http://exhibits.library.stonybrook.edu/mfp/files/original/78017191476d8e778612e5c61eff422b.pdf 82ede86cdae7bcc77cb09f6c0bbd0389 PDF Text Text Mammal in studios of Germain ﬁnd Drug max-span mun-ya Theoﬁtio Imitation! In swans a: aonvnluivo, payohophumcmgic and inaulin a» therapist, msalon of "idem tar a mmphysiolozimpuve W011! or the and. of these ﬂux-apt!» has wwmhtod. This hypotmsia “crib“ the officwy 01' each therapy in the trantaont of wohma to their ability to induae a persistent alternates: in cerebral function. mien provides the am“: for u changa in adaptation of the subject to his anviroment. In those studies, in Em have been and as indie» of uttered brain tumuom In convulsive thong, the shift in EEG tmuoneias to the delta range has been directly rented to the behavioral changa (AMA, Arch, Emmi. and analyses at r3;chiat. (J: com be (n) «hangs: 16;: 516, 1957). A maid. H292. 5: “1&1;in has been observed 31:11.: Bk. 1955). classified ascending to their EEG From ﬂat fnqucncios, with in- (mpmbmu, barbiturates); and (c) (domains, bemctysine and asp-nine). then analyses, a shirt in unused synchronisation tnnquiliutim m EEG mggasmd sedation. 1.957): mums». pruning, perphenaame, reserpine); (b) indueo a ahiﬂ. to crewod synchronization frequencies Viviana psychophameologe uganta can offsets: (J. Hillside Ham. 9; 197, mum a mm to delta frequenciu and high dose to insulin «mama frequencies to delta range and in» u the nmrophysiologic concomitanta mmphyaiologimdaptim hypothoais hm applicatim to the ammonia of physiodymmic mempiee, acmning or psychoplumeologic agents and as a trans of refemnce for the study a: bmior arid of and The mmphyaiology. From L010, the Dayna-meat “at; or Workman. rm. Hemlogical Society, MAR 2 6‘85 Why, Hillaido Hospital, Glen mks, March 11, 3.958. �«W W WWW AFTER 225 mg. PRE-DRUG LF-LO RF-RO WIN/WWW SOyvl _ #I64IHH �PRE- DRUG AFTER 150 mg �W WW ”“va W W W WW WW WW + PRE-DRUG + 25 mm 200 mg. LF-LO WWWNVMMJVW RF R0 NWvaw-AAW “T'RWWJWMM H ”ﬁn. MM LF-RFNWWN WWW” LPT'LO WWWM 50 )Lvl I $|631 NH �PRE-DRUG @. AFTER 250 mg. W W W W W W W W W W WW 50pvl_ SEC. 1 #IZQS NH �Effect of Anti-Cholinergic Agent, Diethazine, Significance for Theory of Max From the Department of Experimental L015, NJ. Fink, on EEG and Behavior: lesive Therapy 14.1). Psychiatry, Hillside Hospital, Glen Oaks, in part, by grant M-927 of the National Institute of Mental Health, National Institutes of Health, U.S. Public Health Service. Aided, (in part) at the meeting of the Eastern Association of Electroencephalographers, N.Y., December 1957,‘ 4.7444417 Jazz; Read 33?: 3-58 /“ a M 14/11.” 050,?wa �3.3-58 Effect of Anti-Cholinergic Agent, Diethazine, on EEG and Behavior: Significance for Theory of Convulsive Therapy Recent investigations of convulsive therapy have emphasized EEG delta activity as the neurophysiologic basis for the induced behavioral change (1,2,3,h,5). Little study, however, has been given to the biochemical effects of this therapy, except in the course of investigations of head injuries. In investigations of head trauma significance has been ascribed to in the acetylcholine-cholinesterase systems both for the behavioral and the electroencephalographic effects. An increase in free acetylcholine (6) and an alteration of the ratio of cholinesterases (7) in the spinal fluid have been positively correlated with the degree of EEG abnormality changes and degree of heurologic improvement deficit. in clinical status The EEG patterns were "blocked," and was reported following atropine (7,8). In convulsive therapy, atropine observed to block the appearance of delta some the administration of and scopolamine were activity, (9) although the systemic effects of the large doses of these agents were marked. Recent reports (10) noted that EEG and behavioral effects similar to atropine {were achieved in patients with head trauma by intravenous diethazine a phenothiazine compound systemic effects. with anticholinergic properties - with minimal In our continuing studies of the role of delta activity in electroshock (3), the effect of diethazine was studied. It is the purpose of this report to describe the effects of diethasine on EEG patterns and on behavior of patients during electreconvulsive therapy; and to relate these observations to the present neurophysiologic-adaptive hypothesis of the mode of action of convulsive therapy. �SUBJECTS AND METHODS: Forty psychiatric patients, at various stages of electroshock therapy in an open-ward, voluntary psychiatric hospital have been studied. All observations have been Following a routine at the rate of EEG made in acute experiments in the laboratory. recording, diethazine was administered intravenously 25 ngm per minute, upon the behavioral EEG effect. for a total of Dosage varied from to 250 mgn, depending 2.8 to h.0 mgm per kilogram 175 body weight. Diethazine is a soluble phenothiazine compound with pharmacologic properties similar to atropine. In experimental animals, diethazine blocks the bradycardia, bronchospasm, salivation, fasciculation and seizures induced by acetylcholine, di-isopropyl fluorophosphate and pilocarpine. suppresses salivation, and induces mydriasis and hypotensicn EEG It (ll). Anilxses: Recording was continuous for the duration of the observation period, except during interview periods. Needle electrodes, and an Moderaft instrument were used. All records were analyzed delta activity (3); the per cent time the relative amount of fast activity. measured in anterior temporaldvertex, and The and 8 channel for the degree of principal alpha frequency; and alpha and delta activity were parietal-ear ldbe lead coMbinations. Behavior measures: Prior to drug administration an unstructured psychiatric historical interview and a structured questionnaire period (12) were tape recorded. Following drug administration, periods of recorded interview were alternated �~3- with EEG recording periods, until the me had again manifested the pre- injection pattern on visual inspectioné Two estimates of behavioral effects were used: clinical descriptions subject, interviewer and technician - of the changes occurring during the drug period, and language analyses of the recorded interviews. Changes in language were evaluated by a syntactic analysis (12) and an analysis of the variability in verbal interaction in the dyad (13,1h).