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. C9 Aird, R9 139, Striit’ L A9, Pace, of electrically induced convulsions finch. Neel/1.0L effects Neurophys1ologg§§ (1959. )19: 371— 378 ”WW I Aktivnost kholinesterasy 99999 Alpern, D90 i kholinergicheskaya reaktsiya krovi pri shizofrenii9 [Cholinesterase activity and choliner 10 reaction of the blood in schizophrenia ”J; Fizzéoh 2%{719575 .57 87- Pg\ 9 3%; J 1/9 .9 Vitamins, enzyme systems, and trace elements9 Bodéfly Phyzsiofiogy in Mental. and Emotional Duoadefvs) Grune 8 Stratton, New York, It 1953! .1 Altschule, ‘ W M9 W Augustinsson, V D9 New 913$“. f\ M for cholinesterases9 In WGlick 05 Biochemical Ana/Emu) Interscience Publishers, 3‘,We 5’ 1‘1” [103 Presence and action of acetylcholine in experimental 5% Method/s Bornstein, M9 D9 brain trauma9 J; NewLophyAwL, Wig: J 399— 399 Merritt, H9 H9 Effect of certain choline derivatives ctrical acti ity of the cortex. Aach9 Neww£9 PAychia/t. 99: 382 395, Brenner, 91942. #4.. ' Assay methods K9-B9 York, 1957, f” ________ Augustinsson K '-B9 The normal variation of human blood cholinesterase activity9 A1199 PhyALOL Scand9,\l955 \3__5_: 90——52}/ '/ arr” C9 and ' ‘ M physiological significance of acetylcholine9 In K9 A9 C9 Elliot, I9 H9 Page and J9 H Quastel)116(/y) Thomas, Springfield, 4-1-12, 1955],) NeuaochenuADLy) jam-939911 27s“. M99949», 309 my, and acetyl;2 Chatfield, P909 and Dempsey, E9 W9~ Effects of prostig%ne choline on cortical potentials, (Ame/L9 .79 PhyAzéofw', 1992 135: 633-6M0. )9] Burgen, Cone, ., 9 ,1 99, W9 A9 S9 V9 and MacIntosh, F9 C9 The W V9, Toner, D9 B9 and McEachern, D9 Acetylcholine and neuronal {j activity in epilepsy9 (.79A9 M9A9,119u8 73: 59 63 A9 and Merrick, Crossland, The effect of anaesthesia on the acetylcholine content of the brain9 .79 Phybioh ,\¥l95lt.9125 56- 66 9,! .11 1. (/JJ’j) Dale, H9 H9 The action of certain esters and ethers of choline, and their relation to muscarine. V] Phwunacoh Exp9 Them, 1911+, 1195/ Denisenko, P P9 Pharmacological blocking of central cholinoreactive systems and the possibilities of its therapeutic applicatiom In G B , Koelle, w W. Douglas and A9 Carlssogffzheerefi Phamnacoflogy 06 ChoLLneJLgnc V” and Adaeneagxec Mammmwn. Vol 3 o Glen» J J , J _6_: 9 pj’ 9 Paoceed/cngb 05 W Rascovafienm I‘M" ' and Investigations the Second Inxunafionaz’ Pha/unacofiogicaf. Meetcngjgjgb New York, 1965/ Macmillan)9% D9 F9 ,Hemphill, Early, 9 R9 E9 ,Reiss, M9 Brummel, E9 2499199 into cholinesterase levels in serum and cerebrospinal fluid of psychotic patients (Biochem. ”Li/V“) / .7 ,Fl—E9, M5: 556 -552- DJ a” , I 9. �Elliott, K ‘A Co, Swank, Ro L and convulsants on acetylcholine content of {@93sz brain JiwflhgéLQ£»¢T//’”//JK (AMeagl 1469—44781 _....—_,—.— A . 1 Ellman, G be and Cal.laway,E E1 throcyte cholinesterase—levels in mental patie.nts Natuhe (Land )@961.J192: l2l§)j w'v-xfl 8. rI/J>-~/ Effects of anesthetics and Henderson,_Ng -/7 unifiedtheory of the ac.tion of physiodynamic therapies° HstLde 6: 197 (J 206 H08p)(i1967 (116., “37" “m1 F1nk, Mo Effect of anticholinergic agent, diethazine, on EEG and behavior: significance for theory of convulsive therapy (AfikM (Neon/L01: PbyWaL—WH‘J’IQFM3803875J F1nk M A W F1nk,M Effect of anticholinergic compounds on post onvulsive electro: encephalogram and behavior of psydhiatric patients Lectaoenceph CLLn.