy} Studying the patients mam-atmﬂay upwind fm Micheline activity an.incseaae .ad rxuia in.two in in th. Spinal patients; dwlimsteWII rawnrsal a: a damase in and mum-I with a the ratio of cholinesteruses in five of the six obsewatims time has paints. W they concluded that'the spinal new; convuisions were 11kg those tunic ahansps in induced mm a! than those found in epilepsy. Ragarding the ma patimt in‘the series who failed to show 01th» I’m mtylolnline or a dwlirastemao ratio reversal in this intsmsting the spinal fluid, thoy smote: "It is that pstimtmﬂamlyaaoftrasistosmwnompameto mamt." WM than. a show: in «1mm, cons/Lamb“ augment about ﬂu. note 1,: 1.6 05 “chaste that 7W!- acaytchaune mwmgaammwmmuwsm <1“ch 4:.qu and Adm/Lu enhance. autyb Ls that «sorghum damnation, �“mu-w. v— vaw >W—Wrﬁww.vwam—.m .‘w'wwrr Mr“!!! wrwwumm'm WV - W9 augment wmm 1WW"WYI3"W'FVI'W‘VW wwmmww-zw (”wan-vim -13- Lawn. tww 05 “Midtown whiz: “up and auuthau wetytchauu puduocéou inc/mum about. (was. (2) Central Nervous Sygtem Cholinesterases: Cbneumitant with their observatims of W (1939) muasumnd spinal in acetycholine, Towor md Hcﬁadxem fluid cholinesterase activity. The types of'dholinostoruscs art normally found in the spinal fluid: momentum—I ("trm,” "specific," which has a <92" mdmolyl hydrolyzing) . big: specificity for amtylcholim; and duolinestemseoﬂ ("peeudo,” "um-specific,” or bonnoyldwlinc-hydmlyzing) . wands hydrolyze mtylmolim but have different Both rates of hydrolysis {bu-ulcholyl and banzaylcholine. This diffcrantial rate permits gamma distinctions. By ram-ting the cholimsternse activity as a ratio of the activity with macholyl bonaoyidaonm substrates two mama and with acetyldmbline an to- substrate ratios am fomd: momentum-Ilacetyldnlim md alwlimstcmeII/amtylmolim (with ratios normal CS? Ach/Aeh a 100) . omtains ostemses in the. ratio of cholimstcme—I to dmlincsteme-II. Thus, normal In such 33: 17 CS? for consist. �-.v rmvs 'mm l-F'W'WW wmmmm .mpr—w— rm . . may of "specific" caucuses with a small now-spedfic estemae coupon-mt. In pathmts with hand inmim of tho cm the fluid fraction of the spinal activity. dam the and 'mey also observed a of tha dwlhmstomse with ad mm Wm report and daclizmtomes with a simifioant increase in the “Wm-II Wanna-I mm Tower and of the W a decrease in relation batman with the severity of cummpmlogmpic mun. In patients with increased spinal fluid amtyldxolim as a multofspmm of Wm warm seizmu.‘hdnvor. or total dwlinestcmo activity in the made was found. metimmybomﬂomgamﬂngdmgeainmn mm activity. tha pemability as explaining the WWW-I m1 mm: syatcm is fomd 1n imam Wt in dulimstemse mnomtmtim in mile dwlixmtemesﬂ pmdmimtes in 0th:- tissuaa. especially blood scrum. With an increase in �,- xw- m-mmwm m anatylmolina lawla in intercollular cambml fluids following atimlatim, convulaima or tram, vasodilaticn md cellular pamability my be ﬁlmed pndictod, with a dogma of mmudaﬁm of vascular fluid: into the inter gallular spams mtmmmtmdamimofmvmodimm(mt g; g, 19%). Spiagal and Spiegal~Adolf mutated such pamabmty W 1953). marred inmaaad omchctivity of the tissues Thay associated with W than in mm reports (19%; 19u2, 1m, 19%. appaarmca of various ions as potassim and in the spinal fluid following electrically indumd commie». Thom was also a simificmt-imm in such nm-aloctrolytaa as manic-acid splitting anzymas. (images in of circumstance-11 (Tower and Wm lSth). _ �wwlv mun-am.- V‘r‘ww.\\.sm uwrvvu‘x' ..- me—wwmvmvwn .q-zwuwm pawn-w ., cannwmuw v-Mr-ru-m‘ovr WWWWW «um—a. -.--< www.mm -15.. The increase in dwlinsstsms activity should be associated Its persistence with the rapid dostmctim of free asstyldxolins. ' in spinal fluid after trauma and seizure of the amtyldxolins—dxolixnstsmsvl may be system related to the sensitivity to concentration relation- ships (Nsdmsnsm and Bothsnbsrg, 19%; Tower and 3mm and MscIntosh. 1955). At “physiologic" Wm, 19%; oonosntmtims, hydrolysis of aostyloholins is rapid (3-H mimosaoonds) but at higher and mosntmtims, the activity falls off quickly. In lomr W, the cl'nolimstsms-II-sestylohomm relationship is naiospscific and the rats of hydrolysis increases with concentration. usual levels of sootyldxolim stosll sambmms is specific activity of cimlinsstemss-I in Thus, the destroyed by the few milliseconds. Wm omosntmtion of soatyldioline in emsssivs excitation leads to an mm tissue, the mm of hydrolysis sxosedsd. com. The ssizm threshold may by cholinsstemss—I is be roamed and a seizure me dissociation in mstylduolinwdxolinestemseul relation- ship results in s psrsistsnos of aostyldaolﬁne. The seizure may �mm “a." "W.— .mﬂmpw txm mm Wm-mmwmm—mwm m "m . amtyldiolixn diffunes rapidly, affecting vascular md cellular pamability and and Wins catamaran-II W of in the concentrations of various ions CSP. The nativity of dwlinostamse—II, cfficimw md depuuhnt low on the oonomtmtim kinetics, mmmldnwninmetissmsinhwmtodaystolewls for the physiologic action of dwlinostemse-I. (I) mo md Classificatim of mmm, gmmm . mamas: Altemtion in the blood brain pemability barrier by the continuing actim of mtyldmolim may be the biomenﬁcal sub- strata for the post-3W hypemyndumy of the electro- mmpmom. Such mag, 1956 is possibility o mom in the report by Wmtingm 5.11m intha concentration of‘ miminbmintissmsmmdaysafteraserieaofuinduoed Gambian. this His dun 1m mlccmln, aim the change in momtmion of mutually absent in brain tissue to be ��mm. WV wwwm'wmmww’rr‘v m (memwmw“'m'ww .19- my be mama“ in the. mum nub/mug ad the. dwuuuthu— hypmymmuy Awwu. my mama Whom 1’th be. oﬁ acetyl— dummzd hyd/wtyau to as a mt: {m mm an Law ma mammom wowed mun, u Cthénutcmc-II. Comma (Ly, in and Wmmv! WW, my be muddy 06, mm ~11 ewwc with 5h0u~uv¢d in Mac, to the Wainwmmk Mammy. WW and spinal (laid high) . stat-ﬂea ’meae may also have application 3 chaunutmvr MM}: between the blood problem of )have pmsum mponse of patients to initiated médblyl and their (minim). response to I convulsive mm tram. which is cholinorgic a potent hamlyl amt vaodilatim. tachycardia, mating, axomestemeq hydrolyzed by is It midly astemo—II. "me blood and hemmed peristalsis. and slowly by moun- pmssm of subjects’fans after injgcted manlylmdmtmmtoﬁnbmeuminavariablplmgﬁmofﬁm, �-m. “...u. “v ,,.. ‘mw you ,,, d . ”are". ‘V‘ -- m, mus-www- I vm‘ five to W rm www.- w. m 1 ”3.... v- .-r'l w - way-vr—v- .m-MWWWW. “gnaw-why , Patients more than 20 minutos. Mums to the baseline in 5 an minutes ,,.mu(._“‘,_,m,“ . whose blood classified as present. Groups I, II,’ arm mmmmbaaoline, amHdeIImactions. MW]: or III mactima; ﬁnes mean blood rams hm a 9i Wt the aroup II~III reactors a 35% rate pmsm takes minutes 20 and convulsiva'thompy. with. unwary rate. In umtmst, the MHmmmmmaast'mddnGmupsvnath-wverymu (main 5; g, 1952). Patimtsinmﬂcmaminmltolnmaybelmdm as patimts in whiu the We may the injactgd mdaolyl is rapidly hydrolyzed; Group Hand VII predict, hvels of W when: Won, W H~Vii a slaw hydrolysis rate. that tha blood Esolimstemo activity -I~III would be him; whim the activity of ma be low. regarding the data for eatcmenl, in patina hm We recall hem a similarpmdictim mntmlm which the domiopumt syntax: levels of cholin— of early and sustaimd EEG lypamynclumy and elevated spinal fluid levels of aoetyldlolirm was minted to a low level of dwiineaterase activity. mus, w-n —. wu- �,-.n I ‘ -21- the data of paripiuml stimulation by dwlimrgic agents is wt to the hypothesis regarding mutual “activity to electroshodc. mm system m1? m'.mrrw-uww gum �CIDLINBMIC PECHANISIS IN WV}: m m M, NJ). From PM the Departunt of at the Missouri Institute of Paydziatry. Lhimity of ransom School of Medicine, 5WD Arsenal Stunt, St. Louis, Missouri 63139. Aided, in part, by usms grunts 1914-927, 11-1—2715, mmzus, and Iii-11380; and the Psychiatric Renard: Fomdation of Missouri . �VI: 7-17-65 GIOLINERGIC MICHANISI‘B IN CONVULSIVE W Despite extensive application and study, the mode of the oonwlaive therapy process “mains enigmatic. has been devoted to neurophysiological social ) aspects , ( Much study l, ( ), clinical psychologice1( . of action ), ( elucidating the present neuro- ). physiologioal-edeptive View of the process ( 'me wly development and persistence of signs of {motions were reported to be (Pink and m, activity es the The this and muisite to changes altered cerebral in behavior 1956), with electroencephalogramic slow wave most significant index of altered brain function. demtmtion that pmdicetim with atropine inhibited slow wave activity (Ulett and Johnson, 1957) and the report that mtidaolinergic «wounds reversed these clinical as well as electrogrephic menses (Fink, 1958) suggests that the biochemical basis for the mvulaive therapy process may be in the cholinergic mdmmisms of the central nervous system. This review discusses the available data mending acetyldxoline and �and the dualineetemsw in the convulsive therapy process . Acetylcmlim has been extensively studied w an active agent in the transmissim of nervous impulses since the deecziptiom of Dale (191») and Ioewi (1921). It is first a constituent of nervous tissue, existing in a bound form which is liberated during the excitation pmoess . It is rapidly hydrolyzed through the specific action of molimaterase and is rapidly reconstituted by the choline-acetylase system (Ricmer and Crosslend, 19%). In normal cerebmspinal fluid, free acetylcholine is not present despite the rapid breakdown of bcmd acetylmolim during periow of activity and excitement (Tower and Hailed-tern, wheel). The cerebmepinel dwiimnteme activity, however, medxclyl hylmlyzing type fluid does have maurnble principally of the "true" or (Madman md Rothenberg, 19%) . In the absence of free acetyldmline and under the conditions described, electmenceplumgm fail to show elmozmlity. �(a) Cholinemc Aspects of (kmiooembml Trams: Free eontylcholine was found in the oerebmspinsl fluid within a few minutes after experimental head tmuma in cats and persisted for varying periods up to “8 hours (Bernstein, 191:6). The quantity of gm free acetyldloline varied between 2.7 and 9.0 the wt was Wt related to the degree of induced electroencephalogram menses. The records were percent, and tram. demtmted pet-rm first filled with high voltage fast activity, interpreted as evidence of an intense neuronal disdurge, soon to short period of ﬂattening of all recorded he succeeded by e electrical activity. These phases were then followed by prolonged periods of high saplitude sharp waves in the delta frequencies . Ihe behavioral changes were related both to the degree of tum and to the want of measured free aoetyldwline. 9th higher- levels of aoetylcholine. Bernstein imported greater- degrees of EEG abnormality and greater damages in consciousness . �Spmtanccm post-traumatic seizures mm also related to the mmt of free acetylcholine appearing in the spinal fluid. Bernstein applied ccatylcholine to exposed cat cerebral cortex. M the cmccntmtim of acutyldrolinc WM 1 gm low frequency of waves unplitudc sharp high percent or loss, appeared in the electroencephalogram. men the cmcantmticn was Wed to 2 gm percent, the electroencephalogram: flattened in a fashim parallel to the pcatétmumatic records. Pmllel investigations in neurological patients by and Madam (191ml) Tower dammtmted free acctyldrcline in the ccmbmspiml fluid only in patients with meant head trauma, recent grmdoml seizures or after clactmconvulsivc therapy. Free acetylchclim varied from assaying spinal fluid 0 .2 to 100 gm percent. In drclimstemc activity, they noted a sharp rise in the nonopecific cholincsterasc fraction (benzoylcholimnsplitting) and a drop in the specific cholinestemse fraction (maholyl-splitting) in patients with head trauma and ﬁll-owing convulsive therapy. The cerebrcspinal fluid did not �exhibit such inversion, althougz lit command free acetyldxolim. after Spontaneous seams . that the lavel of They comluded two watylcholim varied directly with the dame of cerebral damage and that reversal of the dzolimsteme fructims a more sensitive indicator of mmbral dmaga. taken at varying intervals following mlntim batman the W EEG 935;, Ehcﬂmmaphalom, also indicated a abnormality and the of fme mtg/10mm in [Add 1 Kovach Thu dogma of mm. was ﬁne cerebmspiﬁal fluid. 1957] mmummmuummcam maumuuam WWWMdﬂwmo‘ (an Widow, the ham and. type. 0‘ WWch abmmutg, mmuummuuaappmu Mandated pm. �Fwy-.. W, .,- V l .7..— (wt‘ mm- M 1-... WWW“ 'mw .. :‘w ,v- a. , , m1. vv vv-uw-u-,o-vw-w.w.w ‘V'I-V-t.mNrIV-WI AntiohoMc (b) wry-urn "I“ wv-mvww—w-wuam—run-mnw—uu—wxw m and tram: ”myr—w—vm—wwwq wrivlwmwwr-wﬂw v: ,«w- me electmmphic, beluvioml md nemlogic Sign of trauma were blocked by the mutual ministration of 0. 5~1.0 ag/kg atropine (Bomatein, 19%). as were similar olinmel oranges occurring after the inmatemel additim of acetylcmline. Word (1950) applied these observations to the Moment of closed head injuries. In 20 patients with varying degrees of amine tram, ministered subcutaneously in done: of 0.1 ng/kg, mating clinical improvamt in some and a reversal of the electmenoepmlogmphic effeots in others. In a study of dictum, mm mticmlinergic drug, Jenkner and warmer (1955) mpwted electmmphalogxm. the postnmtmtic done he in forty patimts with A altemtims in single intmvemua em}. electroenceprulogrmne resulted in normalizing in twenty—m and muted imminent in six others. Similar observations have been reported by Denisenko (1965) using methylbmectyzim and ‘ meantin in poet-trumatic ﬂock and cerebral edem. animal experimts of ‘ . u—v. . .mmrrmm �- .v -'4In v'nvwr»vr Anew—Wt nv -V “war w rr v. I1wurwuu‘wv gm" w'twv‘z' 'or‘ Ila-3 », ~.,r-.mwm-w-—~ v.“ ,1,“ .‘ .v-y m twinw-vp "Ivy" .m.‘ war. .r my rnm ~; . "mam—q .74- ..w w. .... , Thee duet-mums wen eeueeed in the omwleive therapy process by Ulett and Jornem (1957). Then workers eduiniotemd doeegeaofatmpineupto the patients received that the was mt: mper'daydm‘ingthemeke «mm of slow wave therapy. They Wed activity produced in these patients significantly has then the omtrol m who had not mind the atropine ministration. (In a. later study these eutm failed to replicate this etuiy, suggesting that douse factors or populatim changes have Wed may to different results [Jomem 3:311; 1960]). These observations provided the basis otlur 1cm mtieMlinergic W for studies with (Fink. 1958, 1960). The intmmue injection of emerimentally active antiomlimrgid comma es diethedm, benectyzine. the piperidylbenziletes JB-318, JB-336 and JB—329 (Dim). and wan-2299 induced deemmmiution in psychiatric eubjects. These were associated with bernvioml ﬂirting, anxiety. EEG EEG clmges tram, illusions and hallminetima. In patients um had recently �,__.,,__,,.. . V... 7)... W- w -— ....,... . .V-r—w, .wx-7'Uwiwt ~s| '1‘ u u a...” ,.. w‘mmjwlm‘vwnmu‘m . "0...an ”mi—W- .thwuww. ‘ m.,.m-.-.,,, M_ "H". H," ., ,.. .w-.m.1, , a“, r .neqy..-mw—-; - .r» vr'." received eleotmoonwnoive therapy. the eduinietmtim of theseoomomdemeeaooietedwithemdmtioninslowmve activity and meme]. of euphoria, denial Atropine was also EEG emined in desmlumiutim WI m and tension. and confusion. low doses. and obeemd in these administratims, mind At higher superimposed beta tachycardia, We, hyper-8mm slow waves, followed by lower voltage, poorly activity with by activity mined delta “mind by progressive confueim and disorimtatim. Both in oenbral mm and indumd omvulsime, the ehotmﬁmphio clauses my be modified by the comm-rent administmtim of micmmemic drugs, thus Weed mt: of aoetyloholine or- mating that incmeeed cholimrgic receptivity is eeeooieted with the high voltage slou’ wave activity. (o) 13min mmnm and m! mmm : SimilarEBGohmgeemdthblookingthmfheshenobmmd following the direct application: of aoetyloholim to the centre). mam. - .rml... ww—wu-uuwy w— “WY—r! �'lho anninismticn of a chainsaw. inhibitor DP? (di-isopmpyl fluomphocptute) elicited high maplitudo rapid frequency W EEG patterns similar to status cpilcptiws, as well as similar to those of post~tzmmtic states amen 23%, 19%, 1950; and ma: gag, (W We 1950). effocts'wom blodcad by small doses of pmntaral atropine. mat was 91; 5}; EEG The inmaso in acetyldaoline after tetmrdxyl pymphosphate named indumd and routed to the toxic mmisfostatims (Wand 3m, PM: 1952; ('11???) and convulsims 1957;) Chatfiold and Dummy (19h?) pmpamd exposed animal cortex with Tho pmtimim and ma chmmlomic spike activity. prior administmtim of atmpino blodcod this spiking, or pment, the mutuality could he oliminatcd by if atropine. In contrast to those findings, Bram” and Merritt (19%) applied topics-.1 acctyloholim in to the expound cortex mania-ts of 2~1l2 to 10$ of cats. md mted no effect on the electroencephalographic changes after intravenous atmpim (1 Wits.) 'me concanmtims of acatyldnlim in ﬁxes: cxperimanta, �10 harem, wan higher than the topical applications and the inmoistomal (0.2-4.0 Bernstein (19%). Exam» and gm (1-14 gamma percent) pennant) injections of hwitt also made note of electro- m unholy]. onooplulogmphio effects similar to Midtown (nostylhotmﬁayloholine) and doryl (Wlmlinoﬁn mantmtims moh lowor than the acutyloholim oonoonmtiom. 'Ihoy ascribed tho imaged effoctivomos of look of sensitivity duolingio those drugs to thoir to oembml olnlimstemes. Thou data one conflicting and furthr study is masonry to qualify this issue . Gummyiml Fluid mglmlinc (o) of aoetyloholim mtabolism and inﬂates that it is Selma: found in One View mm tissuns in an inactivo band form, wring periods of activity, mtyloholim is liberated at the call midly mum, Mum it is deactiva‘ood by dzolimstomso. 'Iho mount of bomd mtyloboline is the resultant of tho oontinumas pmoosses of synthesis, liberation and broakcbm. It the level has been postulated that rim timing sleep and falls during activity. and Czomland, 19%; Elliott, (Richter Sam): and Hmdorson, 1950; Gianna: �,7... ,r‘ w .w..,» "gun-w WW, _ w w" Rpm. 1962). .1,‘ A. 4w- By ....- a. m brain mg. higher than 3005 tissue levels is mw. 1...,” wr'w".‘— wan mama basin .v—w tho love]. of during :- "w m:a..»=-v~<wmu «we» u-m—v .fr'um-g v.~'mrw-"n—u'w .r‘xm is high mtylcmlim (micro- munch and sleep to b- mm, mini-It. \‘w‘ , air quick freezing Minds. post-ulna! levels. (7 Thu diffm in as the msyntlnais mm for gm/m/ndnuta). Elliot $3; omfimd these observations. also toting that after nan-uncle aonwlaims spinal "Wu-1 tim) wotylcmm in rat (1950) , using liquid Richter and Cmoclmd per ‘v-‘w‘m fm acetylcmlim m «ﬂammable ﬂuidinmncmtmtimamtoagampermm. Pepeu (1962) fomd an qt central mm 11mm in mtylclnlim Wan depressants to in the mm caused by a group be roughly proportional totindamoofdepmasimoftheemmlmmusmummm‘ mdmtim in Prue mm activity. mtylcrolim m 'fluid in mportad in‘tha spinal patients with epilepsy (Cone, Tum“ md and mum. mmud 5.0 m 19149 b). or 56 fm amtylcmlim percent with McEncMm, 19%; epileptic patients, an (77%) in quantities of 0.02 to an average of 1.0 TM:- mm cont. �v— v w. «...v..v,v .-A—W. ,_.1,._,...V,. -v-.»-m—wv —-.~ ammm‘ «wwwm 'y'vvx'v u—wu.uw,n-w.-w.~:.wmw.1». mu '1 “a“. - .vwruw—Nv- l2 Maryldnlim levels wan related to the froqmncy of seizures, mmdcmmmhmiomlﬂy,mdtoﬁm 1b zinc. the lat column, but bore no mlation to medication, type of cpilopsy or level of Tadcr and Wm ($0th (Hugh) Vimd tbs increased acetyldmclim a lay-product of the Stwying the hypothuis that the inducod aim. m activity. (1953) 301m, and not causal. mum We! of acotylcholine the level of acatyldiolim inbmintissucmotmaoh convulsion. Stumtcdarisoinﬂae acetyldaolim content of brain, baton a sebum and a fall during tho convulsion. Below curtain levels of acetyldmolino, convulsion hind-to comm. She smeared that the fall in tissue can due acetylcholim during a cmvulsim acetylcmlim synthesis sue): on by Wed to inhibition of concentrations of natabolites amnim 10m. Wendhpoualsommdclmgosincenmlmm systcn acetylcholim follauins “rims stinulmts . Only after �13 SMDutyhthyIMimte was there a mcholyl and 3, W significant dam in the acutylcholim level. they noted a in association with inmost! omvulsions. drugs which may qumtifiad as atiwlmts 1:me maninaoetyldwlim impmniazid 4» and no W mind + 1309A) comma, them in mtyleholim lava]. muss these by convulsions. (The than WWW duspite int-mo excitation produced by those mu imam. (LSD. mpmma level. other With were diffemnms in observations mmmmmggmrmrmdmm may be related mutants. to the differences in fm‘ methods th: Lunar unwind of biochemical changes in spinal fluid nflcatingttnfmeaoetylmolim,whilnsiamamandhpeu‘ manna tatal Myldwlim in tissue uncaring bound fm form Thu: an and of acetyldmlim.) AW W Auggut ﬂux Apontaum by an u induced We 1mm in law (no. acotyzchouue �-, .4.‘ . rum- .1:.--—.-. -. ‘T r. .l ~,w ':.»"-rx\~\I--«-~-v~’ ‘mw"‘ m~.r...v.w—.m...~»-. . .«m-n vyr -. . 1-.“ , —;..- r...» ,.r;« “a v.—~ 1n tummy-1 La 5pc“: (mid. mmwe bound (on which my Wag dalmatian, “up and mduaﬁon immune mane (d) Oantml Nervous activity. (19%) also ‘mo Austen/ted 6mm «cavity and Aazuu mm:., m Wm be. tum . Sgt” mama enhance Mae. Lama masthead in the W 06 acetytdtoum (holimstomaa: Tour and spinal fluid diolimstema typas of duolimstarms we normally fund in thc spinal fluid: dmlimstume-I ("tr-m," “specific," or Molyl—hydmlyzing) , which has a high specificity for acetyldiolim; and daonmstemo-II <"imudo," "mspadfic," com or benzeyldxolim-hydmlyzing) . Both mtyloholim but rates of hydrolysis for have diffamnt hydrolym diffcmtial rate Molyl and bomoyldmolim . This qualitatiw distinctions. reporting the duolimstemse By permits activity as a ratio of the activity with a maholyl substrate with a bemoyldxolim aubstmtc mud and to a substrate of mtyldmolim, ten mtios are found: dualﬁnatemeJ/mtyldmlim �-- ~ :4: 7r>m\‘-Vrmwu~<hvuwrr. n >--'rw. aw, ww H'VJ’IW'W‘VCu-‘rm'"‘l ~w:wa-w-._,.rm unr— w .vumma .w. "- urﬁ ,. .... 0-» ‘wV.M-a>vﬁ “Tr-aw -r-.-~,:-. 1m.” ~ m 15 and Mm-II/mtyldmlim. comm fluid :30an censuses for “must-men! to In such ratios mall in tho ratio of 33:17 dawn . Inpatimtswithhadtmm.mrmmmmmd mimmimofﬂndnﬂmtmwiﬁ'minmeinm W41 Mum-I fraction of th- spinal fluid and a activity. ‘11:. W in what of tho cholimtomso Wmmuudmtmmtyofmmmdmm m at the In :13qu WW. mints with owned spinal fluid acetyldxolino m:mm,mvar,mm1nﬁnmioof dwlimtm or total mun-statue activity was fomd._ mmmannmmmymmmamm mumimmminanmpombiuty. WWW-Ii: antral mm system while Manama-II pmdminms 1’ththth in other tissue. specially blood scum. in mtyldmlim hula With an inmue in mnbml intcmauular fluids, up“ .7. 7" .- » -~ ..,_, , u �A , . ,_ =...V........ w...” ..l.._, nv'rvxw w." .7 "Myw-IlI-Irwwaur- ‘7 ""Fvwmm“ v raw-4‘7“-” ”Val n”,_~ -17 . "A «rum—u ﬂ,” "mum—.1,“ NW... , 16 vasodilation and Wei with a degree of umudatim of vascular fluids into the inter» cellular permeability cellular spaces varying with the extent vaaodﬂataticn (Kabat and their Wm 35. _a_1_, 19%). and may be pmdicted, dmtion of the 81313301, Spiegel—Adolf, (1981. 19%, 19%, 1938, 1953) WWed sud: permeability changes md maimed mndmtivity of the tissue associated with the appearance of various ions (as potassium and prosphate) in the epiml fluid {alluring electrically induoud convulsions . Such nucleicaoid splitting cellular permeability WWW of aims, may nm-elactmlytes, as also ixmaaed. Changes thus pmvida the basis for the high acetylde and the inmased mntratims of cholimsteme-II in induced animus or head tmuma and Wm 'Ihe in ' (Tamar- 1939c) . persistm of mtyldwlim in spinal fluid after head trauma and after aims daspita increased dwlinastemse activity related to the sensitivity of the aoetyldiolin'e- may be dwlimstarmd system to Wmtim relationships (Nadmansm �,wn‘ww’ ,.. i . ..-.. _‘ “a... n”. “ ‘,,_ .3», .1. m, .Vq‘r‘. am-rw , ~,--‘V~rwtrm—Ww ..~.-—-~—..-w wr".v\-4I"\9-rr"x““w-myrvwrmmwn'v .(-,.‘v.,..._..-..‘_w,,,,rn.—.y~.—_-.r~,- 3“ .~.-. 17 and Withers, 19'65; Towcr and Wm, HacIntosh, 1955) . At ”physiologic” 1909c; Burger: and comtmticns, hydrolysis of acatylcholinc is rapid (34 micxmocondn) but at higher and lower concentratims, the activity what, falls off quickly. In the dmlincatnmo-II acctyldmolim mlatimship is ad ﬁn mn-cpociic m 01’ hydrolysis cmccntmtioc. W witl': increased. anvimcfﬁnscmlatimhipc suggestsﬂmtwhilem usual commtrwticns of acetyldmoline t cell m: are dcstmyud by tbs specific activity of cholimsteme-J. in a fut micro-cm, an emaive concentration following cxcitaticn may exceed the rate of hydrolysis by cholimstemso-I. seizure mmmm the uixum may be mmd and a seizure itself adding to the mm: The induced, with of free amtylcmline. 1110 increased acetylcholinc diffuses rapidly, affacting vascular and cellular minty and increasing the various ism and circumstance-II in the of dialimtcmc-II , mums CSF. The of activity thaugh of low efficiency and depending on �the mien kimtics, mamas tho watyldxolim in the tissuns in hours to days to levols for the physiologic actim of dwlimstame-I... Chaumtemu «ppm is ﬂu. camamemmmm In The. am 5M cu a. gamma gum, mating 5m a“ when pmabuug “mined by imucd changu mm. Wed mm“ me put “the hmmtéc Wm “mucus the ants (n ma agate»: 05 Wu manually «mum. (a) Amgzleholine, Alumina in MW at cm EEG the. blood-brain Mum and Indumd Oomvulsiaw: pemnbility barrier winning action of mtyldwlim may be the by the biodmmioal substrate for tha poatwlectmahock hypemyndmy of the eloctmanmpinlom. 3% a possibility is evident in the Mommim of an immense in the concentration of cocaine in brain tissms thme a series of 12 induced convulsions (Aird army in concentration of this days after 5331., 1956). The 1m mlecmle, ordinarily absent �mnpr- rug—m.» r m «7 r.~L,-»---.--,V-...Ww.‘n - v v '.>T4wmw‘m .mw—z , ru71.,‘ mu mr‘m—D'J.lr>aw' yawn-vanquas,‘ ‘w. - p". yr. -., “wharf” . WV. ”us-apt..." 1.. .19- in brain tissue, was asaociatad with the appoarunoe of hyper» synchrony (delta bursts) We hIVD in the electroencephalogram. confirmed tbs many pruvious reports thut convulsive thaxapy induces olectnngnlphic hyporuynchrcny (Pink and Kahn. 1956; Pink 33.3;, 1961). Duspite a constant application of mmmmuammmty'mmtmo: appoarunnn, the duration and tho cxmnnx of the electrogruphic slow Haws by activity as wall as the sensitivity to modification alnrting, hyporvuntilatian and barbiturates in psychiatric (papulntians. Tho early appoarnnnn of high degxan hyper~ syndhmuny and its puraistnncn throughout a truatmant course has been dnscribod an pmuruqnisite M (Roth, 1951; Roth It is possible that EEG to £11., impruwument ﬁollcwing 1933; Pink md M111, 1956). the diffirnnces in tho degree of indncod hyporuynchrcnv may bc related to differances in the activity or auntrul cholinnrgic mechanisms. patients to davalop hyporsynahruny The may failure of certain thus be associatad precluding a clinical rlsponse to induced convulsions. Tbuer .. l . V , ”.17 v ,, n �w, ._‘_,._..._‘,|,,, r. Wm. ;.,,,,.__ m. ,. ~ "v.0... . (T W . r r, -_ "u . rw.par.-‘W-.~ .erz. .7.” , .1 . _ y . ., 4.1-. . -- n v-uvnwwwv-wm‘uv “wave-«W.www—ur-p—, w-n—w—w M-ru- "n" .,-v , . _ _ , ‘ v—av-um . . woun- 7 -w v-_. .- m 20 and Wm (19%.), in ﬂair study of W231 tmm, hcludcd observaﬁm of six psydtiatric patients mder'going omwlsive mampy. Studying the patients after 3-7 tiny upon“! {me spinal fluid and an inmm mutants Minimum in two patients; in mournstcmvn and a dam in .mvemal pith of the ratio of dxonmatorms a dwiimstame-I in five of the six patients. From mludad that the spinal fluid these obscwations ﬂwy We: in ma commlsiom mmﬁmmoofmioambmltmﬁmmof sputum epilepsy. WWMpntientinﬂwmﬂaawhofanedtom oither {no acetylomnm or a dmlimsteme ratio reversal in iﬁtemsting that this the spinal ﬂuid, tiny. wrote: "It is patimtwaaﬂnonlymafﬂnsixmshwmmsmoto Wt." ‘ at If alectmgraptdc hyporsyndmrmy increased free acetyldmolim, subjects who is a mﬂectim maintain hyper- syndmymdttmeinﬁmitdisappemmidlymybc waiting diffemnoas in the kinetim of the dmolimstemsw » , _ v—-— w . 7 v vamp-omen“ W . p ,. . V... , ‘ �22 “I (21011th 'mooo studios and the Classificatim of a : malochm applioatimtotmpmblanof atomic mootivity and the classification of the Mountain Po mm and ( ) mlatimhip boom the psychoses. how dumstmted blood possum response to injected ndxolyl and the clinical mpomo of psychiatric patients to convulsive ﬁxaapy. Homolyl which W is a percent cholinorgio agent vaoodilation, taduyoudia, sweating, and peristalsis. It is rapidly hydrolyzed dxonmotorm-II . slowly by The blood falls after injoctod Immolyl within five to more than 9mm and takes Group 20 Group VI and VII oholimstemeel md pussum of subjects mtums to the baseline minutes. Patients whose blood {within baseline the returns to classiﬁed as prawn 20 by W 5 ndnutes have been I, II, or III reactors; those whose blood ormminums tomtumto baseline, reactors. M I and thp III—III as mam �.. pr 7: . -r WW..." . . .r. . n .. 7.. .- -. mm». . 1 unw- u . “val ~ « - ....._. v .. wiv'r—z-v .?-'a‘.v~'uV.—T{=n‘)("\ﬁlr- - ,r., "saw-- wry-WW...» N. mv—ﬁ m—m ‘»-y-_I-sﬁ-vvvvx , 23 have a 9 and a 35% recovery and Grow VII mentors 91; gl__. 1952). patients in Group whom while Groups VI 89% rate, mspectivuly, while and 97‘ recovery I to III mactom the injected mornlyl Group VI rates (Funkeastein may he looked upon as is rapidly hydrolymd; md VII have a slow hydrolysis rate. We may pmdiot, thcmfore, that the blood dxolinesteme activity levels of Grow): I-III would Groups VI A uystcm - bu high; while the activity of VII would be low. similar analysis may be mad: regarding central nervous levels of dwlinectemse—I in the duvelownnt of EEG hypersynchrmy and spinal fluid levels of aoetylcholim, providing a basis for a omgment hypothesis regarding centml nervous syntax: reactivity to induced oonvulsims cholinergic agents. and to peripheral �- ~—-~vw=rr'u. . ~ . “,_ w-vvww (“vwxx mu, .- v*'ul""‘v‘“""w“1-c-»w‘mlh-rtr"'4<-Ia‘.—-vuz‘ --— (—1 m-wry_._ 7...," .V, 7 ,_, . ‘ my — . w". ,.c_..,.. .. u... w. Flaw—w. v3. ‘~.,..,,‘w,-." 2‘4 CONCUISION: Central cholinergic mechanism appear to be a significmt factor in the convulsive therapy process. may The published data interpreted to indicate that induced convulsion: are be associated with on increased- in intercellular acetylcholine to levels greater than can be destroyed activity. Vaeodilatim and increased by dmlimsterese—I cellular pemability are followed by increased ammte of clnlinestemee—II and other enzymes and electrolytes in intercellular fluids. These chmgea are hypemynclu'my which can be mdified by reflected in the increased electrical is recorded in scalp electrodes, and which mticholinergic drugs as atropine, benactyzine, and ydieﬁuazine. The changes in the cerebral biochemical milieu alter cellular activities sufficiently to be associated with altered behavior of subjects. Failure to induce high and persistent cmoentrttions of aoetylcmline and failure to induce concomitmt electrolyte changes results in a failure to produce behavioml change. n: M ...1,.“‘..w. “,4 _. ...... ._ �25 Differences in the rates of development of mm reflect differences in their lependance of cubjects mechanism- changes on chom'cergic or in their sensitivity to chmges in acetylcholine levels. mean differences provide the basis for the classification of the mentally ill by kaenstein and by Pink md Kuhn These observations provide the mode a Miami (1961). Mechanical basis for of action of indmed nmvcﬂsims in altering the behavior of psychotic subjects. These views are consistent with the more earlier general neurophysiclcgic-«iaptive theory expressed (Rink, 1957) . �" -v~1r'-W4'VY—,‘V.'Z"V‘."-‘ w "- ---'~-' REFERENCES Aim, R. 8., Strait, I... 1‘... Pace, J. W., Hmnofi', M. K. md S . C. Nemphysiclogic effects of electrically loaned deitch, convulsions. Aach. ucuxoz. Izyahtat. 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Namephgalatu 1955, Jansen, L. C., Ulatt, G. A.. Johnson, 24., Smith, K. 31:! Sims, J. 0. thanpy (with md wiﬂmt atmpim); affact on alantrmioany Julyzad electroencephalogram. Malt. Gan. WWW! mm" 1960, 2: 323—336. 61mm, M. and Knaub, V. Quantitative estimation ofﬁnalbminandgmglnbulininnomlmdpaﬁmlogic cembmspinal fluid by imxmehamiml methods. Mu. J. Meet, Kabat, E. A... 1938, k (5): 653-862. Loud, 0. Fiber hwmrale {Ibertmgbarkait den Hennammiﬂnmg. Mali. 5. d. an. ”quiet" 1921, 189: 239~2u2. Wm, mm, spadficity mm in new on D. and Studies on dualinestame: tissue. J. Biol. (than, H. A. of 19%, 158: 653-666. Richter. D. and unwind. J. Vaziatim in acetyleholim content of the brain with physiological state. MM. 1 . Phyaiatu 19139, 189: 2157-455. W in the EEG mdar bubimmte Mmesia pmdwad by alactm-omvulsiva tumult and thair significance ECT of the action. Manuphguol.” can. Eumuuph. may to? 19 1, 3: 261-280. Roth, H. ‘ W mt. WW. Ruth. 14.. Kay, D. Pmtothal omwlsiva 1957, 9: 225-437. J. md amen, J. Prognosis and ahetmphalogmphic changes in electroW. K... Shae, can. Memphyauln Spiagel, E. A. and Spiagal-Adolf, H. Permability changes in the brain induced by mm). and insulin convulsions. J. New. Matt. v.3... 19M, 93: 750-755. �F ” rum" , ,7“... T9,“ wm.~n..wr.”“.,.,r,.w ..;._‘.,..,_,Vk,»,mqr,..r. 14."... _.-..,.4,. r...“ ‘. ”um-um..." :w-"CRIWJEFIMI-‘wf‘t . .,»;r-,W—;.—‘m'w"Ir-E'WAn-‘n-vu-I 1”“7(IAHV«——l ._ - n -.--~ 7»-v—-———~r-—-n~—w-v-—. -3Spicgol, E. A. and Spinal-Adolf, H. Physioochemiml effects of ohctrically 1mm oonvulsiam (oembxospinal fluid studies) . Tm. Mu. Haunt. AM” 19%, 70: 130-132. Spiogel, E. A. and Spinal-Molt, M. Physiological and physioochemioal mohanim in electroshock tmatmnt. Conga. Newt” 1953, 13: 38-63. Wm Spiegol, E. A., Spinal—Adolf, We dinning“. in the brain Tm. Mu. and Kenny, G. Haysiooodmﬁoal electrically indumd omvulsiw Nunez. AM" 19342, 68: M. m. Wt Spiegcl-Adolf. 21., Wilcox. P. H. and Spiegel, B. A. Oambmpinal fluid in elnctmehodc of psychoses. J. 19%, 10”: 697-706. chm W. 3ch” Stem, W. E. The min of acetyldxolim in bmin metabolism and ﬁmction. Man. J. ”13‘. “£41., 1957, 36: 222-455. Torda. C. Effect of omwlaion ﬂaming agents on the acetyldmlim content of the brain. J. Phyaiol., Amen. 1953, 173: 179—183. Tom, C. Effects of single injection of oortiootrvpin (ACE!) ion and acetyloholim content of brain. on I. “watch, 1953, 173: 175-178. mum W. and nauronal mtyldmline activity. I. Mr. Wm. Cholimterm patterns ma motyldwolim in the oambmspiml fluids of patients with Canad. J. Hum, 19mm, tram. 27 (Seat. E): 105-419. D. a. and Wm the omtmt md WMim of W323, in human cerebmcpinal fluids. Cam. 1. Tower, D. B. and cholimatcmes 191.9», 27 D. D. mm, (Seat. E): 132-435. Tower, D. B. and unis-clam, D. Mutyldxolima md mama]. activity. Motylcholine md daclimteme activity in the In”! osmbmspinal II. fluids of patients with epilepsy. Canal. J. 3.914%, 27 (Scat. E): 120-131. mm, Ulett, G. A. and Johnsm, H. w. Effect of atropine and soopolaminc upm chotmonoeptnhgmphic changes induced by electm—oonwlsive therapy. Eamomuph. can. Monophyunzn 1957, 9: 217—22u. Hard, A. A. Atropine in the tmatmnt of closed hand injury, J. Meano.ung., 1950,‘7: ass-noz. .V. .- - �(July 2, 1965) Jan. 3, 1958 EDIE 0!" ACTION OF TheCNS BIWCAL ms IN EHAVIOR indopendcntupmanmrofenzyne for systems proper mtabolism and functim, including cholimstemae- aoctylcholine, glucose-phosphatase, etc. The bahavior variety of is large, in either direction wt: that affect CNS ﬁmcticn and, thereby, since processes in equilibriun by increasing may be shifted or damaging the available quantity of a metabolite. A. For drug action, thanfom, tho following are cmsideraticns in potency: ‘ (a)mescdrngaffectmmzymsyste1nina reliable my? it (1:) Can (c) What get to CNS to affect the system? defenses does organism process to block or limit drug's actim mac in CNS? metabolism the affect directly amt of a specific system, to that extmt is the CNS dependent upon the system? Is the dafoct thm induced sigiificmt for the metabolism B. of CNS Secondly, while an may mderlying behavior? Rut Menace can body call into play when system has, is affected to substitute other may system? the variatim in drug effects in behavior depend upon: (a) Beluvior at onset; and pmdispositim (personality) to response; (b) mug dosage - availability to has on m mzym system; CNS and the effect it �W'wv‘mw n—m—.n-u.r:~wvmr .v 4-:- \I.’—:r~"!lwwmi‘ mama v; M'er‘ui'v-V-‘P 1‘2'.~vr1v-'wv— (c) Depmdence of war "-3;*..)I(7'4<~<'I‘R,IWT~’:~.~HV~’V~W ~, - an.» :uru.r-owr:< , .. mm? a. mum cvw V:""\ 1 < =- 1 w - -—-v. again on specific enzyme ommimic defenses (Le. substitutim for affected system). (d) Whether effect was gradual (allowing for system -— defenses, and ,r'ia Le. , enema metabolic system) or acute (not allowing defense). Individual differemes in meme may be due, thus, to differences in: (a) Dosage, ratio 8 mute of mainiatmtim (b) dependence on the affected system (c) adaptive ability to biochemical changes. To these changes, EEG is a me approximation and indicator, reflecting the homeostatic balance in various the CNS. enzyme systems of ��21 mtylcholim hydrolysis system. Persistent malt from a damned rate of hydrolysis of aoetylomlme. associated with low mmantmtim of either or Grantham-11 . livcd W, hypemyndmany my (immunised (Oonvamly. in patients with shortcircumstance—I md «II in tissue and spinal fluid my be mustang! high). Fmthuc obawa‘ioumwouldcsuaudetmmduud MW ”mam m «wanted We. and in cmbut pmabuoty 5m. Wag MW mm (at. EEG «the hypwymmny Wow nu 06 wumwmu. Mad a WW and 426 in 6m with as on. attend by amazon 9‘ WM W behauiuat dung“ the blockade“ 50M um 06 muted Mud bum. pubabLgtMtuu the“. dungu Lgtu that The We! men 06 ethyl. 05 campus“. ammummamm- mm 60!: the. attuned wavubiana. mam � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Files: Acetylcholine and Cholinesterase, 1956-1966 (folder title 3/4). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-003-0-003 Date A point or period of time associated with an event in the lifecycle of the resource 1956-1968 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/023fc3470d6cfddf7614342c86456639.pdf b07bb6498b31f3e58fe2ba4d191c8c0f PDF Text Text l+/26/57 To: Dr. Max Fink From: Dr. H. Goldenberg are contemplating a change in our cholinesterase incubation system which would cause significant differences (5-15% increase) in the reported values for true and pseudocholinesterase. This is the primary reason we haven't fOrwarded your spinal fluid values as well as the more recent serum analyses. We cholinesterase method (like all methods) comprises 2 steps: (1) incubation of enzyme with substrate under fixed Our conditions , and (2) analysis of the reaction products, from which enzyme activity is calculated. The second step employs our new and efficient color procedure. Step 1 is essentially that of earlier workers. On reinvestigating step 1 we find objections to the large amount of salt used by others in their system and may eliminate this ingredient. an apparent As salt is inhibitory, this increase in enzyme would cause concentration. All our past analyses can be corrected for this change by using appropriate factors, but the ultimate decision whether we are to shift our medium will be about 10 days in the making. are naturally anxious to get some idea of the relative changes in spinal fluid values following EST, I will forward figures based on the original salt system on Tuesday. However, as you will start running benzoylcholine as well as the butyryl susbstrate to determine whether there are 2 pseudocholinesterases in spinal fluid. This should resolve our uncertainties on this point and just might possibly lead to new findings. Next Friday we �February u , 1966 Dr. Harvey Robinson WW thimsity of The Baltim, Bur Dr. Institute Maryland Maryland 21201 lbbimm: In mid-October. I submitted the muncript ”0101111132310 Marxism in vaulsiw 'mempy" for ymr mitigation for publication in thc Jam 05 Havana and Mental Dame. I Max MP : jmh Fink. NJ). Promoter of Payduatry �L45 SOL.‘NAL OF /" .Nervour and Mental Diyemc ‘ Harvey A. Robinson} Managing Edi'oy' f Psychiatric Instihne u iv r re “’ofM—u‘ Ia d The \ 82mm”, ,, M0250; OCtOber 19, 1965 "’"-”‘\.:;,_. n—~L"""”"W‘m“‘“'°-—ﬂ _ ..._.. of receipt your acknowledge to This is Mechanisms "Cholinergic entitled manuscript " in Convulsive Therapy. �Max Fink, M. D. Department of Psychiatry Missouri Institute of Psychiatry 5400 Arsenal Street St. Louis, Missouri 63139 �Wm' ~ - .m ﬂ 9 .. w w' ‘5w; Hug-«m- - ‘ nun—v- w-pr. W 4mm‘w-q-w—I-sm . . w wwwmvwmm w “a - . m . , , an(rum October 15, 1965 Dr. Harvey Robinam Psychiatric Institute adversity of Huylmd The Baltimn. Maryland 21901 Dear Dr. Robinson: mm Pbdwﬁm in Convulsiw at. publication in the two copios The Joanne 05 of the manuscript " "010111101310 for your midnmtim for mm and W Dame. style of ﬂu citations follow those of this imtitutim, we will aubdt copies following your stylc if the article mots your approval. While the mead Sincumly yours , MIX HF: jun Pink, M.D. Professor of Psychiatry .wW '- 7k "-7“. m."- �THE N JOURNAL 67/92/011 I OF 6111 d M611 ta l lcwrence DifEdje S. Kubie, Editor-in-Chief Harvey A. Robinson, Managing Editor Eugene B. Brody, Consulting Editor The Psychiatric Institute F 0 U N D E D | N 1 University of Maryland Baltimore, Md. 21201 3 7 4 February 10, 1966 Dr. Max Fink Department of Psychiatry Missouri Institute of Psychiatry University of Missouri 5400 Arsenal Street St. Louis, Missouri 63139 Dear Doctor Fink: I am very sorry to have to tell you that your manuscript is still under editorial consideration. I do hope to be able to be able to write to you about it very soon. Sincerely our 8, 9V 5 W H. A.‘ Robinson HAR/sa »' �’4 THE JOURNAL OF New/0m and Mei/Ital Diieme lawrence S. Kubie, ZZZ:23:3,”;3.327.315?" The Psychiatric F 0 U N D E D | N 1 8 7 4 Editor-in-Chief Institute University of Maryland Baltimore, Md. 21201 February 1 1, 1966 Dr. Max Fink Missouri Institute of Psychiatry 5400 Arsenal Street St. Louis, Missouri 63139 Dear Doctor Fink: The Editorial Board has carefully considered your manu" Convulsive in entitled Mechanisms "Cholinergic Therapy. script Subject to your willingness to meet a number of minor criticisms and to make some changes that have been suggested by our readers, we should be very pleased to publish this article. This, then, is in the nature of a provisional acceptance. This consideration of brain cholinergic mechanisms and their significance in convulsive therapy represents an interesting and valuable point of view. Of course, other chemical changes have been demonstrated after seizures and have been assigned equally as important roles as acetylcholine. However, this position is clearly dated, developed forcefully, and the argument is pertinently documented. We feel that the manuscript makes a definite contribution. Nonetheless the Editors are of the opinion that the report embodies some weaknesses which if dealt with would significantly improve the quality of the paper. No one doubts that acetylcholine is important in neural function and that changes in acetylcholine and cholinesterase occur with induced seizures. The assumption that the handling of acetylcholine is fundamentally related to the amount A of hypersynchrony of the EEG is, we feel, an oversimplification. Q) in}. The thesis that the results of treatment by induced convulsions is related to the sensitivity to changes in acetylcholine levels (pp. 18—19).] has no information to substantiate it. Although you describe a "rational biochemical theory" for the mode of action of induced con- �Dr. Max Fink February 11, 1966 2. vulsions, you state only what is already known, that acetylcholine decreases in the tissues and increases in the spinal fluid with induced seizure and that the slow waves can be modified by anticholinergic drugs. Although you cite your own work for the effects ”I of atropine in counteracting the acetylcholine effects of induced seizures, you do not give evidence that the use of atropine changes 1 the therapeutic results in any confirmed study. There is no con— w “7 of evidence in for differences the vincing reactivity or sensitivity (3) central nervous system between psychotics and normals to r" acetylcholine or cholinesterase. ‘ recommend that you consider the following ideas for inclusion in the summary: We There is as yet no consistent evidence for differences in anticholinesterase or acetylcholine senstivity or levels between the psychotic and the normal brain. 