* by the participants ~ Both measures have been shown to be sensitive to induced by changes in the central nervous system. * Detailed analyses of these observations DPS. J. Jaffe alterations in behavior and Re In Kahn. will be reported separately by �OEERVATIONS: (a) Clinical: Within two to five minutes of the start of the injection, subjects manifested spontaneous coughing follow ed by a dryness of the of speech. and a thickness They reported a feeling of lassitude, mouth and a heaviness and weakness of extremities which was soon succeeded by increased difﬁculty in maintaining eyelid closure. Reports of visual and haptic illusory sensations, feelings of unreality distance, and delusional thoughts about their illness, the setting of restlessness and and test procedures or identity were voiced Spontaneously in eighteen subjects in the period between 15 and 60 minutes after drug adninistration. the our In three instances, increasing agitation and panic led to a cessation of the In two subjects withdrawal and negativism was the prominent recording. behavioral response. Such patterns of behavior were transient and had disappeared in (b) EEG 1% - h hours in all subjects. Patterns: Alteration in the EEG patterns was concurrent with the behavioral effects. In all records, changes occurred during drug administration and were sustained, with gradual diminution and restitution of the pre-injection patterns, in one to five hours. The initial response was a decrease in voltage and desynchronization of all frequencies. There prominence of prevailing rhythms. was a decrease in In patients without delta activity (pm-electroshock), desynchronization and voltage decrease was occasionally activity, symmetric and prominent in frontal and anterior temporal leads (Figure l, 2). The alpha frequency was not altered. accompanied by low voltage 5-? cps �~5The build-up in voltage and appearance of slower frequencies with hyper- ventilation was blocked. In patients with varying degrees of high voltage delta activity there was a prominent decrease in voltage and desynchronization of the record. burst delta activity diminished or disappeared, and irregular voltage alpha and beta frequencies became prominent (Fig. 3, h). The Both random and low hyperventilation response was no longer apparent. (c) Language Patterns: In previous studies, an intimate relationship between changes in syntactic language patterns and the behavioral response in electroshock had been reported (12). With alteration in brain function, increased use of third person, veroal denial, qualification, displacement and cliches became prominent. These effects could be enhanced by the administration of intravenous amobarbital (1h). In the subjects in the present study, syntactic analyses demonstrated a reversal of the patterns noted in electroshock. Use of third person, qualification and displacement decreased. Explicit verbal denial was modiﬁed and replaced by minimization and displacement, or by a reiteration of complaints of illness. In dyadic analyses, the verbal interaction was characterized by a greater diversity of vocabulary and less variability in the diversity scores for 25 word units. qualitative nature of these changes in the language patterns is opposite to that of amobarbital and electroshock. The duration of language changes was concurrent with the changes in the electroencephalogram. The �DISCUSSION: These observations confirm the report of Jenkner and Lechner of the effects of diethazine in "nonmal" subjects (10). Diethazine also alters electroshock induced delta activity in a fashion similar to atropine and sncpolamine, as described by Ulett and Johnson (9), with minimal unpleasant symptoms. EEG The effects of intravenous diethazine are immediate, both and behavior, and thus provides a cholinergic" properties. Two on the useful experimental agent with "anti- aSpects of these experimental observations warrant discussion: the role of acetylcholine-choldnesterase in the electroconvulsive therapy progress, and the significance of die thazine "alerting" for concepts of hallucinogenic activity. 1. Biochemical Basis of the Convulsive Therapy‘l’rocess: While there has been considerable study of the psychologic neurophysiologic aspects of convulsive therapy, biochemical processes is available. The little and infomation concerning studies of biochemical changes following head trauma and spontaneous seizures provide some analogic data. Bernstein (6), in a classical experimental study of head trauma in cats, that within a few minutes after trauma, free acetylcholine appeared in the Spinal fluid and persisted for periods up to 148 hours. He further demonstrated a positive relation between the severity of head trauma demonstrates and the quantity of free acetylcholine, degree of electroencephalographic the severity of the behavioral changes. The electroencephalographic records initially showed short periods cf high voltage fast activity, alteration and transient period of flattening of electrical activity, followed by prolonged periods of high amplitude sharp waves in the delta frequencies. Concomitantly, a �-7alteration in consciousness, changes in reflexes seizures EEG change. Tower and HbEachern (7) confirmed studies in man. In post-traumatic highest concentrationSOf free acetylcholine were most prominent with and greatest degree of and 112 neurologic these observations in clinical patients, free acetylcholine was found in the cerebrospinal fluid only in patients following head trauma and recent grand mal seizures; and the level of free acetylcholine varied directly with the degree of cerebral damage. In addition, these authors assayed the cholin- esterase activity of the spinal fluid, (7, 16). In patients following head trauma, they noted a sharp rise in non-specific cholinesterase (benzqylcholine- in.the specific cholinesterase (meoholyl-splitting) activity of the spinal fluid. No such inversion was noted in fluids containing splitting) and a drop free acetylcholine following spontaneous seizures. Electroencephalograms were taken at varying intervals following correlation of the extent of EEG trauma, and demonstrated a direct abnormality and the appearance of free acetylcholine in the spinal fluid. Tower and MhEachern also reported observations in six patients In patients after 3-7 induced convulsions, they noted free acetylcholine in the spinal fluid in two, and an increase in non-Specific cholinesterase with reversal of the cholinesterase ratio in five receiving electroconvulsive therapy. of the six. They concluded that the spinal fluid changes in electroshock are more like those of craniocerebral trauma than those found in epilepsy. * patient of the six who failed to show either free acetylcholine or a reversal of the cholinesterase ratio, they noted: “It is interesting that this patient was the only one of the six to show no * Regarding the one response to treatment." �-8recently, Sachs (17) confirmed the reports of free acetylcholine in the spinal fluid after head trauma and after electroshock. In his studies, Bornstein (6) administered 0.5-1.0 lug/kg atropine Mcre effects, and a modiﬁcation of the behavioral and neurologic signs. Atropine also blocked the EEG and clinical signs induced by intracisternal acetylcholine. and demonstrated a reversal or a blocking of the Ward (8) applied these observations with varying degrees of head trauma. atropine induced both clinical EEG to the treatment of Subcutaneous doses of 0.1 mg/kg of improvement and reversal of These observations were recently confirmed by Sachs Hughes (19). Based on subjects human these observations, Ulett (l7), EEG effects. Rugs (16) and and Johnson (9) noted the effect of atropine and scopolamine in