http://exhibits.library.stonybrook.edu/mfp/files/original/ab4087755279fc01b94c0135ed348fc4.pdf b42318ee79fcb2ebd0a6f398dbb0a0b0 PDF Text Text EFFECT OF ANTICHOLINERGIC COMPOUNDS (IN POST CONVULSIVE ELECTROENCEPHALIIGRAM AND BEHAVIOR 0F PSYCHIATRIC PATIENTS MAX FINK, M.D. Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L.I., N.Y. Reprinted from "Electrrrrrephalography and Clinical Neurophysiology Ioumal" Vol. 12, No.2, May 1960. �EFFECT OF ANTICHOLINERGIC COMPOUNDS ON POST CONVULSIVE ELECTROENCEPHALOGRAM AND BEHAVIOR OF PSYCHIATRIC PATIENTS 1 MAX FINK, M.D. Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L.I., N.Y. (Received for publication: March 11, 1959) Demonstrations of the significance of high voltage EEG delta activity in the convulsive therapy process (Roth et al. 1951, 1957; Fink and Kahn 1957) and the report that this delta activity was blocked by the administration of atropine and scopolamine (Ulett and Johnson 1957) provided the basis for these studies. As there were attendant unpleasant systemic effects with the administration of these agents, reports describing diethazine as an antieholinergic compound with potent neurologic but minimal systemic effects (J enkner and Lechner 1955; Lechner 1956) led us to undertake studies similar to those of Ulett and Johnson using this compound (Fink 1958). Observa— tions with diethazine led to the investigation of other experimental anticholinergic agents. This report describes clinical and electroencephalographic observations incident to the intravenous administration of various anticholinergic agents in psychiatric patients at various stages of convulsive therapy and relates the observations to hypotheses concern— ing the mode of action of convulsive therapy and of hallucinogens. Patients have been observed at various stages of the treatment process. The observations were made in the EEG laboratory, using a standard 8 channel EEG recorder and needle electrodes applied in 17 lead placements following Strauss et al. (1952). In each trial, the compound under study was administered intravenously at a set rate per minute until clinical behavior or electrographic changes were observed. The compounds studied have been dietha— zine (Heymans et al. 1949), Win-2299 (Pennes and Hoch 1957), benactyzine (Jacobson 1955), JB-318 and JB-336 (Abood et all. 1958) and atropine. Diethazine was administered at 25 mg. per minute for a total of 175-250 mg. (2.5-5.0 mg/kg.) ; Win-2299 and benactyzine at 0.5 mg. per minute for 2 to 5 mg. (0.02-0.15 mg/kg.) ; and JB-318, JB-336, and atropine at 0.4 mg. per minute for 1.2 to 4.0 mg. (0.01-0.10 mg/kg.). OBSERVATIONS (a) Diethazine. The administration of diethazine in 15 patients prior to convulsive resulted in a decrease in EEG volttherapy SUBJECTS AND METHOD ages an-d a desynchronization of all freThe subjects were 90 psychiatric patients quencies. Prevailing rhythmic patterns bereferred for convulsive therapy. Ages ranged came less pronounced. In some instances, symfrom 18 to 67 years, and diagnoses included metric low voltage 6—7 c/sec. activity appeared schizophrenic reactions and manic-depressive and was most apparent in frontal and anterior and involutional-depressive psychoses. A va— temporal leads (Fink 1958). ried number of subjects were studied for each In 25 patients with varying degrees of induced high voltage delta activity during compound for a total of 107 observations. convulsive therapy (Fink and Kahn 1957), 1Aided, in part, by grants M-927 and MY-2092 there was a significant decrease in voltage and of the National Institute of Mental Health, National in per cent time of slow wave activity. From Institutes of Health, US. Public Health Service. 45 of in frontothe delta cent an average per Atlantic Read at the American EEG Society, occipital leads, there was a reduction to a City, June, 1958. [359] . �MAX FINK 360 mean of 20 per cent. Both random and burst delta activity diminished. Low voltage alpha and beta frequencies became more prominent. The usual increase in per cent time and in voltage of slow wave activity with hyperventilation was no longer apparent. These electrographic effects appeared during drug administration and persisted for 1 to 5 hours (Fink 1958). Concurrent with these electrographic effects, we observed distinctive systemic and complaints of abdominal griping. Such effects were generally less prominent than the electrographic or behavioral. Behaviorally, patients became irritable, restless, tense and excited, and it was difficult to maintain eyelid closure. They complained of feelings of unreality and of tingling, weakness and heaviness of the extremities. Complaints that colors were pale or more intense, halos about lights and changing shadows were accompanied by delusional thoughts about W W W mm W W W W W W W W W W WWWW PRE-DRUG LF-LO WWW/(WWW RF—RO + 40 MINS. AFTER 3.2 mg. WM + 80 MINS. wwwwvuwwmm WWWM wwwmmmw LAT-LF MAM-«Mm RAT-RF LF-RF LPT-LO 0-0 RPT'RO SouVLlsfi- #2016 HH Fig.1 Effect of i.v. Win-2299. Note desynchronization of frequencies after behavioral changes. The initial systemic effects were episodes of coughing and complaints of dryness of the mouth. Skin remained dry and the heart rate increased by 5 to 10 per cent. This increase was rarely noted by the subject, and was not accompanied by precordial distress. There was no change in pupillary size, and constriction in response to light was prompt. There were occasional 3.2 mg. (Female, age 41). their illness, the setting of the test procedure or the examiner ’s identity. (1)) Win-2299. The report by Pennes and Hoch (1957) that Win-2299 induced illusory and hallucinatory states in man, led to this next study. On intravenous administration of Win-2299, both electrographic and behavioral effects similar to diethazine were observed. In 5 patients without EEG slow wave �ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG activity, desynchronization of frequencies and a decrease in voltages were noted in four (fig. 1). In 11 patients with high voltage delta activity there was a decrease in amplitude and per cent time of slow wave activity with an increase in the per cent time of alpha and beta frequencies. The mean delta activity dropped from 50 to 23 per cent (fig. 2). Associated with these electrographic effects were clinical patterns of restlessness and excitement, and minimal systemic effects. PaPRE-DRUG 361 rate was unaffected except in patients who became. overtly excited and fearful, in whom tachycardia appeared during this excitement period. Dryness of the mouth was reported only on direct inquiry. (c) Benactyzine. Reports that benactyzine induced EEG desynchronization (Coady and Jewesbury 1956), its anticholinergic nature, and the structural similarity to diethazine and to Win-2299 led to our testing of this compound. Intravenous administration in 12 subjects elicited similar clinical and + 40 MINS. AFTER 2.0 mg. + 60 MINS. LF-LO W WW W” W WW W WWWW Wm Wm M W MW RF- R0 Wm WM RAT-RF WWW WNW LPT-LO 0-0 RPT-RO 50ml I SEC. # 1977 HH Fig. 2 Effect of i.v. Win-2299 on post—convulsive delta activity. Record taken 24 hours after convulsion #8. Note desynchronization of frequencies and persistence after 2.0 mg. (Female, age 51). tients became fearful and tense. Visual illusory sensations were reported and were associated in these subjects with delusional elaborations about their hospital experience. Excitement was accompanied by ideas of reference, and in two subjects, intravenous chlorpromazine was administered to halt this process. These behavioral changes appeared during drug administration or within 10 min, and disappeared within 2 to 3 hours. Systemic effects were slight. There were neither cough nor respiratory distress. Heart electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, desynchronization was prompt. Delta activity decreased from a mean time of 39 to 16 per cent in 8 subjects (fig. 3, 4). These electrographic patterns were again accompanied by clinical restlessness, irritability and excitement. Artifact-free recording was more difficult. The illusory sensations and delusional thoughts seen with the initial compounds were not noted at these dosage �MAX FIN K 362 levels. Systemic effects were similar to Win2299. activity and clinical somnolence, we administered this anticholinergic agent intravenously in 15 subjects, in dosages of 0.8 to 4.0 mg. (.01-.10 mg/kg.). In 6 subjects without EEG delta activity, there were no changes in EEG pattern during drug administration nor for 10-20 min. thereafter. During a period of lassitu-de, decreased voltages, minimal desynchronization, and an increase in per cent time delta were noted. In subjects with delta activity, there was (d) Piperidylbenzilates. Following recent reports by Abood et al. (1958) that various piperidylbenzilates with measurable anticholinergic activity induced hallucinations in psychiatric subjects, we tested JB-318 and JB— 336 in 24 subjects. The electrographic patterns were identical with the other experimental anticholinergic compounds. Desynchronization of frequencies was noted during W W W W WM W W W WWW WWW WW PRE-DRUG LF-LO + 30 l0 MINS. AFTER |.5 + 50 MINS. MINS. mg. RF-RO LAT-LF RAT-RF LFTRF .. LPT-LO .. "A“... WWW/w WWW/WW 0'0 RPT-RO WM 50ml— WNWMNW‘AMAM. I Fig. SEC. WWW # |922 HH 3 Efftct of i.v. benactyzine. Note persistent decrease in voltages and desynchronization after 1.5 mg. (Female, age 34). the injection or within 15 min. and persisted for one to 4 hours (fig. 5). In each instance in which desynchronization was observed, clinical restlessness, excitement, illusory and hallucinatory activity were noted, and were concurrent with the electrographic changes. In two instances the behavioral changes were halted by the intravenous administration of chlorpromazine. (e) Atropine. Considering the numerous reports that atropine induced EEG slow wave an apparent initial decrease in voltage and per cent time of such activity during the first 10 min. after administration, followed by a return to original values during the period of quietude. In neither period were the changes significant (fig. 6). Systemic effects were prominent during the injection with increased respiratory rate, pallor, dry skin and dry mouth, precordial complaints and an increase in heart rate up to 100 per cent. Subjects became restless and �ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG recording became difficult. Within 10 min. these symptoms subsided and the subjects became drowsy and relaxed. 363 atropine under similar experimental condi- tions. These observations can be related to theories of the mode of action of convulsive DISCUSSION therapy; to concepts of the basis of experIn these studies, various experimental imentally induce-d hallucinations; and to recompounds with measurable anticholinergic ports of the effects of atropine on EEG patactivity have been observed to have similar terns. electrographic and behavioral effects. Elec(a) Convulsive therapy process. Earlier trographically, each agent induced a desyn- studies indicated that the development of high PRE-DRUG LF-LO RF-RO LAT-LF W + l0 2 MINS.AFTER MINS. |.5 mg. M +50 MINS. WW Wm «MW—MAW .AWNV'VW W W W WM W W W WW WW RAT-RF LF-RF LPT-LO Wm MWM'W 0-0 WWW/v RPT-RO WW4{)0qu #ZOIB HH Fig.4 Effect of i.v. benactyzine on post-convulsive delta activity. Record taken 24 hours after convulsion # 7. Note desynchronization of frequencies after 1.5 mg. (Female, age 33). chronization of frequencies and a decrease in voltages, which was most prominent in subjects with delta activity following convulsive therapy. Behaviorally, these electrographic patterns were associated with stimulating, excitatory, illusory and hallucinatory activity. To a lesser degree, minimal systemic changes in heart rate, salivation and sweating were noted. These latter systemic effects were more prominent in patients given intravenous voltage slow wave activity was a neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement (Fink and Kahn 1957). In summarizing the observations of numerous authors on the relation of acetylcholine metabolism to trauma of the central nervous system and to convulsions (Fink 1958) it was suggested that a biochemical concomitant of the induced EEG slow �MAX FINK 364 WWW WWVWWWW PRE-DRUG LF-LO AFTER 2.4 MG.IV l0 MINUTES AFTER WWW mm WWW WWW W W WWW W PR=|08 PR=96 .18 318- N-ETHYL, 3-PIPERIDYLBENZILATE PR=84 SOuvL—_ # 2|50 HH ISEC. Fig. 5 Effect of JB-318 on post-convulsive delta activity. Record taken 24 hours after convulsion #9. Note desynchronization of frequencies, decreased voltages after 2.4 mg. Cardiac rate shows 10 per cent increase. (Female, age 27). Similar records observed with PRE- DRUG JB—336. AFTER 2.0 MG. IV AFTER 30 MINUTES LAT-LF # 2|90HH HR=78 HR=|50 Fig. 50va__ l 6 SEC. Effect of small doses of i.v. atropine on post-convulsive delta activity. Record taken 24 hours after convulsion #6. Note minimal effect on delta activity and associated increase in heart 2.0 mg., 025 mg/kg.) rate, with persistence. (Male, age 18. Atropine : �ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG wave activity was an increase-d level of acetylcholine-cholinesterase activity of the central nervous system. The present observations of alterations in the slow wave activity of convulsive therapy by these experimental anticholinergic compounds are consistent with this suggestion. That the problem is more complex is indicated by reports of compounds with other biochemical activity also affecting slow wave activity in a similar fashion. Amphetamine (Lennox et al. 1951), Mescaline (Merlis and Hunter 1955; Denber 1955), lysergic acid diethylamide (Bente et al. 1957 a, b) and diphenhydramine (Diaz—Guerrero ct al. 1956) also reduce-d post-convulsive slow wave activity. In these reports, such a reduction was accompanied by excitatory and stimulating effects on behavior. These compounds, how— ever, are primarily sympathomimetic and antihistaminic in pharmacologic activity and not anticholinergic. The similar effects of these diverse biochemical agents on electrographic patterns and on clinical behavior may be considered within theoretic constructs of the relation of synaptic activity to behavior as expressed by Marazzi (1953, 1957), Bradley and Elkes (1957), Evarts (1958 a, b), Sherwood (1958) and Woolley (1958). These authors suggest that two types of interacting chemoresponsive receptors exist within the nervous system which are selectively responsive to cholinergic or to adrenergic agents. Where such receptors exist, they exert opposing stimulatory or inhibitory action. Thus, repeated induced convulsions may lead to a change in synaptic cholinergic activity, reflected in surface electrodes as high voltage slow wave activity. Administration of anticholinergic agents may alter synaptic activity, resulting in a decrease in the manifest cortical electrical activity to preconvulsive levels. Administration of sympathomimetic agents may achieve the same electrical effects by increasing the level of adrenergic activity. The manifest slow wave activity, so prominent and so persistent in the post-seizure EEG, may thus be viewed as resulting from a persistent alteration in the synaptic activity of large numbers of cells of the central nervous 365 system. The delicate nature of this balance is seen in the ready reversibility with alerting, time, and the wide variety of pharmacologic agents noted here. While an alteration in synaptic activity may underlie the behavioral changes in convulsive therapy, the mechanism by which such alteration is developed or sustained is unclear. The observation by Aird et al. (1956 a, b, 1958), that an increase in permeability of the blood brain barrier followed repeated induced convulsions suggests one way in which synaptic changes may be mediated. The consistent nature of these neurophysiologic observations makes an exclusively psychologic explanation of the mode of action of convulsive therapy less tenable. These studies are consistent, however, with the neurophysiologic-adaptive view of the convulsive therapy process which suggests that neurophysiologic changes provide the substrate for alterations in all aspects of the subject’s clinical behavior; the type of behavioral alteration being dependent upon the type and degree of neurophysiologic change, the personality of the subject and the expectations and tolerance of the milieu (Weinstein and Kahn 1955; Fink and Kahn 1957; Fink 1957). (b) Neurophysiology of hallucinogenic activity. The effects of anticholinergic compounds-on EEG and behavior may also be related to the understanding of experimental hallucinogenic activity. Each of these experimental compounds induced