1) \/" as yet no reproducible evidence that anticholinesterases given before, during or after electroconvulsive therapy change the results of the treatment. 2) There is 3) Cholinesterase and acetylcholine levels change in response to electroconvulsive treatment and in response to trauma may be a result of other biochemical changes resulting in vasodilation and increased cellular permeability which affect the level of consciousness, EEG, and behavior as well as acetylcholine distribution. At a more superficial level, we should also recommend that the manuscript be carefully scrutinized so as to ensure consistency in drug terminology. We would recommend that the generic names be used throughout the manuscript and that the capitalized trade name be included in parentheses, e. g. , methacholine (Mecholyl). We have indicated a few of these changes on p. 7, p. 9, and p. 10. I regret to note that the references do not follow the style we prefer to use. I am enclosing an information sheet, which may be of some help. Please note that the references should be alphabetized, then numbered, and cited by number in parentheses in the y / �Dr. Max Fink February 11, 1966 3. text. Please note, too, that the references should be typed double-spaced. This enormously facilitates preparing copy for the printer. On the hopeful assumption that you will be of a mind to undertake the recommended changes, I am returning one COpy of the manuscript, and will retain the other for purposes of reference. Please let me know how you feel about all of this. Very sincerely, H. A. Robinson HAR/sa Enclosures �February 16, 1966 mwmmwm Mm Manny mm Dmﬂuvoybmum Psychiatric of mm. Maryland 21201 M 3:321th Myoum andingm W"ﬂwmﬂcmin0mwlsiwnunpyﬂ MWWWmmWW Ivdﬁuﬂacmaffwttompem mum-mm. including meanwmmmmmmnwd. ﬁndtatian following tin style: whidnmmmmud. mmmmmmumamymwimmw mks. 11'. Rabin-cm ’nunkyou formant-aim. Stanlyymm, ﬂux Pink. NJ). Professor of Paydﬁatry fokp �Harsh n, 1986 Hr. Haw-y A. Roux-won, Hanging Editor 1?. Journal a! Havana and Hmtal Dim Psychiatric Institute m Lhimdty of Maryland Baltim'e. Manama new it. Robina: 21201 My" "(2le Wthunofgmdcma,mdmdﬂiedmcitatima toftttlnstyloottmjoumu. than Follovdngymmuwsﬂmn,1hvomdmfmdpmdmsuof in Oanvulsiw hernia: apart Mmemmhth meunincludad,udngayomlmm. Ihawdmdﬂntiﬂewdnhmdmmtimaddoh wanemtmdiatm. Ihopethntthiadmft.michI11hnmmttor,m dthyumappzovnl. M you for your mu. Stanly yams, Fink, NJ). Manor of Psychiatry Max 31‘? �‘5: i THE N JiOURNAL or I 67.120“ 5‘ 3' Men ta ﬂyld lawrence 1 D1336“? Harvey A. Robinson, Managing Editor Eugene B. Brody, Consulting Editor The Psychiatric F O U N D E D | N 1 Editor-in-Chief S. Kubie, Institute University of Maryland Baltimore, Md. 21201 3 7 4 March 9, 1966 Dr. Max Fink Missouri Institute of Psychiatry 5400 Arsenal Street St. Louis, Missouri 63139 Dear Doctor Fink: revision of your manuscript, for which many thanks. This now looks perfectly fine in all respects, and we shall be pleased to schedule it for publication. We have the best guess is that this material should get to the printer in five weeks' time or so. Galley proof, then, should come to you some time late in April. My When you receive the galley proof, I hope you will be able to correct it and to return it to me promptly. Very sincerely, H. A. HAR/sa Robinson 02,9 8“! �THE JOURNAL OF NERVOUS AND MENTAL DISEASE Copyright © 1965 by The Williams & Wilkins Co. Vol. 140, No. 2 Printed in U.S.A. Information for Authors Manuscripts and correspondence pertaining thereto should be addressed to the Managing Editor: DR. H. A. ROBINSON, The Psychiatric Institute, University of Maryland, Baltimore, Maryland 21201. Manuscripts should be typed double spaced on one side only of 8% x original and one clearly legible carbon copy should be submitted. 11 paper. The It is helpful if the author supplies a short title for use as a running head. This should be typed on a separate sheet and be the ﬁrst page of manuscript. Type the complete title of the article on a second sheet, and the authors’ names and afﬁliations on a third sheet. Type double-spaced on separate sheets: tabular matter, case histories, quotations, formulas, and other subsidiary matter in the text, footnotes, bibliographies, and legends for illustrations. Legends must not be attached to or written on the illustration copy. Positions for tables and ﬁgures in the text should be indicated in the margin of the text page. Manuscripts should be accompanied by two copies of an abstract of 300 words or less. Illustrations should be drawn in India ink on white paper with clear lettering. Photographs should be glossy prints. The title Of the article, name of author, and number of the ﬁgure should be written with a soft pencil on the back of each illustration, and the top designated. References should be designated in the text by number in parentheses, e.g., (7). The list headed REFERENCES at the end of the paper should be arranged in alphabetical order and numbered. Abbreviations should follow the style of the Index Medicus. Examples: Book reference: 3. Critchley, M. The Parietal Lobes, pp. 171—181. Arnold, London, 1953. Journal reference: E., Mirsky, A. F. and Pribram, K. H. Inﬂuence of amygdalectomy on social behavior in monkeys. J. Comp. Physiol. Psychol., 47: 173—178, 1954. 11. Rosvold, H. Costs of author’s alterations of type or cuts, in excess of $1.00 per page, will be charged to the author. Corrections of printer’s errors are not charged to the author. Also the author will be charged with the cost of engravings in excess of $50.00. One invoice will be sent covering cost of reprints, alterations and engravings. The editorial ofﬁce should be notiﬁed promptly of any change of address. Galley proofs are sent to the author, and should be returned with manuscript to the editorial ofﬁce. A table of cost of reprints with an order slip. is sent with galley proof. �runs-“mm” w'u‘. \ q. WJ~F'WWWWMW'W rerI-Iw-um w-mrwmwwz—mr urn—rm—v- mmrﬂrvmuu (HOMO ASPECTS NIX 0? rim, mm W HJ). "mt—amt“: �....‘.;v- I-‘mm ..r.-- .. ... v t . .. .... -- . 71-17”W‘ m .wn -.-»r.-n---» 1'- ~ 1* ~- the Department of Psychiatry, Washingtm University School and the Dapummt of Psychiatry at the of [ﬂasmri Institute of Paydmiatry, University of Missouri Sdhool of Madicino, SHOO Arsenal St., St. Louis, Missouri 63139. mam Aidad, in by usms grants m—sm, m—2715, menus, and PEI-11380; and thc Psychiatric Ibsen-cm medatim of Missouri. Ix: 65-8 part, 2—25-66 Ravisod for the Iowa 05 Nuvoua and Mental Dame. �GiOLIhEIRGIC ASPECTS OF CONVULSIVE 'DiERAPY While the mode of action of convulsive therapies remains enigmatic, one theory holds that the early development and persistence of changes in brain function are rﬁquisite to change in behavior (17, 20, 22). A useful index of murophysioloﬁical changes is the appearance of high voltage electroencephalographic slow wave activity (22, 23). While the biochemistry of this activity is poorly understood, damstretims that it may be inhibited by atropine premedicaticn (3k,66) or blocked by anticholiner-gic coepomds (18, 19) suggest that crolinergic system may play an active part. 'lhe EEG patterns and the response to anticholinergic drugs issimilar-inexperdmntalmdclinicalheadtrmmamdtoa lesser extent, in spontaneous seizures to that seen with convulsive trerepy. 'Ihe activity and changes in concentration of cholinesterases in brain and spinal fluid in head trams, spontaneous seizures and convulsive therapy also slow many similarities . This review discusses these observations to provide the basis for a hypothesis of the role of oholinergic changes in the convulsive therapy process . Acetylcholine has been extensively studied as an agent in the trensmissim of nervous impulses since tion by Dale (12) and Load (38). in a bound form, acetylcholine process . It is A its early identifica— constituent of nervous tissue is liberated during the excitaticm rapidly hydrolyzed through the radiation of acetylcholnesterase and is rapidly reconstituted by the cholineacetylase systemMS) . Free acetylcholine has not been measurable �in normal oerebmspinal ﬂuid despite the rapid bound aoetylcholine during periods But breakdown of of activity and excitementms) . tl'e normal cerebrospinal fluid does have mamble oholimstemse activity, principally of the "tune" of mcholyl hydrolyzing type ChoLéuuch Mpew 05 Wombat Tum. Free acetylcholim was fomd in the oerebrospinal fluid of cats (I41) . within a few minutes after experimtal heed trauma and persisted forvaryingperiodsuptouam. 'Ihequantityoffree eostylomline varied between 2.7 and 9.0 game percent, and the mmt was related to the degree of indmed trams (6). Conctmnt electroencephalogram first denmstrated high voltage fest activity, interpreted as evidence of an intense mutualdismarge,whichwassomsumededbyasmmperiod of flattening of all recorded electrical activity. 'Ihese phases were followed by prolonged periods of high mlitude sharp waves in the delta mquencies. 'Ihe behavioral changes related to the degree of induced of manned free aoetylcholine . With to the aunt higher levels of acetylcholine, Bernstein reported greater degrees of EEG abmvrmlity and greater changes in mciousness. trams and Spontaneous post~trmnnetic seizures were also related to the emunt of free acetylcholim appearing in the oerebrospmal ﬂuid. �em the concentration of ccctylcholim Bomstcin applicd acetyloholinc to cortex. When out oercbrul m l gonna porcentcrlcss,hizhmlitudosharpwavosof1wfmqucn¢m appeared in tho doctmmceptulcgrm. was mm in flattened to 2 gm: When tho concontmtim percent, the cloctromcapmlogmm a fashion parallel to the post-mtic records . Investigatiom in neurological patients by Tower and in the free ccctylcholinc com-Wmtod Wm spinal fluid only in patients with meant head trauma, meant seizures or after olectroconvulsivc thwapy (63). Mal Fun acctylcholim varied from 0.2 to 100 gm pcrctmt. In assaying spinal fluid circumstance activity, they noted a rise in the mpccifio oholimstcmsc fructim (bcnzoyloholinc— splitting) and a drop in tin swcific circumstance {motion (unﬁmdnlim-splitting) in patimts with head tram and sharp following convulsive tmmpy. Artur spontmoms seizures, fluid did not exhibit such inversim contained free acctylcholim. They concluded that however. the ccmbmapiml although it with the varied of free directly acotyloholim m1 and that mammal of the oholinestcmse dome of cerebral functions was a more mitivc indicator of ocmbml damage. the W Bloctmencophalom. talent at varying intervals following also indicated a relation betwum the degree of EEG m. abmmlitymdtmappwmocoffmcmtyldnlincintm combmapinal fluid. �-7- 1......» um"... —— u r. mﬁ" 57—..- .. -- 1"...” y-w.-u~m-v»- vows-r r, wlma-«w- ”a: u . ...v - -. mmased aoetylolnlim in net brain after trumatic also reported by Kovach, activity was inhibited in was to the muscle preparation. 9:5}; m ., n '- e . 71‘ —_.... - "MW“, shock (36). This aoetylcholine by the adninistmtion of atropine eleotrogruphic, behavioral and mmrologic signs of head me trauma were blocked by the parenteral administrvatim of O.5-—1.0 tug/kg atmpins, asweresimilar'clinicaldmgesooomringaftertm inhmisterml additim of anetyloholine (6). observations to the mamnt of closed head Ward applied these injtmies (67) . In 20 patients with varying degrees of trauma, he administered atropine subcutamxsly in doses of 0.1 rug/kg, mting clinical inpmvemnt in scan and a reversal of the electrogrephic effects in others. ‘Ihe some oranges in the post-trumtic electroencephalogrm were mporhsdbyJemmerandDednmrinastmyofdieﬂnazim, another mtidmolinergic drug (33). A single intravenous dose in forty patients resulted in normalizing the abtmal electroencephalogram in twenty—two and marksdnpmvementin six others. of post-Wtic shock and Similarly, in Wm oembraledemainminals, Denisenkorepor'tedablodcingofme clinical changes and trunntin by such (13) . Thu, the mount Aptnat (no. mticholinergio ounpomds as mthylbenaltyzim 05 (up. acetytdwune my thymus 4'1: the mum and the amount as 5w (cumming Wombat “Layman, the dzgue and type abnalmauty, and changu in demomcephatoguphtc W mm“ Md behavtm appm pheuauena, which may be udueed by the «Mugs. 05 «A 05 antéchounugtc _, t , �Bmu'n eeetytchoune and Mahounugic dkugA . The effects of the direct application of acetylcmline to the central nervous systemmyalsobeblookedbymtidmlinergic drugs. The aaninietntion of the clmlineeteme hmibitor diuisopmpyl flmrophoaphate (DFP) elicited high amplitude mpid frequency EEG patterns similar to status epileptiws and ecu post-traumatic states (2!, 31, 32, 68). These EEG effects were blocked by small doses of parenteral atropine and sccpolamine. The great increase in acetylcholim after tetmethyl pyrophosphate ('13P?) was measumd and related to the toxic effects and the induced cmwlsions (29, 59). Wield and Denpsey prepared exposed animal cortex with pmstignﬁne and evoked electroencephalographic spike activity. prior ministration of atropine blocked the appeamoe of spiking, or if present. this electrical activity could be 'Ihe eliminated by atropine (9) . In contrast to these findings, Brenner and Merritt applied topical acetyloholirm in concentrations of exposed cortex of cats , and noted no encephalogmphic chmges The 2—1/3 to 10% to the effect an the electro- after intravemm atropine (1 tug/kg) (7). concentrations of coats/lemme in these experimnts, however, were higher than the topical applicatims (1-H gamma percent) and the intmcietemal (0.240 game percent) injections of Bernstein (6). Brenmr and Merritt also noted electroencePMJogr'aplﬁc effects similar to acetyloholine after meﬁuolnline (rbctwlyl) and car‘bmxyldlolim (Daryl) in concentrations mob lower than the acetylcholine cmcentmticns . They asmibed the increased �effectiveness of these choliner-gic drugs to their lack of sensitivity to cerebral cholinasterases . These data are conﬂicting and to qualify this issue. Cmbnaepémc Fluid View Mar study is necessary Amman of aoetyloholine mtsbolism finds and it Su'wuu. One in nervous tissues in an bustive and bomd form. wring periods of activity, sootyloholixnis libemtedattheoellmmbmwl'nmit is rapidly deactivated by dnlinestemses . The mom“: of bound acetyloholine is the resultant of the oontimnous processes of syntl'nsis, liberation and It has been postulated mm. that the level rises during sleep and falls during waking activity (15, 29, #5, 60). Tobias egg};mported increased free and total sootyldmoline after chloroform and nonbutal (ck) anesthesia in net and frog brinui but no changes after strychnine or piorotoxic oawulsims (60). Richter and levels in transient, however, as the msynthesis rate for aoetyloholim in rat brain is high (7 ganm/gm/minute) (as). mass observations were confirmed by Elliot 51:. 514. (15) and Ckossland and Merrick (ll). Giarm and Pepeu found the increase in acetylolwline following various depressants to be rwghtypr'oportimltomedogmeofdopmsimofthe central mus system mad the redaction in motor Rayner-t and Buck, activity (29). however, studying brain acetylcholine levels �during sedation cone-1m that some sedatives were associated with elevated bmin acetylcholine, but that no rigorous mletimships existed (39). In part, this may be related to the earlier observations of and Elliot that acetyldwline synthesis assured in rat brain slices is accelerated by low dosages of mm narcotic drugs, but irhibited by high dosages (140). Free acetyldaoline was reported in the spinal ﬂuid in patients with epilepsy (10, 63). 0f 56 epileptic patients , m; demxsmtod free acetyldlolinc in qumtiﬁes of 0.02 to 5.0 with an average of 1.0:bgannn percent. Acetyldaoline percent gm levels were related to the fmqmncy of seizms, the extent of electroencephalographic abtmmlity, and to the time since the last seizure, but bore no relation to medication, type of epilepsy or level of cholinesterase activity. Elliot 9}; 114 also noted fme aoetylcholine in the spiral fluid in mundane up to 3 gm percent after pentylene tetremol (Mammal) convulsions (15) . Mechem vimd the increased acetyloholine as a by—pmchct of the seizure, and not came]. (63). Studying the hypothesis that seizures were imhced by the commution of mtyloholine, ’lbrde measured the level of acetylcholine in hm tissue after pontylenetetmzcl convulsions. She noted a Tower and �rise in the acetylcholina content of the conwlsion. failed . to occur. hash before and a fall during certain levels of aoetyldwline, convulsions suggested that the fall in tissue aoetylcholine Below She during a convulsim was due to the inhibitim of acetylcholine syntresie by increased concenmtions of metabolites such as ammonium ions (61, 62). GiummmdPepeualsomeasmdclmges incenmlnewous system acetylcholine following various after mﬂadmlﬂle stimlatts (29) . Only and 3, 5-dimthylbutylethyl-baxbitm'ete was there a significant changein the acetyldmolim level . They noted a decrease in association with induced convulsions . With other drugs which they classified as ipmniazid + stimnam ipmiazid, (LSD, hydrmcytryptophan, and iprcniazid + DOPA) there in acetylcholine level . they concluded that despite intense excitation produced by these conpomda, them were no changes in acetylcholine hols unless these were observations ('lhe in convulsions. differemes by awarded were no changes betwentheseobservemandOomgtglﬁimdlbmrmdeadmem related to the differences in mthods of biochemical masummnts, for the latter measured chmges mflecting free may be acetylcholine only, while Siam and Pepeu measured the total acetylcholim. including forms of These AW“ bound and m acetylcrmlineluol). suggest that spontaneous an induced mm 4;qu in 5m. acetylehoLéne an abound 5m m bound 50m which my be Reﬂected in the enhance and Auzuau Cmbxal acetylchoune (Laid. activity spud deemed“, teaming tum Levels 06 acexyzehoune, whue deep and anesthesia augment Wicca“ plwduduon taming tame Levels . accompanied by an inc/Lease �t ~ .wr, ~ also Two ,7 w“ in... gym. m.“ cm u , . .......w....w,,.,_ .7... , , .7 , ,...,. “ﬂu..." ......._ , ». __‘ -7, N-... .. n"... -..—.. - .u»...——..r.n Wm m -gNuvom 3mm Chounutwuu. m:- and Wm maid spiral fluid momesternae activity (63, types of dumnstemes 614, 65). whioh hydrolyze acetylcholine are mutually found in the spixml fluid: ctnlimstemse~1 ("trm," "amcific," or mom—hydrolyzing) which has a high specificiw for anatyldnlino; and cholinestemse—II ("pseudo," "mnapccific," or bamyldmolimahydmlyzing) . The diffemt rates of hydmlysis for nothao‘noline and benaoyloholim permits qualitative distimtiom . By reporting tho dwlinestemse activity as a ratio of the activity with mtrudloline and huuoyldmlim substrates empamd to an acetyldxolim substrate dnlimstomseJ/aoatylcholﬁxe and armlimstemse—II/ aoetyldnlim ratios are derived. Normal oembxospinal fluid contains estemses in the ratio of 33:17 for dnlixxestemsa-I to dmlimstemse-II . In patients with head mum. 'lbwer and McEac-Mm reported m inwnion of the oholhnstemses with an shamans in the okxolia‘IIstomean fraction of the spinal fluid and a decrease in dxolimstemao-I activity. 11» extent of the oholimstemse malwasmlttadtoﬂmsewrityofmmmdtothedagzu of the elootmumphalomphio abnormality. In patients with elevated spinal fluid aoetyloholim after ratio of dolineatemoes or total oknlixmstemse activity was fomd. spontaneous seizures, mwever, no chmge in the �Following the recent denmstratims that neurol stinmlation produces changes in brain weight and acetylcholinesterase (37, ), Pryor M9, induced swims in and Otis studied the activity effects of repeated Wistar rats ('43). After as little as u weeks, they observed increases in brain weight and in acetylcholinestemse activity, related to decrements in behavioral performance. in cholinestemse activity may be related to which was Changes changes in cell membrane permeability. Qualinesterese-I is found in highest concentration in the central nervous system while cholinestemse—II predominates in other tissues, especially cerebral acetylcholine, vesclilaticn blood serum. With immersed and increased cellular permeability may be predicted, with a vucﬂai‘}uitrgnswatim varying with the extent and duration degree of of the vasodilation (35). Spiegel, Spiegel-Adolf, and their coworkers demtrated such permeability changes and increased conductivity of the tissues associated with the appearance of various ions (as potassimn and phosphate) in the spinal fluid following electrically induced convulsions (Bu-58) . Such non- electrolytes as nucleic—acid splitting enzymes also increased. Changes in cellular permeability may be the basis for the high concentrations of acetylcholine and increased concentrations of cholinesterase-II after induced seizures or head trauma (65). The persistence of acetylcholine in spinal fluid after trams and after seizures despite increased cholinestemse activity may be related to the sensitivity of the acetylcholine— head cholinesterase-l system to concentration relationships (8, #1, 85) . �.At "physiologic" concentrations , hydrolysis of acetylcholine is rapid (34+ microseconds) but at higher. and lower comentrations, the activity falls off quickly. In contrast, the cholinestemse-II acetylchcline relationship is non-specific and the rate of hydrolysis increases with increased concentratim. ' relationships are related to the induction of seizures. the usual concentrations of ecetylchcline at cell membranes These While are destroyed by the specific activity of clmlimsterese-I in a few microseconds, an excessive concentmtim following excitation may exceed the rate of hydrolysis by dualinesterase-I. is seizmre threshold seizure reached and a seizure induced, with the wt scetylcholine affects vascular itself adding to the increased The of free scetylcholine. and The cellular pemeebility, altering the concentrations of various ions, including dialinestemse-II, in tissues and in the derebrospinel fluid. The activity of dwlinestemse-II, though the low efficiency and depending on cmcentmtion kinetics, remces the acetylcholine in the tissues in hours to days to levels for the physiologic action of chcljnestemse-I. Chawutuase theta ins/wade in appeals. in the spinal (ﬂuid as a uéueaon 06 ﬂuids, mulling (Item chaugu in mm sea numb/tans pumeaway occasioned by teamed aeetylehoune. The teamed ehounutuasu Me paint 06 the homeostatic mechanism canWLung the Leveu 6M. nmuoub system 06 acetyzchaune at can mmbmu necessary datum. �-12.. t-!ypeluync/wny and Induced EC?! Canvuuiom. The significance activity for the convulsive therapy process has been repeatedly stated (22, 23, SO, 51). The early appearance of high degree hypersynchrony and its persisof the deVelopment of high voltage slow wave tence throughout a treatment course has been described as pre- requisite to inpmvennnt. Both the electrograﬁiic and the behavioral clunges of inde cmvulsions were transiently reversed by the acute aministmtion of experimntal anticholimx‘gic alnpomds (18, 19). The intmvernus injection of diethazine, benactyzine, the piperidylbenzilatea and WIN-2299 induced These EEG JB—318, JB-336 and JB-329 BBQ (Ditran), deayncruonizatim in psychiatric subjects. changes were associated with behavioral aka: alerting, anxiety, tremors, illusions , and railucinatims. In patients who had recently received electromnvulsive therapy, them was a reduction in slow wave activity and a reversal of euphoria, dnnial and oonfmion. Atropim in low doses was associated with EEG desynolmnizatim accompanied by tachycardia, nervousness and tension. At higher dosages, hypersynchrmws slow anes, followed by lower voltage, poorly organized delta activity with activity fusion and diswientatim. superimposed beta was associated with progressive con- effect of anticholinergic drugs on slow wave activity was also assessed in convulsive therapy by the chronic adminis— tration of atropine (5 mam per day) and scapalomine (1 - 3 mg) The of-WW during the weeks of tmatmmt. The �-13.. mm of group who alwing was significantly less than in a cmtrol had not moiived the amine adminietretim (66). EEG The sasnples were too small for clinictl correlation, but the date is maistent with a definite blocking of the clinical effect. Marked improvement was seen of 5 in 2 of '7 atropine treated, none scapolmnine treated and in four of the six waiving mmdified authors may have Ad who ECT. cmtmls this study we not replicated by the suggest that dosage factors or population changes contributed to the different results (34). in mam Mam, the demoguphic changed induced continuum my be modiﬁed by the 06 muchounugic 06 acctywzounz ad anou’ated 9W1. dlmgd, dugguzéng inc/Lead ed that WWO): anemia inc/Lead ed chaunctgic adaptivity the high wattage Mow wave 05 x16 activity. AcetyMaune and Induced Couvwionc. Despite a constant application of mm , however, there is a greet variability in the time of eppeardnce, the duration and the exxent of the electmgrephic slow ween activity as well as the sensitivity of to modification by alerting, hyperventilation and barbiturates in psychiatric populations(30). The differences in the demo. of induced EEG hypersyncmrcny may related to differences in central duelinergic activity. The failure of certain patients to develop hypersynchmny be may be associated with the absence of free acetylcholine and with minimal clmxges in cerebral function, thus precluding a clinical response to induced convulsions. Tower and HcEachem, �-33.. in their study of omniooerebml tram, included observations of six psychiatric patients undergoing convulsive therapy (63). after 3-? treatments they reported free spinal fluid acetylcholine in two patients; and an increase in clnlinestemseull and a decrease in cholinestemse-I with a reversal of the ratio of oholinestemses in five of the six Studying the patients patients. the one patient in the series who failed to show either free aoetyloholine or a oholinestemoe ratio reversal in the spinal fluid was described as: "It is interesting that this patient was tmtmt.“ From the only one of the six to show no response to these observations they omeluded that the spinal fluid changes in induced convulsions were more like those of cmniooerebml trams than those of spontaneous epilepsy. Other evidence of altemtimas in the pemability barrier seen in the damstmtions of an increased cmoentmtim ofoooaineinbmintissues threedays aftersseriesole induced omvulsions (l). The change in concentration of this large molecule, ordinarily absent in briin tissue, was associated may be with the appearance of hypersynohmny (delta btmsts) in the elect'oenoephslogram. Fm thus obsmvauam we would conducts that induced command, Like mucouebmﬁ Mama and spontaneoua balm/ms, an associated with an inc/Laue in ﬁne. acetyzchoune in am, mey enhancing the. «:2qu as chaunutmuu. The Level. 05 ﬁne Macadam sawing «mm and �a hypUuynchlwny a one mama 06 mend Leveu 05 magichouue maintained by upewted induced Aazwlu. acetytchaune and the. melted mey including chewable/(Mu. 05 The momma», changu in Lym, including acetytchoune (that Aubamue 504 the. pwutent EEG and 04‘.th Aubetancu, mmummm elect/w- H movide the behavioml. changu and EEG hypn- the. Maﬁa Aynchhong ﬁauomlng induced convulsions. An 05 application the medic/tan Medication 06 05 05 «than couoquonA 424 (men in the convuuive zhmpy aupome and the paychoeu (21.). Chounuteluuu and the Medication 05 Peychaeu. Funkenetein g_t_ g}: demnstr‘ated a relationship between the blood pressure response to methocholine, an active cholinergic agent, the and the clinical response to omvuleive therapy (25-27). Inmdiately after the injection of methaoholine, blood pressure falls, usually returning to the baseline within 5-20 minutes. A return within 5 minutes places in the patients in Groups I, II or III; while a return after 20 minutes places the patient in Groups VI and VII. Group I and Group II-III have a 9 and a 35% recovery 89% VI VII and while Group Group respectively, motors rate, and 97% recovery rates to induced convulsions (27). Group I to III reactors may be looked upon as patients in whom methecholine is rapidly hydrolyzed; while Groups VI and VII have a slow hydrolysis rate. (The response to injected epinephrine was suggested as a second criteria in the �-16.. While (H8). value of limited but discriminating is classificatim, we have no biochemical explanation of the differences metabolism of nethachcline in these psychiatric in the it M8, is possible that the blood and tissue cholinestemse activity levels of Groups I-III is high, while that of Groups VIJII is to genera psychiatric populations. differences in blood oholinestemse levels in normal and low ccnpared The ill subjects have been extensively titled studied. Despite differences in methods ('4, 5) , elevated cholinesterase levels mntally ccupared to normal populations have been reported for depressive subjects (W, #6, H7, 52), schizOphrenic subjects (1“, 28, 53) and a mixed psychiatric population (#2) . Alpem reported lowered cholinestemse levels in schizophrenic subjects (2). mile these studies appear inconclusive, they provide data that the variations in blood cholinesterase levels are generally greater and frequently elevated in the mntally ill. Negative reports include the failure by Bllman and Callaway (16) to confirm Rubin's study; and Altschule's review of the data suggesting no abnormality of cholinesterase Conclusion. levels in the mentally ill (3). This review stunnerizes sane of the available data suggesting that cholinergic mechanism may be central to the convulsive therapy process. Induced convulsions are associated with vasodilation and increased cellular permeability, followed by the pppeamnce of increased amomts of enzymes and electrolytes in �intercellular and cerebrospinal fluids. Amng the changes are immase in intercellular acetylcholine to levels greater than can be destroyed by aoetylcholinestemse activity, and enhanced amounts of butyrylcholinestemse. The increase in an acetylcholine, vasodilation, and increased cellular permeability appear as interrelated phenomena associated with trauma, seizures and induced convulsions. These biochemical changes are associated with increased electrical hypersynohmny which is recorded as EEG slow wave activity in scalp electrodes, and which can be modified by acute and chronic ediﬁnistmtims of many anticholinergic dmgs, including atropine. benactyzine, diethazine, pmcyclidine and various piperidylbenzilatus. In these regards, induced convulsions are more similar to cerebral trauma. than to spontaneous seizures. in cerebral biochemistry alter cellular activity sufficiently to affect consciousness and the behavior of subjects. Failure to induce persistent biochemical changes , including the concentration of acetyloholine, results in failure to produce The changes behavioral change. Thin! is, as yet , no consistent evidence for differences in the sensitivity or dependence of populations on cholinergic medianisms; the differences in the rate of development of cerebral changes to the same number and frequency of induced convulsions and the classification based on the blood pressure response to mthacholim suggest, however, that such differences may be important in the pathogenesis of different psychoses. ��E' U ‘6 :6 _J! U m 3: = g 0 D. YOUR :3 I) Ta. 41: E O ° 8 : z a £3 'u E as. WITH .- g o 5 .— ‘E 3 e “ n:<3 0? DESK £5 :a: “1’" = 0 0)|.um :3? 1:5a o ‘ﬂ :1: III z....a) co n— .I I) o- '. ”-0 c: :3 0 >~ 3: 5 ” 9 '23: :2 a - c: 1.: U an 3.. 0>§ E "E g0 " L D. a; 0w a0 £5 z13 (g i: (U .—l ._ \— 3 13 U! w e 13 U < .g 23 at- 3 0 o - ac il ,~ 3" :2 '3 E PRESENT ea " ‘- 2'5o AT o 5" a»5 °E n.—O mi 1:8 m “ Ex a Illa REGISTRATION “" ”'7 a: c c q, u:3 32:) «n- m '0 C m >‘ 3: Q h” o: a: 0< c E 5‘: h o55 ON Eucu 0 1 IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII|IIIIIIIIIIII|IIIIIIIIIIIIIIIIlllllIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 122nd ANNUAL MEETING AMERICAN PSYCHIATRIC ASSOCIATION ATLANTIC CITY, N. J.—MAY 9-13, 1966 HIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIHIL_ IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII First Name City state Last Name �CHOLINERGIC ASPECTS OF CONVULSIVE THERAPY Max Read M.D. at the May Now, Fink, l22nd ﬂeeting of the American Psychiatric Association, 12, 1966, Atlantic City. Proféssor of Psychiatry, 5-9-66. New York Medical College, New York City. �The mode of action of induced convulsions is still puzzling. Various theories have been proposed, including those best described as wholly psychological in scope, and those wholly biological or Neither extreme point of view is consistent organic - structural. with the available facts, and the neurophysiological - adaptive models — combining, as they do, both the biological data and the personality historical facts - are the most satisfactory today. One of the neurophysiological - adaptive theories suggests that persistent alterations in brain fUnction are a necessary condition fOr behavioral change and inprovement in the convulsive therapies. While many measures of altered brain function have been studied, similar relationship of change in measure to behavioral change, the appearance of high voltage slow wave and each has shown a activity in the scalp recorded electroencephalogram.has been the The induced delta activity most useful index in these studies. is readily observed, easily quantified and the amount, distribution over the scalp, amplitude and persistence are each directly related the frequency of the induced seizures and are independent of the mode of induction of the seizure. to the number and While the biochemical basis for these EEG changesgii=3 poorly understood, observations that the induced slow wave activity was inhibited by the intravenous administration of anticholinergic that cholinergic mechanisms may play an active part not only in the EEG activity but in the therapeutic compounds, suggested process as well. �patterns and the response to anticholinergic drugs M. in convulsive therapy were—seen to be similar to the EEG and The EEG behavioral changes in experimental and clinical head trauma and to a lesser extent, in spontaneous seizures. This was clearly reflected in measures of the cholinesterases in brain and spinal fluid in these conditions. These observations led to a review of the neurological and biochemical data in induced convulsions, head trauma and spontaneous seizures, to attempt to relate the available observations to the neurophysiological and therapeutic changes observed in the convulsive therapy process. The activity of acetylcholine in the transmission of nervous impulses has been extensively sutdied since the early descriptions by Dale and Loewi.in 1914 and 1921. A constituent of nervous tissue in a bound ﬁorm, acetylcholine is liberated during the excitation process. It is rapidly hydrolyzed through the mediation of acetylcholinesterase and is rapidly reconstituted by cholineacetylase. Free acetylcholine has not been measurable in normal breakdown of bound the fluid despite cerebrospinal rapid acetylcholine during periods of activity and excitement. But the normal cerebrospinal fluid does have measurable cholinesterase activity. �In_exparimenta&—trauma—ie—eaes, free acetylcholine was found in the cerebrospinal fluid within a few minutes after head trauma lk.(4T$ and persisted for varying periods up to #8 hours. The quantity of free acetylcholine varied between 2.7 and 9.0 and the amount was gamma percent directly related to the degree of induced trauma - the greater the induced head trauma, the higher the amount of neasured acetylcholine. Concurrent electroencephalograms first demonstrated high voltage fast activity, interpreted as evidence of an intense neuronal discharge, which was soon succeeded by short periods of flattening of all recorded electrical activity. were fbllowed by prolonged and These phases persistent periods of high amplitude sharp waves in the delta frequencies. The degree to which the animal's behavior was disorganized related both to the degree of induced trauma and to the amount of measured free acetylcholine. The higher the observed levels- was of acetylcholine, the greater the degree of EEG abnormality and the greater the changes in consciousness. The development and the persistence of spontaneous post—traumatic seizures were also related to the amount of free acetylcholine measured in the cerebrospinal fluid. In a parallel study, acetylcholine was applied directly to the exposed cat cerebral cortex. acetylcholine was 1 gamma When the concentration of percent or less, high amplitude sharp �waves of low frequency appeared in the electroencephalogram. the concentration was increased to 2 gamma When percent, the electro- encephalogram flattened in a fashion parallel to the post-traumatic a relationship between the EEG changes records, thus again showing and the concentration of free acetylcholine. Investigations in neurological patients by in 1948 demonstrated Tower and McEachern free acetylcholine in the cerebrospinal fluid only in patients with recent head trauma and recent grand-mal seizures, but also after electroconvulsive therapy. Free acetylcholine varied fron10.2 to 100 gamma percent. In parallel studies they measured the spinal fluid cholinesterase a sharp rise in the butyrylcholinesterase (non-specific) fraction and a fall in the acetylcholinesterase activity. They noted (specific) fraction both in the patients with head trauma and in those fbllowing convulsive therapy. After spontaneous seizures, however, the cerebrospinal of cholinesterases although fluid did not exhibit such it an inversion did contain free acetylcholine. They that the level of free acetylcholine varied directly with the degree of cerebral damage and that the reversal of cholinesterase fractions was a more sensitive indicator of cerebral damage. concluded Electroencephalograms taken at varying intervals following trauma also indicated a relation between the degree of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal fluid. �Continuing a review of head trauma, we note behavioral and neurologic signs of head trauma that the may be EEG, blocked by the parenteral administration of atropine. ward applied these observations to the treatment of closed head injuries. In 20 degrees with of trauma, the subcutaneous varying patients administration of atropine in some and was a reversal of the associated with clinical improvement EEG effects in others. The same changes in the post—traumatic electroencephalogram.were reported by Jenkner and Lechner cholinergic drug. A in a study of diethazine, another anti— single intravenous dose in forty patients resulted in normalizing the abnormal electroencephalogram in twenty-two and marked improvement in six others. That, the amount 06 ghee acetylchouhe may the/LeaAe tn the Aptnat ﬁhee Mia/Cd 5031.0th Wicca/Lewd Mama and the amount acetytchotthe, the deg/Lee and abrzolunaLity, ahd‘changeé type 05 etect/Loeneephaﬂog/Laphéc tn euntcat behautot phenomena, whtch may be ILeduced by the 05 appea/L a4 ammmmon 06 ate/mutated anti- ehotéhejtgtc d/mgb. 3W acetytchoune and antéehouhugtc d/LugA. While the data is not as clear, the effects of the direct application of acetylcholine to the central nervous system by anticholinergic drugs. The may also be blocked administration of cholinesterase inhibitor di-isopropyl fluorophysphate (DFP) elicits high amplitude �patterns similar to status epilepticus and posttraumatic states. These EEG effects have been blocked by small rapid frequency EEG doses of parenteral atropine and scopolamine. Chatfield and Dempsey prepared exposed animal cortex with prostigmine and evoked electroencephalographic spike activity. prior adndnistration of atropine blocked the appearance of spiking, or if present, thes electrical activity could be eliminated by atropine. The Bornstein also reported that the parenteral administration of atropine to modify the behavioral and neurological signs observed after the intracisternal addition of acetylcholine. seemed In contrast to these findings, Brenner and Merritt applied topical acetylcholine in concentrations of 2-1/2 to 10% to the exposed cortex of cats and noted no effect on the electro- after intravenous atropine. not deﬁthtte, the obeehvattone éuggebt that atnoptne encephalographic changes White may bzoch the behautotat and EEG eﬁﬁecté 06 ghee tntaoduced acetytchottne tn the Aptnat glutd. CehebhOAptnat Ftutd Acetytchotthe and Setzuheb. to free acetylcholine and spontaneous seizures ship. One view we of acetylcholine metabolism finds tissues in an inactive and bound fornn Turning again note a relation- it in nervous During periods of activity, �acetylcholine is said to be liberated at cell membranes where it is rapidly hydrolyzed The amount and deactivated by cholinesterases. of bound acetylcholine is thus the resultant of the continuous processes of synthesis, liberation and breakdown. It has been postulated falls during waking that the level rises during sleep and activity. Free ace: Icholine was reported in the spinal fluid in patients with epilepsy. Of 56 epileptic patients, HM denonstrated free acetylcholine in quantities of 0.02 to 5.0 gamma percent with an average of 1.0 gamma percent. Acetylcholine levels were related to the frequency of siezures, the extent of electroencephalographic abnormality, and to the time since the last seizure but bore no relation to medication, type of epilepsy or level of cholinesterase activity. Elliott at aﬁ. also noted free acetylcholine in the spinal fluid in concentrations up to 3 gamma percent after pentylenetetrazol (Metrazol) convulsions. the increased acetylcholine as a by-producifof the seizure and not causal. Studying Tower and MCEachern viewed the hypothesis that seizures were induced by the accumulation of acetylcholine, Torda noted a rise in the acetylcholine content of brain before and a fall during pentylenetetrazol convulsions. certain levels of acetylcholine, convulsions failed to occur. She suggested