blocking the Em changes of electroshock tharapy, without noting the effect on clinical behavior. Concurrently, Jenkner and Lechner (10) reported effects similar to those of Ward, in studies of diethazine in cases of head injury. Another group of investigations complete the available data. Studies of anticholinesterases, as DFP (di-isopropyl fluorophosphate) and (tetraetlwl-pyrophosphate), which block the enzymatic TEPP breakdcvm of acetyl- choline, demonstrate the development of high amplitude rapid frequency mac patterns similar to status epilepticus as well as lesser degrees of abnormality as noted in post-tramnatic states (20, 21, 22, 23). In these studies, atropine blocked both the electroencephalographic and the clinical toxic effects. Thus, both from experimental and trauma we may assume clinical studies of craniccerebral that (a) the acetylcholine activity of the spinal �-9- fluid increases; (b) pseudo-cholinesterase activity increases with a reversal of the ratio of cholinesterases; (c) slowing agents From parallel these biochemical alterations; may EEG tamer-synchrony and and (d) anticholinergic block both the electroencephalographic and the clinical effects. it is probable that the biochemical basis the data available convulsive therapy is similar to that of craniocerebral trauma. of Convulsive therapy results in free aoetylcholine in the spinal fluid (7, l7) and a reversal of cholinesterase ratios (7, 16). The electroencephalographic effects of repeated induced convulsions is the developnent of high voltage, activity, occasionally with spike activity (3, 2h, 25), which is similar to that observed in severe head trauma (26, 27). In symmetric slow wave previous studies we have reported the relationship between the degree of activity and behavioral reaponse (3). The studies reported here and that of Ulett and Johnson (9) demonstrate a reversal of the EEG and the behavioral effects of convulsive therapy by antiinduced slow wave cholinergic In each characteristic, convulsive therapy is thus compounds. similar to cerebral trauma. While the acetylcholine-cholinesterase system is highlighted (17). These studies, other enzyme systems may also be altered studies also suggest that convulsive therapy provides an by these excellent experimental method for studies of craniocerebral trauma. Studies of the brain stem activating system by Jasper and DroogleverFortuyn (28) and Lindsley gt a}, (29) had laid the foundation for the prevailing conclusion that symetric EEG slow wave activity has its origin in mesencephalic structures, and that these structures intimately affect the states of "alerting" and "drowsiness." More recently, Rinaldi and �-10- site of action of atropine and cholinergic to this mesodiencephalic activating system. It is also probable that Himwich drugs (30, 31) have related the these structures may be selectively affected by the convulsive therapy process, and that both the clinical and electrographic effects may be intimately related to changes in this systan. 2. Diethazine "Alerting" The and Hallucinogenic Activity: behavioral effects of diethazine provide information regarding another aspect of the convulsive therapy processxs. In patients without prior convulsive therapy, illusory phenomena and feelings of unreality were observed. These were similar to the hallucinogenic effects of and mescaline (33). Again analogic data about the of these agents may provide some no change, (31;) clinical and EG effects noted that the intermittent or continuous increase in alpha frequency. (32) information about convulsive therapy. In studies of mescaline, Wikler either LSD low voltage EEG danonstrated fast activity or Denber and Merlis (35) noted a similar acceleration of alpha frequency, decrease in per cent tine alpha including its disappearance, and non-specific random beta activity. Delta activity did not occur. In patients with delta activity induced by electroshock, Merlis and Hunter (38) noted that intravenous mesoaline markedly diminished the amplitude and per cent time delta activity with an increase in per cent time alpha activity. The effects of LSD on EEG are similar. Gastaut at g. (36) noted an acceleration of alpha frequency of 0.5 to of beta rhythms. Rinkel gt 9;... 14.0 (37) confirmed cps with an aocentuation this observation and noted, �-11- in addition, a reduced reaponsivity to hyperventilation.* In summarizing his studies Wikler (3h) concluded that " . . . regardless of the drug administered, shifts in the pattern of electroencephalogram in the direction of desynchnonization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness." This generalization provides a meaningful construct may be assessed. Agents that in which these agents evoke EEG desynchronization tend to be are clear examples. Agents that synchronize frequencies, such as barbiturate and meprobamate in the beta delta frequency range, and chlorpromazine, promazine and hallucinogenic, and mesoaline and LSD Wainthe frequency range (39) tend to be sedatives, euphoriants and relaxants. 'Ihe observations on diethazine reported here are consistent with this hypothesis. In patients without delta activity, the EEG demonstrated desynchronization of frequencies, and this was associated with clinical illusory phenomena. In patients with delta activity desynchronieation occurred, and alerting and reversal of the speech patterns induced by electroshock were observed. Electroconvulsive therapy We *- have previously noted a may also be understood in this framework. direct relationship between clinical evaluations Studies are now in progress of the effects of LSD, Win-2299, benactyzine and other anticholinergic compounds on post-convul sive EEG delta activity. Initial experiments m. ah intravenous ISD (50-100 gamma) demonstrated marked diminution in per cent time and amplitude of delta activity. �of improvement and the degree of conditions, sedation Under these EEG slowing induced by electroshock (3). and euphoria are most prominent and hallucinatory activity diminished. In patients in not induced, behavioral change is limited whom hypersynchrony and 'improvement' does is not occur (in) . Previously that the we have concluded therapies is based on the mode of action of convulsive induction of a state of altered cerebral function, in which changes in adaptive interpersonal behavior occur, preted as 'improvement' (3, h, 39). The inter- present studies amplify two aspects of. this neurophysiologc-adaptive hypothesis. substrate of the behavioral change and are is reflected by an The biochemical alteration in the acetylcholine-cholinesterase relationships of the central nervous system. It is also probable that EEG basis of the milieu change euphoria and mpersynchrony provides the neurophysiologic which is evaluated as is clinically manifest as sedation and 'imprcvement.