excitatory behavior, including illusory and hallucinatory phenomena. Here, too, a synaptic model may be applicable. Sympathomimetic agents, as Mescaline, LSD and amphetamine, and anticholinergic agents as those described here, are also potent hallucinogens. A neuropharmacologic basis for such behavior may be characterized as an alteration in the level of synaptic activity in the direction of increased inhibition (decreased transmission) of stimuli. The clinical efficacy of convulsive therapy in modifying hallucinatory activity may lie in alterations at this neurophysiologic level. The effects of such hallucinogenic blocking agents as chlorpromazine and Reserpine on EEG electrical activity are consistent with such a view. Both compounds induce EEG �366 MAX FINK hypersynchrony in man (Bente and Itil 1954, 1958) and block the EEG desynchronization effects of LSD and Mescaline (Schwartz ct al. 1955). Chlorpromazine was found equally potent in aborting the excitatory activity of the experimental anticholinergic compounds in these studies. (0) Relation to atropine. Comparison of the systemic and neurologic effects of experimental anticholinergic compounds with atropine reveals differences in initial focus of action. Experience with atropine at physiologic and toxic levels in man indicate that the predominant effects are focused at peripheral nervous structures. Initial bradycardia, followed by tachycardia, loss of sweating and salivation, pupillary dilation, intestinal relaxation and decreased motility are amongst the effects at low (0.2-1.2 mg.) dosages. At higher dosages (2-5 mg), the neurologic effects of ataxia, irritability, disorientation, and delirium are observed (Goodman and Gilman 1955). In contrast, the experimental anticholinergic agents in dosages sufficient for central nervous system effects manifest little peripheral activity. The central effects are observed early and may continue for extensive the dosage of atropine varied from 0.5 to 7 mg/ kg. — a range roughly comparable to the dosages used in atropine coma therapy (Forrer and Miller 1958) . In the present studies, the EEG effects of low dosages of intravenous atropine (0.01 to 0.10 mg/kg.) were minimal and systemic effects considerable, confirming similar observations by Verdeaux and Marty (1954) and by Danielopolu et al. (1955). The slow wave activity so prominent in animals and man at high dosages of atropine, may not be a manifestation of the initial or direct effects of atropine, but a reflection of a more widespread alteration in body physiology. Thus, while considerable speculation as to central neurophysiology has been based on studies with atropine, such observations provide a special case of anticholinergic effects. The anticholinergic activity established in observations in vitro and in the peripheral nervous system, may not be the effective physiologic activity in the large doses necessary to affect central structures. The experimental compounds, however, provide more suitable agents for the study of central neurophysiologic (anticholinergic) patterns than atropine, as, for example, in a re-evaluation of the studies of craniocerebral trauma and epilepsy. Ward’s (1950) reports of the efficacy of high doses of atropine in altering the clinical manifestations of head trauma indicated that effective doses brought with them severe systemic effects. The failure of atropine and scopolamine to affect epilepsy may be related to the inability of these compounds to reach the central nervous system in adequate quantity. It would seem advisable, therefore, to repeat these studies utilizing such more centrally active anticholinergic compounds as used in the experiments reported here. periods without gastrointestinal, cardiac or pupillary changes. It is within the context of the focus of activity in relation to dosage that the apparent discrepant EEG observations of the effects of atropine (in inducing slow wave activity) and these experimental anticholinergic compounds may be reconciled. Wescoe et al. (1948) administering 1.0 to 3.0 mg/kg. atropine in curarized cats and monkeys and Fun— derburk and Case (1951) using 0.4 to 1.2 mg/ kg. in curarized cats, observed high voltage EEG slow wave activity. Wikler (1952, 1957) reported that 7.2 mg/kg. atropine on SUMMARY unanesthetized, uncurarized dogs produced 1. Experimental anticholinergic comslow similar to wave” sleep. “spindle patterns Rinaldi and Himwich (1955 a, b) reported pounds (diethazine, Win-2299, benactyzine, JB-318 and administered to JB-336), psy0.5 2.0 of doses to that atropine in mg/kg. chiatric patients at various stages of convulin curarized rabbits exaggerated EEG sleep sive associated with: therapy, were of the inhibited and the alerting patterns EEG to peripheral stimuli. Similar observa- (a) desynchronization of EEG rhythms with tions have been reported by Bradley and Elkes a blocking of post-convulsive delta activ(1953) in the conscious cat. In each instance ity ; �ANTICHOLINERGIO COMPOUNDS AND POST CONVULSIVE EEG 367 (a) des effets systémiques de faiblesse musculaire, sécheresse buccale, sécheresse cutanée et tachycardie. Les effets de comportement, électrographiques et systémiques étaient concurrents. 2. Ces observations sont consistentes avec The electrographic, behavioral and systemic la suggestion qu’un concomittant neurophysiologique de la thérapie convulsive soit l’augeffects were concurrent. 2. These observations are consistent with mentation de l’activité cholinergique du systéme nerveux central. the suggestion that a neurophysiologic conco3. Des observations sur le fait que le LSD, mitant of convulsive therapy is an increase in central nervous system cholinergic activity. l’amphétamine, 1e Mescaline, et le diphenhy3. Observations that LSD, amphetamine, dramine — agents sympathicomimétiques et Mescaline and diphenhydramine —- sympatho- antihistaminiques — induisent également une mimetic and antihistaminic agents — also in— désynchronisation EEG, le blocage de l’acti— duce EEG desynchronization, blocking of vité delta post-convulsive et l’activité clinique post convulsive delta activity and clinical excitatoire, soutiennent la suggestion que des excitatory activity support the suggestion that variations de comportement et electrographibehavioral and electrographic patterns may ques puissent étre basées sur des alterations be based on alterations in synaptic activity. de l’activité synaptique. On suggere que l’acIt is suggested that increased synaptic activ- tivité synaptique augmentée (effets cholinerity (cholinergic, sympatholytic effects) is giques, sympatholytiques) soit associée a l’hyassociated with EEG hypersynchronization, persynchronisation EEG, la sé-dation clinique and clinical sedation and euphoria; while de- et l’euphorie; tandis que l’activité synaptique creased synaptic activity (anticholinergic, diminuée (anticholinergique, sympathomimesympathomimetic) is associated with EEG tique) soit associée a la désynchronisation desynchronization and clinical excitatory and EEG et des états cliniques excitatoires et hallucinogéniques. hallucinogenic states. 4. Des observations contradictoires avec 4. Discrepant observations with atropine are related to significant differences in dosage. atropine sont en relation avec des differences Re-assessment of the role of anticholinergic signifi'catives de dosage. Une reevaluation du role d’agents anticholinergiques dans les trau— is seizure and in head states trauma agents matismes craniens et les états comitiauX semsuggested. 5. These observations amplify the neuro- ble étre indiquée. 5. Ces observations amplifient l’hypothese physiologic-adaptive hypothesis of the mode of action of convulsive therapy and of exper- neurophysiologique-adaptive du mode 01 ’action de la thérapie convulsivante et des états halluimental hallucinogenic states. cinogenes expérimentaux. (b) alerting, excitatory behavioral response with illusory, delusional and hallucinatory i-deation; and, (a) systemic effects of muscular weakness, dryness of the mouth, dry skin and tachycardia. RESUME Des composés anticholinergiques eXpérimentauX (diethazine, Win-2299, benactyzine, JB-318 et J 13-336), administrés a des patients psychiatriques a des étapes différentes d’une thérapie convulsivante, étaient associés avec: ZUSAMMENFASSUNG 1. (a) une désynchronisation des rythmes EEG, avec un blocage de l’activité delta postconvulsive; (b) une réponse de comportement excitatoire, vigilante, avec de l’idéation illusoire, délusionnelle et hallucinatoire, et Mischungen von experimentellen anticholinergischen Stoffen (Diethazine, Win2299, Benactyzine, JB-318 und J 13-336) wurden psychiatrischen Patienten verabreicht welche sich in verschiedenen Stadien der konvulsiven Therapie befanden. Hierbei wurde folgendes beobachtet: 1. (a) Eine Desynchronisierung der EEGRhythmen mit Blockierung der postkonvulsiven Delta-Aktivit'at. �MAX FINK 368 (b) Eine Weckreaktion mit erregtem Benehmen, welches mit Illusionen, Halluzinationen und Wahnideen einherging. (c) Allgemeineffekte charakterisiert durch Muskelschwache, Trockenheit des Mundes und der Haut und Tachykar-die. Die elektrographischen- und Allgemeineffekte, sowie die Veranderungen des Benehmens erfolgten gleichzeitig. 2. Diese Beobachtungen stehen nicht in Konflikt mit der Theorie, wonach eine Erhahung der cholinergischen Aktivit'at im zentralen Nervensystem eine neurophysiologische Folgeerscheinung der konvulsiven Therapie darstellt. 3. Die Beobachtungen, dass LSD, Amphetamin, Meskalin und Diphenhydramin sympathomimetische und antihistaminische Stoffe —— ebenfalls die EEG-Desynchronisation herbeifiihren, die postkonvulsive DeltaAktivitat blockieren und die klinische Erregtheit dampfen, unterstiitzen die Annahme, dass elektrographische Veranderungen sowie solche des Benehmens auf Anderungen der synaptischen Aktivit'at zuriickgefiirt werden konnen. Es Wird angenommen, dass eine erh'ohte synaptische Aktivitat (cholinergische, sympathikolytische Effekte) assoziiert ist mit Hypersynchronisierung des EEG’s, mit klinischer Sedation und Euphorie, W'ahrenddem eine verminderte synaptische Aktivit'at (anticholinergische, sympathikomimetische Effekte) assoziiert ist mit Desynchronisierung des EEG und mit klinischen halluzinatorischen Erregungszustanden. 4. Abweichende Beobachtungen mit Atropin stehen mit signifikanten Differenzen in der Dosierung in Beziehung. Die Rolle, welche anticholinergische Stoffe bei Kopftrauma und Anfallszust'anden spielen, sollte erneut in Betracht gezogen werden. 5. Diese Beobachtungen unterstiitzen die neurophysiologische Hypothese fiber die Aktionsart der konvulsiven Therapie und der experimentellen halluzinatorischen Zust'ande. I am grateful for the technical assistance of Mrs. Hannah Mosquera in EEG recording and analyses. Supplies of the various pharmaceuticals were made freely available by Lakeside Laboratories (JB318 and JB—336), Merck Sharpe &Dohme (benactyzine), Sandoz Pharmaceuticals (LSD-25), SterlingWinthrop (Win-2299) and Smith, Kline and French Laboratories (diethazine, chlorpromazine). REFERENCES ABOOD, L. G., OSTFELD, A. M. and BIEL, J. A new group of psychotomimetic agents. Proc. Soc. Exper. Biol. Med., 1958, 97: 483—486. AIRD, R. B. Clinical correlates of electroshock therapy. A.M.A. Arch. Neural. Psychiat, 1958, 79: 633- 639. AIRD, R. B., STRAIT, L. A., PACE, J. W., HRENOFF, M. K. and B‘OWDITCH, S. Neurophysiologic effects of electrically induced convulsions. A.M.A. Arch. Neurol. Psychiat., 1956, ’75: 371-378. BENTE, D. und ITIL, T. Zur Wirkung des Phenothiazinkorpers Megaphen auf das Menschliche Hirnstrombild. Arzneimittelfarschg, 1954, 7: 418-423. BENTE, D. and ITIL, T. A comparison of the action of various phenothiazine compounds on the human EEG. Trans. Int. Gang. of Neurapsychopharm., 1958 (in press). BENTE, D., ITIL, T. and SCHMID, E, E. Electroencephalographic studies concerning the action of LSD-25. EEG Clin. Neurophysiol, 1957, 9: 359. und SCHMID, E. E. Elektroencephalographische Studien zur Wirkungsweise des LSD-25. Psychiat. Neural, 1958, 135: 273- BENTE, D., ITIL, T. 284. P. B. and ELKES, J. The effect of atropine, hyoscyamine, physostigmine and neostigmine on the electrical activity of the brain of the conscious cat. J. Physiol, 1953, 1.90: 14-15. BRADLEY, P. B. and ELKES, J. The effects of some drugs on the electrical activity of the brain. Brain, 1957, 80: 77-117. COADY, A. and JEWESBURY, E. C. A clinical trial of benactyzine hydrochloride (“Suavitil”) as a physical relaxant. Brit. Med. J0ur., 1956, 1: BRADLEY, 485-487. D., GIURGEA, C. and DROCON, G. Electroencephalographic study of the non-specific pharmacodynamics of the stimulatory effect of atropine on the cerebral cortex. Fizialagicheskiy DANIELOPOLU, Zhurnal SSSR, 1955, 41: 601—611. DENBER, H. C. B. Studies on Mescaline: III. Action in epileptics. Psychiat. Quart, 1955, 29: 433-438. DiAz-GUERRERO, R., FEINSTEIN, R. and GOTTLIEB, J. S. EEG findings following intravenous injection of diphenhydramine hydrochloride (Benadrylr). EEG Clin. Neurophysiol, 1956, 8: 299306. E. V. Neurophysiological correlates of pharmacologically induced behavioral disturbances. Res. Publ. Ass. nerv. ment. Dis., 1958, 36: EVARTS, 347-380. EVARTS, E. V. Chemical bases for psychoses. Chem‘ ical Concepts of Psychases. McDowell, Oblensky Inc., N.Y., 1958, pp. 41-62. FINK, M. A unified theory of the action of physio- dynamic therapies. J. Hillside Hosp, 1957, 6: 197-206. �ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG FINK, M. Effect of anticholinergic agent, diethazine, on EEG and behavior: Significance for theory of convulsive therapy. A.M.A. Arch. Neural. Psychiat., 1958, 80: 380-387; and Biological Psychiatry, ed. J. Masserman, Grune & Stratton N.Y., 1959, 184-194. FINK, M. and KAHN, R. L. Relation of electroenceph- alographic delta activity to behavioral response in electroshock. A.M.A. Arch. Neural. Psychiat, 1957, 78: 516-525. FORRER, G. and MILLER, J. J. Atropine coma: A somatic therapy in psychiatry. Amer. J. Psy- chiat., 1958, 115: 455-458. FUNDERBURK, W. H. and CASE, T. J. The effect of atropine on cortical potentials. EEG Olin. N enraphysial., 1951, 3: 213-223. GOODMAN, L. S. and GILMAN, A. Pharmacological Basis of Therapeutics. MacMillan, N.Y., 1955. HEYMANS, C., ESTABLE, J. J. et DE BONNEVEAUX, S. C. Sur la pharmacologie de la phenothiazinylethyldiethylamine (2987 RR). Arch. Int. Pharmacadyn., 1949, 7.9: 123-138. JACOBS'ON, E. Suavitil, et nyt stof med specifik virkning pa centralnervesystemet. Ugeslcrift for Laeger, 1955, 117: 1147-1151. JENKNER, F. L. and LECHNER, H. The effect of Diparcol on the electroencephalogram in the nor— mal subject and in those with cerebral trauma. EEG Olin. Neurophysiol, 1955, 7: 303-305. LECHNER, H. On the influence of anticholinergic drugs on the EEG of recent closed cranicerebral injuries. EEG Olin. Neurophysiol., 1956, 8: 714715. and GUTERMAN, B. The effect of benzedrine on the post-electroshock EEG. EEG Olin. Neurophysiol, 1951, 3: 63-69. MARAZZI, A. S. Some indications of cerebral humoral mechanisms. Science, 1953, 118: 367-370. MARAZZI, A. S. Effects of psychotomimetic drugs on cerebral synapses. Psychotropic Drugs. Elsevier, Amsterdam, 1957, 283-284. MERLIS, S. and HUNTER, V. Studies on Mescaline: II. Electroencephalogram in schizophrenics. Psychiat. Quart, 1955, 29: 430-432. PENNES, H. H. and HOCH, P. H. Psychotomimetics, clinical and theoretical considerations: Harmine, Win-2299 and Nalline. Amer. J. Psychiat, 1957, LENNOX, M. A., RUCH, T. C. 113: 887-892. 369 F. and HIMWICH, H. E. Alerting responses and actions of atropine and cholinergic drugs. A.M.A. Arch. Neural. Psychiat., 1955, 73: 387- RINALDI, 395. F. and HIMWICH, H. E. Cholinergic mechanism involved in function of mesodiencephalic activating system. A.M.A. Arch. Neural. Psychiat., 1955, 73: 396-402. ROTH. M. Changes in the EEG under barbiturate anesthesia produced by electro-convulsive treatment and their significance for the theory of ECT action. EEG Olin. Neuraphysial., 1951, 3: RINALDI, 261-280. ROTH, M., KAY, D. W. K., SHAW, J. and J. GREEN, Prognosis and Pentathal induced electroencephalographic changes in electroconvulsive treatment. EEG Olin. Neuraphysiol., 1957, .9: 225—237. SCHWARZ, B. E., BICKFORD, R. G. and ROME, H. P. Reversibility of induced psychosis with chlorpromazine. Prac. Maya Olin., 1955, 30: 407-417. SHERWOOD, S. L. Central cerebral chemicals and their relation to psychoses. Chemical Concepts of Psy- chosis. McDowell, Oblensky, N.Y., 1958, 268-276. STRAUSS, H., OSTOW, M. and GREENSTEIN, L. Diag— nostic Electroencephalography, Grune & Stratton, N.Y., 1952. ULETT, G. A. and JOHNSON, M. W. Effect of atropine and scopolamine upon electroencephalographic changes induced by electroconvulsive therapy. EEG Olin. Neurophysiol, 1957, 9: 217—224. VERDEAUX, G. et MARTY, R. Action sur l’électroencé- phalogramme de substances pharmacodynamiques d’intérét clinique. Rev. Neural, 1954, .91: 405-427. WARD, A. Atropine in the treatment of closed head injury. J. Neurosurg., 1950, 7: 398-402. WEINSTEIN, E. A. and KAHN, R. L. Denial, of Illness: Symbolic and Physiological Aspects. C. Thomas, Springfield, 111., 1955. 