that the fall in tissue acetylcholine during a convulsion was due to the inhibition of acetylcholine Below synthesis by increased concentrations of metabolites such as ammonium ions. �that AponianeOuA on induced Aeizunei incneaie in inieiceiiuian ﬁnee aceiyichoiine Theee etudicb AuggeAi ane accompanied by an iibenaied 5iuid. gnom iii Ceaebnai bound 50am which may be neﬁiecied activity in the Apinai and Aeizuneé enhance aceiyichoiine deeinuciion, iowening iiAAue ieueiA 05 aceiyichoiine, whiie bicep and anebihebia augment aceiyichoiine pnoduciion incneaAing iibéue £evw . EEG Hypenbynchnong and Induced ConuuiAionA. of high voltage EEG slow wave The significance activity for the convulsive therapy process has been repeatedly described, with numerous observers indicating that increased slowing is associated with behavioral In the usual course of convulSive therapy, inter- improvement. treatment electroencephalogram record progressive increases in amplitude and in theta activity and a reduction in beta activity. As treatment continues, delta activity appears in bursts and is the dominant activity in all leads. These changes eventually are directly related to the number and rate of induced convulsions, and is not specific ﬁor a method ofinduction. While some relationships to type of electrical current has been observed, all _ seizure inducing methods or inhalant —— —- exhibit the electrical, intravenous same type of EEG chemical pattern changes. �early appearance of high degree hypersynchrony and its persistence throughout a tre-tment course has—bean—éeuné4834xr The «Milan... prerequisite to inprovement. Both the electrographic and the betavioral changes ofincuced conVulsions are transiently reversed by the acute administration of experimental anticholinergic compounds. The intravenous injection of diethazine, benactyzine, the piperidylbenzilates JB—318,JB—336 and JB- 329 (Ditran), WIN-2299 These EEG induced EEG desynchronization in psychiatric subjects. changes were associated with behavioral alerting, anxiety, tremors, 'llusions and hallucinations. In patients had recently received electroconvulsive therapy there was a reduction in slow wave activity and a reversal of euphoria, who denial and constion. Adztpine, in low doses, was also associated with EEG desynchronization accompanied by tachycardia, nervousness and tension. At higher dosages, hypersynchronous slow waves followed by lower voltage, pooly organized delta activity with superimposed beta activity was accompanied by progressive constion and disorientation. effect of anticholinergic dimugs on the slow wave convulsive of activity therLapy was also assessed by the chronic administration of atropine (5 mgm per day) and scopolamine (1-3 The during the weeks of treatment. The amount of EEG slowing was significantly less than in a control group. The samples were too small fora dinical correlation but the data is consistent mg) �-10with blocking of the clinical effects of electroconvulsive therapy. treated, Marked improvement was none of 5 scopolamine-treated and in controls receiving unnodified replicated ECT. of 2 u atropine- 7 of the 6 This study was not that dosage factors have contributed to the different by the authors who suggest or population changes may results in a second study. A6 reported in tn eeaebaat thauma, the eteetnognaphtc changeb 05 thduced convutttont may be modtﬁted by the adhthtbthatton 06 anttchottnehgte dnugt buggeétthg that tncheabed 05 acetytehottne on amountb tncneated chottnehgte necepttvtty t4 abboctated with the htgh wattage atow wave aettuttg. Convutttonb. Aeetytchottne and INduced Despite a constant application of treatments, however, there is great variability in the time of appearance, the duration, amount, and sensitivity to modification by alerting, hyperventilation and barbiturates activity in psychiatric populations. we would suggest that these differences may relate to differences in central cholinergic activity. The failure of of the electrographic 81 w wave certain patients to develop hypersynchrony may be associated with the failure to liberate excessive amounts of free acetylcholine, and with the minimal changes in cerebral fUnction ��-11a clinical response to induced convulsions is precluded. in their study of patients with head trauma, included observations of six psychiatric patients undergoing Tower and MCEachern after to 7 treatments they reported free spinal fluid acetylcholine in two convulsive therapy. Studying the patients 3 patients; and a reversal of the ratio of cholinesterase ratio reversal in the spinal fluid, the authors stated: "It is interesting that this patient was the only one of the six to show no response to treatment." From these observations they concluded that the spinal fluid changes in induced convulsions were more like those of craniocerebral trauma than those of spontaneous epilepsy. Fnom thete obtenvattont we woutd conctude that induced convutétont, tthe chantocenebnat tnauma and Apontaneout tetzuneé, ate attoctated wtth an tncneate tn ﬁnee acetytchottne tn tnten- cettutun gtutdb, attentng cehebnat penmeabttttg and enhanctng the appeanance 05 chottnettenateb. The tevet t4 matntatned by nepeated tnduced tetzunet. tA one ncétectton 05 attened penmeabtttty attened tevett 05 06 06 ghee EEG acetytchottne hypenégnchhony acetytchottne and the etectnotgtet and othen Aubttanceb; tnctudtng ehottnebtehabet. The changeé tn tntencettutan etectno- tyte4,'tnctudtng acetytchottne, ptoutde the btochemtcat Aubttnate ﬂat the penttbtent behautonat changeA and EEG hypeneynchhony ﬂottawtng induced convutetont. ��-12- CONCLUSIONS This review summarizes some of the available data suggesting that cholinergic central to the convulsive have observed that induced convulsions are mechanisms may be therapy process. We associated with cerebral vasodilation and increased cellular perneability, fbllowed of by the appearance of increased amounts electrolytes in intercellular and cerebrospinal increase in acetylcholine, vasodilation and increased enzymes and fluids. The permeability appear as interrelated phenomena associated with trauma, seizures and induced convulsions. These biochemical changes accompany increased hypersynchrony which is recorded as EEG slow wave electrical activity in scalp electrodes and which can be modified by the acute and chronic administration of anticholinergic drugs as atropine, benactyzine, diethazine, procyclidine and various piperidyl- benzilates. In these regards, induced convulsions are more similar to cerebral trauma than to spontaneous seizures. The changes in cerebral biochemistry alter cellular activity sufficiently to affect consciousness and the behavior of subjects. Failure to induce persistent biochemical changes, including the concentration of acetleholine, results in failure to produce behavioral change. �-13There is, as yet, no consistent evidence for differences in the sensitivity or dependence of the cerebral mechanisms underlying interpersonal behavior of populations on Cholinergic mechanisms. Differences in the rate of development of cerebral changes to the sane number and frequency of induced convulsions and of the mentally ill classifications based on the blodo pressure response to methacholine suggest, however, that such differences may exist and may be related to the pathogenesis of different types of psychoses, as well as the success or failure of our present varieties of biologiCal treatments . �CHOLINERGIC ASPECTS OF CONVULSIVE THERAPY max Read at the Now, Professor of Psychiatry, Fink, M.D. 122nd meeting of the American may 12, 1966, Atlantic City. 5—9~66. New York Psychiatric Association, Medical College, New York City. �of action of induced convulsions is still puzzling. Various theories have been proposed, including those best described The mode - as wholly psychological in scope, and those wholly biological or Neither organic - structural. extreme point of view is consistent with the available facts, and the neurophysiological models — — adaptive combining, as they do, both the biological data and the personality historical facts - are the most satisfactory today. One of the neurophysiological - adaptive theories suggests that persistent alterations in brain fUnction are a necessary condition fbr behavioral change and improvement in the convulsive therapies. While many measures of altered brain fUnction have been studied, and each has shown a similar relationship of change in measure to behavioral change, the appearance of high voltage slow wave activity in the scalp recorded electroencephalogram has been the useful index in these studies. delta activity is readily observed, easily quantified and the amount, distribution most The induced over the scalp, amplitude and persistence are each directly related to the number and the frequency of the induced seizures and are independent of the mode of induction of the seizure. While the biochemical basis for these EEG changes were poorly understood, observations that the induced slow wave activity was inhibited by the intravenous administration of anticholinergic that cholinergic mechanisms may play an active part not only in the EEG activity but in the therapeutic compounds, suggested process as well. �patterns and the response to anticholinergic drugs in convulsive therapy were seen to be similar to the EEG and The EEG behavioral changes in experimental and clinical head trauma and to a lesser extent, in spontaneous seizures. This was clearly reflected in measures of the cholinesterases in brain and spinal fluid in these conditions. These observations led to a review of the neurological and biochemical data in induced convulsions, head trauma and spontaneous seizures, to attempt to relate the available observations to the neurophysiological and therapeutic changes observed in the convulsive therapy process. The activity of acetylcholine in the transmission of nervous impulses has been extensively sutdied since the early descriptions by Dale and Loewi,in 191” and 1921. A constituent of nervous tissue in a bound form, acetylcholine is liberated during the excitation process. It is rapidly hydrolyzed through the mediation of acetylcholinesterase and is rapidly reconstituted by cholineacetylase. Free acetylcholine has not been measurable in normal breakdown fluid the of bound cerebrospinal despite rapid acetylcholine during periods of activity and excitement. But the normal cerebrospinal fluid does have measurable cholinesterase activity. �In experimental trauma in cats, free acetylcholine was found in the cerebrospinal fluid within a few minutes after head trauma persisted for varying periods up to H8 hours. The quantity of free acetylcholine varied between 2.7 and 9.0 gamma percent and and the amount was directly related to the degree of induced trauma the greater the induced head trauma, the higher the amount of measured acetylcholine. Concurrent electroencephalograms first demonstrated high voltage fast activity, interpreted as evidence of an intense neuronal discharge, which was soon succeeded by short periods of flattening of all recorded electrical activity. These phases were fbllowed by prolonged and persistent periods of high amplitude sharp waves in the delta frequencies. The degree to Which the animal's behavior was disorganized related both to the degree of induced trauma and to the amount of measured free acetylcholine. The higher the observed levels was of acetylcholine, the greater the degree of EEG abnormality and the greater the changes in consciousness. The development and the persistence of spontaneous post-traumatic seizures were also related to the amount of free acetyldholine measured in the cerebrospinal fluid. In a parallel study, acetylcholine was applied directly to the exposed cat cerebral cortex. acetylcholine was 1 gamma When the concentration of percent or less, high amplitude sharp �waves of low frequency appeared in the electroencephalogram. the concentration was increased to 2 gamma When percent, the electro- encephalogram flattened in a fashion records, thus again showing parallel to the post—traumatic a relationship between the EEG changes and the concentration of free acetylcholine. Investigations in neurological patients by in 19H8 Tower and MeEachern demonstrated free acetylcholine in the cerebrospinal fluid only in patients with recent head trauma and recent grand-mal seizures, but also after electroconvulsive therapy. Free acetylcholine varied from.0.2 to 100 gamma percent. In parallel studies they measured the spinal fluid cholinesterase activity. They noted a sharp (non—specific) fraction and a rise in the butyrylcholinesterase fall in the aeetyldholinesterase (specific) fraction both in the patients with head trauma and in those fellowing convulsive therapy. After spontaneous seizures, however, the cerebrospinal of cholinesterases although fluid did not exhibit such it an inversion did contain free acetylcholine. They that the level of free acetylcholine varied directly with the degree of cerebral damage and that the reversal of cholinesterase fractions was a more sensitive indicator of cerebral damage. concluded Electroencephalograms taken at varying intervals following trauma also indicated a relation between the degree of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal fluid. �Continuing a review of head trauma, we note that the behavioral and neurologic signs of head trauma may be EEG, blocked by the parenteral administration of atropine. ward applied these observations to the treatment of closed head injuries. In 20 patients with varying degrees of trauma, the subcutaneous administration of atropine was associated with clinical improvement in some and a reversal of the EEG effects in others. The sane changes in the post-traumatic electroencephalogram were reported by Jenkner and Lechner cholinergic drug. in a study of diethazine, another anti— single intravenous dose in fbrty patients resulted in normalizing the abnormal electroencephalogram in A twenty-two and marked improvement in six others. That, the amount 06 ﬁnee acetytchottne may tncneabe tn the Aptnat ﬁtutd ﬁottownng enatnoeenebaat thauma and the amount 06 ghee aeetytchottne, the degnee and type 06 eteetaoencephatogaaphte abnoamattty, and changeA tn cttnteat behavton appeah ab tnteanetated phenomena, which may be deduced by the athntAtnatton 06 anti- ehottnengte dnugb. Baatn acetytchottne and antichottnengtc daugA. While the data is not as clear, the effects of the direct application of acetylcholine to the central nervous system by anticholinergic drugs. The may also be blocked administration of cholinesterase inhibitor di-isopropyl fluorophysphate (DFP) elicits high amplitude �patterns similar to status epilepticus and post— traumatic states. These EEG effects have been blocked by small rapid frequency EEG doses of parenteral atropine and scopolamine. Chatfield and Dempsey prepared exposed animal cortex with prostigmine and evoked electroencephalographic spike activity. prior administration of atropine blocked the appearance of spiking, or if present, thes electrical activity could be The eliminated by atropine. Bornstein also reported that the parenteral administration of atropine seemed to modify the behavioral and neurological signs observed after the intracisternal addition of acetylcholine. In contrast to these findings, Brenner and Merritt applied topical acetylcholine in concentrations of 2-1/2 to 10% to the exposed cortex of cats and noted no effect on the electro— after intravenous atropine. not deﬁtntte, the obbchvat£0n4 tuggebt that ataoptne encephalographic changes White may btoch the behautoaat and EEG eﬁﬁeeté 06 ﬁaee tntaodueed aeetytehottne tn the Aptnat ﬁtutd. CeaebaaAptnat Ftuid Aeetytchottne and Setzuaea. Turning to free acetylcholine and spontaneous seizures we again note a relationship. One view of acetylcholine metabolism finds it in nervous tissues in an inactive and bound fbrnn During periods of activity, �acetylcholine is said to be liberated at cell membranes where it is rapidly hydrolyzed The amount and deactivated by cholinesterases. of bound acetylcholine is thus the resultant of the continuous processes of synthesis, liberation and breakdown. It that the level rises during sleep and falls during waking activity. Free acetylcholine was reported in the spinal fluid in has been postulated patients with epilepsy. epileptic patients, denonstrated free acetylcholine in quantities of 0.02 to 5.0 gamma percent with an average of 1.0 gamma percent. Acetylcholine Of 56 HM levels were related to the frequency of siezures, the extent of electroencephalographic abnormality, and to the time since the last seizure but bore no relation to medication, type of epilepsy or level of cholinesterase activity. Elliott et al. also noted free acetylcholine in the spinal fluid in concentra— tions up to 3 gamma percent after pentylenetetrazol (Metrazol) convulsions. Tower and MCEachern viewed the increased acetylcholine as a by-produce of the seizure and not causal. Studying the hypothesis that seizures were induced by the accumulation of acetylcholine, Tbrda noted a rise in the acetylcholine content of brain befbre and a fall during pentylenetetrazol convulsions. certain levels of acetylcholine, convulsions failed to occur. She suggested that the fall in tissue acetylcholine Below during a convulsion was due to the inhibition of acetylcholine synthesis by increased concentrations of metabolites such as anmonium ions. �ane accompanied by an tibenated ﬁiuid. that Apontaneoub an induced Aeizuneé incneaAe in intetceiiuian ﬁnee acetyichoiine Atudiei buggeét TheAe iib gnom Cenebnai in the Apinai bound 60km which may be neﬁiected activity and Aeizunei enhance acetyichoiine duuuctéon, tom/ting tame Lewis and aneatnebia augment acetytchome, white deep acetyichoiine pnoduction incneaeing tiibue 06 ieveii. EEG Hypenaynchnony and Induced Convuiiioni. of high voltage EEG slow wave The significance activity for the convulsive therapy process has been repeatedly described, with numerous observers indicating that increased slowing is associated with behavioral In the usual course of convulsive therapy, improvement. inter- treatment electroencephalograms record progressive increases in amplitude and in theta activity and a reduction in beta activity. As treatment continues, delta activity appears in bursts and eventually is the dominant activity in all leads. These changes are directly related to the number and rate of induced convulsions, and is not specific fbr a method ofinduction. While some relation— ships to type of electrical current has been observed, seizure inducing methods or inhalant -— -— electrical, intravenous eXhibit the same type of EEG all chemical pattern changes. �early appearance of high degree hypersynchrony and The its persistence throughout a treatment course has been fbund to be prerequisite to inprovement. Both the electrographic and the behavioral changes of hduced convulsions are transiently reversed by the acute administration of experimental anticholinergic compounds. The intravenous injection of diethazine, benactyzine, the piperidylbenzilates JB-318, induced WIN—2299 These EEG EEG JB—336 and JB-329 (Ditran), and desynchronization in psychiatric subjects. changes were associated with behavioral anxiety, tremors, illusions and hallucinations. alerting, In patients who recently received electroconvulsive therapy there was a reduction in slow wave activity and a reversal of euphoria, had denial and confusion. Atropine, in low doses, with EEG was also associated desynchronization accompanied by tachycardia, nervous- ness and tension. At higher dosages, hypersynchronous slow waves fbllowed by lower voltage, poorly organized delta activity with superimposed beta activity was accompanied by progressive constion The and disorientation. effect of anticholinergic drugs activity of convulsive therapy administration of atropine (5 was mgm on the slow wave also assessed by the chronic per day) and scopolamine during the weeks of treatment. The amount of EEG (1—3 mg) slowing was significantly less than in a control group. The samples were too small fbr a clinical correlation but the data is consistent �-10with blocking of the clinical effects of electroconvulsive therapy. Marked improvement treated, none of 5 was of 2 scopolamine-treated and in controls receiving unmodified replicated reported in of the 6 This study was not ECT. by the authors who suggest or population changes u atropine- 7 that dosage factors contributed to the different may have results in a second study. A4 tn cehebhat thauma, the eteetnoghaphte changeb 06 tnduced eonkutows may be modiﬁed by the achntnatjwtéon 06 anttchottnehgtc 06 acetytchottne dhugA Auggebttng on tnmeazsed that tncneabed amountA choltnetgtc heceptéw’ty t6 aAAoctated with the htgh voltage Atow wave activity. Acetytchotthe and INduced Convutbtoné. Despite a constant application of treatuents, however, there is great variability in the time of appearance, the duration, amount, and sensitivity to modification by alerting, hyperventilation of the electrographic slow and barbiturates activity in psydhiatric populations. we would suggest that these differences may relate to differences in central cholinergic activity. The failure of certain patients to develop hypersynchrony may be associated with the failure to liberate excessive amounts of free wave acetyldholine, and with the minimal changes in cerebral function �-11a clinical response to induced convulsions is precluded. in their study of patients with head trauma, included observations of six psychiatric patients undergoing Tower and MCEachern convulsive therapy. Studying the patients after 3 to 7 treat- ments they reported free spinal fluid acetylcholine in two patients; and a reversal of the ratio of cholinesterase ratio reversal in the spinal fluid, the authors stated: "It is interesting that this patient was the only one of the six to show no response to treatnent." From these observations they concluded that the spinal fluid changes in induced convulsions were more like those of craniocerebral trauma than those of spontaneous epilepsy. Fnom theée obAenvationA convuibionc, we wouid tihe cnaniocenebnai ane aAAociated with an inn/Lease eonctude that induced tnauma and Apontaneoui beizuneb, in ﬁnee acetytchotine in inten- cettuian ﬁtuidb, ditching cenebnat penmeubiiity and enhancing the appeanance 06 choiinebtenabei. The tevet 06 ﬁnee acetyichotine i2: maintained by nepeated induced bunt/(.66. i6 one neﬁiection 06 attened penmeabiiity ditched ieveté 05 06 EEG hypeuynchnony acetyichotine and the eiectnoiytea and othen iabAt‘ance/s, inciuding choiineAtenaAeA. The changeA in intencetiuian etectno- iyteb, inciuding acetyichoiine, pnouide the biochemicat bubbtnate 50h the penAiAtent behavionai changeé and EEG hypenaynchnony ﬁattowing induced canvutbionb. �-12- CONCLUSIONS This review summarizes some of the available data suggesting that cholinergic medhanisms may be central to the convulsive that induced convulsions are associated with cerebral vasodilation and increased cellular therapy process. we have observed perneability, followed of by the appearance of increased amounts electrolytes in intercellular and cerebrospinal increase in acetylcholine, vasodilation and increased enzymes and fluids. The permeability appear as interrelated phenomena associated with trauma, seizures and induced convulsions. These biochemical changes accompany increased hypersynchrony which is recorded as EEG slow wave electrical activity in scalp electrodes and which can be modified by the acute and Chronic administration of anticholinergic drugs as atropine, benactyzine, diethazine, procyclidine and various piperidyl— benzilates. In these regards, induced convulsions are more sinilar to cerebral trauma than to spontaneous seizures. The changes in cerebral biochemistry alter cellular activity sufficiently to affect consciousness and the behavior of subjects. Failure to induce persistent biochemical changes, including the concentration of acetylcholine, results in failure to produce behavioral change. �-13‘5 There is, as yet, no consistent evidence for differences in the sensitivity or dependence of the cerebral mechanisms underlying interpersonal behavior of populations on cholinergic mechanisms. Differences in the rate of development of cerebral Changes to the sane number and frequency of induced convulsions and of the mentally ill based on the classifications blodo pressure response to methacholine suggest, however, that such differences may exist and may be related to the pathogenesis of different types of psychoses, as well as the success or failure of our present varieties of biological treatnents. �CHOLINERGIC MECHANISMS IN CONVULSIVE THERAPY MAX FINK, M.D. DEPARTMENT OF PSYCHIATRY AT THE MISSOURI INSTITUTE OF PSYCHIATRY UNIVERSITY OF MISSOURI SCHOOL OF MEDICINE 54-00 Arsenal Street St. Louis, Missouri 63139 PSYCHIATRIC RESEARCH FOUNDATION OF MISSOURI Pulilicntion No. 65 - 8 �CHOLINERGIC MECHANISMS IN CONVULSIVE THERAPY Max Fink, M.D. Psychiatric Research Foundation Publication 65—8 September, 1965 �From the Department of Psychiatry, washington University School of Medicine and the Department of Psychiatry at the Missouri Institute of Psychiatry, university of Missouri School of Medicine, 5400 Arsenal Street, St. Louis, Missouri 63139 Aided, in part, by USPHS grants MEI—927, NIH-2715, MH-o72u9, and MH—ll380; and the Psychiatric Research Foundation of Missouri. VIII: 8/21/65 65-8 �CHOLINERGIC MECHANISMS IN CONVULSIVE THERAPY Despite extensive use, the mode of action of the convulsive therapy process remains enigmatic. The neurophysiologicalradaptive theory attempts an assimalation of neurophysiological, psychological, clinical, social aspects of the process (Fink, 1957, 1962)° In this View, the early development*and persistence of signs of altered cerebral function are and requisite to changes in behavior (Pink and Kahn, 1956), with electroc encephalographic slow wave activity as the most significant index of altered brain function, Demonstrations that premedication with atropine inhibited this slow activity (Ulett and Johnson, 1957) and that-anticholinergic compounds reversed clinical as well as electrographic changes (Fink, 1958) suggests that the biochemical basis fbr wave “the convulsive therapy process may be of the central nervous system. The in the cholinergic mechanisms role of acetylcholine and the cholinesterases in the convulsiVe therapy process is discussed in this review, Acetylcholine has been extensively studied as an active agent in the transmission of nervous impulses since the first descriptions by Dale (191%) and Loewi (1921); It is a constituent of nervous tissue. existing in a processa bound form Which It is rapidly is liberated during the excitation hydrolyzed through the specific action of cholinesterase and is rapidly reconstituted by the choline— acetylase system<Richter andessland. 191:9)w In normal. �cerebrospinal fluid, free aoetylcholine is not present despite the rapid breakdown of bound acetylcholine during periods of activity and excitement (Tower and McEachern, 19u9a)° The cerebrospinal fluid does have measurable cholinesterase activity, principally of the "true" or mecholyl hydrolyzing type (Nachmanson In the absence of free acetylcholine and Rothenberg, 19MB), under’resting conditions, electroencephalograms fail to (a) Cholinergic Aspects of Craniocerebral Trauma: acetylcholine was found after experimental up to H8 show and abnormality. Free in the cerebrospinal fluid within a few minutes head trauma in cats and persisted for varying periods hours (Bornstein, 1946)o varied between 2,7 and 9,0 gamma The quantity of free acetylcholine percent, and the amount was related to the degree of induced trauma, Concurrent electroencephalograms demonstrated records first filled with high voltage fast activity, interpreted as evidence of an intense neuronal discharge,which was soon succeeded by a short period of flattening of all recorded electrical activity, by prolonged periods These phases were then fOIlowed of high amplitude sharp waves in the delta frequencies, The behavioral changes were related both to the degree of trauma and to the amount of measured free acetylcholine, With higher of acetylcholine, Bornstein reported greater degrees of EEG levels abnormality greater changes in consciousness, Spontaneous post-traumatic seizures were also related to the amount of free acetylcholine and �appearing in the spinal fluid. Bornstein applied acetylcholine to exposed cat cerebral cortex, the concentration of acetylcholine When was 1 gamma percent or less, high amplitude sharp waves of low frequency appeared in the electroencephalogramo When the concentration increased to 2 gamma was percent, the electroencephalogram flattened in a fashion parallel to the post-traumatic records° Investigations in neurological patients McEachern (19M9a) demonstrated by Tower and free acetylcholine in the cerebro— spinal fluid only in patients with recent head trauma, recent grand—mal seizures or after electroconvulsive therapy° Free acetylcholine varied from 0,2 to 100 gamma percent, In assaying spinal fluid cholinesterase activity, they noted a sharp rise in the nonSpecific cholinesterase fraction (benzoylcholine—splitting) and a drop in the specific cholinesterase fraction (mecholyl—splitting) in patients with head trauma and following convulsive therapy. After spontaneous seizures, however, the cerebrospinal fluid did not exhibit such inversion although it contained free acetylcholine. that the level of free acetylcholine varied directly with the degree of cerebral damage and that reversal of the cholinesterase fractions was a more sensitive indicator of cerebral damage. ElectroThey concluded encephalograms, taken at varying intervals following trauma, also indicated a relation between the degree of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal fluid. �These observations were recently confirmed by Kovach, Who recorded increased acetylcholine in rat brain inhibition of this activity and an by gt_§l. (1957) after traumatic shock the administration of atropine to the muscle preparationo ThuA the amount 06 ﬁnee acetytchottne may tncneaAe tn the Aptnat ﬁtutd ﬂattening chantacehebnat tnauma and the amount 06 ﬁnee aeetytchottne, the degnee and type changed tn cttnteat behavton appean (b) 06 a4 eteetnaencephatognaphtc abnonmattty, and tntennetated Anticholinergic drugs and trauma: The phenomena° electrographic, behavioral and neurologic signs of head trauma were blocked by the parenteral administration of 095-100 mg/kg atropine (Bornstein, 19u6), as were similar clinical changes occurring after the intracisternal addition of acetylcholine. Ward (1950) applied these observations to the treatment of closed head injurieso In 20 patients with varying degrees of trauma, he administered atropine subcutaneously in doses of 001 mg/kg, noting clinical improvement in some and a reversal of the electrographic effects in otherso Similar alterations in the post—traumatic electroencephalogram were reported by Jenkner and Lechner (1955) in a study of diethazine, another anticholinergic drugl A single intravenous dose in forty patients resulted in nornalizing the abnormal electroencephalogram in twenty~two and marked improvement in six otherso �Similar observations have been reported with methylbenactyzine and trasentin in animal experiments of post—traumatic shock cerebral The and edema (Denisenko, 1965), effect of atropine was assessed in the convulsive therapy process by Ulett and Johnson (1957), With the administration of to per day during the weeks the patients received electroshock therapy, the amount of slow wave activity atropine was up 5 mgm significantly less than in a control group received the atropine administration. who had not (These authors failed to replicate this study, suggesting that dosage factors or population changes may have contributed to different results [Johnson et_al., 1960])o Both the electrographic and the behavioral changes of induced convulsions were also reversed by the administration of experimental anticholinergic compounds (Fink, 1958, 1960), The intravenous injection of diethazine, benactyzine, the piperidylbenzilates JB-336 and JB-329 (Ditran), and in psychiatric subjects, These WIN—2299 EEG induced EEG JB—3l8, desynchronization changes were associated with behavioral alerting, anxiety, tremors, illusions, and hallucinations. recently received electroconvulsive therapy, a reduction in slow wave activity and a reversal of euphoria, In patients there was who had denial and confusion, Atropine in low doses, was associated with BEG desynchronization accompanied by tachycardia, nervousness and tension. �At higher dosages, hypersynchronous slow waves, followed by lower voltage, poorly organized delta activity with superimposed beta activity was associated with progressive confusion and disorientation, Both in eenebhat eteethoghaphte changeA 06 thauma and induced convutétOhA, the may be modtﬁted by the adhinttthatton anttchottnehgte dnugb, buggebtthg that tncheabed amountb aeetgtehottne on thcaeabed ehottnehgtc heeepttvtty t5 aMoctated with the high wattage stow wave aetéuttg, 06 Brain acetylcholine and anticholinergic drugs: (c) Similar EEG changes and similar blocking by anticholinergic drugs has been observed following the direct application of acetylcholine to the central nervous system, The administration of a cholinesterase inhibitor DFP (di-isopropyl fluorophosphate) elicited high amplitude patterns similar to status epilepticus, as well as changes similar to those of post—traumatic states (Freedman et_al., 19H93 rapid frequency EEG et_alf, EEG effects Himwich Hampson 1950; These were blocked by small doses of scopolamineo The 3:.Els’ 1950; and Wescoe et_al,, 1948). parenteral atropine and great increase in acetylcholine after tetraethyl pyrophosphate (TEPP) was measured and related to the toxic and convulsions induced (Giarman and Pepeu, 1952; Stone, 1957). Chatfield and Dempsey (1942) prepared exposed animal cortex with prostigmine and evoked electroencephalographic spike activity. The prior administration of atropine blocked this spiking, or the abnormality could be eliminated by atropine. if present, �In contrast to these findings, Brenner and Merritt (19u2) applied topical acetylcholine in concentrations of 2-1/2 to to the exposed cortex of cats, and noted no effect 10% on the electroencephalographic changes after intravenous atropine (l mg/kg)o The concentrations of acetylcholine in these experiments, however, were higher than the topical applications percent) and the intracisternal (002—10 gamma (l—M gamma percent) injections of Bornstein (19%)° Brenner and Merritt also made note of electroencephalographic effects similar to acetylcholine from mecholyl Cacetylbetamethylcholine) and doryl (carbamylcholine) in concentrations They much lower than the acetylcholine concentrations. ascribed the increased effectiveness of these cholinergic their lack of sensitivity to cerebral cholinesterases. These data are conflicting and further study is necessary to qualify this issue° drugs to (d) View Cerebrospinal Fluid Acetylcholine and Seizures: of acetylcholine metabolism indicates that nervous tissues in an inactive bound fornn it is One found in During periods of activity, acetylcholine is liberated at the cell membrane where it is rapidly deactivated by cholinesterasea The amount of bound acetylcholine is the resultant of the continuous processes of synthesis, liberation and breakdown. that the level rises during sleep (Tobias gt_al., 19u6; Richter and It has been postulated falls during activity. Crossland, 19u9; Elliot, Swankt and and Henderson, 1950; Giarman and Pepeu, 1962). Tobias et_al. found �8 increased free and total acetylcholine after chloroform and nembutal anesthesia in rat and frog brain, but no significant changes after strychnine or picrotoxin convulsions. Richter and Crossland measured the level of acetylcholine (micro-gamma per anesthesia and sleep in rat brain to be seizure levels, The brain tissue) during higher than postdifference in tissue levels is transient, however, as the resynthesis high (7 gamma/gm/minute)o Elliot et_§1f mg, 300% rate for acetylcholine in rat brain is These observations were confirmed by (1950) and Crossland and Merrick (195M). Pepeu (1962) found the increase Giarman and in acetylcholine following various depressants to be roughly proportional to the degree of depression of the central nervous system and the reduction in motor activity. Maynert and Buck (196”), however, studying brain acetylcholine and sedation concluded that some levels sedating agents are associated with elevated brain acetylcholine, but that no rigorous relationships existed. In part, this may be related to the earlier observations of Melennan and Elliot (1951) that acetylcholine synthesis measured in rat brain slices is accelerated by low dosages of narcotic drugs, but inhibited by high dosageso Free acetylcholine was reported in the spinal patients with epilepsy (Cone, fluid in Tower and McEachern, 19MB; Tower epileptic patinets, nu demonstrated free acetylcholine in quantities of 0.02 to 5.0 gamma percent with and McEachern, 19u9b), an average of 1,0 gamma Of 56 percent. Acetylcholine levels were related �to the frequency of seizures, the extent of electroencephalographic abnormality, and to the time since the last seizure, but bore no relation to medication, type of epilepsy or level of cholinesterase activityo Elliot §t_al3 (1950) also noted free acetylcholine in the spinal fluid in concentrations up to 3 gamma percent after metrazole convulsions, Tower and McEachern (19u9b) viewed the increased acetylcholine as a by—produce of the seizure, and not causal, Studying the hypothesis that seizures were induced by the accumulation of acetylcholine, Torda (1953) measured the level of acetylcholine in brain tissue after metrazole convulsions, She noted a rise in the acetylcholine content of brain befbre a seizure and a fall during the convulsion° Below certain levels of acetylcholine, convulsions failed to occur° that the fall in tissue acetylcholine to inhibition of acetylcholine synthesis She suggested during a convulsion was due by increased concentrations of metabolites such as ammonium ions. Giarnen and Pepeu also measured changes in central nervous system acetylcholine following various stimulants. Only after mecholyl and 3, 5-dimethylbutylethyl-barbiturate was there a significant change in theacetylcholinelevel° They noted a decrease in association with induced convulsions. With other drugs which they iproniazid + classified as stimulants iproniazid, hydroxytryptoghan, and iproniazid + DOPA) there were no changes in acetylcholine level. (LSD, They concluded that �10 despite intense excitation produced by these compounds, there were no changes in acetylcholine levels unless these were accompanied differences in observations between these by convulsions, (The workers and Cone gt ale and Tower and McEachern may be related to the differences in methods of biodhemical measurements, for the latter measured changes reflecting free acetylcholine only, while total acetylcholine reflecting bound and free forms of acetylcholine, [McLennan and Elliot, 1951]). TheAe AiudieA Auggebi that Aponianeoui an induced beizuheb ane accompanied by an incheaAe in inienceiiuian ﬁnee aceiyichoiine iibenaied ﬁnom ii» bound 60am which may be neglected in the Apinai ﬁiuido Cehebnai aciiviiy and Aeizuneb enhance aceiyichoiine Giarman and Pepeu measured the debtnuction, iowehing iiAAue ieveii 06 acetyichoiine, whiie Aieep and aneéiheéia may augment aceiyichoiine pnoduciion incneaiing iiiéue ieueiie (e) Central Nervous System Cholinesterases: Tower and McEachern also measured spinal fluid cholinesterase activity. TWO types of cholinesterases are normally found in the spinal fluid: (19H9) cholinesterase—I ("true," "specific," 0r mecholyl-hydrolyzing), which has a high specificity for acetylcholine; and cholinesterase-II ("pseudo," "non—specific," or benzoyldholine—hydrolyzing)o compounds hydrolyze Both acetylcholine but have different rates of hydrolysis for mecholyl and benzoylcholine. This differential rate perndts qualitative distinctions. By reporting the cholinesterase �11 activity as a ratio of the activity with a mecholyl substrate and with a benzoylcholine substrate compared to a substrate of acetylcholine, two ratios are found: cholinesterase—I/acetylcholine and cholinesterase-IIlacetylcholineo In sudh ratios normal cerebrospinal fluid contains esterases in the ratio of 33:17 for cholinesterase-I to eholinesterase—IIo with In patients head trauma, Tower and McEachern reported an inversion of the cholinesterases with a increase in the cholinesterase-II fraction of the spinal fluid and a decrease in cholinesterase-I activity. The extent of the cholinesterase reversal was related to the severity of trauma and to the degree of the electroencephalographic abnormality. In patients with elevated spinal fluid acetylcholine spontaneous seizures, however, no change in the cholinesterases or total cholinesterase activity in cholinesterase activity after ratio of was found. related to changes in cell membrane perneability. Cholinesterase-I is found in highest concentration in the central nervous system while cholinesterase-II predominates in other tissues, especially The change may be blood serumo With an increase in acetylcholine levels in cerebral intercellular fluids, vasodilation cellular permeability may be predicted, with a degree of transudation of vascular fluids into the intercellular spaces varying with the extent and duration and increased of the vasodilation (Kabat et_alo, 19u8). Spiegel, Spiegel—Adolf, �12 and their co-workers (19u1, 19u2, lguu, 19H8, 1953) demonstrated such perneability changes and increased conductivity of the tissues associated with the appearance of various ions (as potassium and phosphate) in the spinal fluid following convulsions° electrically induced Such non—electrolytes as nucleic—acid also increased, Changes in cellular perneability Splitting enzynes may thus provide the basis for the high concentrations of acetylcholine and the increased concentrations of cholinesterase-II in induced seizures or head trauma (Tower and MCEachern, 19H9c)o The persistance of acetylcholine in spinal fluid after head trauma and after seizures despite increased Cholinesterase activity may be related to the sensitivity of the acetylcholinecholinesterase-I system to concentration relationships (Nachmanson and Rothenberg, lQHS; Tower and McEachern, 19u90; Burgen and MacIntosh, 1955)o At "physiologic" is rapid concentrations, hydrolysis of acetylcholine (3-H microseconds) but the activity falls off quicklyc at higher and lower concentrations, In contrast, the cholinesterase—II acetylcholine relationship is non-specific and the rate of hydrolysis increases with increased concentration; These relationships are related to the induction of seizures. at cell membranes are destroyed by the specific activity of cholinesterase-I in a few microseconds, an excessive concentration following excitation While the usual concentrations of acetylcholine may exceed the rate of hydrolysis by cholinesterase-I. The seizure �13 threshold is reached and a seizure induced, with the seizure itself adding to the amount of free acetylcholine. The increased acetylcholine diffuses rapidly, affecting vascular and cellular perneability and increasing the concentrations of various ions, including cholinesterase—II, in tissues and in the cerebrospinal fluid, The activity of cholinesterase-II, though of low efficiency and depending on concentration the acetylcholine in the tissues in hours to days kinetics, reduces to levels fbr the physiologic action of cholinesterase—I. Chounutemu appeal: in the meme Maid Iheih anheaee in Lhzeheeﬂluiah ﬁﬁuidb, hebuﬁting in cell memblume The Una/Leaded a4 a heﬁKeetéon 05 ghom changee pumeabLU/ty oeeaAioned by incheaeed aeetyZehoLéne. emanate/wees connotahg the [evea 50h rte/wow byAtem 05 ahe pant 06 the homeozstauc mechahbsm acetyzehouhe at eeu membhahu heme/54mg activity, (f) Acetylcholine, EEG Hypersynchrony and Induced Convulsions: Alteration in the blood-brain perneability barrier by the continuing action of acetylcholine may be a biochemical substrate for the postelectroshock hypersyndhrony of the electroencephalogram, Such a possi- bility is evident in the demonstration of an increase in the concen- tration of cocaine in brain tissues threeidays after a series of 12 induced convulsions (Aird et_§lo, 1956)o The change in concentration of this large molecule, ordinarily absent in brain tissue, was associated with the appearance of hypersynchrony(delta bursts) in the electroencephalogram° �11+ We have confirmed the many previous reports that convulsive thrapy induces electrographic hypersynchrony (Pink and Kahn, 1956; Fink 1951)° Despite a constant application of treatments there is §t_al., a great variability in the time of appearance, the duration and the extent of the electrographic slow wave activity as well as the sensitivity to modification by alerting, hyperventilation and barbiturates in psychiatric populations (Green, 1957). degree hypersynchrony and has been described as (Roth, 1951; Roth its persistence prerequisite to stain, in the degree of induced The early appearance of high throughout a treatment course improvement following electroshock 1957; Pink and Kahn, 1956)o EEG The differences hypersynchrony may be related to differences in central cholinergic activity, The failure of certain patients to develop hypersynchrony may be associated with the absence of free acetylcholine and with minimal changes in cerebral function, thus precluding a clinical response to induced convulsions° Tower and McEachern (19H9a), in their study of craniocerebral trauma, included observations of six psychiatric patients undergoing convulsive therapy. Studying the patients after 3—7 treatments they reported free Spinal fluid acetylcholine in two patients; and an increase in cholinesterase—II and a decrease in cholinesterase-I with a reversal of the ratio of cholinesterases in five of the six patients, The one patient in the series Who failed to show either free acetylcholine or a cholinesterase ratio reversal in the spinal fluid was described as: "It is interesting that this patient was the only one of the six to show no response to treatment." �15 From these observations they concluded that the spinal fluid changes in induced convulsions were more like those of creniocerebral trauma than those of spontaneous epilepsy° If electrographic hypersynchrony free acetylcholine, subjects whom it disappears rapidly who may be is a reflection of increased maintain hypersynchrony and those in exhibiting differences in the kinetics of the cholinesterase~acetylcholine hydrolysis systems. Persistent hypersynchrony may result from.a decreased rate of hydrolysis of acetylcholine, associated with low concentrations of either cholinesterase—I or cholinesterase—II. (Conversely, in patients with short—lived hypersynchrony, cholinesterase—I and in tissue and spinal fluid may be unusually higho) Fnom —II these obaehvationi uh uuuid conciude that induced convuiiionb ahe accociated with an incheaie in ghee acetyichotine in intehceiiuian ﬁiuidt, aitehing cehebhai pehmeabiiity enhancing the appeahance 05 choiinettehatei. The ieuei and 06 ﬁnee it maintained by nepeated induced beizuneb. EEG hypencynchhony it one heﬁiection 06 aiteaed ieveii 06 acetyichoiine acetyichoiine and attehed penmeabiiity 06 otheh eiectnoiyteb° that theAe changec It i4 phobabie in intenceiiuiah eiectnoigteb phovide the biochemicai Aubcthate ﬂan the penAiAtent behavionai changei ﬁoiiowing induced convuitionia �16 t.