‘ The neuropklysiologi.C-adaptive hypothesis of convulsive therapy has provided a meaningful basis for studies of other physiodynamic therapies (39) . In this study, it has been possible to amplify our understanding of neurophysiologic aspects of hallucinogens as well. �SUMMARY: effect of an anticholinergic agent, diethazine, on the behavior and language patterns was observed in to psychiatric patients, 1. EEG, The at various stages in the course of electrooonvulsive treatment. (a) Behavior: Increased restlessness and agitation, haptic and visual illusory sensations, and delusional thoughts about their illness or examiner's identity were observed. (b) Egg; Alteration in There was a decrease in voltage EEG was concurrent with behavioral changes. and desynchronization of In patients with delta activity, the per cent time all frequencies. and voltage of delta activity decreased. (c) Language: Syntactic patterns described for convulsive therapy were reversed. Use of third person, qualification and displacement decreased. In dyadic analyses, there was a decrease in the coefficient of variation. 2. These observations are discussed in the framework of the neuro— physiologic-adaptive hypothesis of the action of convulsive therapy; and it is concluded that: (a) the biochemical basis for convulsive therapy is similar to that of craniocerebral trauma; (b) changes in acetylcholine-cholinesterase metabolism are intimately related to the behavioral effects; (c) EEG desynchronization may be and a physiologic concomitant of hallucinogenic activity; and EEG-hypersynchrony associated with euphoria and sedation. �.m. W 1. Weinstein, E. and Kahn, R.L.: Denial of Illness, 0.0. Thomas, Springfield, I110, 1955. 2. Roth, M., Kay, D.W.K., Shaw, J. and Green, J.: Prognosis and Peutdzhal Induced Electroencephalographic Changes in Electroconvuleive Treatment, EEG 225‘237’ 1957. Clin. Neurophxsiol. 2: and Kahn, R.L.: Relation of Electroenecephalographic Delta Activity to Behavioral Response in Electromock, A.M.A. Arch. Neurol. and Psychiat. 1Q: 516-525.. 1957. 3. Fink, h. Fink, 24., Green, M.A. and Kahn, R.L.: Experimental Studies of the Electroehock Pracess, Dis, Nerv. SE . (in press). 5. Ulett, G.A., Smith, 6. Bornstein, M.: Presence and Action of Acetylcholine in Experimental Brain Trauma, J. Newcphzsiol. 2: 3113-366, 191:6. 7. Tower, 13.3. and McEachern, D.: Acetylcholine and Neuronal Canad. J. Research, 3.1: 105-131, 191:9. 8. Ward, A.: Atropine 9. Ulett, M. K. and Glaser, G.C.: Evaluation of Convulsive and Subconvulsive Shock Therapies Utilizing a Control Group, Am. Jo Pszghia‘b. gala-3 795’802, 1956c in the Treatment of Closed Neurosurg., 1: 398—102, 1950. G.A. and Johnson, M.W.: Head Effect of Atropine Injury, Activity, ,1. and Scopelamlne Electroencephalographic Changes Induced by Beetroconvulsive Therapy, EEG Olin. Neurophlsiol. 2: 217-2224, 1957. Upon 10 . Jenkner, F.L. and Lechner, H.: The Effect of Diparcol on the Electroencephalogram in the Normal Subject and in Those with Cerebral Trauma, EEG Olin. Neuromzsio . _7_: 303-305, 1955. 11. Heyman, Sur la 0., Estable, J.J. and de Bonneveaux, 8.0.: de la menothiazinyl-Etlnrldiethylandne (2987 R.P.) , Pharmac 12. in Language During Electroshock in {exchomthologg of Communication, pp. 126-139, Stratton’ NoYo 9 o Kahn, R.L. and Fink, 11.: Changes Therapy, Gr‘me 13. . 12: 123-138, 1919. Pharmacologie Arch. Int. Jaﬁ‘e, 8C Objective Study of Comuuﬁcation in Psychiatric Interviews, J. Hillside Hospital, é: 207-215, 1957. J.: An �.15.. Jaffe, J.: Language of the Dyed: A Method of Interaction Analyses in Psychiatric Interviews, mchiatgy, (in press). 15. 16. Weinstein, E.A., Kehn, R.L., Sugarman, L.A. and Linn, 1...: Diagnostic Use of Amobarbital Sodium in Organic Brain Disease, Am.J. mchia . 1-}.2.‘ 889-8911, 1953. Tower, D.B. and McEechern, D.: The Content and Characterization of Cholinesterases in Human Cerebrospinal Fluids, Canad, J . Research, 21: 132-115, 19349. 17. Sachs, E.: Acetylcholine and Serotonin in the Spinal Fluid, Neurosurg., 11*: 22-27, 1957. 18. Rugs, D.: The Use of Cholinergic Blocking Agents Cranio-Cerebral Injuries, J. Neurosurg., ,1. in the Treatment of I_l._1_: 77-83, 19514. Injury, J. Neural. of Acetylcholine in Head 1957. chia . g9; p.70, 19. Hughes, B.: The Role Neurosur . and 20. Freedman, A.M., Bales, P.D., Willis, A. and Himwich, H.E.: Experimental Production of Electrical Major Convulsive Patterns, 21. Am. J. @8101” ﬁg: 117-1214, 19149. GrOb, Do, Harvey, A.M., Iangworthy, 00R. and Lilienthal, Jolie 3 The Adminis tration of Di-Isopropyl Fluorophosphate (DFP) 257.266, 19,47. Man, B11110 Jo H0215. Hogan, to a: 22. McCauley, A. and Hinmich, H.: Effects of Di-Isopropyl Fluorophosphate (DFP) on mectroencephalogram Hampson, J., Essig, C.F., EEG 23. 01in. 3: 141448, Neuropﬂsio . Activity, angocmlinesterase 19 . Himwich, H.E., Essig, C.F., Hampson, J.L., Bales, P.D. and Friedman, A.M.: Effect of Trimethadione (Tridone) and Other Drugs on Convulsions Caused by Di-Isopropyl Fluorophosphate (DFP), J. Psychiat., 106: 816-820, 1950. Am. 2h. Callaway, E.: Slow Wave Phenomena in Intensive Electroshock, Egg. Clin. Neurophysiol., g: 157-162, 1950. 25. Green, 26. Jasper, H.H. , Kershman, J. and Elvidge, A.: Electroencephalographic Studies of Injury to the Head, Arch. Neural“: Psychiat” 1A: Significance of Individual Variability in EEG Reaponse to Electroshock, J. Hillside Hosp” _6_: 229-2ho, 1957. M. : 328~3h8’ 19,400 �~16~ W Ostow, M. and Greenstein, L.: Dia Gmne 8: Stratton, N.I., ostic $35. Electro- 27. Strauss, H., 28. Jasper, H.H. and Droaglever-Fortuyn, J .: Experimental Studies on the Functional Anatonw of Petit Mal Epilepsy, Res. Publ. A. Nerv. Mt. Dis. 2-6-3 272-298’ 19117. Lindsley, 1)., ‘Schreiner, L.H., Knowles, W.B. and Magoun, H.W.: Behavioral and EG Changes Following Chronic Brain Stem Lesion in the Cat, EEG Olin. Neuropmsiolu 2: 1:83-1:98, 1950. Rinaldi, F. and Him-rich, H.H.: Alerting Responses and Actions of Atropine and Cholinergic Drugs, A.M.A. Arch. Neural. and 29. - PﬁzChiate, 123 387-395) 19530 31. Himwich, H. and Rinaldi, F.I:'The Effect of Drugs on Reticular System, in Brain Mechanism and Dru Action, 15-4411, C.C. Thomas, Springfie d, 19 7. 32. Stall, W.: Lysergsaure Phantaetikum aus der Arch. Neurol. PsEhiat. , §_Q: diethylamid, ein -Schweiz Mutterkomgruppe, 1-h7, 19m. ' Neural. Psychiat., 1-315, 33. Beringer, K.: Der 'Meskalinrausch Springer, Berlin, 1927. 3h. Wikler, A.: Clinical and Electrencephalographic Studies on the Effects of Mescaline, N-allylnarmorphine and Morphine in Man, J. Nerv. Wilt. 1318., 120: 157-175, 19%. i Monog. on Mescaline I: Action in Schizo~ Psychiat. Quart., g2: 1.21-1.29, 1955. 3.: Studies 35. Denber, H. and Merlis, 36. Gastaut, H., Ferrer, S. and Castello, 0.: Action de la diethylamide de l'acide d-lysergique (LSD 25) sur lee fonctions psychiques at l'electroencephelograxme, Conf. Neuro1., 12: 102-120, 1953. 37- Rinkel, H., DeShon, H.J., Hyde, R.W. and Solomon, H.C.: Experimental Schizophrenia-Like Symptoms, Am. J. Psychiat., 108: 572-578, 1953. 38. Merlis, S. and Hunter, W.: Studies on Mesaaline II: nectroencephalogram in Schizophrenics, Psychiat. Quart. , g2: 1:30-4:32, 1955. 