0., GREEN, R. E., MCNAMARA, B. P. and KR-OP, S. The influence of atropine and scopolamine on the central effects of DFP. J. Phar- WESCOE, W. macol, 1948, .92: 63-72. WIKLER, A. Pharmacologic dissociation of behavior and EEG “sleep patterns” in dogs: morphine, N’allylnormorphine and atropine. Prac. Soc. Exper. Biol. Med., 1952, 79: 261—265. WIKLER, A. The Relation of Psychiatry ta Pharmacology. Wm. Wilkins, Baltimore, 1957. WOOLLEY, D. W. Serotonin in mental disorders. Res. Publ. Ass. nerv. ment. Dis., 1958, 36': 381-400. Reference: FINK, M. Effect of anticholinergic compounds on post convulsive EEG and behavior of psychiatric patients. EEG Olin. Neuraphysial., 1960,12: 359-369. W w IN �ANNOUNCEMENT WEEK—END COURSE IN "EEG AND CLINICAL NEUROPHYSIOLOGY IN PAEDIATRIC PROBLEMS” Institute of Child Health, Hospital for Sick Children, University of London, London, England Saturday, June 18th, 1960 9.45 a.m. Introduction. 10.00 a.m. Electrocorticography During Operations for Partial Epilepsy. 11.15 a.m. Coffee. 11.30 a.m. Motor Function and The Basal Ganglia. 1.00 p.m. Lunch. 2.00 p.m. Behaviour after Cerebral Lesions in Children and Adults. 3.15 p.m. Tea. 3.30 p.m. Diffuse Systems in the Brain: Physiological and Pharmacological Mechanisms. Dr. Otto Magnus, Head EEG Dept, St. Ursule Clinic, Wassenaar and “Meer en Boslk’ ’, Hemsteede, Holland. Dr. John A. V. Bates, Neurological Research Unit (M.R.C.), The National Hospital, Queen Square. Prof. H. L. Teuber and Dr. R. Rudel, Dept. of Psychiatry and Neurology, New York University, Bellevue Medical Centre. Dr. Philip Bradley, Dept. Experimental Psychiatry, University of Birmingham, Hon. Director M.R.C., Neuropharmacology Research Group Sunday, June 19th, 1960 10.00 a.m. Circulatory Arrest. 11.15 a.m. Coffee. 11.30 a.m. The Clinical Physiology of the Lower Motor Neurone. Dr. G. Pampiglione, Dept. Clinical Neurophysiology, Hospital for Sick Children, Lecturer Institute of Child Health, University of London. Dr. J. A. Simpson, Neurology Unit, Northern General Hospital, and University Department of Neurology, Edinburgh. ��,. ,r" . 7/ Editor-imChief E L E C T R O E N C E p H A LO G R A p H Y Montreal Neurological Institute 3801 University Street Montreal 2' Canada AND HERBERT H. JASPER CLINICAL Editorial Assistant Montreal IItlleurological Institute 3801 niversity Street “m“l 2. R' S. SCHWAB . Massachusetts General Hospital Boston 14. Mass” U.S.A. H. FISCHGOLD 9 ans “élP‘FQ‘” . rance l NEUROPHYSIOLOGY PIERRE GLOOR M Associate Editors Clinical and Laboratory Notes can“ d ° . An International )ournal European Office Managing Editors W. STORM VAN LEBUWEN OTTO MAGNUS THE E.E.G. JOURNAL Aid. Electro-Neurologie Academisch Ziekenhuis Leiden, Holland. StreEt Montreal 2' Canada . 3801 univerSity my 6 , 1959 a Technical Notes _H. {WM 3,1111%??? D.lVlSlon o e rca ec romcs College of Medicine Iowa City. Iowa. LI.S.A. F. BUCHTHAL Universitetets Izeurofysiologiske Institut Copen aaen. Denmark _ _ Index and Review of Literature C. E. HENRY Institute of Living 200 Retreat Avenue Hartford, Conn., U.S.A. Dr. Max Fink, Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L. N. Y. Dear Dr. Fink: I., - Effect of Anticholinergic Compounds on Post Behavior of Psychiatric Patients Convulsive I am pleased to inform you that the above manuscript has been reviewed by members of our Editorial Board and recommended for publication with some revision. < .. ”by/finwfilw... l , Re: MS 981 EEG & In the first place, I am sorry to have to ask you to condense the manuscript to about two thirds of its present size, since we have had to institute a more stringent regulation regarding the length of manuscripts, due to an excessive amount of material for publication. I should think that this condensation could well be made in your study by reducing the length of your discussion and trimming up descriptions in places where elaboration of drug action is perhaps not necessary, as such information may well be available in current pharmacological literature. also that you consider alternative hypotheIt is recommended modes and of action. Reference to the work by Aird, other possible see; on Cerebro-vascular Permeability, to be found in the Archives of 1956, the Journal of Nervous and Mental Disease of 1956, the Archives of 1958 and the Journal of Neurosurgery of 1952 might be worthwhile. Your synaptic theory would be stronger if it was not over-emphasized and made clear that it is only a tentative hypotheses throughout, perhaps particularly in the conclusions where it should be quite clear that your statements are hypothetical rather than proven, since the relationship between the EEG patterns and synaptic activity is a very tenuous one and may, at times be inverted. We also would like to have some legends for your illustrations make them to clear and independent of the text. Official organ of the International Federation of Societies for Electroencephalography and Clinical Neurophysiology, Inc. �ELECTROENCEPHALOGRAPHY Editor—in-Chief HERBERT H. JASPER Montreal Neurological Institute 3801 University Street Montreal 2. Canada R. S. SCHWAB Massachusetts General Hospital Boston 14. Mass.. U.S.A. AND C LI N I C A L Editorial Assistant H. FISCHGOLD NEUROPHYSIOLOGY PIERRE GLOOR Montreal Neurological Institute 3801 University Street Montreal 2. Canada H. W. SHIPTON THE EEG. JOURNAL Division of Medical Electronics College of Medicine Iowa City, Iowa. U.S.A. F. BUCHTHAL Universitetets Neurofysiologiske Institut Copenhagen. Denmark 3801 University Street. Montreal 2, Canada Index and Review of Literature EurOpean Office Managing Editors OTTO MAGNUS Afd. Electro-Neurologie Academisch Ziekenhuis Leiden, Holland. 1 rue Lu Cases Paris VII. France Technical Notes An International Iournal W. STORM VAN LEEUWEN Associate Editors Clinical and Laboratory Notes C. E. HENRY Institute of Living 200 Retreat Avenue Hartford, Conn.. U.S.A. _ 2 _ to your illustrations, we compliment you on their clarity and clean presentation; but there is some question as to whether they are all needed to make your points. If you can find some way of reducing their number to enable further condensation of your presentation, it would be adWith regard visable. sorry to cause you this extra trouble with your manusa splendid piece of work; but we feel that due to our own publication problems, and for the benefit of the clarity and conciseness of your presentation, the above alterations would be advisable. cript, which I am is obviously Yours sincerely, / Wt Herbert H. Ja Editor-in-Ch' f e rmrx HHJ/nb Official organ of the International Federation of Societies for Electroencephalography and Clinical Neurophysiology. Inc. �lurch 9, 1959. the Editor, EEG Journal, 3801 University Street, Hentranl, 2, Clnldl. Dear Dr. Jasper: I :1 enclosing a copy of a report entitled Effect of Anticholinargic Compounds on PostOonvulaivc EEG tad Behavior of Psychiatric Patients“ for your consideration for publication in the EEG Journal. Ran: thanks for yam: consideratiun. “The Sincortly yours, m Junk, 31:33 14.». �Hay 20, 1959. Dr. Herbert H. The EEG 3801 Jasper, Editorain-Chier, Journal, University Street, Montreal, 2, censda. Re: as 981 Jasper: I as pleased.to return the enclosed manuscript which has been edited according to your suggestions. I found your comments and reoosnendatiens helpful and have been able to condense the manuscript oonsidersbly. I trust that it will still read intelligibly. Dear Dr. by I have reduced the nnnber of illustrations 1958 the since the tee diethasine deleting cots, report has adequate pictures. I have also taken out one each or the piperidylbensilate and atropine figures, leasing but six figures for the final manuscript. Legends for each of the illustrations are eppended after the rersr~ CBCOEe I had seas difficulty in encespassing the obsersetiens or iird in this report, since he has not attempted a generalisation of nenrophyeiologic change and behavior. As I interpret his studies, he has observed changes in distribution of large molecules in spinal fluid after convulsive therapy. This observation say or say not be consistent with changes in cholinergic, adrenerxio or synaptic relationships but in no wise excludes the concoaitsnt changes suggested by our studies. In any case, I have screed that the synaptic theory has been rather strongly pot and have modified the language considerably, including what I believe is a relevant reference to iird's studies. Except for the hypotheses suggested by Roth and Blett, which I believe are consistent with the suggestions or this report I know or no other systeaatio atteapt to relate nenrophysiologic and behavior changes after convulsive therapy. I would be pleased to include such studies. �Dr. Earhart H. and Jaipur, (Contd) #2 I an grateful for your vary kind caaoidcratioa nest £hut¢htrul criticism. I stunt that this copy a: the unnuseript any aunt with your approv:1. Sincoruly yours, an aran Fink, rm. �Anticholinergic Hellucinogene and Post Convaleive' EEG From and Behavior the Department of Experimental Psychiatry, Hillside Hoepitel, Glen Oaks, L.I., N.I. Aided, in part, by grant M~927 and HY~2092 of the National Institute of Mental Health, National Institutes of Health, 0.8. Public Health Service. Read at the VII: 1/59 - American EEG EEG Society, Atlantic City, June, 1958. �Anticholinergic Hellucinogens and Post Convuleive EEG and Behavior In 1956 Ulett and Johnson ( ) reported that atropine and scopolanine blocked the eppesranee ot the high voltege activity usually induced by convulsive therapy. that the dose of atropine necessary to affect the They EEG delta also noted EEG was such es to be associated with unpleasant systemic effects. Reports by Jenkner compound & Lechner ( ) describing diethaeine es en enticholinergio with potent neurologic but minimal systemic effects led us to undertake studies using this compound ( similar to those of Ulett and Johnson ); and these observations, in turn, led to an investigation of other experimental anticholinergic agents. It is the purpose of this report to describe clinical and electro- encephalographic observations incident to the intravenous administrao tion of various anticholinergic agents in psychiatric patients at verious stages of convulsive therapy and to relate these observations to hypotheses concerning the node of action of convulsive therapy ( ) and of exogenous hellucinogene ( ). �-2SUBJECTS AND METHOD: subjects were consecutive referrals for convulsive Our therapy in an open ward volunhry psychiatric hospital. While varying numbers of subjects have been studied for each compound, subjects in 106 experiments have been essayed. 88 Iron 18 Agesranged to 67 years, and diagnoses include schizophrenic reactions, manioudepressive and involutional depressive psychoses. Patients have been studied at various stages of the treatnent process. EEG The observations were laboratory, using a made standard 8 in acute experiments in the channel EEG recorder and needle electrodes applied in 17 lead placements following Strauss 33_5l ( ). In each experiment, the compound under study was administered intravenously at a set rate per minute, until clinical behavioral or electrographic changes were observed. have been atropine. diethasine, Each is a Win~22§9, The compounds studied benactysine, JB-318, JB-336, and potent enticholinergic agent in vitro. Diethasine (diethylaminoethylwxwdibensoparathiazine), for example, induces nydriasis end hypotension, suppresses salivation and blocks the bradycardia, salivation and seizures of acetylcholine and �-3fluorophclphntc ). ( win-2299 (2-diethylnninoethyl cyclopcnty1-2, thienyl-glycolnte) end benactysine (2-diethy1nninocthy1 benzilnte) are synthetic nnticholinergic agents with potent central neurologic effects nininal peripheral systemic effects and cnd JB~336 two ). Diethazine 175-250 ninnte for ). JBnBlB 2 to of a recent series of synthetic antichclinergic central potency compounds or high total of , (N-ethyl-3~piporidy1benzilatc, X-nethy1o3~piperidy1~ bennilcto) are ( ( was mgm; and high administered at hallucinogenic activity 25 mgm. Win-2299 and benactyzine 5 mgm.; and per minute for a at 0.5 mgm. JB-318, JB~336, and atropine :31. per minute for 1.2 to h.0 mgm. at per O.h �OBSERVATIONS: (a) Diethaeine: As previously reported administration of diethacine in 15 ), the ( patiente prior to convulsive therapy resulted in a decrease in voltages and a deaynchronisation of all frequencies. Prevailing prominent. instances, symmetric In some activity appeared, temporal leede. rhythmic patterns beoane leee most prominent in the The low voltage 6;? cps frontal and anterior alpha frequency fies not altered, but the build-up in voltage and the slower frequencies induced by hyper- ventilation vere blocked (Fig. 1). -Q-‘-Fig. 1 UUUUU Q-flO-u-n--In 25 patients during convulsive therapy, with varying degrees of induced high voltage delta activity significant decrease both in voltage slow wave hSfi neon activity. From an and in 20%. ) there was a per cent time of average per cent tine delta of in the {route-occipital leads, there per cent time or ( was a Both random and reduction to a burst delta �-5- activity diminished became prominent. slow wave activity increase in per cent time and voltage of The on voltage alpha and beta frequencies hyperventilation was no longer apparent. clectrographic effects appeared during drug administration These persisted for and and low one to five hours (Fig. 2). ‘fl’--“---yig. 2 fi‘-‘~“---Concurrent with those electrographic effects, distinctive systemic effect was an and S The observed initial systemic episode of coughing and the occasional spontaneous complaint of dry mouth. by behavioral changes. we to 10 per cent. Skin remained dry and-heart This increase was rate increased rarely associated by pron cordial awareness. Baring the period of observation pupils were not altered, and responded pronptly to light and near vision. were There occasional complaints of abdominal griping. These effects, however, were generally or behavioral. less prominent than the electrographic �-6. Beheviorelly, patients became more irritable and restless. They became tense end excited, end it use difficult to neintein eyelid closure. They complained of feelings of unreslity and of dysthesias of the extremities. Visual illusory phenomena and delusional thoughts about their illness, the setting or the test procedure or the examiner's identity were also reported. were cherecteristic in behavior. chenges in lenguege There sssocieted with this change Syntectic language patterns ( altered in ) were 1 fashion opposite to that previously described for amobarbitel ( ) so node and that verbal denial, minimization, cliches, third person past tense became less prominent. nese of speech, measured by dyadic TTR, The degree of repetitive- decreased )whieh ( eltered opposite to that described for convulsive therapy (b) Win-2299: Reports by Pennes enticholinergic men ( ) compound, Uin~2299, induced led to this next study. 0n that an is ( en ). eXperinentel excitetory states in intravenous edninistretion of 2—5 n3n., both elsctrogrephic end behavioral effects similar to diethesine were observed. In five petients without EEG slow were �-7- ectivity, deeynohroniaetion of frequencies and a decrease in voltages were noted in four (Fig. 3). -‘h‘-----‘ ‘-0-----~~ In 11 patients with high voltage delta activity there wee a decrease in amplitude and per cent time or slow wave activity with an increase in alpha and beta frequencies. The noun cent tine delta activity dropped from (Fig. h). 50% to 23% per ‘—-~..—“--‘ Fig. h -~--~-~-“Associated with these electrographie effects were minimal systemic effects but prominent clinical patterns of restlessness and excitement. Patients became fearful and tense. Visual eeneetione were reported and in three subjects, delusional eleboretiene about their hoepitel experience were prominent. These beheviorel chengee Appeared during drug administration or within ten ninetel, end disappeered, at theee doeege levels, within two to three hours. �-8Reports that beneetyzine induced Benectzzine: (C) deeynchronizeticn ( and ) EEG its structural similarity both to diethanine end Win-2299 led to our testing of this compound. Intrevenoue adminiatretion in 12 subjects elicited similar clinical end electrogrephic patterns. Both in the well modulated alpha record and in the recerd with high voltage delta activity, deeynchronieetion wee prompt. Delta activity decreased from a teen per cent time of 39% to 16% in subjects (Figs. 5, 6). 