‘ Cg) wfi 0. as. oses= studies have application to the problem of autonomic reactivity and the classification of the psychoseso Funkenstein These between 1952) have demonstrated 1951, a relationship E£;,(19”89 g: the blood pressure response to injected methacholine (Mecholyl) and the clinical response of psychiatric patients to convulsive therapy. is a potent cholinergic agent which induces vasodilation, tachycardia9 sweating, and increased peristalsiso It is rapidly Methacholine hydrolyzed by cholinesterasedI and slowly by cholinesterase-IIo falls after injected blood pressure of subjects to the baseline within five to 20 minuteso returns to the baseline within 5 II, or III reactors; and Group have a VI and Group VII (Funkenstein EE.E£;9 1952)o upon as patients in while Groups VI Patients whom 9 and a reactors Group VI 89% 20 or and VII reactorso 35% pressure Group I, more Group I recovery rate, respectively, and 97% recovery rates I to III reactors mecholyl the injected may be looked is rapidly hydrolyzed; and VII have a slow hydrolysis rateo It is possible that the cholinesterase activity levels of Groups I-III is review, see Rose9 19620] whose blood classified as those whose blood pressure takes IIuIII reactors while Group mecholyl and returns minutes have been minutes to return to baseline, as Group The [For a recent blood and tissue high, while that of Groups VI-VII is low compared to general psychiatric populations° The mentally differences in blood cholinesterase levels in normal and ill subjects have been extensively studiedo Despite differences �17 in methods (Augustinsson, 1955, 1957) elevated cholinesterase levels compared to normal populations have been reported for depressive subjects (Richter and Lee, 1942; Rowntree e£_al;, 1950; Ravin and Altshule9 1952)? schizophrenic subjects (Early 33 Gal9 1963) and a mixed iii, psychiatric population (Plum, 1999; Rubin, 1958; 1960)o Alpern (1956) reported lowered cholinesterase levels in schizophrenic subjectso studies appear inconclusive, they provide data that the variations in blood cholinesterase levels are generally greater While these and frequently elevated in the mentally illo Negative reports include the failure by Ellman and Callaway (1961) to confirm Rubin's study; and Altschule“s (1953) review of the data suggesting no abnormality of cholinesterase levels in the mentally illo A similar analysis may be made regarding the relation of central nervous system levels of cholinesterase in the development of EEG hyper- fluid levels of acetylcholine, thus providing a congruent hypothesis regarding central nervous system reactivity to induced convulsions and to peripheral cholinergic agents° synchrony and spinal �Dig- CONCLUSION: This review indicates that central cholinergic mechanisms are significant in the convulsive therapy processo Induced convulsions are associated with an increase in intercellular acetylcholine to levels greater than can be destroyed by acetylcholinesterase activityo Vasodilation and increased cellular permeability are followed by the appearance of increased amounts of butyrylcholinesterase and other enzymes and electrolytes in intercellular fluidso These biochemical changes are associated with increased hypersynchrony which is recorded as EEG electrodess and which can be modified by slow wave many electrical activity in scalp anticholinergic drugs, including atropine9 benactyzine, diethazine, procyclidine and piperidylbenzilateso In these regards, induced convulsions are more similar to cerebral trauma than to spontaneous seizures° in cerebral biochemistry alter cellular recovery and firing rates sufficiently to alter the behavior of subjectso Failure to induce high and persistent concentrations of acetylcholine These changes or failure to induce concomitant electrolyte changes.does not alter cerebral cellular activities and results in a failure to produce behavioral changeo Differences in the rate of development of cerebral changes to the same number and frequency of induced convulsions may reflect differences in the dependence of subjects on cholinergic mechanisms or �:19- in.their sensitivity to changes in acetylcholine levelso These differences provide the basis for the classifications of the mentally ill based on neurophysiological responsitivity by Funkenstein and by Pink and Kahno These data on cholinergic mechanisms provide a theory for the mode rational biochemical of action of induced convulsions in altering the behavior of psychotic subjects9 and are consistent with the more general neurophysiologicmadaptive theory of the convulsive therapy process expressed earliero �REFERENCES J W9, Hrenoff, M9 K9 and BowditchLS. 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Suence, Spiegel, E A and Spiegel—Adolf, M Permeability changes in the brain induced by Metrazol and insulin convulsions (Jo NULU. Manx. 0125:, 83; 750 755 /0 %% . y“ ,2. ' �Lipton, Tobias, J and convulsants on brain acetylcholine contento *, Med“; ’7 (KS Me MW 0 1:. 51—515 and IJepinat, A, A0 A, Effect of anesthetics Phone Soco Expo BLO£./;~“ ' "I" 1 “t” "‘1’ r7 _ and McEachern, Do Acetylcholine and neuronal activity. I. Cholinesterase patterns and acetylcholine in the cerebrospinal fluids of— patients with craniocerebral traumao x/“Ctinado J Ru ea/Lch m cm 5,, Towem 7. {ﬁn/x”, ' CO ‘ Wm. _, Wk Effect of convulsion inducing a ents on the acetylcholine Ame/Lo Jo Pkg/Maze; 1953, ;l73: 179—183, brain; of the content (ACTH) on of Cc corticotropin Effects of single injection Torda, Jo PhyMLoL, braim,gj'ArrIe/Lo of content and ion acetylcholine ammonium 1953, ll}: 175—178j / Torda, - ,3- a Do Bo Q:W105=1195 W Towem Do Ba 191M313o 2],: and McEachern, molinesterases in jettg ) content and characterization of ., human Do The cerebrospinal fluidso (f'fCanado l32=~ll+53j a «QC/t; Ruea/Lch, J. é)' Do and neuronal and activity. II. Acetylcholine McEachem, B Acetylcholme and cholinesterase activity in the cerebrospinal fluids C’a‘nado p] of patients with epilepsy», \_’\ Tower, D; < 120~l3l> IVWL a Ruem&9?%27“m $0 ’5) and Wo M, of Effect scopolamine upon Johnson, atropine Ulett, electroencephalographic changes induced by electro-ccnvulsive therapy. Ezecthoencepm Cum Neu/Lophyaiozo,fI§S’7‘g"ig_: 217-221;} Go A, and ’/wt" 1 WardiAu AU, tropine (1950, E3 3984020) 1 ‘ in the treatment of closed head injuryoﬁJo Co, Green, RC _ V :1: r7?“ , . V___“,_,,_-..._. W0 1 Neu/LOAu/Lg., E0, McNamara, Bo Po and Krop, So The influence J. -7“~Phalmmroi. Exp. (”of atropine and scopolamine on the central effects of DFP°_ "»»».N..r lgu8'5‘_9_‘2;: 63-720 We‘oea ' /’ (“L-9““ The/Lo , �.l mI ,l I II, .I Al. _I ”I .l .I ,l 'l I JI I _l �SET DuPQCAaTE MAY 24 1966 (m (FINAL EG—J 68 HR �(mm (FINAL EG—J 68 EG—J 68 (CL oE-NMD-Mar 5-20-5D (COG 6131 MAX FINK MAX FINK MAX FINK MAX FINK MAX FINK (READ 660 BY PROVE!) MAX FINK THERAPY CONVULSIVE OF ASPECTS CHOLINERGIC THERAPY CONVULSIVE OF ASPECTS CHOLINERGIC THERAPY CONVULSIVE OF ASPECTS CHOLINERGIC THERAPY CONVULSIVE OF ASPECTS CHOLINERGIC THERAPY CHOLINERGIC ASPECTS OF CONVULSIVE THERAPY CONVULSIVE OF ASPECTS CHOLINERGIC THERAPY CONVULSIVE OF CHOLINERGIC ASPECTS MAX FINK, MD.1 �ﬁUPLECﬁzTE SILT MAY 24 1966 EG—J 71 W Ward-BMW Gal 2 %E-NMD-Mar 5/20-5Gx 6131 P. 15 5/19/66 722(3) 'E]li“l" 1Department of Psychiatry, ... . ’ - H' i I I .o E u - This study was aided, in part, by USPHS grants MH-927, MH—2715, MH-07249 and MH-11380; and by the Psychiatric Research Foundation of Missouri. While the mode of action of convulsive therapies remains enigmatic, one theory holds that the early development and persistence of changes in brain function are requisite to changes in behavior (18, 21, 22). A useful index of neurophysiological change is the appearance of high voltage electroencephalographic slow wave activ— ity (22, 23). While the biochemistry of this activity is poorly understood, demonstrations that it is inhibited by anticholinergic compounds (19, 20, 34, 66) suggest that cholinergic systems may play an active part. (m (FINAL The EEG patterns and the response to anticholinergic drugs in convulsive therapy are similar to experimental and clinical head trauma and, to a lesser extent, spontaneous seizures. Changes in concentration of cholinesterases in brain and spinal ﬂuid also show many similarities in these conditions. This review discusses these observations to provide a hypothesis for the role of cholinergic changes in convulsive therapy. The activity of acetylcholine in the transmission of nervous impulses has been extensively studied since the early descriptions by Dale (12) and Loewi (38). A constituent of nervous tissue in a bound form, acetylcholine, is liberated during the excitation process. It is rapidly hydrolyzed through the mediation of acetylcholinesterase and is rapidly reconstituted by the choline-acetylase system (45). Free ace— tylcholine has not been measurable in normal cerebrospinal ﬂuid despite the rapid breakdown of bound acetylcholine during periods of activity and excitement (63). ///"L.i//>{{ I "'4 1/. ,1/ :J Waéff?.__ �part. mm (FINAL (CL (GOG The EEG patterns and the response to anticholinergic drugs in convulsive therapy are similar to experimental and clinical head trauma and, to a lesser extent, spontaneous seizures. Changes in concentration of cholinesterases in brain and spinal ﬂuid also show many similarities in these conditions. This review discusses these observations to provide a hypothesis for the role of cholinergic changes in convulsive therapy. The activity of acetylcholine in the transmission of nervous impulses has been extensively studied since the early descriptions by Dale (12) and Loewi (38). A constituent of nervous tissue in a bound form, acetylcholine, is liberated during the excitation process. It is rapidly hydrolyzed through the mediation of acetylcholinesterase and is rapidly reconstituted by the choline-acetylase system (45). Free acetylcholine has not been measurable in normal cerebrospinal ﬂuid despite the rapid breakdown of bound acetylcholine during periods of activity and excitement (63). But the normal cerebrospinal ﬂuid does have measurable cholinesterase activity (41). CHOLINERGIC ASPECTS OF CRANIOCEREBRAL TRAUMA (READ 660 BY PROVE!) Free acetylcholine was found in the cerebrospinal ﬂuid of cats within a few minutes after experimental head trauma and persisted for varying periods up to 48 hours. The quantity of free acetylcholine varied between 2.7 and 9.0 ga /100 cc, and the amount was related to t e degree of induced trauma (6). Concurrent electroencephalograms ﬁrst demonstrated high voltage fast activity, interpreted as evidence of an intense neuronal discharge, which was succeeded by a short period of ﬂattening of all recorded electrical activity. These phases were followed by prolonged periods of �f.’u ”1: $3.: .gsi 1:..n‘1' 24 1955 EG—J 71 %E-NMD-Mar 5/20-5Fx 6131 P. 15 5/19/66 722(1) Gal 3 high amplitude sharp waves in the delta frequencies. The behavioral changes related to the degree of induced trauma and to the amount of measured free acetylcholine. With higher levels of acetylcholine, Bornstein (6) reported greater degrees of EEG abnormality and greater changes in consciousness. Spontaneous post-traumatic seizures were also related to the amount of free acetylcholine measured in the cerebrospinal ﬂuid. Bornstein applied acetylcholine to exposed cat cerebral cortex. When the concentration of acetylcholine was one gamma/100 cc or less, high amplitude sharp waves of low frequency appeared in the electroencephalogram. When the concentration was increased to two 100 gamma/ cc, the electroencephalogram ﬂattened in a fashion parallel to the post-traumatic records. by Tower and McEachern (63) demonstrated free acetylcholine in the cerebrospinal ﬂuid only in patients with recent head trauma, recent grand-mal seizures or after electroconvulsive therapy. Free acetylcholine varied from 0.2 to 100 gamma/ 100 cc. In assaying spinal ﬂuid cholinesterase activity, they noted a sharp rise in the butyrylcholinesterase fraction and a fall in the acetylcholinesterase fraction in patients with head trauma and following convulsive therapy. After spontaneous seizures, however, the cerebrospinal ﬂuid did not exhibit such inversion although it contained free acetylcholine. They concluded that the leve 0f free acetVlChnll‘np (FINAL ((1 �Bornstein applied acetylcholine to exposed cat cerebral cortex. When the concentration of acetylcholine was one gamma/100 cc or less, high amplitude sharp waves of low frequency appeared in the electroencephalogram. When the concentration was increased to two 100 gamma/ cc, the electroencephalogram ﬂattened in a fashion parallel to the post-traumatic records. Investigations in neurological patients by Tower and McEachern (63) demonstrated free acetylcholine in the cerebrospinal ﬂuid only in patients with recent head trauma, recent grand-mal seizures or after electroconvulsive therapy. Free acetylcholine varied from 0.2 to 100 gamma/ 100 cc. In assaying spinal ﬂuid cholinesterase activity, they noted a sharp rise in the butyrylcholinesterase fraction and a fall in the acetylcholinesterase fraction in patients with head trauma and following convulsive therapy. After spontaneous seizures, however, the cerebrospinal ﬂuid did not exhibit such inversion although it contained free acetylcholine. They concluded that the level of free acetylcholine varied directly with the degree of cerebral damage and that reversal of cholinesterase fractions was a more sensitive indicator of cerebral damage. Electroencephalograms taken at varying intervals following trauma also indicated a relation between the degree of EEG abnormality and the appearance of free acetylcholine in the cerebrospinal ﬂuid. Increased acetylcholine in rat brain after traumatic shock was also reported by Kovach et al. (36). This acetylcholine activity was inhibited by the administration of atropine in vitro. The electrographic, behavioral and neurologic signs of head trauma were blocked by the parenteral administration of 0.5— 1.0 mg/kg atropine, as were similar clinical changes occurring after the intracisternal addition of acetylcholine (6). Ward applied these observations to the treatment of closed head injuries. In 20 patients with varying degrees of trauma, he administered atropine subcutaneously in doses of 0.1 mg/kg, noting clinical improvement in some and a reversal of the electrographic effects in others (67). The same changes in the post-traumatic electroencephalogram were reported by Jenkner and Lechner in a study of diethazine, another anticholinergic drug. A single intravenous dose in 40 patients resulted in normalizing the abnormal electroencephalogram in 22 and marked improvement in six others (33). (READ “660 mom �2' on I'-.-..AY 24 '“ 1965 EG—J 84 OE-NMD-Mar 5/20-5E GAL 4 6131 P. 18 5/19/66 722(1) Similarly, in experiments of post-trauma- tic shock and cerebral edema in animals, Denisenko (13) reported a blocking of the clinical changes by such anticholinergic compounds as methylbenactyzine and adiphenine (Trasentin). Thus, the amount of free acetylcholine ma increase in the spinal ﬂuid following craﬁicerebral trauma and the amount of free acetylcholine, the degree and type of electroencephalographic abnormality, and changes in clinical behavior appear as interrelated phenomena, which may be reduced by the administration of anticholinergic drugs. BRAIN ACETYLCHOLINE AND ANTICHOLINERGIC DRUGS (REV (FINAL (CL (00G (READ 660 BY PIOVID The effects of the direct application of acetylcholine to the central nervous system may also be blocked by anticholinergic drugs. The administration of the cholinesterase inhibitor di-isopropyl ﬂuoroph sphate (DFP) elicited high amplitude rapid frequency EEG patterns similar to status epilepticus and some post-traumatic states (24, 31, 32, 68). These EEG eﬂ'ects were blocked by small doses of parenteral atropine and scopolamine. The great increase in acetylcholine after tetraethyl pyrophosphate (TEPP) was measured and related to the toxic effects and the induced convulsions (29, 59). Chatﬁeld and Dempsey (9) prepared exposed animal cortex with prostigmine and evoked electroencephalographic spike activity. The prior administration of atropine blocked the appearance of spiking, or if present, this electrical activity could be eliminated by atropine. In contrast to these ﬁndings, Brenner and Merritt (7) applied topical acetylcholine in concentrations of two and onehalf to ten per cent to the exposed cortex of cats and noted no effect on the electroencephalographic changes after intravenous atropine (one mg/kg). The concentrations of acetylcholine in these experiments, however, were higher than the topical applications (one to four gamma/100 cc) and the intracisternal (0.2—10 gamma/100 cc) injections of Bornstein (6). Brenner and Merritt (7) also noted electroencephalographic effects similar to acetylcholine after methacholine (Mecholyl) and carbamylcholine (Doryl) in concentrations much lower than the acetylcholine concentrations. They ascribed the increased effectiveness of these cholinergic drugs to their lack of sensitivity to cerebral cholinesterases. These data are conﬂicting and further study is necessary to qualify this issue. , 0 �(FINA! (CL (COG (READ 660 BY PROVE!) atropine blocked the appearance of spiking, or if present, this electrical activity could be eliminated by atropine. In contrast to these ﬁndings, Brenner and Merritt (7) applied topical acetylcholine in concentrations of two and onehalf to ten per cent to the exposed cortex of cats and noted no effect on the electroencephalographic changes after intravenous atropine (one mg/kg). The concentrations of acetylcholine in these experiments, however, were higher than the topical applications (one to four gamma/100 cc) and the intracisternal (0.2—10 gamma/100 cc) injections of Bornstein (6). Brenner and Merritt (7) also noted electroenceph— alographic effects similar to acetylcholine after methacholine (Mecholyl) and carbamylcholine (Doryl) in concentrations much lower than the acetylcholine concentrations. They ascribed the increased effectiveness of these cholinergic drugs to their lack of sensitivity to cerebral ch0linesterases. These data are conﬂicting and further study is necessary to qualify this issue. CEREBROSPINAL FLUID ACETYLCHOLINE AND SEIZURES One View of acetylcholine metabolism ﬁnds it in nervous tissues in an inactive and bound form. During periods of activity, acetylcholine is liberated at the cell membrane where it is rapidly deactivated by cholinesterases. The amount of bound acetylcholine is the resultant of the continuous processes of synthesis, liberation and breakdown (15). It has been postulated that the level rises during sleep and falls during waking activity (16, 29, 45, 60). Tobias et al. (60) reported increased free and total acetylcholine after chloroform and pentobarbital anesthesia in rat and frog brain but no changes after strychnine or pictrotoxin convulsions. Richter and Crossland (45) measured the level of acetylcholine (microgamma per mg brain tis— sue) during anesthesia and sleep in rat brain to be 300 per cent higher than postseizure levels. The difference in tissue levels is transient, however, as the resynthesis rate for acetylcholine in rat brain is high (seven gamma/gm/minute). These observations were conﬁrmed by Elliott et al. (16) and Crossland and Merrick (11). Giarman and Pepeu reported the increase in acetylcholine following various depressants to be roughly proportional to the degree of depression of the central nervous system and the reduction in motor activity (29). Maynert and Buck, however, studying brain acetylcholine levels during sedation concluded that some sedatives were associated with elevated brain acetylcholine but that no rigorous relationships existed (39). In part, this may be related to the earlier observations of McLennan and Elliott (40) that acetylcholine synthesis measured in rat brain slices is accelerated by low dosages of narcotic drugs, but inhibited by high dosages. �£.;__1 -C£HTE rJdJl “‘ . 2-59—11! RAY 24 l966 EG—J 84 OE—NMD-Mar 5/20-5E 6131 P. 21 5/19/66 722(3) A) GAL 5 Free acetylcholine was reported in the spinal ﬂuid in patients with epilepsy (10, 63). Of 56 epileptic patients, 44 demonstrated free acetylcholine in quantities of 0.02 to 5.0 gamma/ 100 cc with an average of 1.0 gamma/ 100 cc. Acetylcholine levels were related to the frequency of seizures, the extent of electoencephalographic abmality, and to the time since the last sféizlmre but bore no relation to medication, type of epilepsy or level of cholinesterase activity Elliott et al. (16) also noted free acetylcholine in the spinal ﬂuid in concentrations up to three gamma/100 cc after pentylenetetrazol (Metrazol) convulsions. Tower and McEachern (63) viewed the increased acetylcholine as a by-product of the seizure and not causal. Studying the hypothesis that seizures were induced by the accumulation of acetylcholine, Torda (61, 62) measured the level of acetylcholine in brain tissue after pentylenetetrazol convulsions. She noted a rise in the acetylcholine content of brain before and a fall during the convulsion. Below certain levels of acetylcholine, convulsions failed to occur. She suggested that the fall in tissue acetylcholine during a convulsion was due to the inhibition of acetylcholine synthesis by increased concentrations of metabolites such as ammonium ions. Giarman and Pepeu also measured changes in central nervous system acetylcholine following various stimulants (29). Only after methacholine and 3,5dimethylbutylethyl-barbiturate was there a signiﬁcant change in the acetylcholine level. They noted a decrease in association with induced convulsions. With other drugs which they classiﬁed as stimulants (LSD, iproniazid, iproniazid plus hydroxytryptophan, and iproniazid plus DOPA) there were no changes in the acetylcholine level. They concluded that despite intense excitation produced by these compounds, there were no changes in acetylcholine levels unless these were accompanied by convulsions. (The differences in observations between these observers and Gone et al. (10) and Tower and McEachern ( may be related to the differences in methods of biochemical measurements, for the latter measured changes reﬂecting free only, While Giarman and ) measured total acetylcholine Pepeu includin_ bound and free forms of acetyl- K ya .7; Mageline ”ﬁl- These studies suggest that spontaneous or induced seizures are accompanied by an increase in intercellular free acetyl choline liberated from its bound form which may be reﬂected in the spinal ﬂuid. Cerebral activity and seizures enhance acetylcholine destruction, lowering tissue levels of acetylcholine, while sleep and anesthesia augment acetylcholine production increasing tissue levels. (REV (FINAL 206((1 CENTRAL NERVOUS SYSTEM �bllUl‘U l/oi ’/—\, C/ were LlU Guanges 111 we acetylcnoune level. They concluded that despite intense excitation produced by these compounds, there were no changes in acetylcholine levels unless these were accompanied by convulsions. (The differences in observations between these observers and Cone et all. (10) and Tower and McEachern ( may be related to the differences in methods of biochemical measurements, for the latter measured changes reﬂecting free holine only, while Giarman and ce ) measured total acetylcholine includin bound and free forms of acetyl- K m “Tho («3 in). These studies suggest that spontaneous or induced seizures are accompanied by an increase in intercellular free acetyl choline liberated from its bound form which may be reﬂected in the spinal ﬂuid. Cerebral activity and seizures enhance acetylcholine destruction, lowering tissue levels of acetylcholine, while sleep and anesthesia augment acetylcholine production increasing tissue levels. (REV (FINAL (CL CENTRAL NERVOUS SYSTEM CHOLINESTERASES Tower and McEachern (63, 64, 65) also measured spinal ﬂuid cholinesterase activity. By reporting cholinesterase activity as a ratio of the rate of hydrolysis with two substrates compared to an acetylcholine substrate, acetylcholinesterase/acetylcholine and butyrylcholinesterase/acetylcholine ratios are derived. Normal cerebrospinal ﬂuid contains these esterases in the ratio of 33:17. In patients with head trauma, Tower and McEachern reported an inversion of the cholinesterases with an increase in the butyrylcholinesterase of the spinal ﬂuid and a decrease in acetylcholinesterase activity. The extent of the cholinesterase reversal was related to the severity of trauma and to the degree of EEG abnormality. A similar reversal was observed in patients undergoing convulsive therapy. In patients with elevated spinal ﬂuid acetylcholine after spontaneous seizures, however, no change in the ratio of cholinesterases or total cholinesterase activity was found. Changes in cholinesterase activity may be related to changes in cell membrane permeability. Acetylcholinesterase is found in highest concentration in the central nervous system. while butyrylcholinesterase predominates in other tissues, especially blood serum. With increased cerebral acetylcholine, vasodilation and increased cellular permeability may be predicted, with vascular ﬂuid transudation varying with the extent and duration of the vasodilation (35). Spiegel, Spiegel-Adolf and their coworkers (54—58) demonstrated such permeability changes and increased conductivity of the tissues associated with the appearance of various ions (as potassium and phosphate) in the spinal ﬂuid following electrically induced convulsions. Such non-electrolytes as nucleic-acid splitting enzymes also increased. Changes in cellular permeability may be the basis for the high (ooc (nun 660 8! mom �..._.l!_ﬁ$ .0"de " ;CF;TE MAY 24 55-12%”? 1965 That changes in cholinesterases may be large and measurable is suggested by the acetylcholinesterase activity which was related to decrements in be havioral perform- ance. The persistance‘ of acetylcholine in spinal ﬂuid after head trauma and after seizures despite increased cholinesterase activity may be related to the sensitivity of the acetylcholine~acetylcholinesterase ip is non-speciﬁc, and (m the rate of hydrolysis increases with increased concentration. These relationships relate to theories of the induction of seizures. While the usual concentrations of acetylcholine at cell destroyed by the speciﬁc activity of acetylcholinesterase in a few microseconds, an excessive concentration following excitation may exceed its rate of hydrolysis. The seizure threshold may be (FINAL altering the concentr including butyrylcholinesterase in tissues and in the cerebrospinal ﬂuid. Through the activity of this esterase, though of low efﬁciency and depending on concentration kinetics, acetylchol' ' J (CL (GOG ”J (nun 660 BY mom acetylcholinesterase. Cholinesterases appear in the spinal ﬂuid as a reﬂection of their increase in intercellular ﬂuids resulting fr om changes in cell membrane permeabilit y accompanying increased acetylcholine. EEG HYPERSYN CHRON Y AND INDUCED CON VULSIONS onvulsive therapy process has been repeatedly described (22, 23, 50, 51). In the usual course of convulsive therapy, inter-treatment electro~ encephalograms record progressive increases in amplitude and in theta activity and a reduction in beta activity. As treatment �(FINAL (CL (GOG (READ 660 BY PROVE!) Name wscu adding to the amount of free acetylcholine. Increased acetylcholine affects vascular and cellular permeability altering the concentrations of various ions, including butyrylcholinesterase in tissues and in the cerebrospinal ﬂuid. Through the activity of this esterase, though of low efﬁciency and depending on concentration kinetics, acetylcholine is reduced in tis- acetylcholinesterase. "" ”My Cholinesterases appear ﬂuid as a reﬂection of their ' tercellular ﬂuids resulting fr om changes in cell membrane permeabilit y accompanying increased acetylcholine. EEG HYPERSYN CHRON Y AND INDUCED CON VULSIONS onvulsive therapy process has been (22, 23, 50, 51). In the repeatedly described usual course of convulsive therapy, inter-treatment electroencephalograms record progressive increases in amplitude and in theta activity and a reduction in beta activity. As treatelta activity appears in methods~electrical, intravenous chemical or inhalant—exhibit the same type of EEG pattern changes (21, 22, 23, 30). The early appearance of high degree hypersynchrony and its persistence throughout a treatment course has been found to be prerequisite to improvement. Both the electrographic and th e behavioral changes of induced convulsio us are transiently reversed by the acute administration of experimental anticholinergic compounds 19 20). The intravenou injec ion 0 diethazine, benactyzine, t e piperidylbenzilates JB—318, JB—336 and JB—329 (Ditran), and WIN—2299 induced EEG desynchronization in psychiatric subjects. These EEG changes were associated with behavioral alerting, anxiety, tremors, illusions and hallucinations. In patients cently received electroconvu lsive therapy there was a reduction in slow and a reversal of ' euphoria, d fusion. Atropine, in low doses, was also associated with EEG desynchronization accompanied by tachycardia, nervousness and tension. At higher dosages, hypersynchronous slow waves followed by lower voltage, poorly organized delta activity with superimposed beta activity companied by progressive confusion and disorientation. The effect of anticholinergic drugs on the slow wave activity of convulsive therapy was also assessed by the chronic administration of atropine (ﬁve mgm per day) and scopolamine (one to three mg) during the Weeks of treatment. The amount of EEG slowing was signiﬁcantly less than S �J anaema WKY ,— 24 ("f “" -' 1965 EG—J 85 OE-NMD-Mar 5—20-5Fx Gal. 7 6131 P. 28 5/19/66 722(3) Marked improvement was reported in two of seven atropine-treated, norx of ﬁve scopolamine-treated and in four of the six controls receiving unmodiﬁed ECT. This study was not replicated by the authors who suggest that dosage factors or population changes may have contributed to the different results in a second study (34). As in cerebral trauma, the electrographic changes of induced convulsions be may modiﬁed by the administration of anticholinergic drugs suggesting that increased amounts of acetylcholine or increased cholinergic receptivity is associated with the high voltage slow wave activity. ACETYLC‘HOLINE AND INDUCED CON VULSIONS Despite a constant application of treatments, however, there is great variability in the time of appearance, the duration, amount, and sensitivity to modiﬁcation by alerting, hyperventilation and barbiturates of the electrographic slow wave activity in psychiatric populations (30). These differences relate to differences in central cholinergic activity. The failure of certain patients to develop hypersynchrony may be associated with the absence of free acetylcholine and with minimal changes in cerebral function, thus precluding a clinical response to induced convulsions. Tower and McEachern (63), in their study of craniocerebral trauma, included observations of six psychiatric patients undergoing convulsive therapy. Studying the patients after three to seven treatments they reported free spinal ﬂuid acetylcholine in two patients, and an increase in butyrylcholinesterase and a decrease in acetylcholinesterase with a reversal of the ratio of cholinesterases in ﬁve of the six patients. Only one patient in the series failed to show either free acetylcholine or a cholinesterase ratio reversal in the spinal ﬂui They concluded that the spinal ﬂuid anges in induced convulsions were more like those of craniocerebral trauma than those of spontaneous epilepsy. Other evidence of alterations in the permeability barrier may be seen in the demonstrations of an increased concentration of cocaine in brain tissues three days after a series of 12 induced convulsions ( 1). The change in concentration of this large molecule, ordinarily absent in brain tissue, was associated with the appearance of hypersynchrony (delta bursts) in the electroencephalogram. From these observations we would conclude that induced convulsions, like craniocerebral trauma and spontaneous seizures, are associated with an increase in free acetylcholine in intercellular ﬂuids, altering cerebral permeability and enhancing the ‘ (FINAL 06((1 �”renown; m cm; patients, and an increase in butyrylcholinesterase and a decrease in acetylcholinesterase with a reversal of the ratio of cholinesterases in ﬁve of the six patients. Only one patient in the series failed to show either free acetylcholine or a cholinesterase ratio reversal in the spinal ﬂui They concluded that the spinal ﬂuid anges in induced convulsions were more like those of craniocerebral trauma than those of spontaneous epilepsy. Other evidence of alterations in the permeability barrier may be seen in the demonstrations of an increased concentration of cocaine in brain tissues three days after a series of 12 induced convulsions (1). The change in concentration of this large molecule, ordinarily absent in brain tissue, was associated with the appearance of hypersynchrony (delta bursts) in the electroencephalogram. From these observations we would conclude that induced convulsions, like craniocerebral trauma and spontaneous seizures, are associated with an increase in free acetylcholine in intercellular ﬂuids, altering cerebral permeability and enhancing the appearance of cholinesterases. The level of free acetylcholine is maintained by repeated induced seizures. EEG hypersyn— chrony is one reﬂection of altered levels of acetylcholine and the altered permeability of electrolytes and other substances, including cholinesterases. The changes in intercellular electrolytes, including acetylcholine, provide the biochemical substrate for the persistent behavioral changes and EEG hypersynchrony following induced conv onsM. An application WM““WWWM‘MMMK of these conclusions is seen in the studies of the prediction of the convulsive therapy response and the claspsychoses. I ., / l \\ W CHOLINESTERASES AND THE CLASSIFICATION OF PSYCHOSES 69‘ / Funkenstein et al. (25—27) reported a relationship between the blood pressure response to methacholine and the clinical response to convulsive therapy. Immediately after the injection of methacholine the blood pressure falls, usually returning to the baseline within ﬁve to 20 minutes. A return within ﬁve minutes places the patients in Groups I, II or III; while a return after 20 minutes place the patients in roups VI and VII. Group I and Group II have a nine per cent and a 35 per ent recovery rate, respectively, while Group VI and Group VII subjects have 89 per cent and 97 per cent recovery rates to induced convulsions (27). Group I, II and III reactors may be looked upon as patients in whom methacholine is rapidly hydrolyzed; while Groups VI and VII have a slow hydrolysis rate. (The response to injected epinephrine was suggested as a second criteria in the classiﬁcation, but is of limited discriminating value [48].) While we have no biochemical explanation for the differences in the metabolism of methacholine in these psychiatric groups, it is possible that the blood and tissue choline— sterase activity levels of Groups I—III is I/ high while that of Groups VI—VII is low compared to general psychiatric populations. (m (FINAL (CL (COG �1»:er 24 1966 EG—K 5 %E-NMD-(March) 5/20-5FX 6131 P. 31 5/19/66 722(1) a» (mm /’ ' J (run. , (CL (GOG (READ 660 BY PROVE!) Gal. 8 The differences in blood cholinesterase levels in normal and mentally ill subjects have been extensively studied. Despite differences in methods (4, 5), elevated cholinesterase levels compared to normal populations have been reported for depressive subjects (44, 46, 47, 52), schizophrenic subjects (14, 28, 53) and a mixed psychiatric population (42). Alpern reported lowered cholinesterase levels in schizophrenic subjects (2). While these studies appear inconclusive, they provide data that the variations in blood cholinesterase levels are generally greater and frequently elevated in the mentally ill. Negative reports include the failure by Ellman and Callaway (17) to conﬁrm Rubin’s study; and Altchule’s review of the data suggesting no abnormality of cholinesterase levels in the mentally ill (3). -. ..-_-- _ HeSe studies suggest that cholinergic measures may play a signiﬁcant role in the therapeutic response to convulsive therapy and in the pathogenesis of psychoses. ., ' , 7 CONCLUSION This review summarizes some of the available data suggesting that cholinergic mechanisms may be central to the convulsive therapy process. Induced convulsions are associated with cerebral vasodilation and increased cellular permeability, followed by the appearance of increased amounts of enzymes and electrolytes in intercellular and cerebrospinal ﬂuids. The increase in acetylcholine, vasodilation and increased permeability appear as interrelated phenomena associated with trauma, seizures and induced convulsions. These biochemical changes accompany increased electrical hypersynchrony which is recorded as EEG slow wave activity in scalp electrodes and which can be modiﬁed by the acute and chronic administration of anticholinergic drugs as atropine, benactyzine, diethazine, procyclidine and various DineridVI-hﬂnzilnqu �“lose stuures suggesr, that cholinergic measures may play a signiﬁcant role in / ( (CL ((IJG (READ 660 BY PROVE!) the therapeutic response to convulsive therapy and in the pathogenesis of psy- { choses. , ,- ' ’ CONCLUSION This review summarizes some of the available data suggesting that cholinergic mechanisms may be central to the convul— sive therapy process. Induced convulsions are associated with cerebral vasodilation and increased cellular permeability, followed by the appearance of increased amounts of enzymes and electrolytes in intercellular and cerebrospinal ﬂuids. The increase in acetylcholine, vasodilation and increased permeability appear as interrelated phenomena associated with trauma, seizures and induced convulsions. These biochemical changes accompany increased electrical hypersynchrony which is recorded as EEG slow wave activity in scalp electrodes and which can be modiﬁed by the acute and chronic administration of anticholinergic drugs as atropine, benactyzine, diethazine, procyclidine and various piperidyl-benzilates. In these regards, induced convulsions are more similar to cerebral trauma than to spontaneous seizures. The changes in cerebral biochemistry alter cellular activity sufﬁciently to affect consciousness and the behavior of subjects. Failure to induce persistent biochemical changes, including the concentration of acetylcholine, results in failure to produce behavioral change. There is, as yet, no consistent evidence for differences in the sensitivity or dependence of populations on cholinergic mechanisms. Differences in the rate of develop— ment of cerebral changes to the same number and frequency of induced convulsions and classiﬁcations of the mentally ill based on the blood pressure response to methacholine suggest, however, that such differences may be signiﬁcant in the pathogenesis of different psychoses. 