39. Fink, M.: ha. Fink, phrenic Patients, A Unified Theory of the Action of Physiotbmamic Therapies, J. Hillside Hosp. , {3: 197—206, 1957. and Green, M.A.: Electroencephalographic Correlates of the Electroshock Process (in proparation). M. ‘ ��~24... 1m 1955. mm:- and WM )mpwm that EEG and human-n oﬂam swim to abopinn were achieved by mm mama in paﬁenta with head trauma. Fran thaw report in mute“. the ayatemic attacks of We at ( am- theme and diam nppamd mam. intamt in the nativity 1n enmeshed: r613 of 6311;: ), an immigauon a: the «that of dint-hum, in patients manning eomlain therapy wmsuport to describe the oft-hats bazwiw sf pitienta mm in was both m EEG and behavior, mama. 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It in also probable that. mmmmmmummmmimmmmamwm momwaammnwmummmmmmummm u ’Wﬂt’ ., �WWW at cm“ thirty form mWanu blathuamdnitmmlmuﬁhtonwxym ﬂmmdodynnue thanpﬁu( mammamotmmmsunn. �Effect of Anticholinergic Agent, Diethazine, on EEG and Behavior Signiﬁcance for Theory of Convulsive Therapy MAX FINK. M.D.. GLEN OAKS. N. Y. �Reprinted from the A. Ill. A. Archives of Neurology 6“ Psychiatry September 1958, Vol. 80, pp. 380—387 Copyright 1958, by American ﬂiedical Association Effect of Antieholinergic Agent, Diethazine, on EEG and Behavior Signiﬁcance for Theory of Convalsive Therapy MAX FINK, M.D., Glen Oaks, N. Y. Recent investigations of convulsive therapy have emphasized EEG delta activity as the neurophysiologic basis for the induced behavioral Changel"5 Little study, however, has been given to the biochemical effects of this therapy, except in the course of investi— gations of head injuries. In investigations of head trauma signiﬁ— cance has been ascribed to» changes in the acetylcholine—cholinesterase systems both for the behavioral and for the electroencephalo— graphic effects. An increase in free acetyl‘6 choline and an alteration of the ratio of cholinesterases 7 in the spinal ﬂuid have been positively correlated with the degree of EEG abnormality and degree of neurologic deﬁ— cit. The EEG patterns were “blocked,” and some improvement in clinical status was reported following the administration. of atropine.“8 In convulsive therapy, atropine and scopolamine were observed to block the appearance of delta activity,9 although the systemic effects of the large doses of these agents were marked. Recent reports 10 noted that EEG and behavioral effects similar to atropine were achieved in patients with head trauma by intravenous diethazine—a phenothiazine compound with anticholinergic properties— Submitted for publication March 24, 1958. From the Department of Experimental Psy— chiatry, Hillside Hospital. Aided, in part, by Grant M-927 of the National Institute of Mental Health, National Institutes of Health, U. S. Public Health Service. Read (in part) at the meeting of the Eastern Association of Electroencephalographers, New York, December, 1957. Awarded A. E. Bennett Psychiatric Research Award of the Society of Biologic Psychiatry, May, 1958. 380 with minimal systemic effects. In our con— tinuing studies of the role of delta activity in electroshock,3 the effect of diethazine: was studied. It is the purpose of this report to describe the effects of diethazine on EEG patterns and on behavior of patients during electroconvulsive therapy, and to relate these observations to the present neurophysiologic— adaptive hypothesis of the mode of action of convulsive therapy. Subjects and Methods Forty psychiatric patients, at various stages of electroshock therapy in an open-ward, voluntary psychiatric hospital were studied. All observations were made in acute experiments in the EEG lab— oratory. After a routine EEG recording, diemhazine was administered intravenously at the rate of 25 mg. per minute, for a total of 175 to 250 mg, depending upon the behavioral effect. The dosage varied from 2.8 to 4.0 mg. per kilogram of body weight. Diethazine is a soluble phenothiazine compound with pharmacologic properties similar to those of atropine. In experimental animals, diethazine blocks the bradycardia, bronchospasm, salivation, fasciculatio-n, and seizures induced by acetylcholine, ﬂuorophosphate, and pilocarpine. It suppresses salivation and induces mydr‘iasis and hypotension.11 EEG Analyses.~—Recording was continuous for the duration of the observation period, except dur— ing interview periods. Needle electrodes, and an eight—channel Medcraft instrument were used. All records. were analyzed for the degree of delta activity,3 the per cent time and principal alpha frequency, and the relative amount of fast activity. The alpha and delta activities. were measured in anterior temporal—vertex, parietal-ear lobe, and frontal-occipital lead combinations. Behavior Mensures—Prior to drug administra— tion an unstructured psychiatric historical interview and a structured questionnaire period” were tape-recorded. Following drug administration, �EFFECT OF ANTICHOLINERGIC AGENT ON EEG periods of recorded interview were alternated with EEG recording periods, until the EEG had again manifested the preinjection pattern on. visual inspection. Two estimates of behavioral effects were used: clinical descriptions by the participants—subject, interviewer, and technician—of the changes oc— curring during the drug period, and language analyses of the recorded interviews. Changes in 1“ evaluated by a syntactic analysis language were and an analysis of the variability in verbal interaction in the dyad?"14 * Both measures have been shown to be sensitive to alterations in behavior induced by changes in the central nervous system. W W W W WW W WW AFTER I50 mg. PRE-DRUG LF-LO RF.“ LAT‘LF RAT-RF LF-RF LPT-LO 0-0 RPT-RO WWW-MN WWW“ MWVVUWVV’WMWM 50va___ SEC. l Observations (a) C1inicwl.—Within two to ﬁve minutes of the start of the injection, subjects mani— fested spontaneous coughing followed by a dryness of the mouth and a thickness of speech. They reported a feeling of lassi— tude and a heaviness and weakness of the extremities, soon succeeded by increased restlessness and difﬁculty in maintaining eye— lid closure. Reports of visual and haptic illusory sen— sations, feelings of unreality and distance, and delusional thoughts about their illness, the setting of the test procedures, or our identity were voiced spontaneously by 18 subjects in the period between 15 and 60 minutes after drug administration. In three instances increasing agitation and panic led Detailed analyses of these observations will be reported separately by Dr. J. Jaffe and Dr. R. L. Kahn. * AFTER 225 mg. PRE-DRUGI 0-0 W {Wyn-— SEC. =0? IGQI HH 1 Fig. 1.—Effect of intravenous diethazine prior to electroshock in a man aged 27. Fin/e #1125 NH Fig. 2.——Effect of intravenous diethazine prior to electroshock in a woman aged 57. to a cessation of the recording. In two subjects withdrawal and negativism were the prominent behavioral response. Such patterns of behavior were transient and had disappeared in one and one~half to four hours in all subjects. (I?) EEG Potterns.