-~~ NeuhuphyéLOL Jl§66;JlEW(2); 359— 369 convulsive The M mode of action of Fink, therapy: the neurophysiologicadaptive View (9: NeuhopAychLato,J1962Jc3: 231—~233)\ \ )J [AK—y... 7! um: 17% A, m "lat/"M1- Fink, Mo and Kahn, Ru L Quantitative studies of slow wave activity following electroshock ELecLLoenceph CLLn NeuaophyALOLO, @fififiiq:_;;l58?J Fink, Mo, Kahn, Lefkowits, H 1961,u: R0 J 259 266 Le, Karp,E o, Pollack, Mo, Green, M AC, Alan, B and Inhalant-induced convulsions (:Ahch Geno PAychLa§>((3K; . Freedman, A Mo, Bales, P D, Willis, AG production of electrical major convulsive 117— 121% fIgfié'Jfi—J: “£11-“.V./ FUnkenstein,D and Himwich, Ho Ea J. ,Ameao patterns — Experimental,€$§£;7 PhgoLoLo, ,. , ”kw—.-Wn J Greenblatt, M and Solomon, H C Autonomic nervous Nehvo MenM 0L6 system changes following electric shock treatment :yatt77M Ho, [1988,L108: 1109422, FUnkenstein, DOH a, J Greenblatt, Solomon, M and paralleling psychologic changes in mentally 1 ill H C Autonomic changes patients 5:T Neav Mani.”’fi . 1951. 011%“ 18,.I Funkenstein, DQH o, Greenblatt, Mo and Solomon, Ho Co Autonomic nervous system test of prognostic si ificance in relation to electroshock Made, {Pbychozsomo treatmento 13: 1952, 3u7—3629” {as 1__1___~u Gal, E0 M8 Cholinesterase activity of who blood from healthy and Sohizophrenic individuals° (Natune" 1963. 19821118-1119> WW (M) ) \9=*" , 5 6%-,“ V �and Pepeu, Go Drug-induced changes in brain acetylcholineo Jo Phanmac0£o," [meg/1&1: 226—2311, 5 Qiarman, (But, J M, o Signi ficance of individual variability in Home, :19574 fig, 229-21104; electroshocko NJ, Green, A, MD Hampscn, w Jo wae " Essig, Co 1:1, ((muuw; and McCauley, f luorophosphate Himwich, A0 EEG response to Effects of H9 Ea electroencephalogram and cholinesterase asvivityo_(Ekectaoencepho Ciino Neuhophybio£0,f1950, g; ulgug> / div-isop‘ropyl (DFP) on Hinwich, Ho E0, Essig, Co Po, X-Iampson, Jo Lo, Bales, Po Do and Freedman, AU Mo Effect of trimetnadione (Tridione) and other drugs on convulsions caused by di—isopropyl fluorophosphate (DFP) Amen. J. R\“”” ““1950,‘1062 816-829) o * fM W . ” ”rm Lo and Lechner, Ho The effect of Diparcol on the electroencephalogram Jenkner, and in those with cerebral trauma, E£eot2wenceph. can. in the normal 1E"o flax iwx subject /”Neun0phy4£o£o,{1955,LZE 303-6053 1M, Johnson, Ulett, Co, Lu J “3 '7 - A0, Johnson, Go Smith, MD, K0 and Sines, Jo Electroconvulsive therapy (with and without atropine); effect on electronically analyzed electroencephalogram Allah, Geno Pbychj. 1/ WM"' Kabat, E0 A0, Glusman, 0%., 0/ > and Knaub, V0 Quantitative estimation of the albumin and gamma globulin in normal and atholo ic cerebrospinal fluid by immunochemical methodso Wells 10 Mada, [194845;E 653—66253 ‘ “NW Mo / brain of the content Acetylcholine ’ Hung, if E53,: 13; 1—H >J 1;::11 t I44wéhjié. humorale Ubertragbarkeit der Herznervenwirkungo Fonyo, A0 and Halmagyi' in traumatic shocko (Aota Pkg/31.0 Kovach, A, Ga Bo , Mo ,1 ‘\ ’ ‘ _ , §’ Loewi, Anch, O.) 55 Maynert, Ube fits, E0 W; Ho and Buck, 1319: 239-292, Effects of Eo Go onacetylcholine synthesfigofjo Phwumcoz, Nachmansohn, specificity Plum, (cum /. f; I, iflw 0‘ depressants on brain . convuls and narcotic drugd/ Expo ThULo, 1951, 103:_ 35,5433 { and Rothenberg, M, A, Studies on cholinesterase: on of enzymes in nerve tissueo (J. Mob Chmo,ffgu5.