8 n--fi-¢-----Figs. 5, 6 ”0.“--“u-fi'flfiu- These electrcgraphic patterns were again accompanied by clinical restlessness, irritability tree recording wee here difficult. delusional thoughte seen with the noted et these dceege levels. orienteticn ( wee an excitement. Artifact- The illusory eeneeticne initiel compounds were and not In patients with nenifeet die- end language changes ), however, there end associated with convulsive therepy alerting petterne, as noted with diethezine. and a reversal cf the language �-9(d) Piperioylbensilstesz Following recent reports by Abood ( ) that verious piperidylbensilates both manifested cnticholinerzic activity tested and induced two of hallucinations in psychiatric subjects, these, JB-318 end JB~336 in 2h subjects. we The electrographic patterns were identical to these other experimental Onset of desynchronizetion was during coupounds; injection or within 15 minutes and persisted for one to four hours (Fig. 7, 8). .n...‘..“... Figs. 7, 8 ---0------uIn each instance in which desynchronizetion was observed, restlessness and clinical excitement, illusory and hallucinatory activity iwere noted, and were concurrent with the electrogrsphic changes. In two instances the beheviorel chenges were halted by the subsequent intravenous edninistretion of chlorpronesine. (e) itrogine: Continuing our study of enticholinergic compounds, we administered atropine intravenously inlh subjects, in doseges of 0.8 to h.0 ngn. Systemic effects were prominent during the iniection with increased respiratory rate, pellor, dry skin end dry mouth, precordiel complaints and nerked techycerdie �-10- (Pig. 9). Subjects became restless and fearful and recording became and the difficult. Within ten minutes these symptoms subsided subjects became drowsy and relaxed. In six subjects without delta activity} no change in pattern was seen during drug administration or for minutes thereafter. During the period of voltages and ninisal desynchronisetion was no was EEG 10—20 lassitnde, decreased observed, but there significant difference in per cent tine delta. Fig. 9 -fi.--‘.& In subjects with delta activity, there was an apparent initial decrease in voltage and per cent time of such activity during the first ten minutes after administration, followed by a return to original values during the period of quietude. period were the changes significant (Fig. 10). “-~-“---~ In neither �-11DISGUSSIOH: Various experinentel compounds with measurable enti— cholinergie activity have thus been shown to have similar electrographic and behavioral effects. Electrogrephicslly, each agent induces a desynchronizstion of frequencies and s in decrease Ind voltages, which is most prominent in subjects with delta activity following therapeutically induced convulsions. Beheviorally, these electrogrsphic patterns are associated with stimulating, excitstory, illusory and hallucinatory ectivity. To e lesser degree, nininsl systemic heart rate, sslivetion, sweating letter systenic effects ere and changes in ptpil are noted. more prominent in These patients given intravenous atropine under sinilsr experimental conditions. These observstinns can be relsted to theories of the node of action of convulsive therapy and the basis for the induced slow were activity; to concepts of the besis of experimentally induced hallucinations; and to the conflicting reports of the effects of atropine on nervous ectivity. �-12- (a) Convnlsive therapyuprocees: In earlier studies we indicated that the develcpnent of high voltage slow wave activity was the neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not eufficient, condition for clinical improvement ( ). During the past ten years, numerous authors including Bernstein, Tower and chachern, Ward, Sachs and Huge have reported similarities in the biochenical changes of the central nervous system in convulsive therapy to that seen in crania— cerebral trauna ( ). They observed an increase in cholinergic activity, nanirested by an elevation of free acetylcholine and pseudocholineaterase in the spinal fluid, and associated with high voltage slow wave activity. Sinilar high voltage slow wave activity has been reported after the administration of the cholinesterase blocking agent (di-isoprcpylfluorophoephate),I with attendant increase in cholinergic activity. In addition, the increase in central nervous system cholitergic activity by topical administration of acetylcholine induces high voltage ~ bursts and spike activity ( ). blocking of the behavioral and electrographic effects of convulsive therapy by the antichelinergic actiyity of atropine and scopolanine (Ulett and Johnson) are replicated by these observations on diethazine, Win-2299, benactyzine and the piperidylbensilates. The potent anticholinergic activity or The cent!!! each of these compounds (with apparent predominant locus or activity in the central nervous system) supports the �suggestions that the biochenioal basis for the induced activity of convulsive therapy results slow wave from an increased level of central acetylcholine~cholinestereos activity; While these observations demonstrate that anti— choliuergic compounds are effective in reducing slow activity, reports of other compounds with have also appeared. ( ), nescaline similar effects Agents such as anphetanine (Bensedrine) ), lysergic Acid diethylanide“ ( wave and diphenhydrasine (Benedryl) convulsive slow wave ectivity. ( ) ( ) also reduce poet~ These compounds are primarily synpathoniuetio and antihistaminic in pharmacologio aytivity, yet each has excitstory and stimulating effects ( and , , , ). The on behavior relations of these various anticholinergic synpathoninetic agents say be related within constructs of synaptic activity. observations have been confirmed in this laboratory. Intravenous adainistration of So~1oo genus LSD in subjects withoutldelta activity induced EEG desynchronisation one to two hours after administration. In subjects with delta activity there is a marked reduction of delta with the re-essertion of proainont, high voltage alpha frequencies. These �~1h- In a study or the effects or various agents on the EEG and the behavior of unaneethetised cats with chronic implanted electrodes, Bradley and llkes ( ) postulsted the existence of two, or possibly three, types of interacting chenoreeponsive receptors within the central nervous system: cholinergie, nonucholinergic susceptible to anphetaeine, nonucholinergic susceptible to Harassi and Hart pathways in the on evoked ( ) LSD eXplondng and tryptaminie derivatives. intercortical (transcellosal) cat, described the effects of various potentials on end oonpounds direct electrical stinulation. They postulated the presence or two chenoreceptive potentialities of the synapse - cholinergic and edrenergic - with opposing stimulatory and inhibitory ectien. been described by Hoolley ( Similar constructs have ), Evarts ( ( ) and Sherwood ). According to these models, the administration of snticholinerzic agents, or of sympathoninetic agents, results in equivalent synaptic electrical effects, and nresnnebly, similar electrogrsphic and snpethnine, nescaline end behavioral effects. LSD Thus adrenaline, inhibit the level of electrical �-15- activity at synapses as effectively as the blocking or inactivation of acetylcholine by atropine end other enti~ cholinergic compounds. In the light of these scggesticns, the present eXperinents permit a mere specific hypothesis regarding the phernacclcgic basis cf the convulsive therapy process. Repeated induced convulsions lead to an increase in the synaptic or xyxplttl cholinergic activity which voltage slow wave activity.; electrical activity (and of is reflected in surface electrodes level ) as angnented high Administration at anticholinergic agents reduces the level of synaptic activity, resulting in a decrease in the manifest cortical electrical activity to precenvulsive levels. may also achieve the Administration or synpathcmisetic agents same electrical effects, not by eltering the level of cholinergic activity but, by increasing the level of adrenergic activity. The nsnirest slow wave prominent and so persistent in the waking state ( ) nay thus be viewed as a EEG activity, so or the pcst~seisure persistent alteretion in synaptic transmission activity or large numbers of cells of the �central nervous system. is seen in the ready ( ) and The delicate nature or this balance reversibility with alerting ( ), tine the wide variety of pharmacologic agents noted here. Repeated induced convulsions may thus be described as a device to create biochemical changes in the brain for their resulting behavioral effects. view a Such/formulation that convulsive therapy is process ( a is consistent with the nonuspecifio therapeutic ). the initial suggestion ( ) basis for the convulsive therapy process that the pharaaeologio may lie in an alteration in acetylcholine-oholinesterase relationshipsban thus be focused on the alteration in the level of synaptic activity. In this regard, the observation that diphenhydranine, primarily an anti-histaminic agent, also reduces slow induced convulsions ( ), and the wave activity of observations by Sachs ( ) that increased amounts or serotinin appear in the spinal fluid after convulsions suggest that this image in convulsive therapy is oversimplified. ’ 0; synaptie activity Further studies or the effects or various drugs on the postcseiaure electrical ‘ �activity are warranted. (b) Iearophyeiolggy or hallucinogenic These EEG activity; observations of anticholinergic compounds delta activity also related to concepts of eXperinental may be hallucinogenic activity. Each of these compounds induced excitatory behavior including illusory and Here, too, synaptic models phenomena.* on hallucinatory may be applicable. Synpathoninetic egents, ae mesoaline, LSD, and amphetamine, and anticholinergic agents as those described here, are equally potent hallucinogens. i necrophareacologic basis for such behavior nay be characterised as an alteration in the level of synaptic activity in the direction of increased inhibition (decreased transmission) of stimuli. The clinical efficacy hallucinatory activity biochemical level. ester: ( The may of convulcite therapy in modifying thus In the doses used, higher dosage ( A in alterations at this effects or hallucinogenic blocking agents ), as chlorpronarine for benactysine. lie and reserpine, on EEG electrical hallucinatory phenomena were not observed report of such activity was reported at ). �~18~ ectivity are consistent with EEG hypersynchrony in non effects of LSD end LSD and such a View. ), block the ( nesculine ), ( and Both compounds induce EEG desynchronizetion in animal studies, block neeceline behavioral and electrographic effects ); ( Chlorpronaoine was found equally potent in abutting the excitatory activity of these experimental anticholinergics in these studies. (c) Relation to atropine: Comparison of the oystenic and central effects or these experimental anticholinergic conponnda with atropine reveals significant differences. Extensive experience with atropine at physiologic end toxic levels in men indicate that the predominant Initial effects are focused at peripheral nervous structures. bradycnrdia, followed by marked tachycardia, loss of sweating and salivation, papillary dilation, intestinal relaxation and decreased motility are amongst the effects at physiologic (O.2~l.2) dodagee. At higher dosages (2-5 mg), the central nervous irritability, disorientation, oyeton effects of ataxia, delirinn ( may be observed ( ), anonnta ranging Iron ). In the atropine 32 to 212 some end studies 33:. injected intra- �.19nuacularly into psychiatric petiente resulted in the following ( sequence )t ”There is an induction period or 15 to minutes 20 after adninietretion characterised by restlessness, occasionally mild exoitenent, confusion, and at times nausea and vomiting. This proceeds, smoothly and predictably, to muscular inooordinetion, ataxia, weakness, vertigo and difficulty in articulation. An acute brain syndrome with memory disturbance, disorientation, elouded consciousness, illusions and most frequently visual hallucinations vergee into delirium come... ' Thus and rapidly proceeds to central nervous system effects are preoedodhnd accompanied by marked peripheral effects. In contrast, these experimental enticholinergic agents, in equivalent dosage ranges, manifest and lurked central. The are observed early and effecto may on little peripheral effects the central nervous system continue for extensive periods and in higher dosages with minimal peripheral nervous effects. It ie within this context of central tarsus peripheral predominant sets or activity that the apparent discrepant EEG observations of the etteete of atropine (in inducing elow wave �.20- activity) these experimental enticholinergic compounds and be reconciled. The variable EEG effects, like the verieble behavioral effects are dose related. adminietering l~3 mg/Kg may Weeeae exist 33‘3l ( ) atropine in curarized cats and monkeys using O.h to 1.2 mg/kg in curerized and Funderburk and Case ( ) cats, produced high voltage slow wave activity. Wikler ( ) reported that 7.2 mg/kg atropine in unanosthetized, ancnrarized patterns strikingly similar to dogs produced "epindle slow wave" sleep. 'Rinaldi and Himwioh ( ) reported that atropine in doeee of 0.5 to 2.0'mg/kg in cnrarized rabbits exaggerated patterns and inhibited the electing of the EEG EEG sleep to various peripheral stimuli. _Sinilar observations have been observed by Bradley and Bikes ( ) in the conscious oat. In each instance the dosage of atropine varied from 0.5 g 3 mg/kg- a range roughly comparable to the massive dosages need in atropine coma therapy. Yet what of the electrographie eitects in lower In our observations, the EEG effects of dosage? low dosages of intravenous atropine (006‘ .06 ng/kg) were minimal. Similar obeervatione have been reported by Danielopelie, Guirgee end Drooen �021-: ( ) who specifically releted the effects to dosage level. EEG with high doeeges of atropine (h-B ng/kg) in rabbits einiler high voltage nixed slow and feet (21-30 ope) activity was observed, while with low deeegee (2h~.8 ng/kg) the original rapid rhythms remained unehenged. These authors thus suggested ! flat atropinegs effects were multiple end doee determined, and related the observations to similar findings with regerd to EEG heart rate. Denielopelu atropine slow down ( ( observed that small doses of cardiac rhythm nine while larger doses cenee eexeklteiien acceleration. been confirmed ) These obeervetiene have recently ). Thus, while oonsidereble speculation as to central neurophysiology he: been related to observations with atropine, these observations provide e special case of atropine effects. The entiohelinergic activity, so prominently established in observations in vitroI end in the peripheral nervoue system, may not be the effective physiologic activity in the large doses neeeeee y to reach central structure. It is poeeible that the experimentel entichelinergic compounds used in the present studies �-22protfie more suitable experimental tools fer the elucidation of central neurophysiologic nativity than atropine. In part, these differences may be related to difference- in etrnctnrel chemistry. Each of these experimental cenponnde contain a tertiary canine linkage, while atropine (and ecopolemine) quaternary centnin a qxxtx:xznx linkage. Such differences may be clearly observed in the structure~ectivity relationships or the piperidyl- bennilatee ). ( While Hwnethyl-B-piperidylbenzilete and Nsethyla 3-piperidxlbeneilate have potent enticholinergic and hallucinogenic potency, Hedinethyl~3~piperidylbeneilete - the quaternary conpennd - has considerable in vitro anticholinergic activity, and no hallucinogenic property. The significance of tertiary amine linkage for central neurophysiolcgic effect: he: been repeatedly affirmed by numerous observers, and neat recently by Pennel Denber; ( ), Theee e Hake ( ) and Plodnerk ( ). structure~aetivity relations lend theneelves to re-eveluation or studies or creniccerebrel trenne Ward's ( ) ( and epilepsy. reports orfithe efficacy of high doses of etrepine in altering the clinical manifestations of head trauma indicated ), �-23- that effective dose: brought with Thu them severe systemic effects. failure of the oxtohaive studies a: the efficacy or atropinc and soopalunine in epilepsy ( ) any be related to : failure of these quaternary compounds to reach the central nervous syntax in adequate quantity. It would noun advisable, therefore, to, ropoat those studies utilizing such more potent, more centrally specific, antieholinorgic canpaunds as used in the eXporixonts reported here. �lj MS 981 W Mel 3;..." EFFECT OF ANTICHOLINERGIC COMPOUNDS EEG AND BEHAVIOR OF Max (Received ON POST CONVULSIVE PSYCHIATRIC PATIENTS Fink M.D. for publication: march 11, 1959) v v-u-u. From the Department of Experimental Psychiatry, Hillside Hospital, L.I., Glen Oaks, Aided, in Institute N.Y. M-927 and MY-2092 of the National Health, National Institutes of Health, by grants part, Mental of U.S. Public Health Service. Read at the American W-EEG 3§5357k? EEG Society, Atlantic City, June, 1958. �MS 981 ANTICHOLINERGIC COMPOUNDS AND POST CONVULSIVE EEG �Effect of Anticholinergic EEG and Behavior of Compounds on Post Convulsive Psychiatric Patients Mcsfl—vsflswfi kg 76.: gagifisignificance of high voltage EEG delta activity in the convulsive therapy process (Roth gt_gl, 1951, 1957; report that this delta activity was blocked by the administration of-eniiehnlinersic ealfiifiiaa atropine and scopolamine (Ulett and Johnson, 1957) provided the basis for these studies. As there were attendant unpleasant systemic effects with the administration of these agents, reports describing diethazine as an anticholinergic Fink and Kahn, 1957) and the with potent neurologic but minimal systemic effects (Jenkner and Lechner, 1955; Lechner, 1956) led us to undertake studies similar to those of Ulett and Johnson using this compound (Fink, 1958). “@bservations with compound diethazine led to the investigation of other experimental anticholinergic agents. This report describes clinical and electroencephalographic observations incident to the intravenous administration of various anticholinergic agents in psychiatric patients at various stages of convulsive therapy and relates the observations to hypotheses concerning the mode of action of convulsive therapy and of hallucinogens. �SUBJECTS AND METHOD: subjects were ninety psychiatric patients referred for convulsive therapy. Ages ranged from 18 to 67 years, and diagnoses included amcaai-t!