——Alteration in. the EEG patterns was concurrent with the be— havioral effects. In all records, changes oc— curred during drug administration and were sustained, with gradual diminution and resti— tution of the preinjection patterns, in one to ﬁve hours. The initial response was a decrease in voltage and desynchronization of all frequencies. There was a decrease in prominence of prevailing rhythms. In patients without delta activity (preelectro— shock), desynchronization and voltage decrease were occasionally accompanied by low—voltage 5—7 cps activity, symmetric and prominent in frontal and anterior temporal leads (Figs. 1 and 2). The alpha frequency was not altered. The build—up in voltage and appearance of slower frequencies with hyperventilation were blocked. In patients with varying degrees of high— voltage delta activity, desynchronization of the records became prominent, with a sig— niﬁcant decrease both in voltage and in per cent time of slow wave activity. From an average per cent time delta of 45% in frontal—occipital leads, there was a reduction to a mean of 20%. Both random and burst delta activity diminished or disap‘ 381 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY PRE-DRUG AFTER 250 mg. W W ”W W W W W WW W W WW WW W LAT-LF/W RAT WWWW‘ WWWW RPM/MW LF- +5HRS. +|.HR WVJMWWVV' LPT'LQ’W’W‘VWW 0 ° ”WNW RPT—RW WMw/V *1249 SOpv [TEE—C HH Fig. 3.—Effect of intravenous diethazine on delta activity after electroshock. peared, and irregular low—voltage alpha and beta frequencies became prominent (Figs. 3 and 4). The hyperventilation response was no longer apparent. (c) Language Patterns.——In previous studies, an intimate relationship between changes in syntactic language patterns and the behavioral response in electroshock had been reported.” With alteration in brain function, increased use of the third person, verbal denial, qualiﬁcation, displacement, and cliches became prominent. These: ef— fects could be enhanced by the administra— tion of intravenous amobarbital.15 In the subjects in the present study, syntactic analyses demonstrated a reversal of the patterns noted in electroshock. Use of the third person, qualiﬁcation, and dis— placement decreased. Explicit verbal denial was modiﬁed and replaced by minimization and displacement, or by a reiteration of complaints of illness. In dyadic analyses, the verbal interaction was characterized by a greater diversity of vocabulary and less variability in the diversity scores for 25 word units. The qualitative nature of these changes in the language patterns is opposite that of amobarbuital and electroshock. The duration of language changes was concurrent with the changes in the electroencephalogram. Comment These observations conﬁrm the report of Jenkner and Lechner of the effects of di— ethazine in “normal” subjects.10 Diethazine also alters electroshock—induced delta activity in a fashion similar to atropine and scopolamine, as described by Ulett and Johnson,9 with minimal unpleasant symptoms. The effects of intravenous diethazine are immediate, both on the EEG and on W W “MW MN “$wa W W WM W W W W “”wa PRE-DRUG + 200 mg. +25 min. + 70min. LF-LO Rm MWWW st UT'LWMW ”NM-«MW WVMW“ LF-RF LPT~LO °'° WWW WWW/“M 5°}‘VL._. ISEC. WWW/WWW #l637 HH Fig. 4.—Effect of intravenous diethazine on delta activity after electroshock. 382 Vol. 80, Sept, 1958 �EFFECT OF ANTICHOLINERGIC AGENT ON EEG behavior, and thus provide a useful experi— mental agent With “anticholinergic” proper— ties. Two aspects of these experimental observations warrant discussion: the role of acetylcholine-cholinest‘erase- in the electroconvulsive therapy process, and the signiﬁ— cance of diethazine “alerting” for concepts of hallucinogenic activity. 1. Biochemical Basis of the Convulsive Therapy Process.——While there has been considerable study of the psychologic and neurophysiologic aspects of convulsive therbiochemi— information little concerning apy, cal processes is available. The studies of biochemical changes following head trauma and spontaneous seizures provide some analogic data. Bornstein,‘6 in a classical experi— mental study of head trauma in cats, demonstrated that within a few minutes after trauma free acetylcholine appeared in the spinal ﬂuid and persisted for periods up to 48 hours. He further demonstrated a posi— tive relation between the severity of head trauma and the quantity of free acetylcholine, the degree of electroencephalo— graphic alteration, and the severity of the behavioral changes. The electroencephalographic records initially showed short peri— ods of high—voltage fast activity, and a transient period of ﬂattening of electrical activity, followed by prolonged periods of high—amplitude sharp waves in the delta frequencies. Concomitantly, alteration in consciousness, changes in reﬂexes, and post— traumatic seizures were most prominent with highest concentrations of free acetylcholine and greatest degree of EEG change. 7 Tower and McEachern conﬁrmed these observations in clinical studies in man. In 112 neurologic patients, free acetylcholine was found in the cerebrospinal ﬂuid only in patients following head trauma and re— cent grand mal seizures, and the level of free acetylcholine varied directly with the degree of cerebral damage. In addition, these authors assayed the cholinesterase activity of the spinal ﬂuid.7’1‘6 In patients following head trauma, they noted a sharp rise in. nonspeciﬁc cholinesterase (benzoylcholine— Fink splitting) and a drop in the speciﬁc cholin— esterase (methacholine—splitting) activity of the spinal ﬂuid. No such inversion was noted in ﬂuids containing free acetylcholine following spontaneous seizures. Electroen— cephalograms were taken at varying inter— vals following trauma and demonstrated a direct correlation of the extent of EEG abnormality with the appearance of free acetylcholine in the spinal ﬂuid. Tower and McEachern also reported ob— servations in six patients receiving electro— convulsive therapy. In patients after three to seven induced convulsions, they noted free acetylcholine in the spinal ﬂuid in two pa— tients and an increase in nonspeciﬁc cholinesterase with reversal of the cholinesterase ratio in ﬁve of the six. They concluded that the spinal ﬂuid changes in electroshock are more like those of craniocerebral trauma than those found in epilepsyj' More re17 Sachs conﬁrmed the reports of cently, free acetylcholine in the spinal ﬂuid after head trauma and after electroshock. In his studies, Bornstein6 administered 0.5—1.0 mg/kg. of atropine and demonstrated a reversal or a blocking of the EEG effects and a modiﬁcation of the behavioral and neurologic signs. Atropine also blocked the EEG and clinical signs induced by intra— cisternal acetylcholine. Ward8 applied these observations to the treatment of human subjects with varying degrees of head trauma. Subcutaneous doses of 0.1 mg/kg. of atropine induced both clinical improvement and reversal of EEG effects. These observations were recently conﬁrmed by Sachs,17 Ruge,18 and Hughes}9 On the basis of these observations, Ulett and Johnson 9 noted the effect of atropine and scopolamine in blocking the EEG changes of electroshock therapy. Con— 10 currently, ]enkner and Lechner reported ' Regarding the one patient of the six who failed to show either free acetylcholine or a re— versal of the cholinesterase ratio, they noted: “It is interesting that this patient was the only one of the six to show no response to treatment.” 