1. REFERENCES Aird, R. B., Strait, L. A., Pace, J. W., HrenoH, M. K. and Bowditch, S. C. Neurophysiological effect of electrically induced A.M.A. Arch. Neurol. Psychiat.,convulsions. 75: 371— 2. 378, 1956. Alpern, D. O. Aktivnost kholinesterasy i kho— linergicheskaya reaktsiya krovi pri shizofrenii. (Cholinesterase activity and choliner— gic reaction of the blood in schizophrenia.) Fiziol. Zh. (Kiev), 4: 87—90, 1956. 3. Altschule, M. D., Bodily Physiology in Mental and Emotional Disorders, pp. 169—172. Grune & Stratton, New York, 1953. 4. Augustinsson, K.-B. The normal variation of human blood cholinesterase activity. Acta Physiol. Scand., 35: 40—52, 1955. 5. Augustinsson, K.—B. 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Funkenstein, D. H., Greenblatt, M. and Solo26. mon, H. C. Autonomic changes psychologic changes in mentally illparalleling J. Nerv. Ment. Dis, 114: 1—18, 1951. patients. 27. Funkenstein, D. H., Greenblatt, M. and Solomon, H. C. Autonomic nervous system test of prognostic signiﬁcance in relation to electroshock treatment. Psychosom. Med., 14: 347—362, 1952. 28. Gal, E. M. Cholinesterase blood from healthy and activity of whole schizophrenic individuals. Nature (London), 198: 29. 1963. 1118—1119, Giarman, M. J. and Pepeu, G. Drug-induced changes in brain acetylcholine. Brit. J. Pharmacol., 19: 226—234, 1962. 30. Green, M. A. Signiﬁcance of individual variability in EEG response to electroshock. J. Hillside Hosp. (Glen Oaks), 6‘: 229—240, 1957. 31. Hampson, J. L., Essig, C. F., McCauley, A. and Himwich, H. E. Effects of di-isopropyl ﬂuorophosphate (DFP) on electroencephalogram and cholinesterase activity. Electroenceph. Clin. Neurophysiol., 2: 41—48, 1950. 32. Himwich, H. E., Essig, C. F., Hampson, J. L., Bales, P. D. and Freedman, A. M. Effect of trimethadione (Tridinmn) A—--~— (REV (FINAL :OG(CL �“““““““ vuuvululULlS. Arch. Gen. Psychiat. (Chicago), 4: 259—266, 1961. 24. Freedman, A. M., Bales, P. D., Willis, A. and Himwich, H. E. Experimental production of electrical major convulsive J. Physiol., 156': 117—124, 1949.patterns. Amer. 25. Funkenstein, D. H., Greenblatt, M. and Solo— 347—362, 1952. 28. Gal, E. M. Cholinesterase blood from healthy and activity of whole schizophrenic individuals. Nature (London), 198: 29. 1118—1119, 1963. Giarman, M. J. and Pepeu, G. Drug-induced changes in brain acetylcholine. Brit. J. Pharmacol, 19: 226—234, 1962. 30. Green, M. A. Signiﬁcance of individual variability in EEG response to electroshock. J. Hillside Hosp. (Glen Oaks), 6: 229-240, 1957. 31. Hampson, J. L., Essig, C. F., McCauley, A. and Himwich, H. E. Effects of di-isopropyl ﬂuorophosphate (DFP) on electroencephalogram and cholinesterase activity. Electroenceph. Clin. Neurophysiol., 2: 41—48, 1950. 32. Himwich, H. E., Essig, C. F., Hampson, J. L., Bales, P. D. and Freedman, A. M. trimethadione (Tridione) and other Effect of convulsions caused by di-isopropyldrugs on ﬂuorophosphate (DFP). Amer. J. Psychiat, 106: 33. (mm (FINAL (CL (COG 816—820, 1950. Jenkner, F. L. and Lechner, H. The effect of Diparcol on the electroencephalogram in the normal subject and in those with cerebral trauma. Electroenceph. Clin. Neurophysiol., 7: 303—305, 1955. 34. Johnson, L. C., ilett, G. A., Johnson, M., 660 B! 35. 324—336, 1960. i ' ’ Kabat, E. A., Glusman, M. and V. Knaub, Quantitative estimation of the albumin and gamma globulin in normal and pathologic cerebrospinal ﬂuid by immunochemical methods. Amer. J. Med., 4: 653—662, 1948. 36. Kovach, A. G. B., Fonyo, A. and Halmagyi, M. Acetylcholine content of the brain in traumatic shock. Acta Physiol. Acad. Sci. Hung, 13: 1—4, 1957. 37. Krech, D., Rosenzweig, M. R. and Bennett, E. L. Effects of environmental and training on brain chemistry.complexity J. Comp. Physiol. Bsychol., 53: 5093519, 1960. 38. Loewi, O. Uber humorale Ubertragbarkeit der Herznervenwirkung. Pﬂueger Arch. Ges. Physiol., 189: 239—242, 1921. 39. Maynert, E. W. and Buck, E. G. Effects of CNS. depressants on brain acetylcholine. Pharmacologist, 6: 191, 1964. 40. McLennan, H. and Elliott, K. A. C. Effects of convulsant and narcotic drugs choline synthesis. J. Pharmacol. on acetylExp. Ther., 103.- 35—43, 1951. 41. N achmansohn, D. and Rothenberg, M. A. Studies on cholinesterase: On speciﬁcity of in enzymes nerve tissue. J. Biol. Chem., 158: 653—666, 1945. 42. Plum, C. M. Study of cholinesterase activity in nervous and mental disorders. Clin. Chem., 43. 6’: 332—340, 1960. Pryor, G. T. and Otis, L. S. Effects of chronic administration of electroconvulsive shock on behavior, brain weight and brain chemistry. Paper presented at the American Association for the Advancement of Science, Berkeley, 1965. 44. Ravin, H. A. and Altschule, M. D. Serum cholinesterase activity in mental disease. A.M.A. Arch. Neurol. Psychiat., 58: 645—650, 1952. 45. 46. Richter, D. and Crossland, J. Variation in acetylcholine content of the brain with physiological state. Amer. J. Physiol., 159: 247—255, 1949. Richter, D. and Lee, M. Serum choline esterase and anxiety. J. Ment. Sci. (London), 88: 428—434, 1942. PROVE!) �Dupucmr. MAY SET 241966 EG—K 6 EG~K 6 %E-NMD6131 p. 12 5-20-66 640 (4) 47.R h M. ee, Serum choline and depression. esterase J Ment. Sci. 435—439, 1942. (London), 88: extension. J. 429—437, 1962. 50. Roth M. , Changes in the EEG under barbiturate anaesthesia vulsive treatment pro duced by electro-conand their signiﬁcance the theory of ECT for a ction. Electroenceph. Clin. N 51. Roth, M.,europhysiol., 3: 261—280, 1951. K physiol., .9: 225—237, 195 . 52. R owntree, D. W., Nevin, :I‘he eifects 53. Rub' 54. (REV 55. Spiegel. E. (FINAL (CL �J. , .,Kay, ' .W.K SI 52. Rowntree, D. W., The effects of Nevin, S. and Wilson, A. in schizophreniadiisopropylﬂuorophosphonate and manic depressive chosis. J. Neurol. psyNeurosurg. 47—62, 1950. Psychiat., 13: 53. Rubin, . . . .. /W_g3, v logical and . Physio, physiocochemical mechanisms lectroshock treatment. in C . N ' 1953. 57. Spiegel, E. A., Spiegel-Adolf, M. and Henr G. Physicochemical Chan of psychoses. Amer. J. Psychiat., 104: 697—706, 1948. 59. Stone, W. .E' Th brain acetylcholine Biol. Med., 61: 51—54,content. Proc. Soc. Exp. 1946. 61. Torda, C. ' Effect of ' Amer. J. Physiol., 173: ontent of the brain. 179—183, 1953. 62. Torda, C. Effects of single injection of corticotropin (ACTH) on ammonium ion and acetylcholine content of Physiol., 173: 176—178, 1953. brain. Amer. J. 63. Tower, D. B. and McE achern, D. Acetylcholine and neuronal activit y. I. Cholinesterase terns and acetylcholin ' patﬂuid Canad. J. Res. Sect E, 64. Tower, D. B and McEachern, D. The content and characterization human cerebrospinal of cholinesterases in Sect. E, 97: 132—145, ﬂuids. Canad. J. Res. 1949. 65. Tower, D. B. and convulsive thera anges induced by electroNeurophysiol., .9: y. Electroenceph. Clin. 217—224, 1957. 67. Ward, A. A., Jr. Atropine in the treatment of closed head injury. J. Neurosurg., 7: 402, 1950. 398— v h I E a � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Files: Acetylcholine and Cholinesterase, 1956-1966 (folder title 4/4). 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Title A name given to the resource Herman Lowenthal (bottom, center) and Bronia Lowenthal Fink (top, second from left) Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-006 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Description An account of the resource Maternal grandfather of Max Fink Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/866335cd8b6a0e848ec4f05bda1e57d7.pdf 610411ecffe18c07ab2ae5b0c8adcc8c PDF Text Text ZJ’W 4r 9, I; /y’7'.rf [E Wsﬁ%w‘> In a series of investigations of the role of neurophysiologic factors in the changes in behavior induced by convulsive therapy, that an alteration in brain function prerequisite, for behavioral it was concluded necessary, though not a sufficient was a change and "improvement" ( ). Changes in brain function were measured by a variety of indices, of which alteration in the waking was EEG induces a the most satisfactory shift in the EEG ( ). convulsive therapy consistently Spectrum to slower frequencies, with the development of runs and bursts of high voltage delta activity. m frequencyI? per-cent ‘ The degree and rate of development frequ However, there is'uide variability in the I‘ A voltageandr‘degree ,t/ ~e£-~h2rstr time treatment process [lay activity different subjects. With-equal—numbers—and developed ’7 at various stages of delta activity have been related to the age of the subject of treatment 1 Yet, when 1’ ), and mode ), frequency of induction (electrical, chemical, photo-chemical). the degree of delta these factors are held constant, variability in activity is it” ( ( of the still manifest (. ). Previous experience has danonstrated that both the behavioral reSponse Y and ratings of improvement to convulsive therapy a perceptualm processes as may be related to various " . number and type of Rorschach responses ( ), �score on the California F scale ( , ( ), and errors on figure-ground tasks dud. ); and to such sociologic factors as age, education level, place of fail.‘ W‘ M treatment m to explain the degree of the EEG the variability, this W W“? their perceptual-psychologic aﬁﬁability wt mm “a“ pie-treatment ofA W subjects, Ma ‘ ‘ EEG M“ characteristics WWWWMWW» Was“ can—ad. this M. It is the purpose of j study m~--~m to elate pre-treatment. SUBJECTS AND METHOD : W Gonsecutive patients referred for convulsive therapy in a voluntary psychiatric hospital were studied. 22 to so with a median of 149 c and depressive, schizophreniﬁ The patients ranged in age from years; and were diagnosed as suffering from psychotic cyclothymic reactions. While the range of conventionally applied diagnostic categories was ML 5" broad, the population exhibit} the cannon characteristics. MAI. (7414:444aA4;€7 a single ethnic f“ �OBSERVATIONS: l. Quaint. Variability of Induced-Beita—Activityt In the patients receiving convulsive treatment and investigated Mimi Mm , a} 1 M/b/ by the methods outlined, the variability in the Wed-Wotivity is considerable. We have summarized the observations in 1146 patients in Table I0 While the per-cent of records in the high degree category increases with successive treatment given at three tines a week, half the population has Aral“, a; Z:/£ not achieved..:the’ degree of—éelta activit}; in the third week, and in the fourth week. in all subjects. By the fourth week, however, 5% m ‘ y 140%“ is apparent �TABLE I £24 4314/4. Degree of Inducedﬁsihe Activity With Gonvalsive Therapy gPerﬁzem of Groug, Name) Treatment Period W ~lHts-Aetjjri’ox Mao—k ## First Rx High Degree Moderate Degree Low None Degree # Week Second Week ‘l‘hird Week Fourth Week 1-3 h-b 7-9 10-12 ‘ 14% 28% he?! 60% 12% 21% 27% 2275 68% h8% 25% 18% 16% 3% 2% 0% HH 3/58 �-72. BA «MM Relation of Pre-Treatment Rorschach to 3.4.3 *4 Variabili ”“2" In the analyses of parable-meat 21:3... Rorschach 7%). the number of responses andAqualitative aspects *ann—Iimaw.._ .. i’movement Mbﬁuywa/‘iée' related to the degree of induced tel-ta activity. Wm—uummuw z.»_..mM.m.w.w—m:"g:od Me “mum—.9... h re were signiﬁcantly fewer cup-us t W EEG and color were WWW ‘nv mu» magnum-u “a...“ m.» .own-ru‘m-v-u-m: ”4/. ML. m mm.mm wulmw‘w.m mm,,. ‘ that With gh "‘ were observed. WW We activity \ manifesting moderate and low degrees of such activity. degrees of Be W 133121911135 m deem-96") in patients with highNRgrees of -.._-----_---_:.§ w on those activity t , 3* - van.” w rv: .-mm—Nw-w,.bv,W M. In patients who were observed) avid; taéeported signii‘'ican significant differences in Mw‘m.mmq_,m.m-.~=m~ failed to report 44». M ”iv! movement WK ﬂy fewer EEG Low reactivity "égher degrees of 7 ”WW’ / , �... -_’.. .ymrw—W‘w~——-- -w'r“"" ~- v-vwam- / W- --»—',.w erw w �W-num z 19*; III ff ; “¢“-'—-h nqh-II-uylL-" '51? A expressed y‘TAIB'I-E ------ similar relationship is noted for color responses. Patients form-color“ in the Rorschach developed lower degrees of delta activity with treatment than those l or a , greater degrees of human movement who W4. expressed color, coior-forxnll . olor responses. Combining both 1W My who & movement and b color) 4“, Wobserved in patients w who gave nor form-color reSponses, than in those patients who neither expressed either or both these responses. Analyses for number of whole responses (W), per-cent of good form responses (F‘s-$5), significanttx 444% populago) and per-cent oi responses, failed to demonstrate Sawwuﬂ—v M relationships 1; the degree of induced an» activity. �II TABLE Relation of Number of Rorschach ReSponses to Induced wide-«4L EEG 9* Mean Activity $.13. Diff. Number High Degree Moderate, am Low Degree 3m 114.2 7.2 20.8 15.0 High Degree Moderate, b... Law Degree h. of Resgonses 6.6 Number 2.9 3J4 5.0 5.]. ’0 2.8 4L SR2 (.01 of Movement Reagonse 2.1 2.3 wE305 gM+Fm+m2 �TABIE Relation of Movement and To A/ Induced III Rorschach Responses golor EEG M» Activity Ht High Degr_ee .— 9* Moderatesz Degree h Sign; . Human Movement (M) 3? 20 (53%) 18 (147%) Other Movement (FM-m) 2f 20 (71%) 8 (29%) I? 16 (814%) 3 (15%) 33 17 (52%) 16 (h8%) x2== 39 (75%) 13 (25%) P 93 11 (148%) 12 (52%) x2= 7.60 25‘ 15 (60%) 10 (140%) p L .05 37 3o (81%) 7 (19%) No - Movement Form Color (FC) Other Color (C, or None Both mm Either M Neither M or FC nor FC CF 0-0) 52‘- X2= p 6.19 4 .05 3.88 4 .05 �.11.. 3. Relation of Pro-Treatment Errors §g§§gglo"1Variabilit In a previous study ( ) related to changes in the degree of on drug: is scored bveo Smx to q errors on the hidden-figures test were EEG ,1, $.4va eel-be activity and positive reaponses the amobarbital test for cerebral dysfunction physiologic responses into a to on Hidden—Figures Test % ). ( Combining the index, a range of changes from zero (Table Did)- The larger the pre-treatment error score, the greater the degree of physiologic change with treatment. The triserial ILL correlation is +0.3h, significant atA .05 level. TABLE IV In a similar analysis of the pre-treatment errors to /\ the difference just fails of significance Relation of Pre-Treatment 1;. Considering the Spectrum made. An initial some EEG Pattern to amongst EEG ( Variability. ) or these and frequency the subjects, an analysis of the of these characteristics and the study variabilityﬁlm./ (Table Nb). variability in modulation, voltage, in the pro-treatment relation between EEG EEG patients EEG nesponsivity was whose pre—treatment EEG �TABLE IV Relation of Pre-Treatment Errors in Hidden-Figures Test to Physiologic Variabili 132 (a) Combined EEG - Amobarbital Index: Miologic Changes Mean # Errors 6+ (8) 13.3 3+, u+ (19) 11.2 0 (lb) 7.9 5+ ) , 1+, 2+ ~= p +0.31; 4.05 34.» Mark (b) EEG Ma Activity nghﬂai‘ha No Highiﬁ: 5.13. Diff. 3,2, (31) 11.1; 7,7, (13) 8.2 4.? t p M, ms. �.13... manifested slow wave activity had demonstrated that high degrees of delta activity appeared earlier such activity, As was as per-cent M confirming earlier report} of Kennard and W'illner 1" Jawwnw correlated with the degree of induced dean activity, time/)del-ta- activity.* MIX; / in patients without ( ). 13h; pre—treatment per-cent time alpha one approach to the problem, activity h and were sustained longer than measured In 44 subjects, a correlation of +0.35) ‘05‘ week (10-12 treatment). treatment the observed fourth during level/was DISCUSSION : In these studies, the degreeof induced EEG delta activity during convulsive therapy has beer- related to pre-treatment perceptual and dwwations ure, patterns. “i limited and are scope in \\ 2' / concluszwgarding I these\ and d bservati theor data with clini of s th\consistencz \\ explomtiglng; ,2; 1,7 further warrants constructs "”” ‘"‘ ”” "W“ ‘ EEG [While {a 1m.“ reports the behavioral patterns of euphoria, hypcmania and denial were shown to be consistently inter- preted by the psychiatric observer or family as "improvement," While somatization, ).Improvement "unimproved,"( and in excitement rated were as paranoia panic, convulsive therapy has been related to such lire-treatment variables as high * Previously demonstrated as a correlation of +0.81; with degree of delta activity ( ). �scores on denial personality indices anal-eerie the California F scale )t , ( W M ); absence of ( cam-W color, human movement, form-color responses, low number of responses, or high number of whole and tests good form responses on Rorschach and foreign birth ( most highly esteemed, educational ( ) ). Thus, ( ); and low educational attainment in an environment where verbal therapy is patients least like the therapist in social Mattributes W are referred for somatic (or non-verbal) therapy. Under the conditions of induced altered brain WM function, those subjects with least ability Wm hypomania, '\ WW ‘ " , she I; reapond with non-verbal behavioral mode; of euphoria, denial, displacement and minimization, and are rated as M "W ” "“76"“! while Subjects with greater perceptual and linguistic discrimination respond with the more verbal patterns of paranoid, panic, somatization and anxiety, and are I/ rated unimproved. II In the observations reported here, the pre-treatment perceptual also related to the degree of physiologic response. 4 discrimmtion and verbal discrﬁptive ability degree of induced gum» The greater the mode is M“! on the Rorschach, the lower the delta activity; the fewer the Rorschach responses, the less ., �.15discriminating and the less the ability to separate figure from ground, W the greater the physiologic responsivity to induced convulsions. difficult to formulate a causal relationship fer—the—eepeetc—e£ It is clinical behavior,(both pre and post-treatment) perceptual patterns and physiologic response. But M M behaviors it ’L“’Z° is operationally meaningful to interpret these various W of the subject tainteraction with the environment, with each measure of behavior representing an abstract or sample of subjectexaminer relationship. In this framework the problem of the relationdhip between personality and physiologic measures is transformed "whether" to one of "how" and ”under What ccnditions." from one or In these series—aﬂ- subjects, heightened perceptual discrimination appears related to low degrees My» W25 MW Wluf / of alpha activity in routine, suite recording and decreased delta-activity- f06ﬂ””‘$ responssnity to convulsive therapy. In clinical behavior sudn subjects are prone to A tutu: introspection, anxiety and ideastional disturbances; and show poor improvement ratings to convulsive therapy. These observations are and EEG consistent with previous studies relating personality a5pects by Kennard, Ulett and Shagass. Kennard and Schwartzman related resting EEG spectra of low alpha index ( to schizophrenic personality, ) �~16- psychotics , non-mm, while high alpha index to Ulett gt_ a_l_. ( ) psychopaths and young individuals. indicated anxiety prone7ness was ﬂying: correlated with v M poor alpha activity, slow and fast activity in the resting record, and poor response to photic stimulation the sedation threshold amplitude of beta ( ), ), ( activity and with poor in the alpha range. In Shagass' studies of low was responsivity to barbiturate as measured by positively correlated with anxiety clinical response to convulsive therapy ( ' ). and tension Thus, behavioral reaponsivity and interaction, reflected in personalitytheoay ltheenyand psychiatric nosology by EEG may be m related to neurophysiologic reactivity as reflected patterns, within the limits of the sensitivity of our measurements or methods of experimentally altering (activating) both behavior Inherent in neurophysiologic responsivity are all and EG. the aspects of the internal milieu, as reflected in individual differences in biochemistry, and in the pre-treatment continuum as EEG record characteristics; the individual environment reflected in perception, motor patterns, mood’ and verbalization; but also the sociologic aspects of the individual's experience. In the series of patients studied here, an ardysis of educational level with degree of . responsivity demonstrated a I.‘ 24.,q me $45 a: D . 3 EEG V] ( - p< .02) relationvship. Subjects �years of formal education had a lower percentage of high 6&b’tgd7’a" 56w! degree records than subjects with less than eight years or education. \ with nine or m more /CONCLUSI ON: The variability in the degree of induced 5am) mm deb: activity manifest during convulsive therapy has been related to technical factors of the treatment. Yet, when these are held constant, (regs-365%; ' ' y has studies, been patterns. Patients with fewer variability is still manifest. In these related to pretreatment perceptual and EG number of responses, fewer movement responses, and absence of human movement, color and form-color responses on the Rorschach; greater errors on figure-ground discrimination alpha activity 026m) 00'“ ' had higher degrees or induced eel-te- activity. 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In eerlier reperte the behevierel patterns at euphoria, hype-enie end deniel were eheen he be ceneietently interpreted by the peyehietrie tenily eheerver e! ee 'ieprevenent', while eenetieetion, penis, pereneie end excite-eat were reted ee Inniepreved( ). leprevenent in eenvuleive therepy hee been releted te each pre-treeteent veriehlee ee high eeeree deniel pereeneiitw indicee (e )3 eheence Beele ( ) end an the Geiiternie r or been: eeveeent, color, toreoeolor whole or anther high nether 1e! e! er reeveneee, reepeneee, end seed for: reepeneee on lerecheeh teete )3 end ( lee edecetienel etteineent end tereign birth ( ). Thus, in en environment where verhel therepy ie eeet highly eetee-ed, petiente 1eeet like the therapist in eoeiel end edncetienel ( ) ettrihutee are referred for eeeetie (er nonuverbel) therepy. Under the aenditiene of induced �altered hrein reaction, thoee eanecte with leeet diearieineo ve tiee ehility reepend with non—verbal hehevierel Iedee o: enphorie, hype-enie, deniel, diepleceeent end linieieetien, end ere reted ee 'eueh improved”, while enhjecte with greeter peroepteel end linguietie dieerininetien reepend with the mere verhel petterne or pereneid, penic, eoeetiee~ tiou end enxiety, end ere reted 'uniepreved.“ In the ebeervetione reparted here, the prentheeteent perceptuel node ie elea releted to the degree of physiologic reeponee. the xreeter the perceptnel diecrieinetion end verhel dieeriptive ehility on the Boreahech, the lower the degree of induced elew were activity, the fever the hereeheeh reepeneee, the ieee dieerieiheting end the 1eee the ehiiity to eeperete figure In: ground, the greeter the phyeielosic reepeueivity te induaed aonvuleiene. It ie difficult to rereelete e eeeeel reletiehehip between clinical hehevior (both pre end peetetre%teent) pereeptuel �pottorno and phyoiologic rooponlo. But it in oporotionolly looningtul to intorprot thou. various tasks to rolotod behaviors of tho oubjoot in hit intorootion with tho onvironnont, with ouch nonsuro or bohovior roprouoating on obstruct or Io-plo or oubaootuoxoninor rolotiouohip. In thio tronowork the problon of tho rolotionship botvoon poroonolity and physiologic noosuroo 1| transfornon tron on. or 'whothor' to can of 'hov' and 'ondor what conditions." In than. Jobs-eta, hoizhtouod porooptuol disoriuinotion dogrooo of alpha oppooro rolotod to low activity in routino, waking rooordo and docroosod amount: of inducod slowing in such bohovior In oonvuloivo clinical to thoropy. coupons. ond idootionol to anxiety introopootiou, oro subject: pron. dioturhouooo: and shot poop inprovolont voting: to oonvnloivo thoropy. an... 1/ oboorvotioao oro conoiotont with proviouo studio: toloting personality and EEG oopooto by Konnord, Ulott and �shagaae. Kannard and subvertaaan EEG ( ) related reating apectra of low alpha index to aehinophrenic pereouality, while high alpha index to non-paycbetice, payebopatha and young indiviﬂuale. Ulett g§_5;, anxiety ereneneea and elow and wee ( indicated ) correlated with peer alpha activity, feet aetivity in the reating record, and poor reapenea to phetie atiaulatien in the alpha range. abaxaae' atadiee at the aedatien threshold ( In ), lav reepenaivity to barbiturate aa aaaaurad by amplitude of beta activity teneien wee peaitively correlated with anxiety and ), ( aonvulaire therapy and and with peer clinical reepenee te ). Thee, behavioral reapenaivity ( interaction, retleeted in personality concepta psychiatric neaolexy nay reactivity ae tetlected be by and in related to neurophysiolocio BEG patterna, within the liaita at the aeneitivity at our aeaaureaente er aethoda at experiaentally altering (activating) both behavior and mac. �Ink-rent in nonrophyliologic rcapensivity uro .11 the tnpccta of tho inturuni lilicu, a: rotlnotod in individual prootrostn§nt and 336 ditterouccu in biochonistry, in tho rtcord entrnotorictiolg the individual onvirounont continuum I! rctloetcd in porccption, notor patterns, need lad varbdiiaation; but also tho oeeiologio 33poctn of th- iudividnal'a .xparionec. In the scrioi at pati¢utc otudiud hnro, an anulyuiu of cduentional lovol with dear-o of rooponuivity danonatratud a aiguiricuut ( - p EEG (.02) relationship. Subjects with nine or sore yunra of tarsal cducttion had a lover parcentago at high degree slow unto oleotronruphie rccords than aabjcct- with yuurn or education. lot. thin eight �- 19 . COICLUSIOII The veriebility in the degree of induced aloe eotivity eeniteet during convuleive therepy to technieel feature at the treeteent. held cenetent, etudiee, BEG fit, were hee been when releted theee ee veriehility is still eeniteet. In theee slowing hee been releted to pretreeteent pereeptuel end EEG petterne. Petieute with fewer number of reepeneee, fever reverent reepeneee, end ebeence of hneen eaveeent, color end Rorecheohg greeter errore for-acoler responses on on the figure-ground diecriniwetiou teeke; end higher percent tine elphe edtivity hed higher decreee e: induced elee were eetivity. 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Variability in the dam- of 1mm 01.0w um activity mm‘nwmmmmmmrm ofﬁnmt. “MmMMtht.m. Inmpmmswa,mc thsﬂnmifut. ummmmmmpmmmmpmmm putt-m. Paintswimfmtotalm,fmw mm,mdmefmw,mlorw’w10r mpmmtbm,mmmﬁmw «Wm..mmmmmmvm hadhiﬁurdumofiuﬁndslmmmvity. Wamutynmdiuﬁmmm, www.mzyummmmm «memmarzmmdm mummWammmmwm. www.mmpomutym-hmemhm‘dminﬁu Mudmmiﬁvityofﬁumm. ��v.‘_,-..-...—, .w—~ .ku— __.—_.. 11__V.,~......——mr -- ym—‘W‘Fm__ -WV..-——.7—w...7Ww-.... [ m ,, w __ v—v _ W u "—— v W— ‘v «mm-m mmw.ww V‘mw.)-—_‘—m~ vm‘wm I ! E 17 . W, mwmmmmuapmmmmmmmh. Jana, Mu. J. PAM... W mm m 10. Kim, a. to 19. Canny. K. 1-!"i R. '1‘” 1965. 122: E. and Layla. R. S. _ 3341. L.wﬁnk,ﬂ. J. Wityfminwmimlmpm #548. 1959. l: Wyeth!” W. mmmm. m. chdmofmmaitmin 2u2~2N5. 1: 1960, J. 1 to WV umywm” W; R. 1... PM, H. ad Sisal. N. “mythological upsets of m, in than mammary hospitals. mm. M. mm" Wt m. n. W m W m. W. aid Kuhn. K. 1... Pink H. w clinical (cum), 195$, 18: m, Witll in Wok. Auk. Mamet. 7391M. “013313513, 23-29. E. A. W111} of W m M. ma. n. n. 1... in a wimtuy mm hospital. J. ‘22.. mm”949., 1:! or «harm 1957, W Palm, mini: We! WeWinamem rating mm” diam $95,211:??? 63 2 c. 3 ma diagnosis. Melt. "“0 $ Win W. 2". Man. 3. I... Polladc. souls and Pom. W, ,lmﬂl. Mo, 28. I‘d Pink, J. H. and m, Gen. Social limit-nan (Cnlifmia F 915.. 1960.. 130: 187-192. ﬂow. 14. H. m. Flam-gum diowinimtim 1‘ "'5 10 ILA. 27. 14. W W. 25. mm. 3.1... 23 Mop-yanlogm aspects of H. and Fink. H. 23. Kuhn. R. L., 'nn 1953, 15: ’5’1150 in paydmologtml diam. r W,H.A.mw.s. mmammmmwm. 1952. 115: “13423. 1. km. Beat. in 9426.. W. Wsmwmmmwmmammummmmm can. dim. WW. ummm" in a. 6mm mm. J. ﬂuid“... malts fm ahehomplulm W. ad 3.. m,inMuwywﬁa unrammotmmm m, J. mm" We:Mt.«action disarm. far «ﬂaming mien mm W6. W, can. NW”... in Eummpk. patina. We H. A” Mimitdu, 3. ad rimmw. The m at 1mm 1955, 7: 29.38. A. 19%, 30. 1.05: and Winner, A. Significmaa of which shod: “0-35. H. Grass, 3. a... mamas. A. 1968.110: 651-661. 31 . C. ‘1'!» A tho th M. ‘ 195“, 6: 221-233. �32. 33. 3'5. mm. W. Pam“. Win: m. Shun- c. C. Sod-tin: A .W. m. mm Awaits“ W Ammumyamrmammmd 9: mass. can. lawman” A. L. 1!; 750 patient. (3. diam-13:1 11k: 100 0guns - . . , “9 . <2.st but prsyehiatric mm” 1958. ' . WWmlwdvityinmdmic Winn. Melt. madam" 1962, 6: 235432. H. Wmﬁatﬁuinpoymimc macaw Add. 5:34:12. . Am. 3. v. 3%, mu, m: 3km: 3’ 0 z ham. 1. 1957‘. mmmmamowa Sims,c.mdﬂdm,d. 37. tool for Wyniolncim M... 1956, 18: #10419. 1988. 121: ‘ 11. may. H. «I. A... - W. Martian. tam. m1 0.. m Vimmlmmm Wm. W m,n.mdm,u. ”MMMW madam: Weird-tic. shag-s H. J. Hmmyem” J. mam... 1962, 3 ' (mid: tbs-58. Uhtt 6.A.andm 3. mmmdwwimmlmwmn thl Many mama we. 1952. 115: urn-sea. 3m, “1. mm. mm York. 1353. Haw s Wihy Sons. Inc... m mm 1mm. . �February 21, 1957 Individual Differences in EEG Responsivity Fink, MJD. to present observations Nbx 1) Problem tonight is in the laboratory of Ex- made perimental Psychiatry at the Hillside Hospital and then try to discuss their significance. we have no the clarification The problem explanation but wish to present this material for it may bring. is to account for the variability in EEG re3ponse to electroshock. The Observations: 1) Repeated EST induces EEG changes. These are of many kinds includ- ing disorganization of frequency; decrease in beta frequency, amplitude; increase in delta % % time and amplitude; delta bursts; spike charges; increased sensitivity to hyperventilation, amobarbital, There 2) is a direct relation in group data of (a) with degree of induced EEG time and dis- - # of treatments changes (b) frequency of treatment (c) type of ' treatment Note (gm or pm). that our analyses are devoted to one aspect of the EEG response - i.e., delta. quantitative measurements The and myself and included were bursts; slowest frequency 3) % and were described here time delta, highest 1955 by Dr. Kahn time delta, duration of highest amplitude of delta. But analysis of our records, so classified as high, middle and demonstrated a definite relation between the ment" % in EEG response and the "improve- in the behavioral\response. Presented at the Metropolitan EEG low Society, February 21, 1957. �In the first 2h table the was obtained: following patients, % High Abnormality 1-3 h—o 7-9 10-12 25 80 91 88 Moderately improved (6) o 16 so ho Unimproved (7) 0 0 O 20 (ll) Much improved first we were struck by this correlation, and, devoted the subsequent year to demonstrating the significance of this relationship. our conclusion - that, improvement You may know of in electroshock therapy requires the induction of a state of altered brain fUnction, of which the EEG-delta index is a cardinal sign. recently, More notes that 3 we at the part of our table which of 2h patients had high records within 1-3 treatments, and that after 10-12 treatments 5 ord! Why Let took a second look patients still had not achieved a single high rec- this difference? me demonstrate some of our records to show the difference in EEG responsivity to electroshock. It is first series all treatments were given in the in the latest by Medcraft - three important to note here that by Reiter instrument; and times a week. That extraneous ulus was eliminated, all factors as threshold or suprathreshold stim- recent treatments have been given at threshold stimulation, achieved by Dr. Green by repeated PM a seizure resulted. 1) . High EEG 2) Moderate 3) Low EEG response. EEG - Lesnick response. - response. Baum - Silverwater in increasing dosage until �To what can we ascribe the difference in response? immediately come to mind, and I will discuss each one A number of factors briefly: (a) .553: is a factor in this varying responsivity, but not the sigIt is true that some younger patients achieve high EEG abnormal- Age nificant one. ity early; as first two patients over 60; but an analysis of the data of our electroshock studies, for which I am indebted to Dr. Green, indicates do some age to play a small role. Analyzing the records of h9 patients, Dr. Green divided the results in- to those above and below hS; above and below 50 - as significant cut-off points. There was a tendency for the older group to have lower EEG ratings in the h-é period; but by the 7-9 period, the differenCe was gone. ' (b) ‘ §_egc_: Clearly not a factor. (c) Clinical diagnosis: is difficult to assess. As you know, clinical diagnoses have no independent reliability. They are approximate descriptions of experience, clinical states and depend largely‘on the examiner's‘bias, setting This factor [of the examination, purpose,etc; also on the patient's age; and only incident- ally on any operationally defined observable pattern in the patient. For these reasons, this analysis is deferred. However, gross more inspection shows that patients with low reactivity have often been called schizophrenic and paranoid, than involutional depress- ives and manic depressive- and that patients with high reactivity have more often been called involutional depressives and manic depressives than schizophrenia-paranora. -_-——-————————-——— of treatment: �-h- significant factors, and since we are describing the results of individuals treated in groups in whom these factors were constant, we are Both are not going to explain this further than to say that stances, to convert a low a high EEG it is possible, in some in- response to three times per week electroshock to response by going from Reiter to Medcraft; or by going from three EEG times per week to five times per week or twice a day. But these factors only amplify further the variation in response. Egg. DeFede We have assumed abnormality We is have looked appear that the development of cerebral changes, of which delta a prototype, for is the logical outcome of repeated electroshock. an explanation, therefore, of the after adequate courses of It may be may reSpond by failure of delta to shock. that not all patients respond to brain trauma by delta, but other changes (as increased beta voltages and frequency; or increased disorganization; or increased responsivity to hyperventilation). Regardless of the construction, a difference in responsivity exists, and is manifested in our series. we have The factors conceptualized the problem as one of "cerebral reactixdty." we have already outlined are important in such reactivity, as have described, but we believe that more is involved. Out studies are we new in the progress along the following lines: 1) 222 Factor of Personality: In the course of our study of factors which bare on the type of behavioral response euphoria, paranoia, withdrawal define personality -), we to electroshock (i.e., denial, undertook a study of personality. To is extremely difficult. But Dr. Kahn in our laboratory has done so by the use of a variety of indices. The Rorschach; an interview with relatives designed to elicit premorbid behavior, eSpecially denial; figure-ground perception; tachistoscopic recognition of words, 32g. �To our surprise, significant correlations between the degree of delta abnormality and two Rorschach factors I score were achieved. 63 and the patients, EEG have listed the table of in the h-6 score reflects a low or middle The IS as well as the denial interview M & C initial in scores our responsivity. The EEG's were done CHART (M & C) EEG and 7-9 treatment period. The negative response; the plus, a high reSponse. THEN REFERRED TO significance of this chart is in the "apparent" diverse phenomena that it purports to relate. If borne out by future observations, it states, that patients who'have no movement responses and either no color or color-form responses have hh% chance of high EEG delta reSponse in the 2nd and 3rd week of treatment; while patients with Form-color reSponses have only a for such a 16% chance result. it be that one's perception of the world is directly related to one's cerebral respOnsivity? Or, do the conditions which permit delta to appear, that is, those that require an ability to withdraw and assume a passive Could ree Ostow described attitude as by for alpha index, also midify the patient's sponse to the Rorschach? we have become increasingly interested in this problem of passive choose to describe attit- it - in the problem of "vigilance" - "alertness.“ In our laboratory, Drs. Pollack and Kahn are engaged in developing psychophysical ude, or, as we measures of such "vigilanceg" while we have become increasingly aware of the influence of the observer's activity on the ongoing 2) A second factor which EEG. interests us with regard to the problem of in- dividual responsivity is the concept of physiologic reactivity. Electroshock �EEG (17) ResRonsiviﬁz to ECT or R (58) GM 00 2 OM czyc h (33) h (33) 7 M CE/C 3 (30) u (no) M 00 1 (25) 2 (50) OM M m FC 5% level of conf. S (71) 9 (50) h (22) 12 10 �is a way of inducing certain diffuse chemical changes in the nervous system. So is metrazol - barbiturate - activation technics it is show - hyperventilation. significant variation in responsivity. hypoglycemia Each of these For example, that hyperventilation induced delta readily in some patients - eSpecially children - but in others, no such response is noted. Dr. commonly known Green of our laboratory has hypothesized, and is now studying, the possibility that a degree of physiologic responsivity - which is measurable - is an inherent characteristic'of organisms. To this end, he is carrying out pretreatment activation records in all our subjects; as well as measuring their threshold for in EEG depend. electrically induced convulsions. I am confident that there are other "factors" on which responsivity to electroshock - and perhaps to all activation - we the variation may the ones described, namely personality, vigilance, are excited by and physiologic responsivity. tonight, not the common characteristic of the EEG response to activation, but the individual variability and the factors on we have emphasized which this depends. 'We have tried to exemplify our problem by our data of the variation in delta response to electroshock. Further study of each act- ivation technic to relate the role of personality, vigilance and physiologic reactivity to the variation in EEG responsivity. �-3and middle (lower socio-economic upper lower (Jewish)! ' j , ~ first The generation, group. and _ ideation‘ mood , responses. W; in the first hospitalisation, of Psychiatric . psychiatric bellman” «read-tune class), immigrant and were ' patterns we 114' W. They use voluntaﬂeﬁon‘ar predominantly 1, with a short period (few months to few years) illnesjzlectroconvulsive treatment was administered three «W “M'- _ times a week using 1hr % WM mthods. rﬂ L3 r . suprathreshold unidirectional or alternating current A“n*”"t ”WA a Jayne/1nd“! 11’ ﬂat man !0 ti 3.: Wig Ml’" {M-dtun ﬂit/“23‘ Within a week prior to treatment subjects were tested with Rorschach and figure-ground discrimination for presence or absence of j ,x’”‘\_, [I 2 responses and total (H + EM+ tasks. The Rorschach human movement protocol was scored responses (M), total m), type and number of color responses (0, movement CF and F0) In the figure-ground discrimination task, a, () modification of Gottschaldt's hidden figures, the subject number of responses (R). L niacin-mam is presented with and below it a page containing two forms a cmnplex figure in which the - a simple geometric figure, simple figure is embedded. The task is to outline the embedded figure in the complex figure. I' ”A4€ "- ad‘ Electroencephalograms were obtained prior to treatment, andweekly“ on a day following a Mamie, treatment. Patients whose pre-treatment records contained �measurable delta activity were excluded from the study. slow wave activity frequencies of and 7 W MW was measured 04, wave actiﬁty, Based on these activity in the record. of induced by determining the per-cent time of and—less three selected in cps, highest amplitude of slow The amount and leads; the slavest frequency / longest duration of burst indices, records were classified as pan/40M "low," "moderate" or "high" degree delta- W previously described of high degreesdeébba ( activity, according to criteria ). In the observations reported here, the activity in the second and third development weeks of treatment treatment intervals) was used in the tabulation. Patients who M. (We, developed high WWactivity during either or both these periods were classed in 3 of delta degree the high degree group. Those whose records did not demonstrate activity in either ,week were classed in the moderate-low class. 7-9 tt%gree or" �watt—baa WI? “H.“HQ mammmuormmmummmwm "mu alum, that «warm ant m1: of “Mom (W m). In Guide“ the “mummy in mum, vellum, m rmwmmwmmmmmtm mm,“ Wsamunugmmwmmmmmumum mﬂWNudl. MMM3M( )orthmputmtlm mmzmwmnmcmutmwmammwmtw mama in aetiﬁirapmﬁ muormdmmmalmthm such with“ «mum mm mmm< mm an «mu- apart at W )., «mapmwmmmmpmmmm ”mtg-lam muey m “rant-d nth tho W W ma of as pass-mm was at such wuvﬂyw In mum «1' ”3.“, +0.35, " m1: {'“4‘. ..., am “tax”; 44”.. a l1" an activity. tom-rm autism, tho .05, w a WW 2.3.2.1.