=s£ schizophrenic The reactions‘ and manic-depressive and involutional—depressive varied number of subjects were studied for each compound for a total of 107 observations. Patients have been observed at various stages of the treatment process. The observations were made in the EEG laboratory, using a standard 8 channel EEG recorder and needle electrodes applied in 17 lead placements following Strauss gt_§l (1952). In each trial, the compound under study was administered intravenously at a set rate per minute until clinical behavior or electrographic changes were observed «a -'w ‘M psychoses. Www'” mam. "4”,...“ A." A Hm , ‘5 was”“My HM A r-m new M, -J:,M-,_.m,..\. "was... “A...“ i, ,1“. The ine, JB3l8 JB~336, and atrOpine.{ Each is a potent “p' a: icholinergic agent in vitro. Diethazine (lgflgéwdaetfiyl- \\ ‘H‘benact v. __~ ‘ (2-diethylamipdéthyl fignzilate) are synthetic anticholinergic '- 3‘ .h u k‘ ‘ ‘ �W [M fiW/émgw (m w 1,?de //h)1 (Maw (WW. a /¢‘¢¢) ’ f flux-322.497“ f E (W . 7’6’33“ wit/4&4, xiJ'C) 7 I (W fig?) 17”} M .7313”: W �agents with potent neurologic effects and minimal peripheral P’w ‘nwV""' systemic effects W JB- 318 and JB~336(N~et§gl~3flwiperidylbenzilafe N-methyl-~3two of a new series of syntfiébiq piperidylbenzilatafl (Pennes and Hocn%wl9§7?“§:c9bson, 1955) """ ‘m‘,’ anticholiHErgic compounds w'th a»? éfimm‘ distinct hallucinogenic 1958). et a1, g Diethazine administered at _activity __ ’ total (Abood was mac?“ 25 mg per minute for 2.5-5.0 mg/kg); Win-2299 and mg per minute for 2 to 5 mg (0.020.15 mg/kg); and JB-318, JB-336, and atropine at O.h mg per minute for 1.2 to h.o mg (0.0l~0.10 mg/kg). of 175-250 benactyzine at 0.5 a mg ( �OBSERVATIONS: administration of diethazine in fifteen patients prior to convulsive therapy resulted in a decrease in EEG voltages and a desynchronization of all frequencies,€¥$§3;=;$§8%. Prevailing rhythmic (a) Diethazine: patterns became The less pronounced. In symmetric low voltage 6-? cps most apparent in W frontal and some activity appeared and was _ (F3416 anterior temporal leads. ammmmmwmmm~.w fequencyas not send, ”Mm“ Thz“‘;“i”;“n. instances, ,, .1. >u-L—‘7‘? mm»- ,.... .14.“ mm“. We they”; In twenty~five patients with varying degrees of induced high voltage delta activity during convulsive therapy (Fink and Kahn, 1957), there was a significant decrease in voltage and in per cent time of slow wave activity. From an average-pal—Icnt-ttne delta of h5% in the front-occipital leads, there was a reduction to a mean uggzggntntine of 20%. Both random and burst delta activity voltage alpha and beta frequencies became more prominent. The usual increase in per cent time and in voltage of slow wave activity with hyperventilation sans-no diminished. Low 51, \} "it; 2’ lfJ?e>» �-5longer apparent. These electrographic effects appeared during drug administration and persisted for one to five hours Mfifl (Fun/t} xqs’f) Concurrent with these electrographic effects, we observed distinctive systemic and behavioral changes. The initial systemic effects were episodes of coughing and complaints of dryness of the mouth. Skin remained dry and the heart rate increased by S to 10 per cent. This increase was rarely noted by the subject, and was not accompanied by ,n» precordial distress. -9ar&ng—tho—peried~e£w- , Gems/haflhv observationnfihere was no change in pupillary size, and their response to light was prompt. There were occasional complaints of abdominal griping. Ihfiégweffects were generally less prominent than the electrographic or behavioral. Behaviorally, patients became irritable, restless, tense and excited, and it was difficult to maintain eyelid closure. They complained of feelings of unreality and of tingling, weakness and heaviness of the extremities. Complaints that colors were pale or more intense, halos about lights and changing shadows were accompanied by delusional thoughts about their illness, the setting of the test procedure or the examiner's identity.4p . AM �-7(b) Win-2299: The report by Pennes and Koch (1957) that Win-2299r—aaother_axparamoatalwaatieholinergée~eempound1 induced illusory and hallucinatory states in man, led to this next study. 0n intravenous administration of Win-2299, both electrographic and behavioral effects similar to diethazine were observed. In five patients without EEG slow wave activity, desynchronization of frequencies a decrease in and voltages were noted in four;éi§igggg; {Vfgf / ), In eleven patients with high voltage delta activity there was a decrease in amplitude and per cent time of slow wave activity with an increase in the per cent time of alpha and beta frequencies. dropped from 50% to 23% The mean pea—eoat—tine (Fig.1;3. Fig.3 delta activity 3" Associated with these electrographic effects were clinical patterns of restlessness and excitement, and effects. Patients became fearful and tense. Visual illusory sensations were reported and were minimal systemic associated in these subjects with delusional elaborations �-3about their hospital experience. Excitement was accompanied by ideas of reference, and in two subjects, intravenous chlorpromazine was administered to halt this process. These behavioral changes appeared during drug administration or within ten minutes, and disappeared within two to three hours. effects were slight. There were neither cough nor respiratory distress. Heart rate was unaffected except in patients who became overtly excited Systemic fearful, in and whom excitement period. on ' tachycardia appeared during this Dryness of the mouth was reported only direct inquiry. (c) Benactyzine: Reports that benactyzine induced EEG desynchronization (Coady and Jewesbury, 1956), its anticholinergic nature, and the structural similarity to diethazine and to Win-2299 led to our testing of this compound. Intravenous administration in 12 subjects elicited similar clinical and electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, desynchronization was prompt. Delta activity decreased in 8 subjects from a mean pti—OUI$ time of Wfifi/d} 39% to 16% �-9These electrographic patterns were again accompanied clinical restlessness, irritability and excitement. Artifact-free recording was more difficult. The illusory by sensations and delusional thoughts seen with the initial compounds were not noted at these dosage levels. Systemic effects were similar to Win-2299. (d) Piperidylbenzilates: Following recent reports by Abcod et a1 (1958) that various piperidylbenzilates with measurable anticholinergic activity induced hallucina- tions in paychiatric subjects, we tested JB-318 and JB-336 in 2h subjects. The electrographic patterns were identical with the other experimental anticholinergic compounds. —¥he— ur ng e njection or Waffles ync hroniza ti onA? ?- duufdtvthhfhfl within 15 minutes and persisted for one to four hours (Fig. 5: t). ‘ , Figs. 5f In each instance in which desynchronization was observed, clinical restlessness, excitement, illusory and hallucinatory activity were noted, and were concurrent with the electrographic changes. In two instances the behavioral changes were halted by the intravenous administration of chlorpromazine. �-10Considering the numerous reports (e) Atropine: that atropine induced EEG slow wave activity and clinical somnolence, we administered this anticholinergic agent intravenously in 15 subjects, in dosages of 0.8 to h.0 In six subjects without EEG delta mg (.01-.10 mg/kg). activity, there were no changes in EEG pattern during drug administration nor for 10-20 minutes thereafter. During a period of lassitude, decreased voltages, minimal desynchronization, and an increase in per cent time delta were noted. In subjects with delta activity, there was an apparent initial decrease in voltage and per cent time of such activity during the first ten minutes after administration, followed by a return to original values during the period of quietude. was» In neither period (@3925) were the changes significanta �-11- Systemic effects were prominent during the injection with increased respiratory rate, pallor, dry skin and dry mouth, precordial complaints and an increase in heart rate up to 100%. Subjects became restless and recording became difficult. Within ten minutes these symptoms subsided and the subjects became drowsy and relaxed. �-12- arious experimental compounds with measurable anticholinergic activity have been observed to have similar electrographic and behavioral effectsignmthnsematudiOOVM Electrographically, each agent induced a desynchronization of frecuencies and a decrease in voltages, which was most prominent in subjects with delta activity following convulsive therapy. Behaviorally, these electrographic patterns were associated with stimulating, excitatory, lesser degree, minimal systemic changes in heart rate, salivation and sweating were noted. These latter systemic effects were more prominent in patients given intravenous atropine under similar experimental conditions. These observations can be related to theories of the mode of action of convulsive therapy;and-ofirthevastS“fvr' illusory and hallucinatory activity. ‘thauaadnoedfiaiew—wamowaewévttyj To a to concepts of the basis of experimentally induced hallucinations; and to.thv reports of the effects of atropine on EEG patterns. (a) Convulsive therapy process: Earlier studies indicated that the development of high voltage slow wave activity was 4:; neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement (Fink and Kahn, 1957). In summarizing the observations of numerous �-13the relation of acetylcholine metabolism to 1;” 4o $vuuna andAconvulsions (Fink, central nervous system Ckxcxnurnsd'éjf 5L biochemical bootseinn the the 1958) it was suggested that induced EEG slow wave activity lay-fin an increased level of acetylcholine-cholinesterase activity of the central authors on nervous system. in the slow wave 1? present observations of tin alterations_ activity of convulsive therapy by these The experimental anticholinergic compounds are consistent with this suggestion. is indicated by reports of compounds with other biochemical activity also affecting slow wave activity in a similar fashion. Amphetamine That the problemis more complex gt_§l, 1951), mescaline (Merlis and Hunter, 1955; ‘Ib (Bente gt_§1, %§?b§i$ 1955), lysergic acid diethylamide ”iuuéig,snd diphenhydramine (Diaz-Guerrero et a1,1956) also reduced post-convulsive slow wave activity. In these reports, such a reduction was accompanied by excitatory and stimulating effects on behavior. These compounds, however, are primarily sympathomimetic and antihistaminic in pharmacologic activity and not anticholinergic. The similar effects of these diverse biochemical agents on electrographic patterns and amuauibusfi be behavior may rat-ind within theoretic on clinical (Lennox «K2~Kssrsr'6247 ‘fitfiix “fi’ constructs of synaptic activity;r— mm w The existence oftwo, or possibly three, Mypee cf interact~ 'AQ/ 1. m.“- ing chemo~re§pofisive receptors withinthd‘central ner::gg,system �/ (I W24: L M7? 5 ,7 v M/ ’46; MW w- M} Arm/a; Ail/”M Wag .- f �“Jamal-un- h awmh'auu: gnaw“WWW WU“we ' lead to a change in synaptic cholinergic activityywhésh—és— reflected:h11llhsurface electrodes as augusntsd high voltage slow wave activity. Administration of anticholinergic agenggijltenfl'synaptic activity, resulting in a decrease in the manifest cortical electrical activity to preconvulsive levels. Administration of sympathomimetic agents 3f-lg-‘Leja-‘fiieve/ the same electrical effectsr-s-s-t-by—ns4tssang—tha—1saol—sfrehoiénsrgss—sstinitanbat by increasing the level of adrenergic activity. The manifest slow wave A activity, so prominent and so persistent in thsffi::;ng£§;:& -ss«the—pust-setzure-statej may thus be viewed as tho resulttnf persistent alteration in the synaptic tssssméssésn activity of large numbers of cells of the central nervous system. The delicate nature of this balance is seen in the ready reversibility with alerting, time, and the wide ~qflra variety of pharmacologic agents.nntsdwhaner-m~m~"~"“ ’jifi/ér\:;> The consistent nature of these neurophysiologic observations all. makes an exclusively psychologic explanation of the mode of action of convulsive therapy less tenable. These studies are consistent, however, with the neurophysiologic-adaptive view of the convulsive therapy process which suggests that neurophysiOlogic chanazMs provide the substrate for alterations in all aspects of cligical behavior} fg’h" �Ma . ,W‘ w, .M Won/7w AC ,W W hyLWM MWMWM'W“ W 5 I414} 2‘5 Maxwu 4; ’ :73? (/ija; Z; W Wag a, WM7£ ILL-«44.1“ 04”), MLIMK W; ”W MW; “4344: a' WM W I a; a. L « �-17- we, of~the—oabaeetp"{fln type of behavioral alteration ts fisvwig dependent upon the type and degree of neurOphysiologic change, the personality of the subject and the expectations and tolerance of the milieu (Weinstein and Kahn, 1955; Fink and Kahn, 1957; Fink, 1957). (b) Neurophysiology of hallucinogenic activity: The effects of anticholinergic compounds on EEG and behavior may also be related to the understanding of experimental hallucinogenic activity. Each of these/tzzgfunds induced illusory excitatory behavior, including 4L phenomena. m Here, too, the synaptic and hallucinatory model] may be applicable. Sympathomimetic agents, as mescaline, LSD and described amphetamine, and anticholinergic agents as those here, are 01-‘3iv potent hallucinogens. A neuropharmacologic basis for such behavior may be characterized as an alteration in the level of synaptic activity in the direction of increased inhibition (decreased transmission) of stimuli. ‘The clinical efficacy of convulsive therapy in modifying hallucinatory activity may lie in alterations at this neurophysiologic level. . The effects of such hallucino- genic blocking agents as chlorpromazine and reserpine on EEG electrical activity are consistent with such a view. Both compounds induce EEG hypersynchrony in man (Bente and Itil, 19Sh, 1958) and block the EEG desynchronization effects of LSD and mescaline (Schwarz et al, 1955). �-19Chlorpromazine was found equally potent in aborting the excitatory activity of the experimental anticholinergic compounds in these studies. (0) Relation to atropine: Comparison of the systemic and neurologic effects of eXperimental anticholinergic with atropine reveals signi£ieaat differences.