1‘ 383 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY effects similar to those of Ward, in studies provides an excellent experimental method for studies of craniocerebral trauma. of diethazine in cases of head injury. Studies of the brain—stem—activating sys— Another group of investigations complete the available data. Studies of anticholines— tem by Jasper and Droogleever-Fortuyn 28 terases, such as fluorophosphate, and tetra— and Lindsley et al.2‘9 had laid the founda— ethylpyrophosphate (TEPP), which block tion for the prevailing conclusion that sym— the enzymatic breakdown of acetylcholine, metric EEG slow—wave activity has its demonstrate the development of high-ampli— origin in mesencephalic structures, and that tude rapid—frequency EEG patterns similar these structures intimately affect the states to those of status epilepticus, as well as of “alerting” and “drowsiness.” More reslighter degrees of abnormality, as noted in cently, Rinaldi and Hivaich 30"” have re— post—traumatic states.”23 In these studies, lated the site of action. of atropine and atropine blocked both the electroencephalo— cholinergic drugs to this mesodiencephalic activating system. It is also probable that graphic and the clinicaltoxic effects. these be structures may selectively affected clinical and both from experimental Thus, studies of craniocerebral trauma we may by the convulsive therapy process, and that both ef— clinical the and the of electrographic the that acetylcholine activity (a) assume the spinal ﬂuid increases, ([9) pseudo- fects may be intimately related to changes in cholinesterase activity increases, with a re— this system. 2. Diethazine “Alerting” and Hallucinoversal of the ratio of cholinesterases, (c) EEG hypersynchrony and slowing parallel gem'c Activity—The behavioral effects of these biochemical alterations, and (d) anti— diethazine provide information. regarding cholinergic agents may block both the elec— another aspect of the convulsive therapy troencephalographic and the clinical effects. process. In patients Without prior convul— From the data available, it is probable that sive therapy, illusory phenomena and feelthe biochemical basis of convulsive therapy ings of unreality were observed. These is similar to that of craniocerebral trauma. were similar to the hallucinogenic effects of Convulsive therapy results in free acetylcho— lysergic acid diethylamide (LSD32) and line in the spinal ﬂuid 7'17 and a reversal of mescalinef“3 Again, analogic data about the clinical and EEG effects of these agents cholinesterase ratios.”6 The electroencepha— information provide about some con— may induced effects of con— repeated lographic vulsive therapy. is the development of high—voltage, vulsions 34 noted In studies of Wikler mescaline, symmetric, slow—wave activity, occasionally that the EEG demonstrated no change, or is which similar to with spike: activity,3"24’25 intermittent continuous low—voltage fast or trauma..2627 that observed in severe head increase in activity, or alpha frequency. In previous studies we have reported the Denber and Merlis 3'5 noted a similar accel— relationship between the degree of induced eration of decrease in per alpha frequency, slow—wave activity and behavioral response.3 cent time alpha, including its disappearance, The studies reported here and, the work of and random beta nonspeciﬁc activity. Delta 9 Ulett and Johnson demonstrate a reversal activity did not occur. In patients with of the EEG and the behavioral effects of delta activity induced by electroshock, Mer— convulsive therapy by anticholiner‘gic com— lis and Hunter 38 noted that intravenous pounds. In. each characteristic, convulsive mescaline markedly diminished the ampli— therapy is thus similar to- cerebral trauma. tude and per cent time delta activity with While the acetylcholine—cholinesterase sys— an increase in per cent time alpha. activity. tem is highlighted by these studies, other The effects of LSD on EEG are similar. enzyme systems may also be altered.17 These Gastaut et al.3‘6 noted an acceleration of studies also suggest that convulsive therapy alpha frequency of 0.5 to 4.0 cps, with an 384 Vol. 80, Sept, 1958 �EFFECT OF ANTICHOLINERGIC AGENT ON EEG accentuation of beta rhythms. Rinkel et al.3‘7 conﬁrmed this observation and noted, in addition, a reduced responsivity to hyper— ventilation: In summarizing his studies, Wikler 34 concluded that “regardless of the . . drug administered, shifts on. the pattern of elec— troencephalogram in the direction of de— . synchronization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness.” This generalization. provides a meaningful construct in, which these agents may be assessed. Agents that evoke EEG desynchronization tend to be hallucinogenic, and mescaline and LSD are clear examples. Agents that synchronize frequencies, such as barbiturate and meprobamate in the beta frequency range, and chlorpromazine, pro— mazine, and perphenazine in the delta fre— 39 tend to be sedatives, quency range euphoriants, and relaxants. The observations on diethazine reported here are consistent with this hypothesis. In patients without delta activity, the EEG demonstrated desynchronization of f requen— cies, and this was associated with clinical illusory phenomena. In patients with delta activity desynchronization occurred, and alerting and reversal of the speech patterns induced by electroshock were observed. Electroconvulsive therapy may also be understood in this framework. We have previously noted a direct relationship be— tween Clinical evaluations of improvement and the degree of EEG slowing induced by electroshock.3 Under these conditions, seda— tion and euphoria are most prominent, and hallucinatory activity diminished. In, pa— tients in whom hypersynchrony is not in— of iStudies are now in progress on the effects LSD, Win—2299 (2~diethylarminoethy1-cyclo— pentylhydroxy—Z-thienylacetate), benactyzine, and other anticholinergic compounds on postconvulsive EEG delta activity. Initial experiments with these compounds have demonstrated marked diminution in per cent time and amplitude of delta activity associated with behavioral changes similar to those seen with diethazine. Fin/a duced, behavioral change is limited, and “improvement” does not occur.4 Previously we have concluded that the mode of action of convulsive therapies is based on the induction of a state: of altered cerebral function, in which changes in adap— tive interpersonal behavior occur, and are interpreted as “improvement.” 