“ Wmudu‘mumormduummwmu � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Individual Differences in EEG Responsivity Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-002-6-006 Date A point or period of time associated with an event in the lifecycle of the resource 1957 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence. Drafts, one with Martin A. Green and Robert L. Kahn Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/0a85dc880c126770a2f4471ab91c4072.pdf 44a73db773213930685e535c3d7c50a0 PDF Text Text Inhalant—lnduced Convulsions MAX FINK, M.D.: ROBERT L. KAHN. Ph.D.: ERIC KARP. B.A. MAX POLLACK. Ph.D.; MARTIN A. GREEN. M.D.: BARRE ALAN, MD. AND HENRY J. LEFKOWITS. M.D. GLEN OAKS. LONG ISLAND, N.Y. �Reprinted from the Archives of General Psychiatry March 1961, Vol. 4, pp. 259— 266 Copyright 1961, by American Medical Association llHllllllll|llllllllllllllllll||llllllllll||llllllllllllllllllllllllllllll MAX FINK, M.D. ROBERT L. KAHN, Ph.D. Inhalant—Induced Convulsions Signiﬁcance for the Theory of the C onvulsive Therapy Process Despite many years of investigation of the convulsive therapy process, there is still much controversy concerning the importance of the seizure itself. Most studies have concluded that the convulsion is a necessary index of cerebral change essential to clinical behavioral change.9'1°'1‘53?"39 Some investigators, nevertheless, have assigned signiﬁcance not to the seizure but to such factors as the psychological meaning of the treatment to the patient, feelings of fear, and the repeated loss of consciousness.3'4'28 The early studies of Kalinowsky et a1.24 and Pacella et al.,3‘0 demonstrating both clinical and electrographic differences be— Submitted for publication Aug. 26, 1960. From the Department of Experimental Psy— chiatry, Hillside Hospital. Aided by grants MY-2092 and M—927 of the National Institute of Mental Health, US. Public Health Service. g ERIC KARP, B.A. MAX POLLACK, Ph.D. MARTIN A. GREEN, M.D. BARRE ALAN, M.D. AND HENRY J. LEFKOWITS, M.D. GLEN OAKS, LONG ISLAND, N.Y tween grand mal and petit mal treatments indicated the signiﬁcant role of the seizure. The various studies comparing convulsive with subconvulsive treatment demonstrated that techniques culminating in a convulsion were uniformly associated with measurable degrees of neurophysiologic and behavioral change, while subconvulsive techniques were not.1‘5'1’7"°’3‘40 In recent studies from this laboratory, similar differences in the 2 treatment types were observed for such aspects of behavior as EEG slow-wave ac— tivity,8’10 language changes after amobar— bital,19"21 and perceptual tasks. 1'3 22 25 A second aspect to the problem of under— standing convulsive therapy concerns the relation of the method of inducing the seizure to the therapeutic outcome. Seizure duration, type of current, and electrode placemerit are among the variables that have 65/259 �ARCHIVES OF GENERAL PSYCHIATRY been studied. While the investigations indicate that changes in behavioral and neurophysiologic indices are related to these parameters, the differences reported for the various seizure—producing methods are small and statistically insigniﬁcant. Major differ— ences, however, are observed between seizure and nonseizure groups. For example, in a recent monograph, Ottosson reported an increase in the duration of unmodiﬁed electrically induced seizures compared with those modiﬁed by premedication with lido— Although the lidocaine—treated pa— tients showed less change in indices of anxiety, retardation, and global behavior than patients treated with unmodiﬁed seizures, the differences were not signiﬁcant. In our studies, while seizure duration 17 and type of current 11 have been related to the degree of behavioral and neurophysio— logic change, there were no differences with relation to therapeutic outcome. Thus, while parameters of the seizure method may bear some relation to therapeutic efﬁcacy, the differences are slight among the techniques, provided that grand mal seizures have been induced. Further exploration of the importance of the seizure was made possible by recent experimental interest in seizures induced by inhalant (hexaﬂuorodiethyl ether, Indoklon,7), and intravenous (PM—10906) agents. This study was undertaken to com— pare the electrical and inhalant seizure—pro— ducing methods with regard to effects on clinical behavior, interseizure electroenceph— alogram, and psychologic test performance in order to clarify the role of the mode of seizure induction in the convulsive therapy process. caine.’29 ‘ In a voluntary psychiatric hospital 27 consecutive unselected patients referred for convulsive therapy were randomly divided into 2 groups using a Gellerman order.16 In 12 patients, convulsions were induced by a Medcraft alternating current in— strument using suprathreshold currents, and in 15 others by inhalation of hexaﬂuorodiethyl ether, following the method of Esquibel et al." Premedication in all cases was limited to sublingual atropine (1.0 mg). Treatments were administered 3 times per week for 10 to 24 applications, the total num- 66/260 her being determined by the clinical judgment of the staff psychiatrist. Ages ranged from 19 to 58, with a mean age of 38.5 years in the electric convulsive therapy (ECT) group; and 19 to 49, with a mean age of 35.5 years in the hexaﬂuorodiethyl ether group. The mean years of education were 11.5 years (ECT) and 12.6 years (hexaﬂuorodiethyl ether). Of the 27 subjects, 12 were classiﬁed as depressive psy— choses, 8 as schizophrenia, mixed type, and 7 as schizophrenia, paranoid type. The distribution of diagnoses, age range and years of education within the 2 samples, did not differ signiﬁcantly. Behavioral change was evaluated weekly in interviews by the patient’s therapist and by the staff psychiatrist. Such aspects as mood, ideation, memory, sleep, appetite, speech patterns, participation in group activities, and relation to staff and to other patients were recorded and changes assessed qualitatively. Electroencephalograms were done prior to treatment, weekly during the treatment course on a day after a convulsion, and 2 weeks after the last treatment. Records were measured for the amount of induced slowing (6 cps and slower) in anterior temporal-vertex leads, in 66 second samples.8 Various psychologic procedures were administered prior to treatment, during the fourth week (10—12 treatment period), and 2 weeks after the last treatment. The measures included Wechsler— Bellevue subtests (information, digit span, object assembly, and digit symbol) ; Gottschaldt type embedded geometric ﬁgures”; perceptions of pseudo— isochromatic embedded colored ﬁgures at high-speed tachistoscopic exposure,31 and a modiﬁed California F Scale.28 In addition, spine x-ray studies were done prior to and at the end of the treatment course. Observations Clinical Behavior.—The inhalation of hexaﬂuorodiethyl ether regularly resulted in a grand mal convulsion, similar to that induced electrically. For the hexafluorodiethyl ether group, induction was slower and the initial cry and opisthotonic posturing were often omitted. In clonic and tonic manifestations, postseizure apnea, and post— seizure behavior, the groups resembled each other closely. In short term evaluations of clinical be— havioral change, the types of behavior manifested were similar in the two groups. Patterns of denial, hypomania, withdrawal, somatization, paranoid excitement, and confusional—memory loss were observed in both 1. Vol. 4, March, 1961 �INHALANT—INDUCED CONVULSIONS TABLE l.—Beham'0ral Patterns TABLE No. of Subjects Recovered Much Improved _—A_. ,_._ Indoklon * ETC Eupho;ia, denial, hypomania Somatization, withdrawal Severe confusion, memory loss 6 6 3 7 2 3 Improved Unimproved Indoklon 7 .5 E C ’1‘ 3 6 5 1 x2 * 2,—Discharge Evaluations < 1.0, not signiﬁcant. Hexaﬂuorodiethyi other. populations with approximately equal frequency (Table 1). Complication rates were similar. While patients tolerated the inhalation procedure, there were frequent episodes of breath holding and leakage about the mask, making this induction less reliable. Fractures were observed radiographically in 3 patients treated with hexaﬂuorodiethyl ether and in during ECT. Administrative evaluations of clinical improvement at the time of discharge from the hospital were equivalent (Table 2). Ratings of recovered and much improved were recorded for approximately half of each group. 2. Electroencephalography.—Interseizure serial electroencephalograms, both qualita— tively and quantitatively were similar in the 2 groups. Progressive symmetric slowing of dominant frequencies and an increase in voltages were apparent in all leads, with frontal and anterior—temporal preponderance. Burst and occasional spike formations were noted in both. Quantitative measures of induced slow—wave activity during each week of treatment were not signiﬁcantly different (Table 3), although the maximum EEG change appeared earlier in the hexaﬂuorodiethyl ether group than in the ECT group. 3 TABLE N o. 3. Psychologic Measures.—Intergroup analyses (Mann Whitney U Test) of the observations for each of the psychological tasks revealed no difference prior to treat— ment, during the fourth week, and 2 weeks after treatment for the 2 treatment groups. Intragroup analyses, however, showed con— sistent changes in various measures from pretreatment to the fourth week; and from the fourth week to 2 weeks after treatment (Table 4), both in the hexaﬂuorodiethyl ether and in the ECT groups. In the Wechsler—Bellevue subtests, group means showed a signiﬁcant decrease in scores (poorer performance) for each sub— test during treatment, and a return to pre« treatment levels in the post-treatment period. One subtest, object assembly, demonstrated signiﬁcantly increased scores after treatment. Similar patterns were observed for the tachistoscopic measures and the F scores. While increased errors on the embedded ﬁgure tests were observed during treatment, the difference was not signiﬁcant. After treatment, the errors in this test decreased signiﬁcantly from pretreatment scores. On the F scale there was an increase in scores with treatment, and a decrease following treatment. For each of these measures, both treatment groups reﬂected a similar pattern of change. 3.—Postconvulsive EEG Slow-Wave Activity (Average % Time) Pretreatment 4-6 Rx 7-9 Rx Wk. After Last Treatment 2 10-12 Rx Indokl'm 15 6.0 29.4 50.3 51.2 16.8 E CT 12 4.0 29.8 39.2 47.5 18.0 Fin/a et al. 67/261 �ARCHIVES OF GENERAL PSYCHIATRY TABLE 4.———Eﬂect of Hexaﬂnorodieth'yl Ether and Electrically Induced Seizures on Psychologic Test Performances (Scores Expressed as Mean Differences) Pretreatment and Fourth Week 1. Wechsler-Bellevue (weighted subtcst score) ((1) Information (b) (c) ((1) 2. 3. 4. Digit span Ind ECT Ind Ind ECT Ind Digit symbol ECT Ind Tachistoscopy (errors) Ind ECT Ind ECT F scale +1.5 1 +1.7 T +2.7 T +2.3 1 +4.1 * +4.81 +3.3 1 +2.3 1 —1.3 —2.4 * +0.2 T -—0.7 —l.9 * +0.8 . —0.4 +2.7 ‘ +3.5 +0.8 1‘ —0.1 —6.5 —4.9 +9.7 * +8.2 * +2.0 +3.3 +7.7 1 +5.2 1 ECT Embedded ﬁgures (errors) Fourth Week and Post-Treatment —2.7 ’ —1.4 —1.3 —2.5 ’r —2.4 I EC‘I‘ Object assembly Pretreatment and Post-Treatment —16.2 —13.1 i ——4.1 1 ——2.1 ——2.6 t ‘ —-—5.9 I --11.6 I —3.9 +1.2 ——4.0 T Ind = Indoklon (hexaﬂuorodiethyl ether). Using Wilcoxon’s T for paired replicates: * p < 0.02' ’r p < 0.05. EEG Correlations. The changes in performance on the psy— chologic tasks from the pretreatment to the fourth week testing period were signiﬁcant— ly related to the degree of induced EEG slow—wave activity for both groups (Table 5). Rank order correlations demonstrated that decrements in performance on the 4. Test Performance: Wechsler-Bellevue digit span and object as— sembly subtests, tachistoscopy, and em— bedded ﬁgures tasks were signiﬁcantly related to the amount of electrographic change. Similarly, an increase in F score was associated with increased EEG slowing. When the observations in the hexaﬂu— orodiethyl ether and ECT groups were individually analyzed, signiﬁcant correla— tions were noted for various tasks. In the hexaﬂuorodiethyl ether group, the deerement TABLE ~ Indoklon ECT Indoklon and ECT ‘ p < in < 68/262 :0 < 0.01. in the Wechsler—Bellevue information and digit span subtests and in tachistoscOpy was related to the degree of EEG slowing. In the ECT group, similar relations were noted for tachistoscopy, Wechsler-Bellevue digit span, and object assembly subtests and the F score. Comment Mode of I ndnction.——The inhalant and the electrically induced seizure groups were indistinguishable on the various measures of behavior at each stage of the treatment process. Since the factor common to both treatments was the induction of seizures and not the method of induction, we may conclude that the method of induction is not a signiﬁcant variable in the therapy be— in the Speciﬁcally, changes process. 1. 5.—Change in Task Performance and Degree of EEG S low—Wave Activity (Pretreatment vs. Fourth Week; Rank Order Correlations) Wechsler-Bellevue Form , I 1 Information Digit Span Object Assembly Symbol 0.73 " 0.28 0.25 0.54 i 0.72 i 0.61 ‘ 0.31 0.60 0.46 0.38 0.34 0.31 1‘ T Digit Tachistoscopy 0.62 0.80 0.67 T * * Embedded Figures 0.13 0.37 0.43 T F Scale 0.12 0.66 0.38 ’r ’r 0.01 0.05 Vol. 4, March, 1961 �INHALANT—INDUCED CONVULSIONS _ havioral and neurophysiologic indices are sider these results as reﬂecting differences dependent upon the induction of seizures, both in population samples and in methods and not dependent on any single property of scoring behavioral change. While acute of the electrical or the inhalant mode of illness and affective-depressive reactions are induction. described for the majority of subjects in Kurland et a1.26 and Chatrian and Peter— the positive studies,1‘°'27'38 70% of the sub sen5 have also compared electrical and jects in one 4 negative and 100% in another 28 inhalant seizures. Kurland and his co-work- were classed as having schizophrenic re— ers assigned convulsive therapy referrals actions. The facilities in these investigations alternately to hexaﬂuorodiethyl ether and serve chronically ill populations, and prior ECT groups. They reported that behavioral courses of convulsive therapy were recorded ratings, complication rates, psychologic test for nearly half the subjects in one group4 performances, and cardiovascular reactions and 90% in the other.” The failure to obwere similar in the 2 samples. Chatrian and tain signiﬁcant differences may also lie in Petersen, studying schizophrenic subjects the small samples used to test the null with implanted intracerebral electrodes, re— hypothesis. ported identical electrographic patterns dur— Changes in behavior are observed in all ing seizures and at various postseizure subjects receiving a course of convulsive periods for hexaﬂuorodiethyl ether, pen- therapy,1052930533,38 but those changes evaltylenetetrazol (Metrazol), and electrical uated as clinical improvement occur only techniques. in some. While induced convulsions are a In studies of seizures induced by various sufﬁcient condition for behavioral change, electrical means, equivalent behavioral, psy— they are only a necessary condition for chologic, and electrographic effects have improvement. Thus, measures of behavioral been reported.3’11’29v39 While these studies change, such as memory,25 language,19'21 equate the effects of different convulsive and perception 1332 readily demonstrate sig— techniques, various nonconvulsive methods niﬁcant differences between convulsive and such as subconvulsive, brief stimulus, uni— subconvulsive techniques within the individ— directional stimulating, monopolar stimu- ual differences in personality organization lating, and focal “convulsive” techniques of the subjects. Ratings of “improvement," have been described, and each in turn however, with the personality organ-vary discarded in routine therapy as ineffec— ization of the subject in adap— as expressed tive.1‘°"27'39'4‘° For example, Bergman,2 in tive patterns and ﬂexibility for change; describing the electrographic effects of the with such environmental variables ther— as “focal—seizure” technique noted that 75% apist, staff, and family expectations and of patients had normal records after 15 tolerance for the elicited adaptive behavior. such applications, while 70% had “abnor— and with the duration and degree of induced mal” records after grand mal seizures. Ulett neurophysiologic changes. In global esti— et al.39 have reported differences in the im- mates of “improvement” the environmental provement rates of patients receiving con— variables become prepotent. The failure to vulsive treatments (60%—80%) and those observe signiﬁcant differences in improve— receiving subconvulsive (33%), or controls ment ratings in convulsive and noncon1‘0 (38%). Our own studies also demon— vulsive groups may be related as much to strate signiﬁcantly greater degrees of these environmental variables and the perbehavioral and physiologic change for con— sonality characteristics of the subjects as vulsive than for subconvulsive treatments. to the induced physiologic changes. A number of investigators, however, have 2. Signiﬁcance of the Convulsion.——The failed to observe differences in improvement evidence indicates that convulsions are, or rates for patients treated by convulsive and reﬂect, the signiﬁcant physiologic events subconvulsive means?”8 We would con— which are basic for the therapeutic efﬁcacy Fink ct al. 69/263 �ARCHIVES OF GENERAL PSYCHIATRY of convulsive therapies. The speciﬁc role of the seizure is, however, not clear. That neither the motor aspects of the seizure nor the accompanying psychologic factors are determining variables is demonstrated by the efﬁcacy of treatments under condi— tions of muscle paralysis and anesthesia?"2 That the loss of consciousness, itself, is not the signiﬁcant variable is seen in the relative inefﬁcacy of repeated administrations of thiopental (Pentothal) or noncon— vulsive techniques under thiopental.1°'2'7’39 Although the means by which various agents achieve such changes are not speci— ﬁed, it is probable that the seizure is but one expression of a diffuse alteration in cerebral functioning?” It is this alteration in brain function which provides the neces— sary conditions for the behavioral changes of convulsive therapy.14»2°v40 Among the behavioral changes we would include the im— mediate alteration in consciousness, recall, motor patterns, and breathing; and the more persistent psychologic, perceptual, vegeta— tive, physiologic, and hormonal patterns, characteristically described in convulsive therapy. Alterations in brain function are reﬂected in neurochemical changes as the acetylcho— line and cholinesterasef"7 transaminase,36 and serotonin '34 content of the spinal ﬂuid. They are also observed in such neurophysi— ologic measures as increased delta and theta 1‘8 decreased and beta in activity8 activity electroencephalograms, and in altered elec— 33735 20"21’4‘0 behavioral re— and trographic sponsivity to intravenous barbiturates and to anticholinergic and sympathomimetic agents"!12 The correlations between the degree of neurophysiologic change and changes in perceptual test performance re— ported here are a reﬂection of these central changes, as are the perceptualf‘ovl‘?”22 lin— guisticf‘w1 and clinical behavioral 10,20 changes described in earlier studies. In a recent review'9 the signiﬁcance of the acetylcholine—cholinesterase system in these neurochemical alterations was dis— cussed. Observations With various anti— 70/264 cholinergic agents and reports of similar patterns with antihistaminic and sympatho— mimetic agents indicate the necessity for a broadly based View of biochemical and brain function relations, with emphasis on synaptic models.” A suggestive mechanism for the prolonged alterations in brain function is seen in the blood—brain barrier studies of Aird,1 who noted persistent changes in cerebrovascular permeability following in— duced convulsions. He related these to the seizure and not to the passage of electric currents, and suggested that these changes may be the enduring physiologic basis for the induced behavioral change. Thus, we would conclude that the convulsion, per se, is not a necessary condition for behavioral change, but neurochemical change, of which the convulsion is the im— mediate reﬂection, is prerequisite. Indeed, were persistent neurochemical and neuro— physiologic effects induced as readily by other means, “convulsive” methods would no longer be necessary. In this regard, the nonspeciﬁc nature of the convulsive therapy process has been repeatedly emphasized.14v4‘° Summary and Conclusions Consecutive patients referred for convulsive therapy were randomly assigned to treatment courses by an inhalant (hexa— ﬂuorodiethyl ether, Indoklon) or electrical inducing agent. There were no differences in the two groups on behavioral, electrographic, or psychological measures prior to, during, or 2 weeks after treatment. Hospital discharge ratings were equivalent. Intragroup test dif— ferences were noted on all measures in both groups during treatment. These differences were related to the degree of induced neuro— physiologic change and the pattern of such changes were similar in both treatment methods. It is concluded that the observed alterations in, brain function are equivalent to seizures induced by inhalant or electrical means. The nonspeciﬁcity of convulsions induced by hexaﬂuorodiethyl ether and the greater difﬁculty of administration are con— Vol. 4, March, 1961 �INHALANT—INDUCED CONVULS‘IONS sidered as deterrents to the continued clin— ical use of this treatment. The mode of induction of seizures is an insigniﬁcant factor in the convulsive therapy process. Seizures are viewed as one index of the persistent neurochemical alterations which are requisite to the behavioral changes of convulsive therapy. These observations are discussed within the framework of the neurophysiologic— adaptive model of the mode of action of somatic therapies in psychiatry. _ The cooperation of Smith Kline & French Laboratories in providing the hexaﬂuorodiethyl ether (Indoklon) used in these studies is grate— fully acknowledged. Department of Experimental Psychiatry, Hillside Hospital, Long Island, N.Y. REFERENCES Aird, R. B.: Clinical Correlates of Electroshock Therapy, A.M.A. Arch. Neurol. & Psychiat. 1. 79:633—639, 1958. Bergman, P. S.; Impastato, D. J.; Berg, S., and Feinstein, R.: Electroencephalographic Changes Following Electrically Induced Focal Seizures, Conﬁnia neurol. 13:271-277, 1953. 3. Brill, N. Q; Crumpton, E; Eiduson, S.; Grayson, H. M.; Hellman, L. 1.; Richards, R. A.; Strassman, H. D., and Unger, A. A.: Investiga— tion of the Therapeutic Components and Various Factors Associated with Improvement with Elec— troconvulsive Treatment: A Preliminary Report, Am. J. Psychiat. 113:997-1008, 1957. 4. Brill, N. Q; Crumpton, E; Eiduson, S.; Grayson, H. M.; Hellman, L. I., and Richards, R. A.: Relative Effectiveness of Various Com— ponents of Electroconvulsive Therapy, A.M.A. Arch. Neurol. & Psychiat. 81:627—635, 1959. 5. Chatrian, C. E, and Petersen, M. C.: The Convulsive Patterns Provoked by Indoklon, Metra— 201, and Electro—Shock: Some Depth Electro— graphic Observations in Human Patients, EEG Clin. & Neurophysiol. 12:715-725, 1960. 6. Edwalds, R. M.; Experimental Studies with PM—1090, Int. Rec. Med. & G P Clin. 169 :469— 2. 472, 1956. Esquibel, A.; Krantz, J. C.; Truitt, E. B.; Ling, A. S. C., and Kurland, A. A.: Hexafluoro— diethyl Ether (Indoklon) : Its Use as a Convulsant in Psychiatric Treatment, J. Nerv. & Ment. Dis. 7. 126:530—534, 1958. Fink, M., and Kahn, R. L.: Relation of EEG Delta Activity to Behavioral Response in Electroshock: Quantitative Serial Studies, A.M.A. Arch. Neurol. & Psychiat. 78:516-525, 1957. 8. Pink 61‘ al. Fink, M.; Effect of Anticholinergic Agent, Diethazine, on EEG and Behavior: Signiﬁcance for Theory of Convulsive Therapy, A.M.A. Arch. Neurol. & Psychiat. 80:380—387, 1958. 10. Fink, M.; Kahn, R. L., and Green, M.; Experimental Studies of the Electroshock Process, Dis. Nerv. System 192113—118, 1958. 11. Fink, M., and Green, M.; Electroencephalographic Correlates of the Electroshock Process, Dis. Nerv. System 19227, 1958. 12. Fink, M.; Effect of Anticholinergic Com— pounds on Post-Convulsive EEG and Behavior, EEG Clin. & Neurophysiol. 12:359—369, 1960. 13. Fink, M.; Kahn, R. L., and Korin, H.; Effects of Diffuse Altered Brain Function on Per— ception, in Proceedings of the 15th International Congress of Psychology, Amsterdam, North— Holland Publishing Company, 1959, pp. 238-239. 14. Fink, M.; Alterations in Brain Function in Therapy, in Psychopharmacology Frontiers, edited by N. S. Kline, Boston, Little, Brown & Company, 9. 1959, pp. 325-332. 15. Fleming, T. C.: An Inquiry into the Mechanism of Action of Electric Shock Treatments, J. Nerv. & Ment. Dis. 124 :440-450, 1956. 16. Gellerman, L. W.: Chance Orders of Alternating Stimuli in Visual Discrimination Ex— periments, J. Genet. Psychol. 42 2207-208, 1933. 17. Green, M. A.: Relation Between Threshold and Duration of Seizures and Electrographic Change During Convulsive Therapy, J. Nerv. & Ment. Dis. 131:117—120, 1960. l8.Hoag1and, H.; Malamud, W.; Kaufman, I. C., and Pincus, G.: Changes in Electroenceph— alogram and in the Excretion of l7—Ketosteroids Accompanying Electroshock Therapy of Agitated Depression, Psychosom. Med. 8:246-251, 1946. 19. Jaffe, J.; Fink, M., and Kahn, R. L.: Changes in Verbal Transactions with Induced Altered Brain Function, J. Nerv. & Ment. Dis. 130:235-239, 1960. 20. Kahn, R. L.; Fink, M., and Weinstein, E. A.: Relation of Amobarbital Test to Clinical Improvement in Electroshock, Arch. Neurol. & Psychiat. 76:23-29, 1956. 21. Kahn, R. L., and Fink, M.; Changes in Language During Electroshock Therapy, in Psy— chopathology of Communication, edited by P. Hoch, and J. Zubin, New York, Grune & Stratton, Inc., 1958, pp. 126—139. 22. Kahn, R. L.; Pollack, M., and Fink, M.; Figure-Ground Discrimination After Induced Al— tered Brain Function, A.M.A. Arch. Neurol. 2 :547551, 1960. 23. Kahn, R. L.; Pollack, M., and Fink, M.; Social Attitude (California F Scale) and Con- vulsive Therapy, J. Nerv. & Ment. Dis. 130:187192, 1960. 24. Kalinowsky, L.; Barrera, E. S., and Horwitz, W. A.: The “Petit Mal” Response in Elec71/265 �ARCHIVES OF GENERAL PSYCHIATRY tric Shock Therapy, Am. J. Psychiat. 98:708-711, Succinylcholine, Dis. Nerv. System 16:237-242, 1942. 25. 1955. Korin, H.; Fink, M., and Kwalwasser, 5.: Relation of Changes in Memory and Learning to Improvement in Electroshock, Conﬁnia neurol. 16:88-96, 1956. Kurland, A. A.; Hanlong, T. E.; Esquibel, A. J.; Krantz, J. C., and Sheets, C. S: A Comparative Study .of Hexaﬂuorodiethyl Ether (In— doklon) and Electroconvulsive Therapy, J Nerv. & Ment. Dis. 129:95-98, 1959. 27. Lancaster, H. P.; Steinert, R. R., and Frost, I.: Unilateral Electroconvulsive Therapy, J. Ment. 26. Sc. 104:221-227, 1958. 28. Miller, D. H.; Clancy, J., and Cummings, E.: A Comparison Between Unidirectional Current Non-Convulsive Electrical Stimulation Given with Reiter’s Machine, Standard Alternating Current Electroshock and Pentothal in Chronic Schizo— phrenia, Am. J. Psychiat. 109 2617—620, 1953. 29. Ottosson, J. 0.: Experimental Studies of the Mode of Action of Electroconvulsive Therapy, Acta psychiat. & neurol. scandinav. Supp. 145, 3521—141, 1960. Barrera, E. S., and Kalinowsky, L.: Variations in the Electroencephalogram Associated with Electric Shock Therapy in Patients with Mental Disorders, Arch. Neurol. & Psychiat. 47 2367-384, 1942. 31. Pollack, M.; Battersby, W. S., and Bender, M. B.: Tachistoscopic Identiﬁcation of Contour in Patients with Brain Damage, J. Comp. & 30. Pacella, B. L. ; Physiol. Psychol. 50:220—227, 1957. 32. Reitman, H. J., and Delgado, E.: Technique for the Modiﬁcation of Electroshock with 72/266 M.; Kay, D. W. E.; Shaw, J., and Green, J.: Prognosis and Pentothal Induced Electroencephalographic Changes in Electroconvulsive Treatment, EEG & Clin. Neurophysiol. 9:225-237, 33. Roth, 1957. E: Acetylcholine and Serotonin in the Spinal Fluid, J. Neurosurg. 14 222-27, 1957. 35. Shagass, C.; Mihalik, J., and Jones, A. L.: Clinical Psychiatric Studies Using the Sedation Threshold, J. Psychosom. Res. 2:45-55, 1957. 36. Stevens, J. D.; Majka, F. A., and Humoller, F. L.: Transaminase Activity in the Spinal Fluid in Neuropsychiatric Conditions, Dis. Nerv. System 20 :460-465, 1959. 37. Tower, D. B., and McEachern, D.: The Content and Characterization of Cholinesterases in Human Spinal Fluids, Canad. J. Research 27: 34. Sachs, 132-145, 1949. Ulett, G. A.; Gleser, G. C.; Caldwell, B. M., and Smith, K.: The Use of Matched Groups in the Evaluation of Convulsive and Subconvulsive Photoshock, Bull. Menninger Clin. 18:138-146, 38. 1954. 39. Ulett, G. A.; Smith, K., and Gleser, G. C.: Evaluation of Convulsive Shock Therapies Utiliz— ing a Control Group, Am. J. Psychiat. 1121795802, 1956. 40. Weinstein, E. A., and Kahn, R. L.: Denial of Illness: Symbolic and Physiological Aspects, Springﬁeld, 111., Charles C Thomas, Publisher, 1955. Printed and Published in the United States of America ��A-4t - signattscunt at Iuhultnt Inna-ad Guuvulttoun to: thrhucrr at ‘8: canvalnavu rhuranr Pronun- MI". IN; “.8. “It; 4‘. '0”. ’0‘... ”03., In It“ m. M“ m. ,“h“. MO ‘1‘“; “an“ m WM“. '0”. tho nuihud tn tndncanc cotstrc at at stunstxnanoc t8. it. In: in ”09.; m nzoc‘rncouvu1ISVI ﬁhnruyy an. tuvcsttsuﬁod ﬁr culpartn. tn Ila. ilhllﬂl‘. hllatincradilihrlothur (IndOkIOI), with it. ciuvunﬁtnnsi ozaatrical staining tnahatqun. fvuntgbnovuu can-mun Mamas“ mum‘wiu ”an" we and“ um GU» randunxV atticnld irtttlsni gringo. fruuunoaﬁ van Id3131ltnru¢ at to m m: than mi: anus-um. y» mu Thiri ﬁll at datturnann xu sun in. stein! in.bohav10ra1. aloatrlanaophnlggrnyhzu I? 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Ihﬁﬁ§ tin muck, naktng ‘hin inttctiia 1:1: :vlhhlc. fruwt‘rta new. obntthd radiogrupttcgllr 1: £lrvc Indolian irattod pciﬁuﬁtn and in throw during 36!. Adminaatrattvu tVIlnnﬁiaaa a: cizuiaul ingravanaut u. £30 an at “an". :m a. was”: an msnzus "an. t). a: Itcnwnrtd and anon tnyravcd nypruxinutvly half at taah ﬁrst». Inﬁdnsu first a warn rucordui fur �inturitasuvu aiﬁina tianrocuunyhaloxruun, town qualtiai$vuiy and qumttttuttvoxy, aura aluilur in the two gvﬂtyic Frucrncnsvu arunntrtn attains ct inhinant trucuuucxtp and an tactvuuc tn Vil‘icil 1;: I’pllih‘ in :11 lnatu. with trintnl in! naiovttrmtaupiwul yruyduiarunaa. lava: and «human an. swam m «m u an. Mann” antt¢tey tutti; tilt such it ivcnI-lnt warn Ilﬁ Iaanltiauliay isttcrwut {tibia 3). taﬁhntgh tan anti!!! III stanza uypntrai «stilt: in ﬁt. thiuklnu trim! than 1: it. In! grin}. nuanurwn OI indsaud ulna Hutu tiltt 3 “~w«.*...u~ mm: 1:1er uhtorvattvau tut tack tic poyvtalociaux twat: (in. man” has It t: or ﬂu rmvuulad a. dattbruaca yriir t9 iroutulnt, ﬂaring tho lihrih unnk, and it! itch: ptntattcutnmnt for ﬁtt it! tsua$naat grﬁ‘ps. Iatrtm hiiivnr, iatlynoa, li‘l!‘ Gduttttcut ataugul in vurtuuu grit: allltfit (was pruutrautuaut it $ha tutti! tuck; and tron ti: Sturﬁh 9“! £3 two that. titty trtatnnat (luﬁli £3, bush in tho Intttiiu sat in tha IQ! grunpo. ....*.....um: I: �an,» x: it: waohalirulililvng tuhsotts, grit; lﬂﬁtﬂ unasud a ﬁllhificnﬁt «ontnama an wcortt (y‘awcr yuvlorannct) tn! Cunt .3h‘nct iuriaa irtgiunnﬁﬁ and u v-ﬁurn t. yruatrnttunut 10'!!! 3: sh: poabwtvcn‘nnut yurtod. 03¢ Ithioxt, «33.6% Inatuﬁlr, dtntastrntui tlzntrlscatar~inuvouocd Ct0r00«’ditv ‘iﬂdilil‘¢ stntltr pattern: 0": oha¢rvud fur thy tnotxutoacapiu unusarca use it. I «tints. will. incrcnund arrow: as ch» «abaddﬁd tight. tutti warn uhtuvvud daring ﬁvtutunas, t3: dt!£:roano an. naﬁ alaniriaﬁut. Paatutrautuunt, tin arrays in its: tunﬁ itartlnca signattcnutlr from prontrouﬂuaat no.9... an tha 1 anti. that; an; incrutso in isﬂrit utth trottunnt, and a Guavaauv tullduan; ‘runinust. in: each at that. unnausol. tic un clmamtl 13>psr£bmnmn¢a an £ha ynruhnaagta tucks tram tun prumﬁroniuuuﬁ riirtt itch tnttinu pnrild warn t. ti: uttnllltauttr rulttad ﬁt til angst. orstuiuuud 3!! 310' all. activity to: tutu urtupa (inhia 5). Isak grant inrcllﬁiun: inunnctvaﬁod thgi attriunuSn in porttruuntu on the'wlnluicvu Inlluvu¢ atgit cyan and thattt unocth: aubtttta; tuthiutnueupy tat rtsaruu stat; wart gignitiacntlr rtlutti to ‘ho anniat .1 oltatxagruphlc ahlnst. stuxxnrly, an innrquac in ? utcrn It! ssndaiatod hath 1nﬂriittﬂ £13 tilting. anh¢¢d¢d -a..*....., till! 5 �mmmumummzummm amalgam mt mama» mm. immt m W tum-mummy. mewmmm. ml was it. mm“... umwmnm «at a mmmuummmmnumum‘mu at: 31m. m m m. umm nun-m an and hr Wm, mnmnm in“ m at out“ numb}, mm m m min-m W 2-. l‘ �1. W!h: crimp. wuro behaviar tt aloctrioul tudnncd iatxlra £n¢£tttnguinhahlt tn ﬁn. variant statur¢t a: etch ttuxo at tun ‘RUtiliﬂt proocsl. 813:: in: 1nh&1:nt and tho taatar ens-tn ‘0 bath trOainuntu vns tn. induction st natuurit tad not thg unthnd a: inauotian, u. may Gﬂﬂﬁlud. thu$ it. netted or 1nduet1¢n 33 has a signtttctnt variihlc in th. £h¢rnpy arsenal. apceatie¢lly, chanson in tho bah:v10rn1 and attraphyiitlnsic inﬂicts ;ro dupcudant tutu the induction 0: taiinrtu, Ind not dapaudout nu nay '1ng1c property or the tluntrieul it tho inhtltnt nod. of induction. Klrland.g§J;;. (26) lad Chutriau and P¢taraoa (5) bath alto conpnrad ¢1natrtea1 ind tahnluut '013Irt3. Karinue and ht: agowurkcru niutgnnd convulylvn thnrapy ruttrraln tltcrw uttoly to Induklua and so: trontnamt cranps. :huy rapcwttd £hnt b¢havtural rataagl, acnyIScutiou rut-a. payehalagia tclt portaru£aeta and aardithluulur roaa‘itun var. 11:11:: in tho tun £3.91... ¢ha%riu| uud itnrn¢a, Itudying schano~ phrcala tahstata with anplantnd inttncurohral altatrodon, ropqrtnd 14¢:Q1aai ultc‘raarsphi¢ pttsoran durzng ncxnurna ind uﬁ vurtonn puttwltialrt psrzcﬂn It: Instilon, untrtlua and tlaatrtnsl tuchniauat. In studtu‘ it :dburan inaun¢d by varituu dlcutr1c¢1.n¢tal, Ignivnloa‘ bﬁhnviorll. ynyahtlogia and �.11. olootrocrophio ortooto hovo boon rovorﬁod (3,11,29,39). Vhtlo thooo otudtoo oqnoto tho otroeto or ditforons convuloivo ‘oehaiquoo, voriouo nonooonvuloivo nothodo ouch oo oubconvalotvo, hriot otinuluo. unidiroetlonol otionlotinx, oonopolor otiouu Intang, and tonal *oouvu1311o* toehniquoo hovo boon dooorlbod, and ooch in turn, diocordod in routino thorny: oo inotroctivo (10,27.39,h0). For oxouplo, Borgnon (2), 1n doocrthinu tho olootroarophio ottonto of tho '1ooo1-oo1:nro* touhntquo uotod that 751 o: potionto bod noraol rocordo ortor tlftoon ouoh opplicottooo, whtlo 703 had 'obaornol' records alto: aroma moi ooiauroo. Blott ggﬂg;& (39) hovo roportod diftoronaoo in tho taprovoaont rotoo at potiouto roooiviag oouvulotvo trootuonto (69.301) sad thooo roooiviag oubconvuloivo (33$), or «outrolo (385). Our own otudioo (10) also dononotroto oignirioontly groooor dogrooo of bohoviorol ond phyoioloaio ohonco zor.eon~ vnloivo than onbaonvuloivoVtrootoonto. A author or inventigotoru, hooovor. hovo toilod to oboorvo dittoroneoo 1n loprcvonout rotoo for potionto trootoa by. convuloivo ond subconvuloave noono (3,h,28). Ho would conoldor thooo rooulta to rolloctiag d;:£oronooo both in popuiotion oonploo and 1a oothodo or ocartng bohovtarol ohonco. whtlo oonto illuooo and orroetivo-dogroooivo rooottono oro doooribod for tho nojority or oubjocto to sho poolttvo otudioo (10.27.38) 70: at tho “Moots 1:. mo and! (h) and 100! 1a anothor (28) voro elooood oo schizophronio rooctiono. rho rootlitioo in thooo 1nvoot1gottono oorvo ohrontoolly 111 ‘ "an“ �~12. populottooo, ond prior oouvooo or ooovuloivo thoropy voro rooordod-tor hourly halt tho oobaooto 1n ouo group (h) and 901 in tho othor (28). 73o toiluro to obtoiu oiguttlolat dittoronooo on: oloo 11o 1n tbo atoll oooploo mood to.toot tho null hypothooto. Chongoo 1n hohovlor oro oboorvod 1a o1! onbaooto roootvio: o oouroo or oonvuloivo thoropy (lo,t9,30,33.38), but thooo chongoo ovoluotoo oo oltntool thyrovooont, occur oaly 1o oooo. whilo induood oonvuloiono oro o ooftiolont condition for hohovtorol chango, tho: oro only o noooooory condition for inprovooont. Thoo, nooouroo or bohovioro1 ohoago, cook to monory (25), longuogo (19,21) ood porooption (13,22) roodtly doooaotroto signittoont d1xtoronooo hotwoon ooavolotvo ono ouboonvuloivo toohniqooo within tho 1nd1vtdoo1 dittorooooo to poroouolity ergoniootlon of tho oohaooto. Iotlago of ”1-provonont', howovor, vary with tho poroonoltty orgootootloo of tho oubaoot oo oxprooood 1n odoptivo yottorno and Iloxibility for ohoogo; with ouch onviroaooutol vortobloo oo thoroptot. ototf and tonily oxpootottono ono toloronoo for tho o11o1tod odopttvo bohoibrg and tho ﬂotation ood dogroo of indoood nourophyoiologio ohougoo. In globol ootiuotoo of “inprovo-ont' tho onvtroa-ontol vortotloo booooo propotont. rho totloro to oboorvo significant dittoronooo 1n taprovolout voting. to rolotod on lock oonvoloivo and noo~oonvu1otvo zroopo no: to to thooo ooviroonontol voriobloo and tho yoroonoltty ohooootorlotion of tho oobaooto, oo to tho indoooo phyotolocio ohoagoo. �.13. 2. Signirtaeuee at the convulsion. The evadenee indicates thet eenvnlaiene ere, er retleet, the eigniticent phyeiolegic event: thigh ere beets tor the therepeuttc ettteeoy e: convuleive therapies. the epeeitie rele e: the eeleure 1:, however, net olenr. Thet nelther the note: eepeete e: the eeteure new the eeceepeuyiux peychelegie fectere ere determining veriehlee 1e deleuetreted by the etrioeey et treeteente under eeudltleue er neeele perelymte end eneetheeie (3!). rhet the leee or ceneeteueueee, iteelf, in net the etzuitteent veriehle 1e seen in the relative luettteeer e: repeated esuintetretiene e: peatethel or not. eenvuletve teehniquee under pentethel (10,2?,39). Without epecityinx the neeae by which verieue egente eohieve eueh oheaxee, it to vrebeble thet the eeieure 1e but one expreeeien e: e dittuee alteration in oerebrel functioning (9.13). It in this elteretien in brain fluetien which prewidee the neeeeeery canditiene for the hehevierel eheasee at oeuvuletve therapy (1h.2o,50). teen: the behevterel chengee we would include the innedzlh exteretten 1a eeueeteueueee, reoell, leter petterne, breethiaa; end the eere pereietent peyehelegie, perceptual, vegetative, phylielacto end heeeenel petterne, characteristically deeerthed in oenvulexve theeepy. titeretieue 1n hretn :enattea ere retleeted in heaven chee1ee1 chengee ee the eeetyleheline end oheltneetereee (3?), trenemueee (36), end "retain (3h) «intent of the epinel fluid. They are elee eheerved in each neurophyeielecle eeeeuree ee inereeeed delta had theta eetivitr (8) end end �«1h. outtvtty (18) out oltorod olootrocrophtc (33.35) and bohovtorol (20,21.h0) rooponotitty to introvououo borbttorotoo sad to outtoholtnorglo and oyspothoolootio ouonto (?,12). rho oorrolotiono botoooa tho dogrno or nooroyhgotologlc choos- ond changoo 1o porooptuol toot portorlouoo roportod how. oro o rotlocﬁiou of thooo coastal chongoo. oo oro tho porcoptool (10.13.22) linguiotto (19,91) ond sliniool hohovtorol (10,20) ohoagoo éoooribod an oorlior doorooood boto 1o oloctroouooyhologrooo; studios. In o roaont roviou (9), tho oicattioonoo of tho oootylnholiuéaholxnootorooo oyotoo in thooo nouroohontool sltoéotiono woo «ioouoood. Oboorvoticno with vortono onticholsoorglo ozonto out roporto or oioslor pottorao with antibiotoointc and oynpothoolnsttc ooooto. indieotoo tho noooooity for o broodly boood vtoo or hioohooiool one broth tunotton rolottoao, with oophooto on oyuoptte Iodolo (12). A oocgoot‘vo ooohoaio: so? tho prolougod oltorotioao in broin tnaotlou :- ooon in tho blood~bro1u borrior otodtoo a: Alva (1) who uotod poroiotont «honaoo 1a oorohrovooonlor porooobillty tollovinx induood couvulotouo. ﬁo rolotod thooo to tho ooiluro and not to tho pooooxo of noon-to cox-routs. out! ounootod that tho-o chongoo ooy ho tho enduring phyo1olo¢1¢ booio for indueod tho bohoviorol chongo. Thus, to would concludo thot tho ounvuloion. or no. to not o nocoooory condition for bohoviorol ehoogo, but nonro~ choliool ohongo, of which tho oouvuloion to tho ionodioto "nation, 1o pronoun“. Indood, won pox-noun noun. �015 a aha-10.1 3nd nauraphyalolosie attoeto image-d a: roadily by bu unthodn Ivnld no loncnr uooonlary. 'convuluivoﬁ other manna, In thin rogurd, tho noun-poclxta nature or «a. couvulatvo therapy proocuu has he’s ropcncndly ouphantuad (lh,h0). �an I mg. cg.mm s, conuauuttva put£¢n£u rotnrrid 1.! 5.3131317. therapy var. tunic-1: assign-i to trtutncut tour... (Ind-klcn) or ulnatrtaal inducing tgcnt. by an inhalant Thor. were no dittoroucau in tho two group. on bohavlnrﬁi, cloatregruphio or psycholcgioul natsuroa prior to, dnrtng. tr lotyttal dicohtrzc rnttnuu var. oqutvalont. tutti-group taat dirt-rtucls unto notad on 311 tun wtcka artor treatunnt. unnanrau in both granps during trnatnont. In... dittuvouaﬁl var. rclutcd to tho dcgrto a: indueod nourophyaioloxie «hang. pattern at such chanzaa not. similar in both troutlau‘ and tho I. th“‘ 0 It is concluded thut tho abhorvod nltarntioul in br‘in function :r. quivnlont with nature: inane“! by inhnlnut or alootrtctl Hanan. rho nououpceitietty of Indaklauconvulnionn and tho ctoattr difficulty of aduintatruston continued the aonnidorod to «ctorrunta clinical at. 3a if. or th£a trtatuant. The nod. or induction or nuisuroa 1: In tuntgnitic.nt (cater in tho convulsivo thornpy process. $e1uutoo tr. “and u on. two: of the ponistont autumnal"). eaavulsiio bchnvicrnl ﬁnance: a: uhioh rcquiaito to tho durum- er tharupy. Th... abuortn£ion| at. discus-ad within the tranoutrk at tho nourophyu1olozie-Idupt1vo nude! or thu of abnttic Vﬁhcr.p1nn 1n payohintry. node of action �0’17. the oo¢90rntion 0! Smith £113. a French Lahcra%orsco in providing the hazarluovodiothyiathar (Indcklon) It’d 1n tho-u atudioo 1n gratefully toknoviodgud. �.15. 1. 11rd, 3.3. clinical Gerrsllﬁta at Electroshaok Thnrapy, Pazphittg lg: 633n639, 1958. 2. larguan, P.8., rapt-tutu, 9.6., Bars, 3. and foinntoiu, a. ﬁloetrounonyhalocraphic changes talluving olqctrioll induced £0331 a-lunrca. cant. laurel. $3, 971-277, 1953. 3. lrtll, 3.0., Ornlp‘el, 8.. Iiduncu, 3., Gray-on. 3.8.. ﬂollnnn, L.I., Richards, 3.4., stra;tnan, 3.9., and Unsor. 1.1. Invuatigntioa a: sh. thorapouﬁto coupounnta and variant raetcrl .saoctatnd with tlpruvousut with olectro~ convulsive trontaontt A preliminary vapors. An, J, Ag; Arch, Huurol. & 3&2, 997e1008, 1957. Ptzghint. h. Drill, 1.0., cr‘upton, 3., atducon, 3., arnyaou, 3.I.. lilllll. 1.1.. and Richarda, R.L. Balattvn eruct$vonaao of tartan: coupon-at: a: oloctrcaonvnlotvo thurapy. nu non. lmal. a "paint. 9;, 627.535, 1959. chattiln, 6.3.. and Itoruun, u.a. Thu convuloivo paﬁt-rnc provokad by Indcklen, Hotrauol and slcetraouheck. Solo dopth clootroxruphio obscrvuticnl in hunnu patiautu. BIO Olin. lturoghzgiol. 33: 715-?!5. 1960. ldvaldn, 1.x. Bxportlnntal utudtoo with Pnn109o. Int. Rue. nod. 1- cm». a g 32;: 1:69-4:79, 1956. 7. lsquthnl, 1., lrants, J.0., tru1t£, 3.3.. Linc. ;.s.c.. tad lurltnd, 1.1. loxntluorodtothyl nth-r gindnklaa) ~ It: us. as a oonvuluant 1n psyuhtctrto trau‘ucat. ' J. larv. ﬂout. nil. 33$: SJO-SJh. 1958. �.19“ EEG end delee activity to of B.L. Kenn, 3. Ieletien link, behesierel reepeaee an electreeheck: Geeetttettve eeriel etudiee. Ant arch. leerel. e Pezehtet, E!) snsasas. 1957. 9. link, I. street of enticheItnercie egent, nietheere. ea :30 eud behevteru atsntrieenee for ﬁheery er aenvuleive theeepy. A5; trek, leurg;. e Pezghte . £21 380~387. 1958. 10- tier, I., Kenn, 3.3. ens Green, I. lapettleetel etedtee e: the eleatreeheek preoeee. Die. lerv. 813, £23 113.118, 1958. 11. r1nk, I. end oreen, n. sleetreeueepheleerephte eerreletee er ‘ the electrocheek preoeee. Die. [eyes a; . g2; 11?, 1958. 12. rink, 8. street e: entteheXLaerste eeepeunde on peetaeeaveleiee 230 end behavior. 380 clin. leergghzetel. 33: 359o369, 1960. 13. fink, ﬂ., Kenn, R.L. end Kevin, 3. Erteete or dattnee eltered brein funciieu en perception. ?ree. 1' Int. Cong. vgzphel. p. 238-239, lerth lullead Pub1., teeterden, 1959. 