«av ax/Aaf compounds {pH/95 s:%bé§i£3§§§§2::ence with atropine at physiologic and toxic levels in man indicate that the predominant effects are focused at peripheral nervous structures. Initial bradycardia, followed,by tachycardia, loss of sweating and salivation, pupillary dilation, intestinal relaxation and decreased motility are amongst the effects at low (0.2-1.2 mg) dosages. At higher dosages (2-5 mg), the neurologic effects and delirium are of ataxia, irritability, disorientation, Mgr...“ observed (Goodman and Gilman, 1955). In atrop' e coma therapy, 7amounts ranging from 32 to 212 g injected int amuscularly into psychiat ic patients resul s in the fell wing sequence (Forrer and Miller, 1958): "Th re is an induc ion period of 15 to 20 minufes after adminis ration charactkrized by V mm:Wm..- ! 2 I . Jonfusion, and . restlessnessg ceaselonally mil excitement, at times naufca and rarely vo ting. This p oceeds, smoothly and predictably, to muscular coordination, ataxia, weakness, vertigo and ifficulty in artffulation. An cute brain syndrome wit. memory dis turbanhe, disorienta ion, clouded illusions and mtst frequently kisual hallucinaconsciousnesf, tions mergesa into delirium and§.:;rapid1y proceehs to coma. ..." I ‘ I ’ ; �-20.. Thus/central nervous system effects arevprecededwwv accompanied by marked peripheral effects?” contrast, the experimental anticholinergic agents in dosages sufficient for central nervous system effects manifest little peripheral activity. The central effects are observed early and may continue for extensive periods without gastrointestinal, cardiac or pupillary changes. It is within the context of the focus of activity and w. -din relation to dosage that the apparent discrepant EEG observations of the effects of atropine (in inducing slow wave activity) and these experimental anticholinergic In reconciled. Wescoe gt_al (l9h8) administering 1.0 to 3.0 mg/kg atropine in curarized cats and monkeys and Funderburk and Case (1951) using O.h to 1.2 mg/kg in curarized cats, observed high voltage EEG slow wave activity. Wikler (1952, 1957) reported that 7.2 mg/kg atropine on unanesthetized, uncurarized dogs produced "spindle slow wave" patterns at-ihiugiy similar to sleep. Rinaldi and Himwich (1955a, b) reported that atropine in doses of 0.5 to 2.0 mg/kg in curarized rabbits exaggerated EEG sleep patterns and inhibited the alerting of the EEG to unit-l: peripheral stimuli. Similar observations have been reported by compounds may be Bradley and Elkes (1953) in the conscious cat. In each instance the dosage of atropine varied from 0.5 to 7 mg/kg - a range roughly comparable to the dosages used in atropine (me'w‘ Md: We’rfrfg. “ma therapy! �: M 4% 1mg,» Jyyzmw f)”; r gag“; m mflfl/w 1:; @c‘jf jaw/(4,4,2... W a; 351,, fgflzfl, �-21'éoueraduuage? Auéf In thelzn;tudies, the ‘g’ flfimal EEG effects of low dosages of intravenous atropine (0.01 to 0.10 mg/kg) were minimalaasfi CMMHKM éfi, ifikbfi iconfirming similar observations by Verdeaux anglflgrfizw (195h) and by Danielopolu et al (1955)., Danielopolu et a1” Wmmwflwawmqum specifically related the EEG effects to dosage levelvfw” ith high dosages of atropine in rabbits ( h to flffig/kg) . W wa‘ianMu-‘rm‘m. -W«m««uw~w ~w-wwmw~wmmw .; m W. ..,..-..g., , m ,u . swan-bani" .twmi-mc”1; ~11.»- . man. ; they observed similar high voltage mixed slofifand fast activity, while with low dosage (.Zh t9 id mg/kg) the original apid rhythms remained hgphanged. These authors It fy~”' thus sugges d that atropinetg effects were multiple and“ related the EEG ob rvationgxtg similar findings with rega dfitfi heart rate. Danie ported earlier that s 11 doses of atropinesloqed cardiac rhythms while/larger dose caused acceleration. These dose determine ’ and cardiac observations have recentlyxbeen confirmed (Morton 232;; ‘ Thus, while considerable speculation as to central neurophysiology has been based on studies with atropine, té§LL——— special case of anticholinergic effects. The anticholinergic activity,—eo—pnonéaeatky established in observations in vitro and in the peripheral nervous system, may not be the effective physiologic activity in the large doses necessary to affect central such observations provide a �.. 2 2 - Th3’2xperimental compounds z:::=zm—the~preeontm the flflfigw provide more structures. s-‘bu-d‘éoo flow/M)“: udtuoédubéon of suitablewe} Wfor central neurophysiologic (anticholinergic) patterns than atropine] M, #AMcuu/eml AM» In part, these physiologic differences may be re to differences in structural chemistry. Each of the experimental compounds contains a tertiary amine linka e, while atropine contains a quaternary linkage. The e fect of structure on in vivo pharmacology may be clea y observed in the structure-activity relationships of e piperidyl- benzilates (Abood 22.21:.1953)' While -methyl-3-piperidylbenzilate and N-ethyl-B-piperidy enzilate have potent anticholinergic and hallucinoge \c-potency, N—dimethyl-B-piperidylbenzilate - the quate ary compound - has considerable in vitro anticholinergic tivity but no hallucinogenic property. nd Hoch (1957), Denber (1958), Naka (1958) and Flodmark i (1958). f_ _-‘_ , f - . in.a re-evaluation 05‘studies ,_”4 , 1 7 ,. _éwr of craniocerebral trauma and epilepsy. Ward's (1950) reports of the efficacy of high doses of atropine in altering the clinical manifestations of head trauma indicated that effective doses brought with �-23- effects. The failure of atropine to affect epilepsy may be related to the them severe systemic and scopolamine inability of these quota-unis compounds to reach the central nervous system in adequate quantity. It would seem advisable, therefore, to repeat these studies utilizing ardfiuf such mere-paten%7~more centrally speeésée..anticholinergic , compounds as used in the experiments reported here. �'Zh' SUMMARY: 1. EXperimental anticholinergic compounds (diethazine, Win-2299, benactyzine, JB-318 and JB—336), administered to psychiatric patients at various stages of convulsive therapy, were associated with: (a) desynchronization of EEG rhythms with a blocking of post-convulsive delta activity; (b) alerting, excitatory behavioral reaponse with illusory, delusional and hallucinatory ideation; and, (c) systemic effects of muscular weakness, dryness of the mouth, dry skin and tachycardia. electrographic behavioral and systemic effects were The concurrent. that an fl; 2. observations are consistent with the suggestion “faxmufaui These We!) thug,” ” ' of convulsive therapy'iilllllr.4fl increase in central nervous system cholinergic activity. 3. Observations that LSD, amphetamine, mescaline and diphenhydramine - synpathomimetic and also induce desynchronization, blocking of post convulsive EEG delta activity antihistaminic agents - and clinical excitatory activity support the suggestion that bUth-hhu behavioral and electrographic based on alterations in synaptic activity,, sis Patterns Increased synaptic activity (cholinergic, sympatholytic effects) we ,4 �-25- hypersynchronization, and clinical sedation and euphoria; while decreased synaptic activity (anticholinergic, sympathomimetic) is associated with EEG desynchronization and clinical excitatory and hallucinogenic is associated with EEG states. Discrepant observations with the-entéehottnergifi agent? atropine are related to significant differences inrfiéfvfifygw’ h. .thawnantzalMnenuensmsaatanmaiflactsmofimhighudeaagamainapinefl Re-assessment in_man_maxanataha4nninanil¥_anaiahnlinargis. of the role of anticholinergic agents in head trauma and seizure states is suggested. 5. These observations amplify the neurophysiologicadaptive hypothesis of the mode of action of convulsive therapy and of experimental hallucinogenic states. �ACKNOWLEDGEMENT: I Hannah {Efl grateful for the technical assistance of Mrs. Mosquera in EEG recording and analyses; and—to— am Supplies of the various pharmaceuticals were made freely available by Lakeside Laboratories (JB-318 and JB-336), Merck Sharpe & Dohme (benactyzine), Sandoz Pharmaceuticals (LSD-25), Sterling—Winthrop (Win-2299) and Smith, Kline & French Laboratories (diethazine, chlorpromazine) �:f/ébétp/g 04M¢MW71M£04¢ W, 2: wow f/éétdi./g.7 JAM/47 7249.; ’9‘” M MW «044ml. W,- m; {fJZ/ E.- 37I-370‘ �-27Abood, L.G., W4} “E:ZLE:D Ostfeld, A.M. and Biel, J. new group of A psychotomimetic agents. Proc. Soc. Exper. Biol. Med., 1958’ 21: hq'é‘h86o Bente, D. and Itil, T. Zfir Wirkung des Phenothiazinkorpers Megaphen auf dasuMehschliche Hirnstrombild. Arzneimittelforsch§:“l95h, Z: h18-h23. Bente, D. and Itil, T. A comparison of the action of various phenothiazine compounds on the human EEG. Trans. Int. Cong. of NeurgpsychOpharm., 1958, (in press). Itil, Electroencephalographic studies concerning the action of LSD-25. EEG Clin. Bente, D., T. and Schmid, E.E. Neuroghysiol., 1957, 2: Bente, D., Itil, 359 (abst.). T. and Schmid, E. E. Elektroencephalon graphische Studien zur Wirkungsweise des LSD-25. Psychiat. et Neurol., 1958, $25: 273-28h. Bradley, P.B. and Elkes, J. The effect of atropine, hyoscyamine, physostigmine and neostigmine on the electrical activity of the brain of the conscious cat. J. thsiol., 1953, lfig: 1h_-15; Bradley, P.B. and Elkes, J. The effects of some drugs on the electrical activity of the brain. Brain, 1957, g9: 77-117. Coady, A. and Jewesbury, E.C. A clinical trial of benactyzine hydro<3hlcride ("Suavitil") as a‘physical relaxant. Brit. Med. Jour., 1956, l: h85-h87. �-2&- Danielopolu, D., Giurgea, C. and Drocon, G. Electroencephalographic study of the non specific pharmacodynamics of the stimulatory effect of atropine on the cerebral cortex. ” Fiziologicheskiy Zhurnal SSSR, 1955, El: 60l~611. Denber, H.C.B. Studies on mescaline: III. Action in epileptics. Psychiat. Quart., 1955, 32: h33-u38. 9.,see;4a;é:§;fs;ag"inasced stgtgg”.gsembiagg“..tur.11y occuring MW psychoses,‘mgM ~jrbpicDrugs. Elseviar, / r Amsterdam. 1957, 263S Diaz-Guerrero, R., Feinstein, R. and Gottlieb, J. S. EEG findings following intravenous injection of diphenhydramine hydrochloride (Benadrylr). EEG Clin Neuro— ‘ 7 Evarts, E.V. Neurophysiological correlates of pharmacologically induced behavioral disturbances. Res. Publ. Ass. Nerv. Ment. Evarts, E.V. Dis., 1958, 2§:3b7-380. Chemical bases for psychoses. Concepts of Psychoses. 1958, Fink, M. A Chemical McDowell, Oblensky Inc., N.Y. hl-62. unified theory of the action of physiodynamic therapies. J. Hillside Hosp., 1957, g: 197-206. Fink, M. Effect of anticholinergic agent, diethazine, on behavior: Significance for theory of convulsive therapy. A.M.A. Arch. Neurol. & Psychiat., 1958, EEG and 29: 380-387; M Wflifi‘f‘féy A2u&“x dad Akhaifin, za37.,/ff4: £1.J./Ita4u/t-W‘Wfi fifi¢’{7¢£ �-29Fink, Relation of electroencephalographic delta activity to behavioral response in electroshock. M. and Kahn, R.L. A.M.A. Arch. Fink,mu. and Neurol. Jarre, J. & Psychiat., 1957, Drug induced changes 1Q: 516-525. in interviEW“‘ patterns.iiconf”“onoFsychodynamic Aspects of Neuro- leptic ‘‘‘‘‘‘ ) FloemargE S. ,afiines ed. J. Sarwer-Foner (in press). effect of some tertiary andwgnatornary QEggs, The EEG Clin. Neuro~ activity. “MM“MW 753 (abst. ). WNW WM 1958,10: mag; on a3”rww¢ m“ at“ M“ Forrer, fik and.Miller, J.J. Atropine coma: A somatic therapy in psychiatry. Am. J. Psychiat., 1958, 115: G. h55~h58. rFunderburk, W.H. and Case, T.J. cortical potentials. EEG The effect of atropine on Clin. Neurophysiol. 1951, 2: 213'2230 Goodman, L.S. and Gilman, A. Pharmacological Basis of Therapeutics. Macmillan, N.Y. 1955. Heymans, C., Estable, J.J. and de Bonneveaux, S.C. Sur la pharmacologie de la phenothiazinyl~ethy1diethylamine P.). Arch. Int. Pharmacodyn..l9h9, 79: 123-138. Jacobson, E. Suavitil, et nyt stof pa centralnervesystemet. Egg: 11b7-1151. med specifik virkning Ugeskrift for Laeger, 1955, \ “1v, . 1.. ... WWW»-.- �-30. Jaffe, J. An % .5 .1...WW... objectiveeWudy6f communication 1npsychiatric . E A. WM... J H11151de Hosp., 1957, 6: 207- 215. L_wwflwaéminterviews.; Jenkner, F. L. and Lechner, H. The effect of diparcol on i A...“ ( 3 _5/ the electroencephalogram 1n the normal subject and in those with cerebral trauma. EEG Clin. Neuroghzsiol., 1955, 1: 303-305. Kahn, R. L., Fink, M. and Weinstein, E. A. Relation of amobarbita1.test to clinical.&mprovement in electroshock.Wégégfkefirch. Neurol. &szchiat., 1956, 76: #‘YMW n Maren Kahn, W» A: ,F1nk, M. RL.and shock. Ps WM““‘0 Changes in language "‘"' Ann/n" .3!" w». déy;gf Communication. Grune c /’”’“MFStratton, NY. MHA./ danng“éIectro- f & 1958, 126- 139. Lechner, H. 0n the influence of anticholinergic drugs on the EEG of recent closed craniocerebral injuries. EEG Clin. Neurophysiol., 1956, 8: 71h-715. The Lennox, M.A., Ruch, T.C. and Guterman, B. benzedrine on the post-electroshock effect of EEG. EEG Clin. Neurophysiol., 1951, 2: 63-69. Marazzi, A.S. Some indications of cerebral humeral mechanisms. Science, 1953, 118: 367-370. -Marazzi, A-S. Effects of psychotomimetic drugs on cerebral synapses. I t .,.«-~,«.... Psrchotropic Drugs. Amsterdam, 1957, 283-286. u s. Elsevier, “.11Relationship gflhAIEucffiéééns mun-qua- a. M. z ._ may, 13;:w365-367. 2 ' aAd Hart E. E. Marauai,A “NW 5%”to adrenergic cerebraineurohumors. Science, 1955, w.“c.m,, ”“Vmw~emn f .1 �-31- Studies on mescaline: II. Electroencephalogram in schizophrenics. Pszchiat. Merlis, S. and Hunter, W. Quart., 1955, 29: u3o-h32. W Morton, H. J. - WM...wr-i“ mm“wv'wm‘ and Thomas, r E T. ,.. MW~;:-a‘ ST MW own—VT“ mam»Warmest“ “: “NM“ 2,1958 13131315 HIM-~14“ humumwnhaartwrat? emfancet Naka, u. Effect of atropineon thew if , ..:. ¢~w m«w. v,;<w~1»~ww-.. Afloé:§€fi?bpgychopharm., 1958, wammwa Pennes, H.E. and Koch, P.H. ,1 I"; anununnwwnmsu ”N; . Trans. Int. Cong. wunme:::;::ZZZZZZZw (in press) Psychotomimetics, clinical theoretical considerations: Harmine, Nalline. Amer. J. Pszghiat., 1957, 112: and Win-2299 and 887-892. Rinaldi, F. and Himwich, H.E. Alerting responses and actions of atropine and cholinergic drugs. fi;fl;§. Arch. Neurol. and Psychiat., 1955, 12: 387-395. Rinaldi, F. and Himwich, H.E. Cholinergic mechanism involved in function of mesodiencephalic activating system. A.M.A. Arch. Neurol. & Psychiat., 1955, 12: 396-h02. Roth, the EEG under barbiturate anesthesia produced by electro-convulsive treatment and their significance for the theory of ECT action. §§§_ Clin. Neurophzsiol., 1951, 2: 261-280. M. Changes in Roth, M., Kay, D.W.K., Shaw, J. and Green, J. Prognosis pentothal induced electroencephalographic changes in electroconvulsive treatment. EEG Clin. Neuro- and �-32Schwarz, R.E., Bickford, R.G. and Rome, H.P. Reversibility of induced psychosis with chlorpromazine. Mega 2522. Clin., 1955, 29: h07-h17. Central cerebral chemicals and their relation to psychoses. Chemical Concepts of Sherwood, S.L. Pszchosis. McDowell, Oblensky, N.Y., 1958,v268-276. Strauss, H., Ostow, M. and Greenstein, L. Diagnostic Electroencephalography, prune Ulett, Stratton, N.Y., 1952. & Effect of atropine and scopolamine upon electroencephalographic changes induced by electroconvulsive therapy. EEG Clin. G. A. and Johnson, M.W. Neurophzsiol., 1957, 2: 217-22h. Verdeaux, G. and gramme de _4kum..u“W" clinique. WhamWmmw uwm “my echovsky, M. Marty, R. Action sur l'electroencephalo- substances pharmacodynamiques Rev. A d'interet Neurol., l95h, 91: hOS-h27. psych031s caused intoxicgtlonwWwAgggBayohiat by benactyzine Wmmwaw 'et www.mo.‘w:_mh‘”w mu... W NW. grams ”KM—i ““"C;L;ww ”w Mes-mm Neurol. Scand. M fi,‘ "”§2}&, A. Atropine in the treatment of closed head injury. J. Neurosurg., 1950, 1: 398-h02. Weinstein, E.A. and Kahn, R.L. Denial of Illness: Symbolic and physiological aspects. Springfield, 111., 1955. C. Thomas, R.E., McNamara, B.P. and Krop, S. influence of atropine and scopolamine on the Wescoe, W.C., Green, The central effects of 63-72. DFP. J. Pharmacol., l9h8, 22: �-33. dissociation of behavior and EEG "sleep patterns" in «iogs: morphine, N-allylnormorphine and atropine. Proc. Soc. Exper. Wikler; A. Pharmacologic Biol. Med., 1952, 12: 261—265. Wikler, A. The Relation of szghiatry to Pharmacologz. Wilkins, Baltimore, 1957. Woolley, D.W. Serotonin in mental disorders. Res. Publ. Ass. Nerv. Ment. Dis., 1958, 2g: 381-h00. Wm. �On this sheet please prepare for publication in BIOLOGICAL ABSTRACTS a typewritten (double spaced) abstract of your paper and attach it to your corrected proof. Since proof cannot be furnished, check your abstract critically—especially the citation, scientific names, formulas, chemicals, and technical terms. An abstract should be an informative digest of the significant content and conclusions of the paper, not a mere description. It should be intelligible in itself, without reference to the original, but is not intended to substitute for it. It should be brief (preferably less than 3% of the original), written in whole sentences, not telegraphic phrases. For directions, please see the reverse. Sample Citation: DOE, JOHN J. (U. Commonwealth, Capitol City), and RICHARD ROE. Metabolism of phosphorus in rats. Jour. Pest Control Res. 37(4): 152-165. 