} _]_._5_8: 653—666“; Do Study of cholinesterase Chemo, 1960; pg: 332-390, Co Mo activity in nervous Serum cholinesterase activity in mental >M195 , } and mental disorders. R Ravin, H, A, and Altschule, Mo Do diseaseo /AItho Newwfic Pbychiaxo a CDNIOSO thacolagi£t,, 1961+, g; 191, and Elliott, K A 9C, Effects; "adetylcholineo Mcbennan, Phybiozo, 1921, . §§: 616-650) �1 Richter, D and Cmssland, J Variation in acetylcho ine content of the Phybioio, 19891159: 2887— 255 a, brain with physiological stateo /Ame8)L88 J 0 M Richter, D and Mo leeI 838 £882,188821 than yfI8828188 ,J’ "T“. <72: D and Lee, 1- Rose , MD 835~83gfj The , W. Ment. 306,8“, 0/1,” 0\ Serum choline esterase and depresmon. 13° Mani. Soc.) f“‘p‘. . 7, Punkenstein est-57K review of the &;8§dand P3ym ,j19625138 , o esterase and anxietyc J. Serum choline (,4 128—153, / ”W i literature. Aota ». in the EEG under barbiturate anaesthesia produced by electroa-convulsive treatment and their significance for the theory of Roth, M Changes C228. action fEZectaoenceph ECT Roth, Ma, Kay, D W Ko , Shaw, ) W28” NeuhophyéLOKO,[1951,[__w261—280 J J and Green, Prognosis and fiPentothal induced electroencephalographic changes in electroyzonvulsive treatment .. Efiemoenceph can NewzophyA/ZOLO, 8f‘1957.;___9: 225- 237 7’ A S [/80 ofd1d1opmpyl——° i and Wilson, A, The effects aflcorophosphonate in schizophrenic-1and manic depre sive psychosis. Newwz NQMOAU/tgo Paychiwto, 1950.313: 87-62, Romtree, D J Rubln, ° We, Nev1n, ° ° WW“ Acetylcholine hydrolysis in psychiatric patients Lo So /.1958,,Ll2___8258-25858) 7 7; /1881, ‘~‘ : 8 .x' )1 Spiegel, E A and Spiegel—Adolf, M Physioochemical effects of electrically induced convulsions (cerebrospinal fluid studies) K Titan/.5 Ame/r.° NewwL AM., 81888.70: 130132 @1111): Spiegel, E A and Spiegel-Adolf, M Physiological and physicochemical mechanisms in electroshock treatment Canéin Weuhoz [195’‘13, 38-63/ A changes Go M and Spiegel—Adolf, Spiegel, E Physicochemical Henry, in the brain accompanying electrically induced convulsive discharges W/TW Spiegel-Adolf, Arnuo ,____ Newwz MAM/Tmfififi: 81783811 ,Wilcox, P H and Spiegel, E changes in electroshock treatment of psychoses 1988, gg_; 697 706); Stwone W E 90] Pkg/8 Amm M A. Cerebrospinal fluid Amen. J Paych/éaio, o role of acetylcholine in brain metabolism and functiom Med ,f19'7'; 3‘6: 222——255>/ The m._._ . ’1qu ,,,,, ~ '~'" - if! 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. Assay methods for cholinesterase. In Glick, D., ed. Methods Bioof Chemical Analysis, vol. 5, 1—63. Interpp. science Publishers, New York, 1957. 6. Bernstein, M. D. Presence and action of acetylcholine in experimental brain trauma. J. neurophysiol., 9: 349—366, 1946. 7. BFe'hner, C. and Merritt, H. H. Effect of certain choline derivatives on electrical of the cortex. A.M.A. Arch. Neurol. activity Psychiat., 48: 382—395, 1942. 8. Burgen, A. S. V. and MacIntosh, F. C. The physiological significance of acetylcholine. In Elliot, K. A. C., Page, I. H. and Quastel, J. H., eds. Nem‘ochemistry, pp. 374—375. Thomas, Springfield, Illinois, 1955. l l l | �SET aumscmi-Z MAY 24 1966 EG—K 5 %E-NMD-Mar 5/20-5Fx Gal 6131 p. 7 5-20-66 640 9. Chatfleld, P. O. 9 (4) and Dempsey, E. W. Effects of prostigmine and acetylcholine potentials. Amer. J. Physiol., 135:on cortical 633—640, 1942. 10. Cone, W. V., Tower, D. B. and Acetylcholine and neuronal McEachern, D. activity in epilepsy. 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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). Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-003-0-004 Date A point or period of time associated with an event in the lifecycle of the resource 1956-1969 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 <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