15. Flat, n. Alteretiune 1n bre1n reaction in therepy. Pezghe~ ghereeeolegz zgenttere, [113e, I.. ed., p. 325~332, 1959c» 39., ”.tCB, ‘1‘”., ”M Fleetng, r.c. An annuity into the lecheniee o: ectzou of electric eheek treeteente. J. lerv. lent. Die. 12h. k hho~h50, 1956. elteruettnc etienli 1n dieerininetien experieeute. I: eeuet. Patchegg 16. cellereen, L.V. v1eue1 chance orders e! g5, 207-208, 1933. 17. Green, H.A. Reletien between threshold end duretten e! eeienree end electregrephio ehenge during ooeveletve therepy. a.n.n.n. (in preee). �.2918. nugzlsnd, l.. nultnud, w.. xguruan, 1.9. and Finest, a. chant-u 1n aluotroauaophtlogrnu and in £h¢ excretion of 1? - kutorctaraoida aceonpnnyiug aluotroshook thcrnpy or agttntud doproallou. razohouon. and. g. ' ab6~251, 19h6. 19. 1n vorb:1 Ghanaoa an! Kuhn, 3.3. u. Jattc, J.. tint, trunlaataono with inducod :ltorcd hrtiu function. 1960. 23$~239, 52g: 91a, nunt: Icav: J. 90. Kuhn, I.L.. tint, a. and wuinutotu, E.A. lolntton of anubnrhttal 1.1% to clinical inprovcuont 1n oloctraé thank. Arch. laurel: and Puzohint.‘1gs 23-39. 1956. 21. Kuhn, 3.1. an: Pink, H. change. in language during electroshock thorupy. ?: who Ithola' at Communicatian, noun, P. and & Bruno 126~139, Struttou, N.Y.. 1958. Zubiu, 3., tau., 9. 22. tuba, n.L.. Pollack, I. tad rink, n. figuro~gronnd diaerintuutian ARA arch. laurel. inéaood tnnotiua. brain sitarad arts: 3,: Sim-551. 1960. R.L.. Pollack. n. and link, a. soc1;1 attitudo (California I Saul.) and convnlcivo thornpy, 1960. 187-192, ggg, J,l,l,3. 25. laltuovuky. L., Darrora, 8.8. and lorvits, v.1. The “Potst unl' roaponst in olnctrtc shook thcrtpy. Al. J. Pszchiut., 2;. 708-711, 19kt. 25. Kevin, 3., link, I. cad Kwalwnuuor. 3. Relation of ehtnxtu in aviary and luarnlns to inprovununt 1n aloctrouhaek. Gout. 303301. gg; 88-96. 1956. 26. Karinnd, 1.1.. Ibuloug, 1.3., Enquibﬁl, A.J., Kr¢ntn, 3.6. and Shoots, 6.5. A coupsratlvu utudy of hoxntlnoro~ dicthyl Rthc1 (Indoklon) and cloetraconvulaivo therapy. 19590 ”‘WQ 95"”, 21 ﬁght. 1: I‘m. 23. Kuhn, �.21. 97. Lnnouatqr, H.P., stcincrt, 3.3.. nan trout, I. ﬁntlltornl oluetroconvulstvt thcrtpy. J. Hunt. 3&1. 323: 221-997, 1958. 28. Killer, 3.8., 61:30:, J. conpnriocu between unidiroétioanl entrant nou~oanvnllivc olcatricul uttnulntaon ngon 31th nuttarta nuoh1ao. standard and cunninga, B. A ultornntaa; carraat electroshock and pontothtl in chronic uahtsophronta. An. 3. ?Izghint. £92: 617—620, 1953. 29. citation, 4.0. Exportuontll stndIGI or ‘hn node at nation at clootrooonvull1vo thnrtpy. tot; Pazghtat. & lturol. 86:34. 8322. ;§2,‘§£, 1960. 30. Pnoolla, 3.1.. Darrcra, 8.8.. Illinovlky, L. Varitttono in the oloctrocuecphnlograu unuoota‘od with aloctriu shook therapy in patiga‘a with nuutgl diaurdorn. 19h2. 367~38h. 31, laurel. szohtnt. 31. Pollack, n., Butt-ruby, v.8. and Sander, H.B. rashictosoopio identitiotttnu of content in putzcutu with brain dalnxo. J. Gagg. ’El'3°1° Pczphol. £9: 220~t27. 1957. 32. Boitnnn, !.J. and 3013140. I. technique for tho Iodxtlcatlon or cloutroshook with nuccinyloholinu. Bin. UOIV. szp. 3g: 237«2h2, 1955. 33. Roth, H., x§y, D.H.l., shat, 3., 3nd Brocn. J. Prague-1n :ad poatothal induced olcctvocncuphnlozrnphic changes in olcctroeonvulatvo trontucnt. £36 c113. luncgghzytcl, Arch. Q 2; 925.237. 1951. 3h. agent, a. tootaioholtau and lavaton1u J. louroourg. Akp 2t-21. 1951. 1n the spinal fluid. �.22. 35. Shaun... 6., ﬂxh‘lik, 4., tad Jouco, l.L. cltnxcal pirahiutrie aging tn. nodntaon thrcthuld. J, Patchoaoag a... g; h5~55. 1957. atovoaa, 4.9.. naakn, r.1. and I‘IOIIOP, I.L. Tflﬁltltutﬂl in activity 1: ﬁt. spinal fluid neuropuyehiutric EGO-hﬁs. 1959. condtttonl. 91a. Harv. gin, g2; attest. 36. 37. I taunt, 9.3., o: choliuottcrason and Bazacharn, B. It: 1n hung» nontnnt and chartuaorluattoa spinal 31:16.. Bahia, g, 31.03roh, 31: 132-1h5. 19h9. 38. 331th; and 0.A., x. 3.x. caldvoll, aloaor. o.c.. Blctt, The to. or natchod group: in thc ova1u§t1¢n at ooavulaivu and Iubeonvulttvo photo-hook. 3311. Inna. czan, 18: 138-1h6, 195k. I. 6.6. Evaluation 0: convultivo thank thoroptcn utilising a control group. £5&4£g 195$. 795-802, ;;ga rgzchtlt. ho. walnutotn, 1.5. sad Kuhn, l.&. Dania: of zllgclns ango;1c and ggzltolo‘tual nggusi. 0.6. than... sprin3t101d, 111., 19550 39. 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For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Inhalant-induced convulsions. Significance for the theory of the convulsive therapy process. Arch Gen Psychiat. 1961 Mar; 4:259-66. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-52-018 Date A point or period of time associated with an event in the lifecycle of the resource 1961 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a>; Kahn, Robert L.; Karp, Eric; Pollack, Max; Green, Martin A.; Barre, Alan; Lefkowits, Henry J. Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint and [preprint]. Reprinted from the Archives of General Psychiatry March 1961, Vol. 4, pp. 259—266 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published http://exhibits.library.stonybrook.edu/mfp/files/original/8ad71ef7a3c44154da4264a3d36d2625.pdf d939faed36329ffba731bbff9e10004f PDF Text Text An Objective Study of Communication in Psychiatric Interviews Joseph Jeffe, H.D. From the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, Read at the New York N.Y. Divisional MBeting, A.P.A. November, 1957. Supported by Grant 565561 of the Foundations' Fund for Research in Psychiatry. 14’! 10-1h-S7 �The clinical interview is the psychiatrist's primary tool for the diagnosis of psychopathology, the modification of behavior, and the collection of research data. Only in recent years, however, have the actual transactions which comprise the interview been studied objectively. Investigators of the interview have usually employed systems of content analysis (1), which are based upon various theories of psychodynamics. Currently, there is increasing emphasis upon formal aspects of interaction such as temporal patterns of speech (1h) drastic change of subject (3), PHYSiological relationships of the participants (2), grammatical patterns of language (S, 6, 9), and speech disturbances and silences (10). These aspects, in contrast to content categories, are relatively independent of theoretical preconceptions, and are more readily quantified and studied statistically. In many investigations of these formal variables, however, the total context of the interview. These approaches neglect the fact that the psychiatrist is a participant observer, i.e., a significant variable in the interaction (11). Others have attempted to control this variable by means of structured interviews in.which the doctor's contribution is standardized patient's communications are abstracted from the according to a predetermined experimental design (6, 7, 1h). These structured situations delete the very quality of living relationship that is the ultimate concern of the psychotherapist (7). methods of verbal We are in need of interaction analysis that neither preclude nor prescribe the doctor's clinical responses. The this paper is to present a method of interview a) is objective and quantitative, b) preserves the purpose of analysis which �.2... natural patient-therapist relationship, and c) treats the interview as an integrated system of interpersonal communication. This is accom- plished by including the doctor's usual clinical behavior in the data to be studied. the The raw material is not the patient's speech, but rather total verbal output of the "two person" or "dyadic" group. �Method: tape recorded interview The is precisely transcribed, without regard to the speaker of the words. Careful attention is given to subtle repetitions such as "I - I mean," "well as - as I say," polated expressions such as "you know," The inter"so to speak," "as I said," etc. and to transcript is then arbitrarily divided into consecutive units of 100, 50 or 25 words depending on the discreteness of the phenomena to be investigated. Thus a unit contains contributions of words from either doctor or patient alone, or from both in varying proportions. The measurement applied to these units of dyadic Speech is the typetoken-ratio (TTR). This is an index of the balance between repetition variety of words (12). The TTR is the ratio of the number of different words (types), to the total number of words (tokensL in a sample of language. For example, in a 100 word sample the repetition of the identical word 100 times in succession would produce the lowest and possible ratio of .01 of 1.0 would different result if (l type/100 tokens). The highest possible every one of the 100 successive words were (100 types/100 tokens). These extremes of stereotypy and diversity are rarely encountered, situations (8). The i.e. "word-type," ratio and then only the numerator of the in grossly pathological TTR, is arbitrarily defined. All words are different which are pronounced or spelled differently. Thus, ive, gives, gave, given and gizipgﬂ are considered different types, as are "know" and "no." Vocalizations not clearly " �.u-‘ identifiable as which is words are omitted, with the major exception of "mmhmm" a frequent utterance of the interviewer in our records. Contractions are retained as single words, but vulgarisms such as "I dunno" are edited to read "I don't know." The TTR scores is calculated for is graphically plotted, additional precision, the units may be advanced 25 words the last half at unit each as and the illustrated in Figures may be first half unit. This often smoothes the resultant curve. is illustrated in Figure 3. TTR have in a single person's language (12). 1 and 2. For overlapped, e.g. 50 word units a time, so that each unit of the preceding and the Previous studies of the pattern of consecutive is composed of of the subsequent The overlapping technique dealt with the overall average The sequential pattern in dyadic language. present method studies the �Observations: In the last eighteen months approximately sixty recorded interviews this method. The material includes forty patients in all diagnostic categories. The dyadic have been inveStigated by found to be sensitive to a variety of clinical TTR patterns have been phenomena (8). This report illustrates the changes in language interaction occurring during the course of hospitalization and therapy, as well as changes in rapport in individual interviews. and defensive operations A - andic TTR Pattern in Clinical Change. first Figure 1 shows the pattern of the three separate 1500 words of interviews during the clinical course of one patient. The doctor is the in each. This case same was selected as an unequivocal example of gross clinical change. In the first interview the patient was agitated and depressed. She refused to be seated and paced about the room, reiterating stereotyped self-recriminations, crying hysterically, with marked pressure of speech. At the time of the second interview, following a course of grand mal electroshock, the clinical picture was grossly altered. She was less agitated and complaining of a memory appeared more deficit. cooperative, although withdrawn and On alert, poised, conversational insightful. She had been The TTR of later, discharge two months and, she at times, surprisingly rated clinically as "recovered." consecutive 25 word units of interaction, for each of the three periods described, is graphically represented in Fig. 1. Consecutive points are connected by lines so that the fluctuations in the graph reflect the difference between successive scores. The mean TTR for �~6- the complete interview from which these samples were taken is represented line through each graph. by a horizontal strates The a The fluctuating equilibrium about the pattern of scores mean. interviews of these three successive stages changes. The mean demon- show a sequence of level of the interaction is seen to increase as the clinical status changes from psychosis to "recovery." There is a concomitant restriction in the amplitude of the pattern, i.e. a decrease in variation about the mean. Comment: The sequence of change in the TTR pattern parallels the progressive in interpersonal communication that improvement clinically. was apparent This suggests an approach to the quantification of clinical change, defined as an altered pattern of verbal interaction in the interview. B - in Communication‘within the Interview: Changes Figure shown 2 is an enlargement of the in Figure 1. first of the three interactions Here the sequence of changes within a.single interview are examined rather than comparing the patterns of successive interviews. As described before, the patient was speaking continuously in a disorgan- ized affective outburst. mﬂrich The lower line indicates the the interviewer participated. Following remarks, units 3 - 12 ﬁne 25 word units in doctor's introductory represent the patient's uninterrupted speech. Wide oscillations of the pattern are prominent. From samples 13 onwards the doctor made repeated efforts to communicate with the patient. Two independent judges reviewed the transcribed protocol, and both identified three areas in which there seemed to be an understandable, rational �-7interchange between the participants. These periods are labelled "rapport" in the upper line. tions of the pattern are much During these three periods the constricted. Compare oscilla- other non-rapport periods such as 23-2h and 39-hl, in which the doctor's participation amplified the oscillations. Cmmmnh This illustrates a method of quantifying interpersonal phenomena, such as the degree of "contact" with a severely disturbed patient. The affective pattern in this patient represents the psychotic integration, for this reason, the occasional occurnnces of conventional,rational conversation are described as periods of "rapport." The restriction in and the amplitude which characterizes these periods is similar to the overall pattern at the time of "recovery." 0 - Analysis Figure 3 of a Complete Interview. initial demonstrates the dvadic TTR analysis of a complete interview. This interview is the discharge evaluation of a patient had been hospitalized following a months of hospitalization, she who bizarre suicide attempt. After seven had "improved" clinically. This took the form of a hypomanic mood and a gross denial of her severe emotional conflicts. word The interview units advancing by is scored by the method of successive 50 ZS word steps. The mean TTR for the interview is shown by the horizontal line drawn through the graph. The pattern falls into several natural segments. There are two areas in which ten consecutive points fall below the mean (areas h and 7). These are unusual in this interview. There are also areas of gross deviation �~8from the mean (such as area determine our criteria for 2). Thus we allow the phenomena for persistent changes in the TTR to be studied. In general, we look level, gross trends or sudden shifts. Several of the deviant areas are described to The objective pattern to illustrate the method. interview begins with a hypomanic monologue in which the patient visit describes her successful home, her euphoric outlook and plans for a rosy future. Area 2 has been delineated because of gross deviation from the mean. The beginning of this period coincides with a change of topic to her plans is interrupted by a period of confusion as she tries, with some difficulty, to recall one of the details of the job. The end of the gross fluctuation coincides with the rationalization "I don't think I'll have too much trouble." Area h was delineated as one of the two sections in which 10 consecutive for going back to her job scores fall two days hence. Her optimism Its beginning coincides with below the mean. about her depression on admission to the hOSpital. a statement This area ends with the lowest score of the interview which,precedes by only a few words a spontaneous reference to her suicide attempt. This large deviation at the end of area h embodies the main characteristics of the following area. Area 5 The is characterized by large content of this area attempts to prove at the is how much fluctuations above and below the mean. completely on the theme of suicide. She live. The doctor's queries with increasing resistance. In the begin- she now wants to end of the period meet ning of the next segment (area 6) she stubbornly refuses to discuss the subject of suicide further, at which point she changes the subject abruptly. �-9Area 7 was delineated on precipitous drop in the the basis of TTR, criteria. It begins with ”two a followed by 10 consecutive scores below rise. Its the mean, and ends with an equally abrupt beginning coincides with a change of subject by the doctor in the form of a question about her feelings at that the "you-me" relationship, period ends Area 9 when she in the interview. This content area, 1.6. moment is at a very It The of an extremely low score enclosed by two coincides with a brief mention of a meeting with a young man who told her how well she looked. remark and her statement These examples repetitive level. abruptly changes the subject. is delineated because large deviations. pursued "I decided to get illustrate areas him It ends with an embarrassed off the topic." of disturbance or disequilibrium in the verbal interaction pattern. In contrast, areas I 3, 6,,23 and 10 are areas of relative stability or equilibrium in the record. These stable areas are marked by a different quality of communication. They consist either of a euphoric, hypomanic monologue which avoids all stressful areas. or of evasion of the doctor's probing questions by superficial rational- ization and conventional cliches. Comment: Recent reports of objective interview studies using other techniques (10), have noted that the interaction goes through a series of definable phases, which may and successful defense and the events The stressful disorganization correspond to periods of respectively. The phases demonstrated here, that delineate them, suggest an analogous fonmulation. content areas that disturbed the pattern in this final interview �also did so the initial interview seven months earlier. we anticipate that the discussion of a subject that had resulted in disequilibrium but now no longer does so, may constitute an operational on definition of "resolution of an area of conflict." �Discussion and Conclusions: Diverse and highly personal interpretations of interview data limit the growth of psychiatry as a science. Systematic study of the actual transactions may lead to operational definitions of hitherto subjective it is likely that the patterns of verbal diversification presented here constitute part of the subliminal cues to phenomena. For example, therapists affect, etc. which reSpond when.making clinical judgments of anxiety, Objective investigations of the interview must encompass the behavior of both participants since the events observed are interpersonal processes. Gill, Heuman & Redlich (h) define even the initial interview as "the diagnostic evaluation of an interpersonal relationship." Reusch (13) has recently stated have the that “observations made in social situations characteristics of a scientific procedure in which do not one aSpect is studied in detail while all other variables are held constant." The method presented here is an attempt to convert these concepts into practical research methodology. It permits a quantitative statement of various clinical phenomena occurring either within single interviews or in the course of therapy. Disturbances of verbal interaction are defined operationally in terms of the configuration of the Applications to the definition of clinical change and pattern. transactions TTR within the interview have been presented. The TTR is only one of many quantifiable aspects of dyadic speech. interaction, time reference, and relative amounts of participation doctor and patient may also be measured. Further applications of these Pace of by techniques are under investigation. �REFERENCES 1. Auld, F. and Murray, E.J. (1955): Content-Analysis Studies of Psychotherapy, Pslchol. Bull. 2a: 377-395. 2. Coleman, R., Greenblatt, and Solomon, H.C. (1956): Physiological M. Evidence of Rapport During Psychotherapeutic Interviews, Dis . Nerv. 3. Eldred, S.H., sttem, ll: 2-8. E.R., Salzman, L., Meyersburg, Hamburg, D.A., IHWOOd, (l95h): H.A. and Goodrich, G. A Procedure for the Systematic Analysis of Psychotherapeutic Interviews, §§zchiatry, l1: 337-3h5. h. Gill, M., Néwman, R. and Redlich, F.C. (l95b): The in szchiatric Practice. Press. 5. Goldman-Eisler, F. (195h): A New York: Study of Individual Differences and of Interaction in the Behavior of Interviews, Jour.. Rent. Sci. 6. Initial_1ntervigg International Universities Some Aspects of Language in lQQ: 177-197. Gottschalk, L.A., Gleser, G.C. and Hambidge, Behavior Analysis, Arch. Neur. and G. (1957): Verbal ngchiat., 21; 300-311. 7. Grinker, R.R., Sabshin, M., HaMburg, D.A., Board, F.A., Basowitz, H., Korchin, Use m? S.J., Persky, H. and Chevalier, J.A. (1957): The an Anxiety-Producing Interview and Its Meaning to the Subject, Arch. Neur. and Psvchiat., 11: hO6-hl9. 8. daffe, J.: Language of the Dyad: A Method of Interaction Analysis in PBychiatric Interviews, Psvchiat , (in press). 9. Lorenz, M. and Cobb, S. (195h): Language Patterns in PBychotic and Psychoneurotic Subjects, Arch. Neur. and Pszchiat., 1g: 665-673. �REFEREEIJCES lO. Mahl, G.F., (1956): Disturbances and Silences in the Patient's Speech in Psychotherapy, Jour. Abnorm. Soc. Psxcholu §_3__: 1-15. 11. Handler, G. and Kaplan, :‘J.K. (1956): Subjective Evaluation and Re- enforcing Effect of a Verbal Stimulus, Science, l2. Mowrer, O.H. (1953): Verbal Behavior (Ed.) szchotheragz: T1139 1.2143 in Paychotherapy. In 582-583. Mowrer and Research, New York: Ronald Press. 13. Ruesch, J. (1957): Disturbed Commnication, New York: 11.14". Norton. 1h. Saslow, G., Matarozzo, J.D. and Guze, S.B. (1955): The Stability of Interaction Chronograph Patterns in Psychiatric Interviews, Jour. Consult. P§Xcholu 1.2: 14174430. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. 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Title A name given to the resource Joseph Jaffe: An Object Study of Communication in Psychiatric Interviews, 1957 Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-002-8-009 Date A point or period of time associated with an event in the lifecycle of the resource 1957 Creator An entity primarily responsible for making the resource Jaffe, Joseph Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. 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Title A name given to the resource Julius Fink and Bronia Lowenthal Fink Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-008 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Description An account of the resource Father and Mother of Max Fink Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/73f23282cc67af28739fea856ee770e8.pdf e300a093a9da17b1283d89c0561639fc PDF Text Text Reprinted from ”Electroencephalography and Clinical NeurOphysiology Iournal" Vol. 10, No. 1, February 1958. LATERAL GAZE NYSTAGMUS AS AN INDEX OF THE SEDATION THRESHOLD 1 MAx FINK, M.D. With the technical assistance of HANNAH MOSQUERA Department 0] Experimental Psychiatry, Hillside Hospital, Glen Oaks, N.Y. (Received for publication: October 17, 1957) On reading the report of Thorpe and Barker (1957) in the recent issue of the Archives, we were moved to assess our own experiences with the sedation threshold, and to report a clinical guide to the “inflection point” that we have found useful. Following the initial description of the technique by Shagass (1954), we modified our tests which included the administration of the amobarbital test for brain dysfunction (Weinstein et al. 1953) to obtain a measurement of the sedation threshold as well. Our technique was identical to that of Shagass, with the addition of the measurement of nystagmus on lateral gaze which the latter test required. The change in beta amplitude in the EEG was measured visually in consecutive samples of record, using the additive ruler described by Shagass. In the initial group of patients, two observers were unable to identify the onset of slurred speech with consistency. Disagreement led to administration of amounts of amobarbital greater than was required, with the frequent induction of sleep. As we were also obtaining a record of the induction of nystagmus on lateral gaze, we became aware that this index was reliably agreed upon by the two observers, and a correlation with the sedation threshold was sought. We, therefore, omitted the instructions regarding counting and substituted the following instructions. Subjects were told that at periodic intervals they would be requested to open their eyes and to look first to one side and then to the other at pre-arranged tion period. The administration of barbiturates con— tinued until nystagmus was observed, and then an additional 2 cc. were given. RESULTS To date, we have 91 measurements. The following table notes the difference between the number of milli- grams of amobarbital per kilogram body weight for the EEG measure (the sedation threshold) and for the onset of nystagmus. Differences greater than one unit did not occur in this series. The two measurements are seen to be reliably related by a unit of 0.5 or less in more than 90 per cent of the observations. M TABLE I Frequency Distribution of Difference in Amount of Amobarbital Necessary to Induce EEG Change and Nystagmus (mg. amobarbital/kg. body weight) No. Tests (91) 1 47 12 +0.5 +1.0 27 4 Test-Retest Reliability: During these studies we have also had the opportunity to repeat the sedation threshold measurement three to five times in the same patient at weekly intervals. These measurements were done in randomly selected patients receiving subconvulsive doses of elec- TABLE II Absolute Range of ST. Values Range 0 0.5 1.0 1.5 2.0 No. Subjects (16) 0 2 6 2 4 fixation points. This was repeated twice in each direction, usually within ten seconds, while the observer noted the development of sustained regular nystagmus on lateral gaze. Such observation was repeated after each injection of 1 cc. of amobarbital solution, between the 25th and 40th sec. of the injecSupported by the Board of Directors’ Research Fund of the Society of the Hillside Hospital. 1 2 tric current under barbiturate premedication as part of a study of convulsive-subconvulsive electroshock. The behavioral changes in this group were small 14 of the 16 were referred for grand mal electroshock within 4 weeks after the subconvulsive treatment -—— period. The range of sedation threshold measurements under these conditions is noted in table II. [162] �LATERAL GAZE NYSTAGMUS OF THE SEDATION THRESHOLD Being unable to ascribe greater validity to one reading than to any other, we determined the mean sedation threshold for each subject, and the range of variability about the mean. In table III we have listed the subjects in each range of variability about the individual mean value. Thus, the intra-patient inter-test variability for this test in this series is considerable. The test reliability of nystagmus as an index of the electroencephalographic change is well within the retest variability of the test in these subjects. 163 lographique mesuré chez ces malades et dont la validité a été démontrée. Il est recommandé d’utiliser cette méthode en remplacement de celle qui est basée sur l’apparence de troubles dysarthriques. ZUSAMMENFASSUNG Das Auftreten von Nystagmus mit lateralem Blick ist ein klinisches Mass fiir die Sedationsschwelle, welche gut mit dem gemessenen EEG-Index iibereinstimmt und dessen Verlasslichkeit nachgewiesen werden konnte. Gebrauch dieser Methode wird daher TABLE III Range of ST. Values from the Mean Range No. Subjects (16) 0.1—— 0.6—— 0 0.5 1.0 0 6 4 CONCLUSION The appearance of nystagmus on lateral gaze is a clinical guide to the sedation threshold, with a variability from the measured EEG index well within the test-retest reliability of the test itself. It is recommended as a substitute, therefore, for the onset of slurred speech. Further studies of the retest reliability of the sedation threshold are necessary. RESUME L’apparition d’un nystagmus dans le regard latéral est une mesure clinique de la sedation qui montre une bonne correlation avec l’index electroencepha- 1.1— 1.6— 2.0 >2.0 4 1 1 1.5 empfohlen als Ersatz fiir diejenige basiert auf dem Auftreten von verwischter Sprache. REFERENCES The sedation threshold. A method for estimating tension in psychiatric patients. EEG Clin. Neurophysiol, 1954, 6: 221-233. THORPE, J. G. and BARKER, J. C. Objectivity of the sedation threshold. A.M.A. Arch. Neurol. Psychiat, 1957, 78: 194-196. WEINSTEIN, E. A., KAHN, R. L., SUGARMAN, L. and LINN, L. The diagnostic use of amobarbital sodium (“Amytal Sodium”) in brain disease. Amer. J. Psychiat, 1953, 109: 889-895. SHAGASS, C. threshold. sedation the of index M. Lateral as an FINK, nystagmus Reference: gaze physiol, 1958, 10: 162-163. EEG Olin. Neuro- 63:3 �‘ “W 9.13.5? W W ma w Mai mm 0 �mmmmtwmwmmmmmeum MWW,wmnwummmmﬂm-uwm amummm,mmmauammmmumﬁmaummv Wtwmfmm. wmvmpumwmmmwmmtz), Wm ”memmwzmmmmumdmmml *mt Warm. {ﬁwo‘hWtWt 92mm“ wwwmxmmmwmtamm.nw mmumwmetummmummmm ﬁﬁwmmm. mmmmwnmmmmmww mmawmmmumm,mmwawmwwm WW: hwqmmeﬁMgMWWWth mmmmawmeapmmmmm. MW“ aim “Wamﬂmdmuaf mammmmotdw. uwmduobmmtmmdw ﬁWmumlmgwmmmtthm numwummmmmmwnWMvmmmm ‘ V “.mm,mimmmmmummmmm MW m 3mm mmmﬁ mm um um am it mom mummymmummmwmmmawwmnmw mramquWWamrmWWﬂanummu. Mm MMMmmmmum,ummymm£-nmm.mum mmmmzﬂmmwwnwamuum we. mmwmmmmatmmmmwxma mummmm,hommzmwmwwmmmm mm. m mumm WWW Mme mm mm m «1’ �mammammmzmmam. mammmﬂmm. thmmm wwmbmwem(wmmmum)mmrmwt Wmummrmmthnwmmwmh ”W; m Mmummwwﬁpmf- mmwammtmﬁu Wmmwmmumtwmmw mmmm«mhmammmwmwwma mmmmmthmwtmmmmmumuu mm Wu awn w We: m: m WW“ Mum umwamwmmmwmmmmm mm mmmwmmmmmwmmt �«2w «mum 11. W m mm (as) mmmmuwmmwummmmmmow,m humammmuwmmmmwmwwwa wwwmmm. hmmwmmwmmmuum M,WWM$WWW£W wumtmmm ummm. MMW‘Wﬂanmmwmnm W‘s-mm“ �mwas-mmmummsummmw ummmmwwmmuw. “MW unmm, Wm,mmmwﬁww. WW �' 1_ W ' ”W «mummy MW “mm.“ wmmm.muwg mm Wigwam m3. é» 3n & 199:. W”; WW 4: ’ “ ' �W WWW Emmtxy WM? 13' 1957‘ W9; Miter, Section or Awhim Baumlm 5:. , AM. 29th a mu ham, W Wm, DP. Roy W mum. 0mm. 7 of ‘ ‘\ \ 16,, Dear Dr. Grimmer: W Inmadmzhoramtmmloafmmdmrmm pmblem. undead short 45an my am vb» m nth-mung an ”gamut of tho «mum tgnsumtoﬂ this that. cmMahala," we are md to “(nativity at w M15192: than 111th this tout, u an as our solution to puﬂlol mama “the be of help to note W this note is I: the taunt. at pinned to follow your momma. would be for the Archives, I m Fink, 1w. K3563 �PUBLICATION OFFICE AMERICAN MEDICAL ASSOCIATION 535 NORTH DEARBORN STREET CHICAGO IO. ILLINOIS AUSTIN SMITH, EDITOR, A. M A. SCIENTIFIC PUBLICATIONS A. M. A. ArChives Of NEUROLOGY and PSYCHIATRY GILBERT s. COOPER, MANAGING EDITOR A. M. A. SPECIALTY JOURNALS SECTION ON PSYCHIATRY DR. EDITORIAL BOARD RCY R. GRINKER $R., M.D. CHIEF EDITOR. CHICAGO STANLEY COBB, M.D.. BOSTON GEORGE E. GARDNER, M.D.. BOSTON ““353?st JOHN WHITEHORN, M.D., BALTIMORE Institute for Psychosomatic and Psychiatric Research 29th Street and Ellis Avenue, Chicago 16 September 20, 1957 Max Fink, M.D. Department of Experimental Psychiatry Hillside HOSpital 75-59 263rd Street Glen Oaks, New York Dear Doctor Fink: it will not be possible to publish and we like to backlog, large have a wide selection of papers on many subjects and feel that we have published already all that seems important on the sedation threshold test as devised by Shagass.. I the in your paper am very sorry, but ARCHIVES. We have a Regretfully yours, Roy R. Grin er, M.D. Editor~in-Chief for Psychiatry RRszm enclosure �3.er Dr. Mort 3. Sam, General Putnamtu Boa: (7&3 {’4’ BOWEN, ah. 1957. Hospital, Mt Du:- Dr. Scarab: In vnading : recent. article on the ”mmuvity of the Station Threshold" in the Archives or Barclay and Paychntx-y, we were mud to parallel «panama with we test, as well as our 301an to the problm. I would appreciate your enumeration of this short clinical not» for the Section of 61mm. uni laboratory Notes of the mm m EEG hum]... Simon]: you", mm, 130th HE‘BJB or menu-m1 Paychutry; “on. �3-8200 EXT. 380 TEL. LAFAYETTE ROBERT s. SCHWAB. M.D. MASSACHUSETTS GENERAL HOSPITAL BOSTON 14 September 27, 1957 Dr. Max Fink 75-59 263rd Street Hillside Hospital Glen Oaks, New York _ C.N. #61 Dear Dr. Fink: received and I would like to conditionally accept for Clinical Notes in the EEG Journal as it stands subject to the approval Your manuscript has been it of the Bditor—in—Chief, Herbert Jasper. MW Yours very RSS:mc sincerely, Robert S. Schwab, M.D. �1g 33 ‘12, McGILL UNIVERSITY MONTREAL Department of Electrophysiology Allan Memorial Institute, 1025 Pine Avenue'West, Montreal. September 30 1957 Dr.Max Fink, Hillside Hospital, 75-59 263rd Street, Glen Oaks, New York. Dear Max, to see you for your note on the nystagmus. It was nice at Zurich, and I hope that we shall be able to meet Thank you again soon. My best regards. Sincerely, Cw CS/ef % , C. Shagass, M.D. �12/3/58 Discussion: Dr. Shagass Dr. H. Fink - Hillside HOSpital Dr. Thompson, Members and Guests: It is always a pleasure to read another chapter in the unfolding saga of sedative tolerance tests as they have been developed by Dr. Shagass.‘ This study, like its predecessors, relates neurophysiologic indices to behavioral measures this area of psychiatry, reflects a welcome application science to clinical problems. a and in of basic appropriate to examine this report in the perspective of recent concepts in experimental psychiatry. During the 1930's, when electroencephalography was a new science considerable effort It seems in relating EEG patterns to "personality types" or ”diagnoses,” without success. With more refined instrumentation, there have been sporadic re-assessments without noticeable success. In the sedation threshold, however, Dr. Shagass, did succeed in achieving such a relationship. In these earlier studies, he was expended related the amount of barbiturate necessary, under standard conditions of rate of administration and concentration, to induce a specific EEG voltage and frequency change, to the personality profiles of the Handsley-Eysenchian school. It is important to note that the relationship was not between any fixed aspect or index of the EEG and behavior but between a measure of reactivity or responsivity of clinical behavior. We may carry this description a bit-further. The electroencephalogram is a reflection of central or brain neurochenistry, and the reactivity of the electroencephalogram to any chemical stress, a measure of the reactivity, or reSponsivity, or buﬁbring the EEG and �of the biochemical enzymatic systems ﬂat make up the nervOus system. It is in this organisnic biochemistry that much activity is now directed in experimental psychiatry. The wide variety of phrenotrOpic agents, the new and more potent hallucinogens, and the expanding technics of enzyme and steroid chemistry are providing experimental psychiatry with research tools of consideraﬂe adaptability. One application of these technics highlighted yesterday by Dr. Gottlieb and his co-workers at the Lafayette Clinic,who reported their ihitial observations on the significant relationships between schizophrenic behavior was and the reactivity of insulin. These of the glucose-enzyme systems to the authors carefully noted that there stress was no relationship between the initial levels of their biochemical measures and behavior. Dr. Shagass' earlier studies of the sedation threshold - end-point - are clearly within this tradition. His report today is also in this general tradition, but instead of a neurophysiologic index of clear definition has utilized a clinical index ~ lack of a verbal motor response to a verbal command - as the end-point. In the report today, he has related the amount of pentothal necessary to induce this state of lack of response (which is defined as "sleep") with the affective state of the individual at the time of the experiment. He has observed that the more fearful,disturbed, tense, angry and worried a subject is, the more barbiturate is necessary to induce using an EEG �-3- quieter, more indifferent, inactive and retarded patient is, the less barbiturate is necessary for sleep. He sleep. a Ehe titration is thus achieving a biochemical titratinn, and is, in essence, measuring the subject's responsivity or reactivity to barbiturate. By repeating the studies seriatim, he is able to report shifts in this state of reactivity. In his desire to extend the sedation threshold technic to situations in which the EEG was not available, and provide for greater clinical applicability, some of the precision of the earlier studies has been forfeited. It is not unexpected, considering the lack of precise definition of behavior as well as the endpoint of titration, that the reactivity-clinical relationships I have noted two puzzling relationships. Increasing sleep thresholds are associated, on the one hand, with excitement, worry, restlessness and anger; but also, with clinical improvement in a course of convulsive therapy. Also, in one are somewhat cloudy. patient, transient induced psychosis sharp drop in threshold, while in the same a LSD is associated with patient, fear of a treatment, restlessness and increased tension are associated with rising thresholds. I would snapect that these apparent discrepancies arise frOm the non-Specific nature of behavioral reaponse to neuro— physiologic change and to the poverty of our descriptive language for behavioral change. I would wonder what shape the curves would take if the change in sleep threshold were plotted against other indices of brain function as predominant EEG frequency pattern or degree of synchronization; or such psychologig indices of brain function as the perception of embedded figures or OFF; or such behavioral indices as dyadic or syntactic linguistic �-hanalyses. Alternatively, more precise,— operational measures of the behaviorll subsumed under "anger," restlessness,¥ "worry” may proiido, again, the relationships indicated earlier by the sedation threshold studies. Lest these comments be misconstrued, let me say, in closing, that Dr. Shagass is to be warmly congratulated in these studies basis for the developing neurOphysiologicadaptive hypothesis of behavior. His demonstrations of central neurophysiologic reactivity in the sedation threshold are in the best exPerimental traditions. We are eagerly looking forward to further experimental neurophysiologic studies from his new which are providing a firm laboratories in Iowa. �12/3/58 Discussion: Dr. Shagass Dr. H. rink — Hillside Hospital Dr. Thompson, Henbers and Guests: It is always a pleasure to read another chapter in the unfolding saga of sedative tolerance tests as they have been developed by Dr. Shagass. This study, like its predecessors, relates neurophysiologic indices to behavioral measures and in /‘this area of psychiatry, reflects a welcone application or basic science to clinical problems. It seaas appropriate to examine this report in the perspective — of recent concepts in experimental psychiatry. During the 1930's, electroencephalography was a new science considerable effort was expended in relating EEG patterns to ”personality types" or "diagnoses," without success. With more refined instrumentation, there have been sporadic re-assessnents without noticeable success. In the sedation threshold, however, Dr. Shagass, did succeed in achieving such a relationship. In these earlier studies, he related the amount of barbiturate necessary, under standard conditions or rate of administration-and concentration, to induce a specific EEG voltage and frequency change, to the personality profiles of the Handsley-Eysenchian school. It is important to note that the relationship was not between any fixed aspect or index of the EEG when and behavior but between a measure of reactivity or resphnsivity of clinical behavior. The e1ectro~ We may carry this description a bit further. encephalogran is a reflection of central or brain neurochenistry, and the reactivity of the electroencephalogram to any chemical stress, a measure or the reactivity, or responsivity, or buﬂhring the EEG and �«2e- of the_biochenica1 ensynatic systems ﬁat make up the nervous system. It is in this organisnic biochemistry that much activity is now directed in experimental psychiatry. The wide variety or phrenotropic agents, the new and more potent hallucinogens, and the expanding technics of enzyme and steroid chemistry are providing experimental psychiatry with research tools of consideraﬂs adaptability. One application or these technics was highlighted yesterday by Dr. Gottlieb and his co-workers at the Lafayette Clinic,vho reported their initial observations the significant refationships between schizophrenic behavior and the reactivity of the glucose-enzyme systems to the stress of insulin. These authors carefully noted that there was no on relationship between the initial levels of their biochemical measures and behavior. earlier studies of the sedation threshold using an EEG endspoint ~ are clearly within this tradition. Bis report today is also in this general tradition, but instead or a neurophysiologic index of clear definition has utilized a clinical index - lack of a verbal notor response to a verbal Dr. Shagass' - as the endnpoint.' In the report today, he has related the amount of pentothal necessary to induce this state of lack of response (which is defined as asleep“) with the affective state or the individual at the tins of the experiment. He has command observed that the more feartn1,distnrbed, tense, angry and worried a subject is, the more barbiturate is necessary to induce �-3sleep. the quieter, gore indifferent, inactive and retarded a patient is, the last barbiturate is necessary for sleep. He titration is/thna achieving a biochemicat titration, and is, in essence, measuring the subject's responsivity or reactivity to barbiturate. By repeating the studies seriatin, he is able to report shifts in this state of reactivity. In his desire to extend the sedation threshold technic to situations in which the EEG was not available, and provide for greater clinical applicability, eons of the precision of the earlier studies has been forfeited. It is not unexpected, considering the lack of precise definition of behavior as well as the endpoint of titration, that the reactivity-clinical relationships are somewhat cloudy. I have noted two ﬁnssling relationships. Increasing sleep thresholds are associated, on the one hand, with excitenent, worry, restlessness also, with clinical improvement in a course of convulsive therapy. also, in one patient, a transient LSD induced psychosis is associated with a sharp drop in threshold, while in the sane patient, tear of treatment, restlessness and increased tension are associated with rising thresholds. I would suspect that these apparent discrepancies and anger; but arise from the nonnspecific nature of behavioral response to neuro~ physiologic changa and to the poverty of our descriptive language for behavioral change. I would wonder what shape the curves would take if the change in sleep threshold were plotted against other indices of brain function as predominant EEG frequency pattern or degree of synchronisation; or such-psychologtg indices of brain function as the perception of embedded figures or 61?; or such behavioral indicee as dyadic or syntactic linguistic �l-h‘ analyses. Alternatively, more precise,~ oﬁerstionsl measures of the behavioral subsumed under ”anger,“ restlessness,1 “worry" hey provide, again, the relationships indiohted esrlier by the sedation threshold studies. Lest these comments he misconstrued, let me say, in closing, that Dr. Shegsss is to be warmly congratulated in those studies which are providing o firm basis for the developing neurophysiologica adsptive hypothesis of behavior. his demonstrations of central neurophysiologio reactivity in the sedation threshold are in the best experimental traditions. we are eagerly looking forward to further experimental neurophysiologic studies from his new laboratories in Iowa. �qt- I ZIN’EIQAL. 