1957. Detach here and return lower portion only �A GUIDE FOR THE PREPARATION OF ABSTRACTS CONTENT—Include: 1. Name of organism, and objective of the study. 2. Materials, manner of use, or route of administration, principal findings, and results. 3. New techniques, their uses and qualities. 4. New apparatus, its intended use, and if commercially available, name and address of its manufacturer. 5. New or verified data of permanent value, e.g., absorption spectra, chromosome numbers, constants, mathematical or chemical formulae. 6. New genera of animals/ plants, new classifications, new distribution records. (For systematic data, see below.) ,7. New theories, new interpretations, evaluations, if possible; if not, reference to them. ‘ -Omit: Information contained in the title. 2. Additions, corrections, or any information not contained in the original published paper. 1. FOR SYSTEMATIC PAPERS—Additional instructions. FORM: 1. Write the name of a subgenus, genus, or any supergeneric taxon, if old, in small letters with a capital initial; if new, all in capitals. The name of a species, subspecies, variety, or form is never capitalized. 2. Alwa rs underline the name of a genus, subgenus, s ecies, su species, variety, and form: with a straight ' e if old, with a wavy line if new. No other group name is ever underlined. Write the name of a new combination of a species from one genus to another) transfer ‘ (e5: a straight line under the old and a wavy line under the new or shifted part, followed by the basonym and its author in parentheses. CONTENT: Be alert to information other than the formal, strictly taxonomic and nomenclatural. Summarize or men— tion new data in any biologic field—life history, morphology, biogeography, cytology, ecolo , evolution. (Nontaxonomists welcome such information. NEW TAXA. Omit detailed descriptions, long synonymies and ~ �DEC 7'5 3.959 m, x. (mm. Hume-1. mm m, a. 1.). mm or MWo W m m. W on Wu But EEG mum- and 101. mm mummrm mm (cu-mum. win-2299‘. administer“ to mum-'10 patent- flung, are «minted with n blocking Wtua Fatima. . JB~318 and 38-1336). Wu of of. with! It various «mutation a: mm, than at EEG rhythm pelt—amid” delta wtivity; darting, mum-y illusory. donning: and mnucinatory mum; and attacks of Ins-mm mimosa, drynosa of the mouth, dry akin md can— halyard“. The cloemgraphic, behaviml and manic offsets behavioral We mt.The“ mom. with m ' Mmtiam suggest. that. a «mimosa: film is an 1mm in mtml mama “timers What at convulsive dim Mastic” that LSD, «momma, 30mm and aynpumm and awakening agomm -. also mam EEG deaymhnoniuum, blocking of post «mun delta activity and clinical Quinton? nativity support. the suggestion hand on that behavioral and durum in mm scum“ mug activity ehctmgnphie panama any be It is suggest“ that. increased (ahelinorzia, mamas atom) 1: associated mm EEG and cumin}. mum and euphoria while Mmud Widen, �‘_ W", . ”-77 .V . ,. . . ,, .. .. w. . ..‘Vr._.wum“.mmm————__——_q‘_ 02¢ mm activity (autumn-31¢, metie) is associated filth Em WWfian and clinical .33th and WWW: cum. Wampum; observations with atropine are round to significant hmmmnt a: the role of mtichonmme agents in head tram md «ism auto-n in mggaltad. no” chain-tum mpnfy the mmyhyaiologimfinptin Wham at the m or motion of cmlsiv. thorny and of ”puma hallucinogenic out». Mfume” in damage. �HS 981 33130? 0! ANTIGBOLINERGIG GOHPGUIDS OI P03? GOHVULSIVE EEG AID BEHAVIOR OF PSIGEIATRIG PATIENTS nux Fink H.D. (Rocoivod for publication: larch 11, 1959) Iron tho Departnont of Exporinonttl Psychiatry, Hillaid. Ronpitnl, Glon Oaks, L.I., 3.1. purt, by grant. H-927 and 31-2092 at the Nationtl Mental Hotlth, lutionul Institutes of Health, 3.8. Public Konlth Serviel. Icad at tho Alcricun EEG fiocioty, Atlantic City, June, 1958. Aided, 1n Institute of 11: 5/59 �HS 981 AlfialflLIlElGIG GOHPOUIDS AID POST GOIVULSIVE EEG �Ettact or Anticholinargie Compounds on Post Convulaiva EEG and Bohavior at Psychiatric Patients BIG Daaanatrationa or the aignificanea or high voltage dolta activity in the gonvulsive therapy procaaa (Roth w, this delta activity report that was blocked by the adniniatration or atropina and acopolanina (Ulatt and Johnaon, 1957) provided the basis for than. studioa. A: there were attendant nnplaaaant ayatoaic effects with the adniniatration of than: agents, report: describing diethalina as an antiehalin~ crgic compound with potent neurologic but minimal systolic affects (Janknor and Lcehnar, 19553 Laehnar, 1956) led an to undartaka studio: similar to those of Blott and Johuaon using this coapound (link, 1958). aboarvationa with diathasine lad to the invaatigation of othar experimental anticholinargic 1951, 1957; Fink and Kahn, 1957) and thc agonta. report daaeribac clinical and olactrooncaphalo» graphiu observations ineidant to the intravenous adniniatration at various anticholinarzie agent: in psychiatric patients at various stage: of convulsive therapy and relates the obaarvationa Thia to hypotheaaa eonaerning tho and. or action a! canvulaivc therapy and of hallucinogcna. �SEBJEGTS LIE KETKODi subjects were ninety psychiatric patients referred for convulsive theraoy. ages ranged from 18 to 67 years, and diagnoeee included schizophrenia reactions end nanio-deoroeaive end involutiona1~depreaeive peyohoeeo. a varied number of eubjeote were etudied for eaoh oonpoond for a total of 107 observations. Patients have been obeerved at variooe etagea or the treatment prooeee. The obeervatione were made in the EEG laboratory, using a standard 8 channel EEG recorder and noodle oleotrodee applied in 17 lead placements following Streuee £t_2; (1952). In eeoh trial, the compound under study we: administered intravenously at a set rato per uinnte until clinical behavior or electrogrephio changes were The obeerved. The compounds et a1, 19h9), studied have been diethezine (Reynane Win-2299 (Pennee and Hooh, 1957), benactyoine (Jacobeon, 1955). JB~318 end JB~336 (Abood ££_5;, 1958) end atropine. Diethaoine was administered at 25 mg per minute for a total or 175-250 I: (3.5-5.9 nelkg); w1n~2299 and bonaotyeine at 0.5 mg per ainute for 2 to 5 e3 (0.02~0.15 eg/kg)3 and JB~318, JB~336, and atropine et O.h mg per minute for 1.2 to h.0 mg (0.01~0.10 mg/kg). �OBSERVATIOHSa- (a) Diethaeine: administration of diethaeine in fifteen patients prior to convulsive therapy reaultea in a decrease in EEG voltages and a deeynchronieaticn of all trequenciee. Prevailing rhythmic patterne becane leee pro» nuanced. In acne inatanoee, symmetric low voltage 6-7 epa activity appeared and wee aoet apparent in frontal and anterior temporal leade (gink, 1958). In twentyative patiente with varying degreee of induced high voltage delta activity during convulsive therapy (rink and Kahn, 1957), there was a significant decreaae in voltage and in per cent tine of aloe wave activity. Iron an average delta or hSS in the trontnoeeipital leade, there was a reduction to a mean of 201. Both render and beret delta activity dininiehed. Low voltage alpha and beta frequencies became more prominent. The usual increase in per cent tine and in voltage or slow wave activity with hyperventilation was no'lenger apparent. Theee electrographic effects appeared during drug administration and pereieted for one to five houra (link, 1958). The . Concurrent.vi}h these electregraphic effecte, we cbeerved dietinctive eyetemic and behavioral changes. The initial eyetenie effects were episodes of coughing and complaints of dryneee of the mouth. Skin reaained dry and the heart rate increased by 5 to 10 per cent. this increase �-5- rarely noted by the preoordial'dietraea. not aoconpahied There was no change in papillary by sine, and constriction in response to light wan prompt. There were occasional oozplainte or abdominal griping. Such effects were generally less prominent than the electrographio or behavioral. was eubja ot, and was lehaviorally, patients hooano irritable, restless, tense and excited, and it was difficult to maintain eyelid closure. they oonplained or feelings of unreality and or tingling, weakneee and heavineea or the extremities. Oonplainte that color: were pale or more intenea, halos about lights and changing shadows were accompanied by delusional thoughts about their illness, the setting of the test procedure or the axaainer'e identity. (h) that Win—2229: Win-2299 induced The report illusory by Pennee and Hoch (1957) hallucinatory states in intravenone aaniniatration and led to this next etudy. 0n o: win-2299. both electrographic and behavioral attests einilar to diethaeine were obaerved. In five patients without EEG aloe wave activity, deeynohronisatien of frequencies and a deoreaee in voltagee were noted in four (Fig.1). “QC“.-.‘-- man, fig. 1 In eleven patiohto with high voltage delta activity there was a decrease in amplitude and per oent time of slow wave activity with an increase in the par cent tine of alpha and �.5beta trequcnciee. tc 235 (Fig. 2). The neen delte ectivity dropped tron Fig. 50$ 2 ,ieeccietcd with these clectrcgrephic effecte were clinicel patterns of reetlceeceee end excitement, end minimal eyetcuic effecte. Petiente becene teertul end tense. Vieuel illuecry eeueeticne were reported end were ececcieted in theee eubjecte with deleeicnel elebcreticne about their hospital experience. Excitenent yea ecccnpenied by ideas of reference, end in two chjecte, intrevencue chlcrprcnesine wee edainietered to halt this process. Theee behevicrel chengee eppeered during drug eduinietreticn or within ten minutes, end disappeared within two to three hcnre. systenic effects were alight. there were neither cough nor rcepiretcry dietrccc. Scert rete wee unettected except in petieate who becene overtly excited and teertcl, in vhcn techycerdie eppeered during thie excitement peried; Dryneee cf the ecuth wee repcrted only on direct inquiry. (c) Benectieine: Reports that bonectyeine induced EEG deeynchrcniseticn (Ccedy end Jeweebury, 1956), its enti~ chclinerzic nature, end the etrccturel cinilerity to dietheeine and to Win-2299 led to our touting ct thin ccnpcund. Intrevencne edninietreticn in 12 subjects elicited similar clinical and electrcgrephic petterne. Bath in the well ncduleted elphe record and in the reccrd with high vcltege delte ectivity, deeynchrcnieeticn wee prompt. Dclte ectivity decreased trcn - �.5a mean time of 391 to 165 in 8 Fig-t, These electroxraphic by subjects (Fig. 3, h). 3, h~ patterns were ngnin acconpuniod clinical roctlenlneol, irrittbility and oxeitcmont. Artifactwrree recording was nor; difficult.. the illusory sensitionl ind dblunional thoughts a¢en with the initinl aénpounds were hot notad at then. dongs. luvtla. Syatcnie effects wore niuilar to Win-229?. ‘ (d) Piparigylbanzilatoa: Following racont reports by Ahead 33_§; (1958) that various pipcridylbcnailatca with nynaurxblo antichoiincrgie activity induced hallucinations in psyehintrie subjects, we taut-d JB~318 and JB~336 in 2h vubjoets. Thu olectrogrnphic'pntterns wort identical with the other experihonttl antiehulinorgia compounds. Dosynchrenination of troquancios wan noted during the injectian or within 15-minute: and pornistod tar due tp {our hanrs (Pig. 5). O’Qflflfiflw Fig. 5 In each inataneq in whieh duaynchronixation was obaarvad,‘ ainicnl restlolancau, excitcnont, illunary and hallucinatory activity were acted, and were eonuurrant with the nloetrographie changes. In two inatuneoa the behaviornl changoa wore haltcd by tho intravonoua administration or chlerprenasino. , �-7-(c) Atronins: Considering the numerous reports that atropine_indnced EEG elow wave activity and clinical eonnolence, we adninistered this anticholinergic agent intravenously in 15 aanecte, in dosages of 0.8 to h.0 as (.01~.1o ng/kg). In six snbjecte without EEG delta activity, there were no changes in EEG pattern during drug administration nor for 10-20 minutes theratter.. During a period of laseitude, decreased voltages, minimal desynchronication, and an increase in per cent tine'delta were noted. In subjects with delta activity, there nae an apparent initial decrease in voltage and per cent tine or each activity during the first ten ninutes after adainistration, followed by a return to original values during the period of quietode. In neither period were the changes significant,: (31:. 6). fi Fig. 6 systemic effects were prominent during the injection with increased respiratory rate, pallor, dry skin and dry precordial complaints increase in heart rate up to 10oz. Subjects became restless and recording became difficult. Within ten ninntes these symptoms subsided and the subjects became drowey and relaxed. mouth, and an �-8DESGU$SION3 In those studies, varione experimental compounds with neaenrable anticholinorgic activity have been obeerved to have similar electrosrephic and behavioral effecte.' Electrographically, each agent induced a doeynchronination of frequencies and a decrease in voltages, which was most prominent in cubjocte with delta activity following convulsive therapy. Behaviorally, theee electrographic patterns were aceociated with stimulating, excitatcry, illusory and hallucinatory activity. To a leeeer degree, ainiaal oysteaic changes in heart rate, eelivetion and eweating were noted. Theeo latter eyeteaic cffccte were lore prominent in patiente given intravenous atropine under einilar experimental conditione. Thceo obecrvatione can be related to theories of the node of action of convnleive therapy; to concepts of the basic of experimentally induced hallucinatione; and to roporte of tho effocte of atropine on EEG patterns. (a) Convaleivo thcrggy process: Earlier etndieo indicated that the development of high voltage slow wave activity wee a nenrophyeiologic correlate of behavioral changc in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement (Pink and Kuhn, 1957). In enanarieing the obeervationc of nuaerone authors on the relation of acetylchcline metabolic: to trauma of the central nervous eycten and to convnleione (Pink, 1958) it wee enggeeted that a biocheaical concoaitant of the induced EEG �.9. alov wove ootivity to. an increased level or acotyicholinoo‘ oholinootorooo activity of tho central nervous system. Tho . pro-ant oboorvations of altorotiono 1n the slow wave activity at oonvnloivo thorapy by that. oxporiuontal antioholinorgic compounds or. oonaiatont with this suggestion. That tho problon 13 not. complex is indicated by reports or oonpoundn with other biochemical activity alto ottocting clot wave nativity in o aililor faahion. Alphotnnino (Lonoox‘:1_g;, 1951), nonoalioo (Karlia and Router. 19553 Dunbar, 1955), lyoorgio acid diothylonido (Dante gg_g;, 1957 a,b) and diphonhydranino (Bios-Guerrero £3;=;, 1956) olso reduced post-convulsive slow wave activity. In these reports, such a reduction vac aooonpnniod by excitntory nod stinuloting effects on bohtvior. Those conponndo, hovovor, are prinarily oynpathoninotio and antihistoninio in pharfiaoologio activity and not antioholinorgie; 81n113r_oftocto of those divoroo bioohomical ngontt on olootrographio patterns and on cliniool behavior may be oonoidorod within thoorotio oooatruota of the relation of synaptic ootivity to behavior on oxproauod by Harolsi (1953, 1957), Brndloy and Blkool(1957), Evarts (1958 .,b), Sherwood Tho thono author: nnzgoot thot tvo ohonoroopon-ivo roooptorl oxiot within (1958) and Hoolloy (1958). typos or interootiog the nervous oyston which or. Iolootively roopoouivo to oholioorgio or to udrenorgio agonto. whore ouch rocoptorl oxilt, they oxort oppoaiog ntinolotory or inhibitory ootioo. �-10Thus, repeeted induced oeuvuleione mey lead to e choose in eyneptio eholiaergio activity, reflected in surface electrodes on high voltage slew wove activity. Administration or enticholinergio egente may alter eyneptie nativity, resulting in e decrease in the manifest aortioel electrioel eotivity to preoenvuleivo levels. Adeinietretion of eyupethoeinetio egente eey eohievo the gene electrical effects by inoreeeing the level of edrenergie activity. The neoiteet elov weve activity, so proninent end so pereietent in the poet~eeisure 328, any thne be vieved ee resulting from n persistent elteretion in the synaptic activity of large hunters of cello of the control rnervone eyeten. The delicate netnre or this balance is seen in the reedy reversibility with alerting, tine, and the wide variety of phernnoologio agents noted here. While an alteretion in synaptic activity may underlie the behavioral changes in coovulsive therapy, the neoheniel elteration is developed or eueteinod is uncleer. The obeervation by iird gt~gl‘(l956 e,b, 1958), that an inoreeee in permeability of the blood brain barrier followed‘ by which such repeeted indooed convulsion: euggeeta one sz in which synoptic ehengee eey be mediated. coneietent neture or these neurophysiolozio observation: nekee en exclusively payehologic explenetion e: the node or action of convulsive therapy lees teneble. These etudiee ere ooneietent, however, with the neurunxmyeiologio~‘ adoptive view or the convulsive therepy preoeee whioh eugzeete The �«11 an that nenrcphyeielcgic chengee provide the enbetrate for alterations in all aepecte cf the enbject'e clinical behavior; the type or behavieral eitereticn being dependent upon the type and degree of neurophyeiclcgic change, the personality or the eubject and the expectations and tolerance of the milieu (Weinetein and Kahn, 1955) link and Kahn, 1957; Pink, 1957). (b) leurcphyeialegy c: hallucinczenic activity: The effects of antichelinergic ccnpcnnde on EEG and behavior nay alec be related to the underetandinz or experinental hellucin» ct theee experinental ccnpcunde induced excitatery behavior, including illneery and hallucinatory phenomena. Here, tee, a synaptic nedel any be applicable. cgenic activity. Each sympathceinetic agente, ae neecaline, LSD and anphetanine, and anticheiinergic agente ea thcee described here, are alee potent hallucinogene. i necropharnacelcgic basis for each behavior nay be characterised ae an alteration in the level or eynaptic activity in the direction of increased inhibition (decreeeed tranenieeicn) or etincli. The clinical efficacy of ccnvnleive therapy in modifying hallucinatcry activity nay lie in alterations at thie nenro~ physiologic level, The effects or ench hallucinogenic blocking agents ae chlcrprenacine and rceerpine on EEG electricl activity are ccneietent with each a View. Both ccnponnde induce EEG hypereynchreny in nan (Bente and 339 deaynchrcnicaticn effects of 1955). Chlorpromazine was Itil, 195k. 1958} and b10¢k thd neeceline (Schware gt_3;, found equally potent in aborting the LSD and �-12. exoitatory activity of the experimental anticholinergic coupouoda in these etudiea. (c) Relation to atropine: Goapariaon or the eyetenic land neurologio effects of experimental anticholioergie compounds with atropine reveals ditterencea in initial focus of action, Exoerienco with atropine at physiologic and toxic levela in nan indicate that the prodoainant effects are :ocuaed at peripheral nervooe ctroctnroa. Initial bradycardia, followed by tachycardia, lose or creating and ealivaticn, papillary dilation, intestinal relaxation and decreased motility are. aaonget the effects at low (0.2-1.2'ug) dooagoa. At higher doaagea (ans :3), the neurolggic effects of ataxia, irritability, disorientation, and delirium are observed (Goodlla and Gilnan, 1955). ‘ In contrast, the experimental anticholinergic agents in doaegoo sufficient for central nervous system effects manifest little peripheral activity. The central effects are observed early and may continue for exteneive periods without gaetro~ intentinal, cardiac or pupillery changes. It ie within the context of the tocue or activity in relation to dosage that the apparent discrepant EEG observations or the effects or atropine (in inducing aloe wave activity) and the-e experimental antioholinergic coapounda nay be reconciled. I weecee 33_g; (19h8) administering 1.0 to 3.0 ag/kg atropine in curariadd cata and monkeys and funderbuzk and Ceae (1951) using 0.h to 1.2 ag/kg in curarised cata, observed high voltage EEG �.13.. aloe wave activity. Hitler (1952, 1957) reported that 7;! Ig/kg atropine on unaneethetiaed, uncurarieed deg: produced "spindle slow wave” patterns eiuilar t6 sleep.) Rinaldi and 'Hinwich (1955a, b) reported that atropine in doses of 0.5 to 2.0 mg/kg in curarized rabbits exaggerated EEG sleep patterns and inhibited the alerting or the EEG to peripheral stimuli. Sinilar observations have been reported by Bradley and Elkee (1953) in the cenecione cat. In each instance the doeage at atrepine varied tree 0.5 ta 7 ng/kg . a range roughly eoeparable te the deaagea need in atropine coma therapy (Ferret and Miller, ; 1958). In the present etudiee, the EEG effects at low deeagee of intravenous atropine (6.01 to 0.10 mg/kg) were minimal and systemic éfteete censiderable,cenriraing einilar observations by Verdeaux and Hartylfl95h) and by Danielepalu g§_3; (1955). the slow wave activify an prominent in animals and man at high doeazea at atropine, may not be a manifestation of the initial or direct effects at atropine, but a reflection of a more widespread alteration in body yhieialogy. Thee, while eeneiderable epeeulatien aa ta central neurophysiology has been based on studiee with atreyine, each abeervatione provide a epecial'caee at anticholinergic affects. the anticholinergic activity eetabliehed in observation: in vitro and in the peripheral nervous eyitee, may net be the effective physiologic activity in the large deaea necessary to affect centraldr‘cturee, rhe experimental cenpounde, however, provide mere euitahle �“15- for thu study of cantrnl nturaphysiologic (tnticholinargic) patterns thnn stropine, as, for oxunplc, 1a a ra~ovu1uut1an or the studio: at ertnieeorcbral trauaa :nd dpilcpay. Wtrd'l (1950)'r¢p¢rtl or the otticney a: high do... of atrepino in altering the clinical n‘n1£0ltatienl of hoad trnuau indicutod that effective dose: brought with than Invor¢ systolic ortoctl. the tntluro of ntgopino and scopolnninc to affect cpilcpny any be rolatod to th; inability agontn that. to rcgah thu cintral norvoua system in tdnquato quanlty. It would stun ndviugblo, thoroforo, to rcpuat that. Studio: utilising inch fiorc ccntrnlly active of eoupounda anticholinargic hora. compound; 18 used in the oxporimonta rapartud �-15SUHNARI: _ 1. Experinontsl natiohclincrgic compounds (dicthntinc, .Win«2299. bannctysino, JB~318 and JB~336), adainintorcd to paychiutric patients nt variant stcgcs c: convulsive therapy, wcro aascciated tith: (a) dcnynchrcniunticn of EEG rhythm: with a blocking of paltnccnvulcivo delta activity! (b) alurtina, cxcitatcry bahtvicral rolpcnao with illnlcry, delusional and hallucinatory idonticng and, (c) systemic Ottocts of muscular Icahn-cs, dryncun of thc month, dry skin cad tcchycardia. 2h. oltctrcgraphic bohavicral and systemic nrfncts were ccn~ current. 2. Thou. obscrvnticna are consist-at with tho auggonticn thut a nourcphysiclczic ccnconitant or convulsive therapy is ca incroulo in contral norvcul Iynton cholinorgic activity. Obscrvctionn that LSD, anphotuninc, nouculinc and diphonhydranino - tynpnthouinctic tad antihiatnninic agents . 31:0 induco BEG dcnynchrcniuaticn, blocking of part convullivc 3. doltn activity an; clinicsl cxcitntcry activity cuppcrt‘thc luggcsticn thut behavioral and clectrographic patterns may be bclud on altcrcticns in syntptic activity. )It is nuggclt that incrca-od synaptic activity (cholinorgic, aynpnthclytic ctructa) in calccintod with EEG hypornynchrcnisaticn, Aka clinicul �~16~ Itdgtion and ourhoria; whilo dtcrtasod synaptic activity (untieholinorgie, uynpathoninottc) is associated with EEG doayuchronization and clinical Ixeitatory and hulluainocanic stutou. nascrcpunt obscrvatiana with gtropinu art rulattd ta significant difroruncca 1n doaagc. Ronaasoaununt or tub h. rain or anticholinorcic taunts state: 1n hild truunt 3nd noisurn luggoatod. 5. These obaurvations amplify the neurophysioloxtcw tdaptivo hypothonia a: the and. at tcticn or convulsive thcrupy and of experinontnl hallucinogenic Itaton. 18 �-17“ AGKEOULBDG§§§§ga I u: gr‘totul far the tcchnicul auuiutanee of Bra. Etnnnh fibuquorn in recording and nnulyaoa. Supplici ot‘tho various pharnncauticals were and. froely availtblc by Lake-1d. Laboratories (JD-318 and JB-336), Herck sharps & Donna (bounctyzinc); Sand»: Pharnnconticaln (nan-25). Sturlingwmthrup (win-2299) sud Smith, x11" und Preach Lnboratorica (ditthnsino, chlarpronastna). EEG �-18REFEREIOEB Ahead, L.G., Oottuld, A.H. and 31.1, J. A now group of psyohotominutic agonta. Proc. Soc. Expor. Biol. 804., 1958, 21: h83~h86. 11rd, 3.3. c11.1..1 oorrolnton o: clootroahook thorapy. 5:5:5: Arch. laurel. & quohiat., 1958, 12; 633-639. Lira, 3.8., Strait, L.A., Puoc, J.W., Hronott, 3.x. and Bowditch, 8. Neurophysiologic ottootn of olootrioolly induood convulsions. A.n.;. Aroh. lourol. & Pglghiot., 1956, 15: 371-»3'28. Dante; D. and Itil, T. Zur Hirknng do: Phonothiuninkorporo out do: Honaohlicho Hirnatronbild. Arsnoinittoltoroogg, 195k, 1} h18~h23. Bantu, D. and Itila I. A conporilon of tho action of various nogaphon phonothhsino compounds on tho human EEG. Trans. Int. Gong. of Houroagycggzyarm., 1958, (in gross). lonto, 9., 1%11, I. and Schnid, 3.3.. Eloctrouncophalographtc atndioo ooncorning the action or LSD-25. lourozhzliol., Bonto, D., I Itil, !. EEG Olin. 1957, 2} 359 (ubo£.) and Schnid, 3.x. Eloktrooncopholoo graphilcho studion our Wirkungauoiuo do: L8D~25. ggyohiut. at louro1., 1958, £25: 273~28h. Bradloy, P.B. and Bikes, J. the ottoct of atropine, hyosoynnine, phyooottgnino and noosttguino on the oleotriool ontivity of tho broin of the conscious cutoo J. thl1o1., 1953, ggga 1h~15. �‘19Bradley, P.B. and Bikes, J. effects of drugs on the electricel activity of the brain. gggég, 1957, fig:' The some * 77~117. 3.0. A clinical trial of benectysine hydrochloride ('8uev1t11') as e phyeiael relexent. gggg. andy, 1. end Jewesbnby, Hed. ‘Ben1e10pelu, Jean, 1956, y 1.85—1.87. 9., Giurgee, c. end Brocan, G. Eleotroencephele~ grephic study at the,non~epoeitic phernecedynenice of the etimnlnigry effect at etrnpine on ths corebrel cortex. Iiiieégggcheekly Zhurnel 8858,'1955. g5: 601~611. Defiber, 3.6.3. Stud1ee on neecelinec III. letien 1n epileptice. 3933.,1955, 29: h33~h38. mm. Die.2~auerrero, R., re1nete1n, R. and eettlieb, J. a. EEG finding: following intrevenoue injection of d1phenhydramine hydrachloride (Benadrylr). Ema. Olin. Beure» 2n;.1.1., 1956, g; 299-306. Everte, E.V. Heurophysiologicel correlates of pherueeologicelly induced behavioral disturbencee. Ree. Publ. lee. xerv. .uent. 91... 1958, 29: 3h7-38o. Everte, 3.7. Chemical bases for peyohoeee. Chenicel Conceggg e! Pezphoeee. XuBovell, Dbleneky Inc., H.!. 1958, k1~62. link, a. A unified theery of the ection or phyeiodyuenic y therapies. J. Hilleide leep.. 1957. g; 197-206. l1nk, K. Efreet e: entichelinergic egent, dietheeine, an EEG and behevier: 81¢n1t1cence for theory at convulsive therapy. I 1.3.1. laurel. a Peyehiet., 1958, 80: 380~3873 end Biologicel Peyvhiet_z, ed. J. neeeernen, Grune & Stretton I. 3., Arch. 1959’ 1811*19he �-20- rink, Rnlation or olectrocncophnlogrqphic delta activity ta bohuvioral rulponao in aloctrolheck. H. and Kuhn, R.L. A.H.A. Arch. tartar, a. lourol. and 3111:», J.J. & szuhint., 1957, 13} 516~525. Atropiuo cont: A‘Ionatic therapy in psychiatry. Lu. J. quehint., 1958, $35; h55~£58. rundcrburk, w.n. 1nd Onto, !.J. rho affect of ntropino an cortical pot-ntiuln. EEG Olin. lburophlniel. 1951, g: 213~223. L.8. and Gilnnn, A. Pharmacolqlgcll Basin of Thorazcntieu. Kacxillan, I.!. 1955. Hoynans,.c., Establo, J.J. and dc Bonncvnanx, 3.6. sir 1: Boodnan, I - pharmacologio d0 11 phonothiaz1ny1-oth71d10thylnninc (2987 R.P.). Arch. Int. Pharmacofizg; 19h9, 12; 123-138. Ito: ltd spacitik virkning p: contruluorvoayltonot. g‘plkritt far Lqugg, 1955, 3E2: Jacobson, E. Susvitil, at nyt ' 11h7~1151. Jonknor, 1.2. tad Lochnor, a. Th0 offset or diparoel on tho olcctrooncophnlogran in tho nnrnul Inhaoct und in than. with corobral iguana. BEG Olin. lenrophyniol., 1955. 1; ' 303-305. Lochnor, the influence or naticholinorgic drugs on the EEG Clin. EEG at rcchnt OIOIId crtniccrobral injuries. lourenhyliol., 1956, g. 71h'71§.' a. 0n Lonnox, H.A., Ruck, 1.0. :nd Gutornnn, B. The the postuoloctroshock lourozhza1a1., 1951, g: 63~69. boas-aria. on oft-ct EEG. EEG of 0113. �-21. 'Hereeei, A.$.- Sene indicetiene e: oerebrel hnnerel necheniene. science, 1953, 1;81 367-370. lereeei, A.8. Etteete ;;“peycheten1eet1c druxe eynepeee. Egyehotrepie Bragg. on cerebrel Eleevier, Aneterden, 1957, 283~28h. Herlie, 3. end Hunter, 7. Studies en eeecelinee II. Electra. eneephelegren in echieephreniee. fezghiet. 93ert., 1955, Pennee, 8.3. mum”. end neck, P.H. Peychetonimetice, clinicel end theoretical eeneideretiene: Hernine, w1n~2299 end leiline. Amer. J. Pelehiet., 1957, ;;3: 887~892. Rineldi, 7. end ninwich, 3.3. Alerting repeneee end ectione or etrepine end chelinergic drnge. A.H.A. Areh. Neural. end Rineldi, I. Pezehiet., 1955, 12: 387-395. Cholinergie nechenien involved in functien of neeodieneephelic ectiveting eyeten. ena ninwieh, H.E. leurel. e Peychiet., 1955. 1;: 396-h02. 3. Chengee 1n the nu unau- bubttnrete mu...“ produced by electroaeonvuleive treetnent end their significance fer the theory or E0! eetien. BEG clin. leureghzeiel., 1951, 3: 261-280. A.H.A. Arch. Roth, 30th, l., D.W.l., Sher, J. end Green, J.‘ Pregneeie end pentethel induced.electroencephelegrephie changes in Key, electreeenvemlve treeteent. E36 6113. leereggzg}el. 1957, 2: 225-237. �a22- 3.2., Bicktord, 3.0. Schwarn, and Rona, H.P. inducod psycho-it with ohlorpronasino. 1955. 2Q; h07oh17. Bhorvood, 3.x. Contrul oorohrol ohoniools dud Rovoroihility or Proc. Hiya Clin.. their rolation to paychonol. chonioal Gonoopto or £329hoaiu. xenowoll, Oblonlky, 3.2., 1958, 268~276. Btrnuol, 3., Ootov, H. and are-nutoin, L. Diagnostic Electroonccpholggrtphz, Gruno & Strntton, R.I., 1952. Vlott, 6.1. and Johanna, u.w. Ettoct o! ntropino and acopolonino upon alootrooncophalogrnphio changos induced by olootroconvulaivo thorapy. EEG Olin. lonrophzgiol., 1957,‘2: 217-22h. a. and Harty, R.‘ Action our l'oloctroonoopholocronno do ouhstancol phnrnacodynauiquoo d'intorot cliniquo. Vordoaux, Rev. Word, A. lourol., 195k, 2;:‘hosuh27. Atropino in the troatnont of cloood hood injury. J. lourouur‘., 1950,‘ls 398-h02. Uninstoin, 3.A. ond Kuhn, R.L. Doniol of Illness: aznholie and_phyoio1o§ict1 oqpooto. c. rhonal, Springfield, 111., 1955. Roscoe, nonunora, B.P. and Krop, 8. Tho influonco of atropine and aeopolonino on tho control ottooto of 91?. J. Phnrnaeo1., 19h8, 23: 63~72. w.c., Groom, E.B. Uiklor, A. Pharnocologic dissociation of behavior and EEG ”sloop pattorns' in dogs: morphine, l'nllylnornorphino and atropine. Ptoc. Soc. up». 31.31. 14“., 1952, 12: 261-265. �«~23. the 1.1915593 or P£Ich1utrl to thaaoLg‘z. Wu. Wilkins, Bathe", 1957. Woollcy, BAY. Scrotum”: in maul disorders. Ru. Pub]... Hitler, A. A". new. Hunt. 913., 1953, 29 381-4400. �aasaaaa '13. 1a Effiflt or :1 313.1299. was. anuyuchraaiiattua a! troqucaatnu nXtur 3.! 3:. (Fig.1.. 88' kl). 11:. 3. Efrhet at 1' Reward satin 31n~2299 an pottueoavu131Vt 2h hoard dulta :ettvtiy: artor aouvulsiau #8. flat. dauznchrinilatioa at tvcguuueaou and yursiniana. nttor 2.0 is. ("l‘l’fi ago 51). ‘ attooz a: It nuuuutwtaaot uni. perutntaut apero¢ac 1n rol‘agu: and duawachviatnntsaa art-r 1.5 It. (Filtllg “. 3’4). Ettoct at 1V aunuotrtfin- an yaatuoauvulatvo.doltt nottvaty. accord tokua 2£ hctru arch: cauvuzntau I7. lot. tetrachruntnttton or {toquuuclco urtor 1.5 ug. (tumult. It! 3)). 9“. 5. . Rttcat I: Jimfllfi an yout~¢¢uvulliau Rigord takun 2% hour: ¢¢I%& tttnr cunrulttan #9. nativity: lat. duarunhroattttiua a: Irvquuuotnn, fineronagd rulingslttar !.h It. eur‘taa vita 330'! 101 tuartalt. (vaunlo. ago :7). 5&l11lr run-van thwarted math £I~336. �’1‘. 6. ”net or «$11 «Inn 62 I? “up“. an ”anemia" «In «an». nun mm: 2!; hour. um amass.» #6. 30%: man an.“ an delta “tint: and ”min“ menu. in heart an, with partition“. (mo. :3. “mam . 2.0 In. «025 Int/u). 18. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effect of antichlolinergic compounds on post convulsive electroencephalogram and behavior of psychiatric patients. Electroencephalogr Clin Neurophysiol. 1960 May; 12:359-69. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-34b-013 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 6 items. 1: Reprint from Electroencephalography and Clinical Neurophysiology JournalVol. 12, No.2, May 1960. 2: Letters. 3: [preprint]. 4: [Post print?]. 5: Publication submission info. 6: Drafts. Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. Stony Brook University Libraries (State University of New York). Language A language of the resource en-US Format The file format, physical medium, or dimensions of the resource application/pdf Publisher An entity responsible for making the resource available Contributor An entity responsible for making contributions to the resource Published