614245 ' ‘ QM r r; m Marlyn»; #ng /% 4n Z/{[ 5/ ’f/e. /3~f7 Ska/177m Amt gnaw; E u, . . 7:va E Wu” E :1va E I . m,“ 1W 1W" ‘ quwr—rrw—nw—v /M /W ﬂaw @524: // M" am/ZEWW/éwu Lb 7%“ @43’ W WM &%M/w/’ Aruéda 54% E E E E M7424 - . �W we moved reading the report of Thorpe and ' in the to assess our own W5 /Q1(LLAAjr Barke%ajm issue of the Archives, we were experiences with the sedation threshold, and to (2 report anether clinical guide to the "inﬂection point" that useful. ' ‘ ’“ n U Following the initial description the adninistration of the amobarbital W / )1 "# WWW Our ’ ' / ' “‘ '* have found, we ,, I _ / " ﬁr of the technique by Shagass we modified ﬂat: is: iiﬁ— our seaside which included test for brain dysfunction (-Weéna-teim, to obtain a measurement of the sedation threshold as well. technique was identical to that of Shagass, with the addition of the measurement of nystagmus on 775: lateral q change gaze which the latter test required. 7h4¢4ww¢16f EEG was done- visually ‘ ‘ in beta amplitude in the in consecutive samples of record, using the additive ruler described by Shagass. In the initial group of patients, two observers were unable to the onset of slurred speech with consistency. identify Disagreement led to administration of amounts of amobarbital greater than was required, with the frequent induction �-2l?!‘ sleep. gaze, As we were also We, ML. Wis-of :_ reliably that this index was we became aware observers, and w/umd 9/ obtaining /“45“¢’7"" nystagmus on ?/ lateral agreed upon by the slur-e W..a.correla.tion withthe sedation thresholdwv W/{Z‘ therefore, omitted the instructions. regarding counting stituted the following instructions. Subjects intervals they would one side and then be requested to were their open and sub- told that at periodic eyes and to look first to the other at pre-arranged fixation points. This to was repeated twice in each direction, usually within ten seconds, while the observer noted the development of Sustained regular nystagmus gaze. Such observation was repeated after The injection of lateral 1 cc of amo— N, ~: ‘ . “42" barbital solution, each on between the 25 and ho seconds of the injection period. administration of barbiturates continued until nystagmus was observed, and. MW ’00 (Lou and then ?WU°: ——————-—_ To more were given. date, we have 91 measurements. ,, difference between the number of thes926an threshold and W W . MW) not!“ the : milligramkl (/19 m7... of ambbarbitaljfo/r Maﬁa,” for the Onset of nystagmus, reﬂects-enemi- Differences greater than one unit did not occur in this series. The two measurements 7,2 79/1; following table 4 The arenreliably related by a unit of 0.5 or lessxw Wamﬂm~ Z... ‘ ' �-3I TABLE Frequency Distribution of Difference in Amount of Amobarbital Necessary to Induce EEG Change and Nystagmus (mg Amobarbital/Kilogram Body Weight) No. Tests .100 .005 0 +0.5 +1.0 l 12 h? 27 h \ ?// ; Test-Retest Reliability: During these studies all» we ' havenhad the opportunity to repeat the sedation threshold measurement three to five times in the intervals.- weekly These measurements were done patient at same in randomly selected patients receiving subconvulsive doses of electrnc current under barbiturate premedicationqi as part of a study of convulsive-subconvulsive electroshock. changes in this group were small - fourteen of the sixteen The were behavioral referred for /z~n/¢‘¢A{4”~*¢¢ég«~0 ' grand mal electroshock within four weeksye7/ngr . ‘ (fl/$4,224. The range of sedation threshold meaSurement?under these conditions noted in Table II. TABLE II Absolute Range of S.T. Values' Range My, Subjects (/4) 0 0.5 1.0 1.5 2.0 o 2 6 2 h >2.S 2 ff’a./§L»«# is �-hBeing unable to ascribe greater é validity . the we determined we have mean sedation threshold for each subject, subjects in the-m mdmadud MM. value. the listed WE: W W one reading than ﬁes any each range of M basis variability ’ mean III TABLE Range Range /o. ﬁubjects (/5) other, of S.T. Values from the e 0.10.5 0.61.0 o 6 h 1.6- 101'- 1.5 ’ “N‘r‘m-wrv .,.m 52.0 2.0 7 h J Mi."- Mean 1 1 , . ., K.,.ﬁm’WhﬁW-am~w-.w:122-w 7 Wat, {is mus-patient;inter-test variability for this test in this series is considerable. test reliability of The electroencephalograpmzhc change is well within the retest variability of test in these subjects. Qéz: the adapted the appearance of nystagmus on m a ; / J1/ J 1/}, C- i ’ / A A f" is / / /z€—— "/5 I I , [KI-A ,5 - ,v clinical guide to a ‘4’; my: M , ﬂ» gray 1.47! /’L! CW/m4‘4ﬂt (331’; ﬁ{ I, ;’(f ﬂ ,Cy «a, ' M; gaze WWK .ma- Asa/2w ,Aaé .4 // My 4 Wﬁffeéé: fr!» WI mat?» lateral WRﬁ—WW the sedation threshold, a; nystagmus as an index of the AA“: iséwtu/MA‘I (2: 7! /)/”/»£¢A/L.( M #63“e/ Ca” we '1’ .11“ ﬂ¢»%ﬂw//L{u¢{304?“:{3’ a? / ,. 3 if '4" ”17’2“" r , _.;__.‘ 4’ "I; a: A" {ﬁ’ﬂg‘t . ,, ,4? Ayiﬁ ”(:4'5‘ Alt—‘3 / A’Jik �, ..‘ )- I *’ Wv .1. C . ya $407M Mann}; 4 M4, /:7 a4“!!- C . 74V galvauE/Zw/ I £44373; 59:7. Z—f: M4. 41% ’7sz /f4/A/75, (”ﬁf) W77er?“ ' #1 %@‘*’5‘“ g CL .‘ «9-9/-'.?33, ‘ /7f¥, M . ‘ / $42M” ~ i ) ﬂtm NA /‘J3, /ﬂf: ff7~ff~c '/ $4,441,, V . ﬂu d {7 . /% (1;.1'5 7. �THE LONG ISLAND JEWISH HOSPITAL 270-05 76th AVENUE Department of MEDICINE 0 NEW HYDE PARK, LONG ISLAND, N. Y. - TELEPHONE: Fleldstone 3-6700 �Suptonbar 21, 1961 ntrtin H. rats, Ph.n. Reiuurch Piyuholosint Paychophurnnaoloxy surviuc Cantu: o: nautnl Bonita lation:1 Institutg Md. Buthnldn 1h, Dcar _ ﬂirtin, tour lattqr regarding 1 r0110! o: it: Iodaiitn thrcihold attack a oynpsthcsia chord, and I an caconr:god to share my Vitus with rat, Buvavcr, tin probla: in acuu plax tad perhaps no as: not anido tan. tin. in Huntington fur a dutuiled diacunuion. Hy interest in tho sedation thronhaid van cooulionnd onrlicr intarout in tho at. 0: intravoaonn snibirhitll an a fast tar brain dynrunation. Hoinltciu and Ichni Donitl at Illa-an c c. ThOIIl, 19 S) In tn. court. of ofcoiﬁucﬁoci 05:310., we curriod out many out13¢tau at tho 8.2. .36 can. to it. eontlalion taut sh. inst was phyliylogically and itchnically Hound. Finding dylgrthriu I difficult ondnpoiut, I lubntitnicd nyutccnuu; but in raulity, thin can b: dilponlod wish, ninco tn. acnlurod and-puini in to. EEO tbs 3.3995: by ny aarpud nhoui drunrthrin, corroct ll tar an int: hlvo (out, but thin dittiauliy intr.not inlnrunuBStblo, uni boar: no aigaitiaing rolgtion to the valet at $8. tout. the critic: who have The quantiann It inane trot II it. tlli stunt. in in: can. individual .v-rtiuo? 2. In thuro a charteturiltio tcapanao which boar: a oiguir10§nt1y high corroliticn with n bchnvioral Vlriibli - ntnnly, sh. oililifiottion by psychiatriltl a! tangent: iuia uolclogic (racy-9 1. �0-2- 3. Thirdlr, your quclhiou, “it true, it (8.1.) ahvioualy can b. very alarm! in trtttnaut ﬁrodiotion nhndicl'. 1. Out Inn uxp.richou indiohtUI that : high intrh~ individual variabiliir; a limited ran 0 at vuluon tar thc halt (tvclvc point. from 1-6 in half than. and an oqnivocnl EEG 0nd»point in 10-20! a: test: lit?! to nuko tha rnlihbla duturu ainntion if tho 8.!. difficult.’ that. vurinblcn soon inhurout in th. taut danish, and Ira not, in :1 opinion, I luck or know-haw by uh. ohlurvcrl. 2. no. Hy nogahiva unuwar to thin question is partly hhoad on (1); Ind partly on tho uuucl dittioaltios at nonology. in somewhat limplowmiadod to uspuat a high corrolntion It betwocn a 'uinplt’ phyiinloxic rotativity naulurc had a “90:91.3” hypnthctie clhatrnat with '0 Inch inhtront unhigui» 3 hy Ind variability. in: 3.2. may hat bu rnlutcd in diagnosis; aha the 3.T. h. unoful in truttacnt prediction? I think it uh: ha, ~~ not for hhc losicul raglan: anuuily IiVOI, but blcinll of the value of tha tout an I .anctivity” nth-urn. In the pulh tow ybnrn variouu indict: huvo blln nhaua to huar IOll rolatiou to trontnont or to diacnnlis ~hnd ouch inﬂux it halt huh-ulna under tho hgru or a 'ruautivio inﬂux”. HO utatod hhht pationth vhe chowod two or nor. tr laughing «hangs. utter intrtvonoun uncharhitnl war. nor. likely to thaw curly EEO ehnnsun httnr uloetrouhock, had to 3. Evan ihough aha: gruntor dncrucn or hohnviortl church and iuprovonnnt of Cenaunieatign, 126 - 139, 1958). Goldntn pantothnl burnt. tr. 010' ’3'; a o thin in uppchrsaoo in achiIOphronic nnhjocta, and ht! unod tout protnouticclly. Siuilhr mittencutl hart bath midi, in £36 Ctt‘uli nor. quantitttivo Itudinu, by Itil (Erlungun) (Milan), why havu rclntod thn changod EEO putt-run to corehrnl ltrophy on pucnnaoneophulozrtphy. In hnothcr type of studios, tho bland prolhnro rcupan-au to nocholyl and to harshnlin have bath roptahcdly Incgnutod an a dilﬂnﬂltic had prognontic 136.3. A cannon bhaiu in thcnc Ithdiou in that u link of reactivity or a alow ranchivihy in zanornlly taunted vith schiloyhruni: 0» brain atrophy ~~ a poor proxnoutic high to: the artillhlo thsrtpiol; whil. high rtnotivity in aquutnd with écprcauivc syndronon ~~10w: [and tauntivprognostic sign with awnilhblh thnrapitu. Than, invoked indux or but hi an high any your prtgnoling a: it: ruaahivity will bchr A high wurrulation with hshhvioral chaugu, had a varinhlo In. with inprOthont rutinzs. (3.0 �.3our views of beteviorel change and inpreveuent ratings, Arch. Gen. Feloniet. g; 259, end 5; 30, 1961) Thus, there is much merit in Shannen 8.1. -- not, in .my View as e diegnoetic index (for age is much more relieble and easier to ascertain), but ea one guide to neurophyeielegic reeetivity -- e eubaect that needs {nether study as e preg- noetic and as]: noeelogicel teal! I trust this in reeponeive to your inquiry. I would 16-1? ?) like to disease it acre fully in doWashington (October the 8.1., in end wenld recommend that if yen get interested on veriene reactivity that you consider 3 eeriee or aeetinge ueeeuree in plyehietry .. the neehelyl test, the 8.2. end the coldnen ee exemplee at the more explicit. My regerde. sincerely yours, Hrcdte ex n , “.5. �I1 I. I. I $5 I [3 EE P1 (3 55 F’ I'T'l\ I. FOR PSYCHIATRIC TREATMENT. TRAINING AND RESEARCH 75-59 263RD A. MILLER, M. D. , , Medical Director JOSEPH S. SIMON KWALWASSER, FIELDSTONE LEON LOWENSTEIN 8-7800 Department Of Experimental Psychiatry M. D. Assoc. Medical Director MAURICE STREET. GLEN OAKS. NEw YORK BACHRACH Honorary Chairman Board of Directors ROY .FOSTER Chairman Board Of DWWOH ALVIN E. COLEMAN Administrator President September 12, 1957. Dr. Roy Grinker, Editor, Section of Psychiatry, A.M.A. Archives Neurology & Psychiatry, 29th Street & Ellis Avenue, Chicago, 16, Illinois. Dear Br. Grinker: In reading the report of issue of the Archives, the sedation threshold, Thorpe and Barker in the latest (August) to assess our own experiences with and to report another clinical guide to the we were moved "inflection point" that we have found useful. During the past two years we have included a measurement of the sedation threshold in our tests of brain function. we initially followed the technique described by Shagass (EEG Clin. Neurophysiol. é: 221-233, l95h). Measurement of the beta amplitude reaponse is done visually in several samples of record using the additive ruler described by Shagass. initial group of patients, two observers were unable to onset of slurred Speech with any consistency. 'We, therefore, the identify omitted this step, and continued drug administration until gradually drowsiness was clearly manifest, combined by a statement by the technician that an increase in beta amplitude in the record had occurred at least 1% In the minutes before. that occasionally amounts of amoreach an inflection point were administered. We, barbital inadequate to therefore, began to note'the onset of nystagmus on lateral gaze as a guide to the sedation threshold. This technique had the drawback Subjects were told that at periodic intervals they would be requested to open their eyes and to look first to one side and then to the other at pre-arranged fixation points. This was repeated twice in each direction, usually within ten seconds, while the observer noted the development of sustained regular nystagmus on lateral gaze. The administration of barbiturates continued until nystagmus was observed, and then 2 cc more were given. The EEG records were then measured for the inflection point by the visual method. AN AFFILIATE OF FEDERATION OF JEWISH PHILANTHROPIES OF NEW YORK �Dr. Roy Grinker (Contd) -2— To date, we have 91 such.measurements. In the following table, the difference between the point of onset of nystagmns (nystagmus index) and the inflection point of beta amplitude change (EEG index) is reported. Difference .100 1 EEG Index s-Nystagmns Index .005 0 +05 +1.0 12 h? 27 h Differences greater than 1.0 unit did not occur. It is apparent that the nystagmus end point for the sedation threshold is reliably related to the EEG end point by a unit of % in more than 90% of the trials. Since the error of the sedation threshold under test - retest conditions is between 0.5 and 1.0 units, this nystagmus index is a satisfactory guide to the sedation threshold, as defined by Shagass. W In our continuing studies of the sedation threshold, we have, therefore, ceased measurement of slurred speech or drowsiness, but have relied on the onset of nystagmns as the clinical guide to this index. I trust that this data may be helpful to other investigators. Sincerely'yours, v ,4 a’V‘wﬂwc has: MF:JB _ Fink, mm. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Lateral gaze nystagmus as an index of the sedation threshold. Electroencephalogr Clin Neurophysiol. 1958 Feb;10(1):162-3. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-28-003 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 12 items. 1: [Preprint]. 2: Reprint from Electroencephalography and Clinical Neurophysiology Journal Vol.10, No.1, February 1958. 3: Letter to Dr. Roy Grinker form Fink. 4: Letter from Grinker to Fink. 5: Letter to Dr. Robert S. Schwab from Fink. 6: Letter to Fink from Schwab. 7: Letter to Fink from C[harlie] Shagass. 8: [preprint] to Dr. Thompson, members and guests discussing Dr. Shagass (2 copies). 9: Handwritten notes. 10: Draft with edits. 11:Letter to Martin M. Katz from Fink. 12: Letter to Roy Grinker from Fink. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Mosquera, Hannah Published http://exhibits.library.stonybrook.edu/mfp/files/original/c779b264e0ba3e779d39ff5db1a0879e.pdf d5ea2d1f830983dbe61a4c62d8e73b61 PDF Text Text Significance of Individual Variability in EEG Response to Electroshock Martin A. Green, From M. D. the Department of ExPerimental Psychiatry, Hillside Hospital, Glen Oaks, N. 10-11-57 "r .50 �Significance of Individual Variability in EEG The assumption Response to Electroshock is often tacitly made in studies of nervous system function that the capacity for neurophysiological change is similar for animals or humans in the groups under study. Differences in response are ascribed to different parameters of the stimulus or to differences in the location and extent of lesions, either spontaneous or experimentally produced. tion may Such an assump» Perhaps another factor in the not be warranted, however. variability of response under these conditions is an individual variability in neurophysio— logical reactivity or responsiveness. The initial "base-line" may not be similar in all individuals. The possibility of different inherent patterns of reactivity has suggested by the studies of the alterations in the have been impressed by the high degree of EEG been during electroshock. variability in such We alterations both in their quantitative and qualitative aspects. Although this variability has been described by previous investigators, it has not been stressed sufficiently; nor have possible explanations been advanced or systematically investigated. present report concerns a description of the changes in the EEG Hillside Hospital during electroshock in the/' material. The concept of neurophysiological The reactivity is presented and studies that may clarify this problem are suggested. �MATERIAL AND METHODS: Eighty-nine patients were studied. The patients who received electroshock for psychiatric illness Hillside Hospital and were voluntary admissions to the majority had not received electroshock previously. The diagnostic groups and schizophrenia. psychosis manic~depressive included psychotic depression, The largest group was patients with depression. Agesranged from 20 to 68 years, with a median of #7 years. Treatments were given three times weekly, each patient receiving at least 12 treatments. The Medcraft instrument (alternating current) was used 61 for current) for 28 patients and the Reiter instrument (unidirectional patients. Electroencephalograms were taken prior to, and two weeks following the course of treatment. EEG was abnormal were to 36 weekly Patients specifically excluded from study. 2h (from day non-treatment a an at whose intervals during, pre-treatment Tracings were done on hours following the previous treatment) with eight channel Medcraft machine using needle electrodes. Frontal, motor, and earlobe vertex temporal, posterior temporal, anterior parietal, occipital, placements were employed with scalp to scalp and scalp to earlobe combinations. �RESULTS : I. Delta Activity. A. Quantitative Differences: delta activity The to the method described by Fink and (8). Kahn The was analyzed according duration of burst activity, the lowest frequency, the average delta index in several leads, the highest measured. were lead one in time delta and the percent highest amplitude, Re— cords were classified as showing a low, middle or high degree of delta activity (Fig. 1) according to criteria previously described (8). All patients developed delta activity during the course of but differences in the amount of the slow activity and were very apparent (Table I). Some early in treatment whereas other even after serial 12 EEG's. not develop in treatments. As treatments of development patients developed "high delta activity" patients showed only "low" or "middle" changes latter patients were followed further with treatment was continued, a high degree of delta activity did some of these patients until on a daily basis. This individual variability in treatments were given change. These its rate 12 20 or more They were EEG treatments, or until resistant to neurophysiologic response was independent of the type of electroshock current employed, being present both with unidirecticnal current applications. alternating and with �- h TABLE Degree of Delta I Activity in Serial Electroencephalograms during Electroshock (2-n records were taken for each patient) No. Activity EEG No change delta activity Low Middle High B. may be ity. - EST 1 delta activity delta activity of Records in Each Treatment Period u L:..§ 3 l 37 21 7 3 20 22 10 1 28 #5 25 1 16 amount of delta the activity Although total Differences: Qualitative activ~ and of delta voltage to frequency records as differ type, similar, One prominent qualitative difference during a course of 12 treatments. is in the form of bursts which as treatments are continued. is the ratio of irregular delta In some patients the become more The show burst activity initial delta change frequent, slower and of higher voltage irregular delta activity in such records is less prominent and usually occurs at faster frequencies. In other patients the reverse occurs. form. 12 0 5 activity to bursts of slow activity. Nearly all records much - 10 Although burst Delta activity appears chiefly in an irregular and scattered activity is also present, third group of patients the amounts of it is not conspicuous. irregular delta and In a bursts are approx- imately equal (Fig. 2). These differences in the form that the delta activity assumes is usually constant during the course of treatment. At times, however, burst activity will �. become more prominent - 5 than the irregular delta only during the latter part of the course of treatment; or burst activity which appears prominent early in treatment may be overshadowed and obscured in later records by a large amount of continuous irregular delta activity. The slow activity is maximal electrodes and less pronounced at the at the anterior temporal more frontal and posterior electrodes. Often asymmetric, being of higher voltage, slower, and in greater amounts anterior temporal Only and frontal electrodes as asymmetry occurs during treatment both with is at the left to the right (Fig. 2). compared rarely is the reverse true, i.e. accentuation it on the right side. This alternating and with unidirectional currents. Another type of abnormality, though an infrequent one, of rhythmic runs of delta activity which (Fig. 2). The may continue for 10 is the to 20 seconds regularity of the frequency and voltage of the slow these runs is very striking. appearance waves in These runs are usually infrequent, but may be the most prominent alteration in the record. In many records the amount of delta activity fluctuates during the tracing. At times, some in other parts of the This variation II. is portions of a record same may appear nearly normal, while record the delta activity may be quite pronounced. independent of the electrode combinations employed. Spike or Spike-Wave Activity: A large number of records or high voltage. Most show single spike activity of low, moderate often such spikes are slower and not as prominent as �- 6 - those present in patients with seizure disorders. show spikenwave A small number of records activity. This is usually at irregular, mixed frequencies and, again, does not resemble the regular rhythmic bursts commonly seen in patients with seizure disorders (Fig. 2). III. Alpha Activity: The alpha activity shows changes both in amount and frequency. As the amount of delta activity increases the amount of alpha activity usually decreases. Changes in frequency occur but are not pronounced. will be slowed by 1-2 cps but tracing. In a small number at times will remain the same The frequency as in the pre-ECT of patients the amount and voltage of alpha activity increases during treatment. This change persists during the post-treatment period after the slow-wave activity subsides (Fig. 3). IV. Beta Activity: The fact that activity in the EEG many and the induce fast barbiturates, particularly sedatives, of administration the in controlling difficulty these drugs in this population studied makes during the course of treatment. are minimal. activity. The most it difficult to evaluate changes In most instances changes in fast activity frequent change, when present, is a decrease in the �Discussion: is that of the individual variability in the As EEG described, electroshock therapy. and of during alteration degree type and of rate slow-wave amount of its the activity manifested in: l) this is (amount slow-wave the in activity differences 2) development; qualitative The problem being raised of burst activity vs irregular delta activity, symmetry, fluctuating appearof 3) slow activity); of presence rhythmic slow of runs ance activity, Spike or spike-z-rave activity; and LL) changes in alpha and beta Previous investigations (2, h, 5, 10, have ll, activity. 12, 1h, 17, 18, 19, 20, 25) stressed possible correlations with age , sex, frequency of treatment, and clinical change. diagnosis, employed, of current psychiatric type Increasin" the frequency of treatment, for example, will increase the degree of similar sex, age and the with same the frequency treatments at given are psychiatric diagnosis same type of electroshock current, variability in the rate of development of alteration in the EEG. However, when "ratients their type anc‘. degree are still very prominent. One explanation for this variability might be the distribution of the electroshock current in the brain. Perhaps minor differences in the resistance of changes in the EEG and and blooc‘ vessels of the distribution of the skull, in their penneability or taken the pathways in differences create of tracts nerve in the arrangement the of brain portions different such Unler circmnstances, the current. by may receive more or less current in one patient as compared to another. variously these by generated of the electrical activity Differences in type affected areas might account for variability in the EEG. Available studies employing direct intracerebral measurements indicate considerable diffusion of current throughout the brain (6, 9, 16, 21). �However, a concentration of current anteriorly and along: large neuronal pathways, such as the corpus callosmn, has been demonstrated. No further infon'ration is available as to amounts of current received. by more Specific cerebral areas. Due to the high resistance of the skull only a small portion of the applied. current actually reaches the brain. The amount of current entering different portions of the brain is said to be determined by the resistance of the skull overlying these areas; the anterior concentration of current being; the result of the thinness of the temporal bone with its consequent lower resistance as compared to other parts of the skull (9, 21). Several considerations, however, indicate that individual differences in these factors of resistance and amount of areas of the brain are of minor, during-g electroshock. It is if current reaching,- different any, importance in the ELG response the occurrence of the generalized seizure 291'. §_e_, rather than the passage of electricity, which is the primary factor. During a course of grand-mall therapy induced by non-electrical means such as metrazol, EEG changes occur which are similar, with electroshock (13, 1h). Diffuse slow-wave in general, to those seen activity, accentuated of The amount described. are activity anteriorly, slow—wave activity increases during treatment but shows individual variability unrelated; to the n unber of treatments. Another observation is that electroand 81‘.de or spike-wave shock therapy nhich induces petit-mal (7, 18) or focal (3) seizures rather than grand-mal, does not produce the characteristic build-up of slow-wave activity. In addition, there is no increase in the degree of delta activity in our patients in whom grand-mal tae rapy is given with high suprathreshold stimuli as compared to those in whom threaiold stimuli are used. �-9- . Factors of current cannot be entirely dismissed, however. Even with grand mal therapy, the type of current employed may influence the we haVe EEG change. confirmed a previous study (20) showing that the rate of increase of delta activity is slower in therapy with unidirectional current than in that with alternating current. Similarly, brief stimulus therapy is said to produce smaller degrees of alteration in the EEG as compared to alternating current therapy (15). The EEG other theory to be considered in explaining the variability in re5ponsiveness, and the one which is probably more determinant, involves inherent differences in neurophysiological reactivity. By this is meant both the quantitative and qualitative aspects of the inherent capacity of the nervous system to respond to stimuli or injury. Not only the degree of response, but also the type of response, type and degree of EEG may have these determinants. The abnormalities developed during electroshock therapy appear to be the reflection of such inherent individual differences in neurophysiological reactivity. Several types of investigation Methods other than electroshock may known serve to to produce test this hypothesis. EEG alterations could be applied prior to treatment. These might include lowering the blood sugar by parenteral insulin, intravenous administration of convulsants such as metrazol or Hegimide, photic stimulation, or the intravenous administration of drugs such as barbiturate. In addition, perhaps the actual electroshock seizure ﬂzreshold or the pattern 0: severity of the seizures measure of nervous system responsiveness. Data from such could be correlated with the degree an? types of shock. In this manner it might be ELG may be a investigations change during electro- possible to demonstrate different patterns �410- classify individuals accordingly. not only help in understanding the variability in reactivity of neurophysiological Such studies may and alterations during electroshock but would have wider application to other problems in clinical electroencephalography and neurology. For example, tie basis for the development of Spontaneous seizures secondary the EEG to traumatic, vascular, or neoplastic lesions of the nervous system known. Patients with lesions comparable in type, size and location or may not develop seizures. As previously described, spike or Spike-wave activity during electroshock. difference in not may subjects some show This suggests an inherent clinical seizures or he capacity to develop is EEG seizure is reflected in the whether the to injury nervous system, "injury" following activity spontaneous or induced. Differences in this capacity may be varying patterns of neurophysiological reactivity. Differences in neurophysiological reactivity in the pre-troatment abnormal (ll), EEG. Patients in whom "instabile" (22), or axons may also be manifested the pre-treatment record is a predominant alpha rhythm (S) LEG the in during electroshock. the alteration to said develop greatest are Other investigators have not confirmed these observations (2, 23). Actually, such correlations depend on the method of analysis of the pre-treatment criteria used for "abnormality." Further investigation of this relationship is necessary. Suggesting that neurophysiological reactivity is an inherent process does not imply that a physiological basis does not exist or cannot be in- record employed and the vestigated. This may reside in the central nervous system itself, consisting of individual differences in neurochemical systems or in the permeability of cells-or blood vessels; or it may be outside the nervous system. Individual �‘11- differences in hormonal or other humeral substances produced during the stress of electrosho k may serve to "sensitize" or "desensitize" the cerebrum with regard to developing ical activity. That such factors following studies. Trypan red different may be amounts and types of electr- operative is suggested by the injected intraperitoneally in cats before a course of electroshock decreased the permeability of the blood~brain barrier and reduced the degree of EEG changes as compared to control animals (1). Atropine and scopolamine adminstered during a course of electnodiock in man blocked the development of the usual slowawave activity (2h). Electroshock therapy affords an excellent opportunity for the experimental investigation of the problem of an inherent neurophysiological reactivity. animals. The One is able to apply studies directly to man, rather than stimulus to the central nervous system can be standardized and the degree of neurophysiological change changing different parameters. controlled, within limits, by Tests of 336 responsivity can be given before such dianges are induced as well as during and after treahnent. Re-study of patients is often possible then subsequent courses of treatment are necessary. �.12.. marl: l. Indiviéual EEG the in qualitative, changes during a course of electroshock treatment in 89 patients are éifferences, both quantitative and described. 2. These differences are pronounced and are not explainable by age, sex, type of shock current, frequency of treatment, psychiatric diagnosis, or clinical change. 3. An inherent capacity for neurophysiological change that has both quan- titative and qualitative aSpects may be the primary determinant of these differences. h. Variation in skull resistance and in the amount of current reaching the brain aspear to be minor factors. 5. Investigations that might serve to described. Such studies may test the hypothesis presented are lead eventually to a classification of individuals as to different patterns of neurophysiological reactivity and clarify other problems in clinical neurology and electroencephalography. �é 13 - REFERENCES l. Aird, R.B., Strait, (1956): S.C. and Bowditch, M.K., Hrenoff, L.A., Pace, J.w., Current Pathway and Neurophysiological Effects of Electri- J. cally Induced Convulsions. Nerv. Ment. & Dis., igg: Bagchi, B.K., Howell, R.W. and Schmale, H.T. (l9h5): alographic and The J. Pszchiat., lgg: h9-61. Am. R. (1953): and S. Feinstein, Berg, Impastato, D.J., P.S., Bergman, Electroencephalographic Changes Following Focal Seizures, Conf. Neurol.hl§: Electroshock, EEG. Chusid, J.G. and Pacella, B.L. (1952): Electric 271-277. Clin. Neurgghxs., g: Shock Therapies, J. Electrically Induced Slow Wave Phenomena Callaway, E. and Boucher, F. (1950): 157~162. Neuro. Ment. H. Dis., llé‘ (1953): shock on the Cortical and Intracerebral shock Process, M. J. Nerv. and Kahn, B.L.: & Response in Electroshock: Arch. Neurol. Hayes, K.J. (1950): Arch. Neurol. & The & 95—107. Electroactivity of the l3: 287-29h. Experimental Studies of the Electro- Ment. Dis. Relation of in Effects of Electrou Brain in Schizophrenic Patients, Conf. Neurol., M., Kabn, B.L. and Green, MLA.: in Intensive The Electroencephalogram Delgado, J.M.R., Alexander, L. and Hamlin, Fink, Electroenceph- Clinical Effects of Electrically Induced Convulsions in the Treatment of Mental Disorders. Fink, 505-512. EEG (in press). Delta Activity to Behavioral Quantitative Serial Studies, A.M.A., Pszphiat. (in press). Current Path in Electric Convulsion Shock, Psxchiat., §§: 102-109. �-1hREFERENCES 10. LC. and Pincus, Hoagland, IL, Malamud, w., Kaufman, G. (19%): in the Electroencephalogram and in the Excretion of 17 Changes Ketosteroids Accompanying Electroshock Therapy of Agitated Depression, Psychosom. Med. , 8: 11. 216-251. Kennard, M.A. and Willner, MD (1908): Electroencephalogram M. lg: 13. Serial (1955): Results from Shock Therapy, 4AM ho-hs. P83111835” £02: Igtz, Which Significance of Changes in the Changes Due to Electrotherapy, Dis. Nerv. $35., 120-122. Knott, G.R., Gottlieb, J.S., Leet, Hull and Hadley, H.D. Jr., (1943): Changes in Electroencephalograph Following Metrazol Shock Therapy: A 1h. Quantitative Study, Arch. Neurol. 8c Psychiat., 29: 529-53h. Levy, N.A., Serota, mm and Grinker, R.R. (19142): Disturbance in Brain Function Following Convulsive Shock Therapy, Arch.Neurol. PsEhiat., ﬂ: Liberson, wur. (1951): 1009-1027. Current Evaluation of Electric Convulsive Therapy, Mento ASS. Nerv. PUbl. R93. D180, 0... nun-U. Lorimer, F.M., Segal, & M.M. and Stein, S.A. 2: 199-2310 (19149): Path of Current Distribution in Brain During Electroconvulsive Therapy, EEG. 17. Clin. Neurophysiol., 3;: 318-3148. Moriarity, J .D. and Siemens, J .0. (19M): Electroencephalographic Study of Electric Shock Therapy, Arch. Neurol. & Psychiat., 21: 712-718. �- 15 REFERENCES 18. Pacella, B.L., Barrera, S.W. and Kalinowsky, L. (l9h2): Variations in of Shock Therapy with Electric Electrocephalogram.Associated the Patients with Mental Disorders, Arch. Neurol. & Pszchiat., 51: 367—381l- 19. Proctor, J.E. (l9h5): Clinical and Electra-physiological L.D. and Goodwin, Observations Following Electroshock, Amer. J. Pszghiat., 39;: 707-800. 20. Proctor, L.D. and Goodwin, J.E. (l9h3): Comparative Electroencephalographic Observations Following Electroshock Therapy using Alternating and Unidirectional Fluctuating Current, 22: 21. Raw 60 Am. Cycle J. Pszghiat., 525-530. Smith, J.w. and Wegener, C.F. (19hh): On Electric Convulsive Therapy with Control??? Electrodes of Application Parietal to a Particular Regard Neurol., et Acta Measurements, Pszchiat. Voltage Intracerebral by lg: 529-5h9. Sulzbach, W., Tillotson, K.J., Guillemin, (l9h3): A Consideration of Some V. Jr. and Sutherland, G.F. Experience with Electric Shock Various to Regard with Special Mental Diseases, Treatment in Psychosomatic Phenomena and to Certain Electro~technical Factors, 23. Taylor, R.M. and Pacella, B.L. (19h8): The Significance of Abnormal Electroencephalograms Prior to Electroconvulsive Therapy, J. Nerv. & Ment. Dis., 291: 220-227. �. 16 - REFERENCES 2h. Ulett, G.A. and Johnson, M.W. (1957): Upon Electroencephalographic Changes Induced by Electro-convulsive Therapy, 25. W911, A.A. and EEG. Olin. Negggghxsiol.,.2: 217-22h. Brinegar, wgc. (19h7): Following Electric 21: Effect of Atropine and Scopolamine 719-729. Electroencephalographic Studies Shock Therapy, Arch. Naurol. & Pszghiat., � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Martin A. Green: Significance of Individual Variability in EEG Response to Electroshock, 1957 Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-002-10-010 Date A point or period of time associated with an event in the lifecycle of the resource 1957 Creator An entity primarily responsible for making the resource Green, Martin A. Subject The topic of the resource <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Research http://exhibits.library.stonybrook.edu/mfp/files/original/b3fea1439cf39d58481542317f0d7a56.jpg d037cfc6cb6328a0c5288a49b0743fdc Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (center) and Martha Fink (left), undated Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-019 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/21957d69cdbec75a3af3c92b80ba3139.jpg 2c3423c56c5b26408e8014d9fe1ae6cb Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (center), Taylor Manor Hospital Award, 1983 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-024 Date A point or period of time associated with an event in the lifecycle of the resource 1983 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/9b0194e8e6e41306ad3951920053d280.jpg f8c888b317c4eb6d66b8b1b4bc7e8c55 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (fourth from right) with Journal of ECT editorial board Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-022 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/5ce7d73c53b35688ef49c36f129295be.jpg 4fa67e66a351f53004b75184ec87b37b Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (left) and Jean Bobon, 1969 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-020 Date A point or period of time associated with an event in the lifecycle of the resource 1969 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/f3d9fb14b2a5f8dfecb2862c52e52124.jpg 647fa901e61ae5e59271252d4c9e96e7 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (right) and Edward Shorter, 2006 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-016 Date A point or period of time associated with an event in the lifecycle of the resource 2006 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/8fb21cedddcd09ee293085e8ddd43092.jpg 4ccc01813c057ee2539defeddfe0f394 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (right) and George Kirov, Edinburgh, Scotland, 2010 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-029 Date A point or period of time associated with an event in the lifecycle of the resource 2010 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/9bec4d07db9cc7bbdca592d03c5631f1.jpg e27ee77bdf6e164226f11d4601b974de Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (right) and Jules Angst, 2005 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-028 Date A point or period of time associated with an event in the lifecycle of the resource 2005 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/c5ea573b4bf4da79451f414252f59775.jpg ceab7141f10775850d473faf1dabf449 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (right) and Turan Itil and Helen Itil, Las Vegas, Nevada, circa 1970s Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-030 Date A point or period of time associated with an event in the lifecycle of the resource c. 1970s Subject The topic of the resource Photographs -- Photographs Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/f0e5d9d531f56323cca97665c0ea6a6c.jpg 21e4fe4b2a226656434d73519da09973 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (right), Danish University Antidepressant Group, 2011 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-021 Date A point or period of time associated with an event in the lifecycle of the resource 2011 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/f44d0c2625f1389edfd0c676eea438c3.jpg 207003d989abb5a29d50b834f258c445 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (right), Taylor Manor Hospital Award, 1983 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-026 Date A point or period of time associated with an event in the lifecycle of the resource 1983 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/34ffc14c69353beb28205e3d083f74c1.jpg 15d767820d5675ff4b8227daac69b607 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink (second, right), Taylor Manor Hospital Award, 1983 Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-025 Date A point or period of time associated with an event in the lifecycle of the resource 1983 Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs http://exhibits.library.stonybrook.edu/mfp/files/original/2f578bbf612a73467db6914635f7abd6.jpg d2a0de5cef8c03d255fbfb5d6d39ea67 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Photographs Still Image A static visual representation. Examples include paintings, drawings, graphic designs, plans and maps. Recommended best practice is to assign the type Text to images of textual materials. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Max Fink, 1940s Type The nature or genre of the resource Image Identifier An unambiguous reference to the resource within a given context mfp-04-01-001-0-014 Date A point or period of time associated with an event in the lifecycle of the resource 1940s Subject The topic of the resource <a title="Photographs" href="http://id.loc.gov/authorities/subjects/sh85101195" target="_blank">Photographs</a> Relation A related resource The Max Fink Collection Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Format The file format, physical medium, or dimensions of the resource jpeg Photographs