3'4'39 The present studies amplify two aspects of this neurophysiologic-adaptive hypothesis. The biochemical substrate of the behavioral change is reﬂected by an alteration in the acetylcholine—cholinesterase relationships of the central nervous system. It is also prob— able that EEG hypersynchrony provides the neur‘ophysiologic basis of the milieu change, which is clinically manifest as sedation and euphoria and is evaluated as “improvement.” The neurophysiologic-adaptive hypothesis of convulsive therapy has provided a meaningful basis for studies of other physiody— namic therapies.39 In this study, it has. been possible to amplify our understanding of neurophysiologic aspects of hallucinogens as well. Summary and Conclusions The: effect of an anticholinergic agent, diethazine, on the EEG, behavior, and lan— guage patterns was observed in 40 psychiat— ric patients, at various stages in the course of electroconvulsive treatment. (0) Behavior: Increased restlessness and agitation, haptic and visual illusory sensa— tions, and delusional thoughts about their illness or the examiner’s identity were ob— served. (b) EEG: Alteration in EEG were con— current with behavioral changes. There were a decrease in voltage and desynchroni— zation of all frequencies. In patients with delta activity, the per cent time and voltage of delta activity decreased. (c) Language: Syntactic patterns de— scribed for convulsive therapy were re— versed. Use of third person, qualiﬁcation, and displacement decreased. In dyadic analyses there was a decrease in the coefﬁ— cient of variation. 385 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY These observations are discusSed in the framework of the neurophysiologic—adap— tive hypothesis of the action of convulsive therapy, and it is concluded that (at) the biochemical basis for convulsive therapy is similar to that of craniocerebral trauma; (1)) changes in acetylcholine-—cholinesterase metabolism are intimately related to the be— havioral effects, and (c) EEG desynchroni— zation may be a physiologic concomitant of hallucinogenic activity, and EEG hyper— synchrony, associated with euphoria and sedation. Mrs. Hannah Mosquera gave technical assistance in the EEG recordings, and Dr. Joseph Jaffe and Dr. Robert L. Kahn made the analyses of the tape recordings. Diethazine was made available through the courtesy of Smith, Kline & French Laboratories, Philadelphia. Hillside Hospital, 75—59 263d St. REFERENCES Weinstein, E. A., and Kahn, R. L.: Denial of Illness: Symbolic and Physiological Aspects, Springﬁeld, 111., Charles C Thomas, Publisher, 1. 1955. 2. Roth, M.; Kay, D. W. K.; Shaw, J., and Green, J.: Prognosis and Pentothal Induced Elec— troencephalographic Changes in Electroconvulsive Treatment, Electroencephalog. & Clin. Neuro— physiol. 9:225—237, 1957. 3. Fink, M., and Kahn, R. L.: Relation of Electroencephalographic Delta Activity to Be— havioral Response in Electroshock, A. M. A. Arch. Neurol. & Psychiat. 78:516—525, 1957. 4. Fink, M.; Green, M. A., and Kahn R. L.: Experimental Studies of the Electroshock Process, Dis. Nerv. System, 19:113—118, 1958. 5. Ulett, G. A.; Smith, K, and Gleser, G. C.: Evaluation of Convulsive and Subconvulsive Shock Therapies Utilizing a Control Group, Am. J. Psychiat. 112:795—802, 1956. 6. Bornstein, M.: Presence and Action of Acetylcholine in Experimental Brain Trauma, J. Neurophysiol. 9:349—366, 1946. 7. Tower, D. B., and McEachern, D.: Acetyl— choline and Neuronal Activity, Canad. J. Res. 27: 105-131, 1949. Ward, A.; Atropine in the Treatment of Closed Head Injury, J. Neurosurg. 7 :39‘8-402, 1950. 9. Ulett, G. A., and Johnson, M. W.: Effect of Atropine and Scopolamine upon Electroencephalo— graphic Changes Induced by Electroconvulsive 8. 3.86 - 7 Therapy, Electroencephalog. & Clin. Neurophysiol. 92217—224, 1957. 10. Jenkner, F. L., and Lechner, H.: Effect of Diparcol on the Electroencephalograim in the N ormal Subject and in Those with Cerebral Trauma, Electroencephalog. & Clin. Neurophysiol. 7:303- 305, 1955. 11. Heymans, C.; Estable, J. J., and de Bonne— veaux, S. C.: Sur la Pharmacologie de la phénothiazinyl-éthyldiéthylamine (2987 R. P.), Arch. internat. Pharmacodyn. 792123438, 1949. 12. Kahn, R. L., and Fink, M.: Changes in Language During Electroshock Therapy, in Psy— chopathology of Communication, edited by P. H. Hoch and J. Zubin,.New York, Grune: & Stratton, Inc, 1958, pp. 126-139. Jaffe, J.: An Objective Study of Communication in Psychiatric Interviews, J. Hillside Hosp. 13. 6:207—215, 1957. 14. Jaffe, J.: Language of the Dyad: A Method of Interaction Analysis in Psychiatric Interviews, Psychiatry, to be published. 15. Weinstein, E. A.; Kahn, R. L.; Sugariman, L. A., and Linn, L.: Diagnostic Use of Amobarbital Sodium in Organic Brain Disease, Am. J. Psychiat. 112:889—894, 1953. 16. Tower, D. B., and McEachern, D.: The Content and Characterization of Cholinesterases in Human Cerebrospinal Fluids, Canad. J. Res, Sect. E. 27:132—145, 1949. 17. Sachs, E., Jr.: Acetylcholine and Serotonin in the Spinal Fluid, J. Neurosurg. 14:22-27, 1957. 18. Ruge, D.: Use of Cholinergic Blocking Agents in the Treatment of Cranio—Cerebral Injuries, J. Neurosurg. 11:77—83, 1954. 19. Hughes, B.: Role of Acetylcholine in Head Injury, J. Neurol. Neurosurg. & Psychiat. 20:70, 1957. 20. Freedman, A. M.; Bales, P. D; Willis, A., and Himwich, H. E.: Experimental Production of Electrical Major Convulsive Patterns, Am. J. Physiol. 146:117-124, 1949. 21. Grob, D.; Harvey, A. M.; Langworthy, O. R., and Lilienthal, J. L.: The Administration of Di-Isopropyl Fluorophosphate (D‘FP) to Man, Bull. Johns Hopkins Hosp. 81 :257—266, 1947. 22. Hampson, J. L. ; Essig, C. F.; McCauley, A., and Himwich, H.: Effects of Di—Isopropyl Fluorophosphate (DFP) on Electroencephalogram and Cholinesterase Activity, Electroencephalog. & Clin. Neurophysiol. 2:41—48, 1950. 23. Himwich, H. E.; Essig, C. F.; Hampson, J. L.; Bales, P. D., and Friedman, A. M.: Effect of Trimethadione (Tridone) and Other Drugs on Convulsions Caused by Di—Isopropyl Fluorophosphate (DFP), Am. J. Psychiat. 106:816—820, 1950. 24. Callaway, E.: Slow Wave Phenomena in Intensive Electroshock, Electroencephalog. & Clin. Neurophysiol. 2:157-162, 1950. Vol. 80, Sept, 1958 �EFFECT OF ANTICHOLINERGIC AGENT ON EEG M.: Signiﬁcance of Individual Variability in EEG Response to Electroshock, J. Hillside 25. Green, Hosp. 6:229-240, 1957. 26. Jasper, H. H.; Kershman, J., and Elvidge, A.: Electroencephalographic Studies of Injury to the Head, Arch. Neurol. & Psychiat. 44:328-348, 1940. 27. Strauss, H.; Ostow, M., and Greenstein, L.: Diagnostic Electroencephalography, New York, Grune & Stratton, Inc, 1952. 28. Jasper, H. H., and Droogleever—Fortuyn, J.: Experimental Studies on the Functional Anatomy of Petit Mal Epilepsy, A. Res. Nerv. & Ment. Dis., Proc. 26 :272-298, 1947. 29. Lindsley, D. B.: Schreiner, L. H.; Knowles, W. B., and Magoun, H. W.: Behavioral and EEG Changes Following Chronic Brain Stem Lesion in the Cat, Electroencephalog. & Clin. Neurophysiol. 2 :483-498, 1950. 30. Rinaldi, F., and Himwich, H. H.: Alerting Responses and Actions of Atropine and Cholinergic Drugs, A. M. A. Arch. Neurol. & Psychiat. 73 :387395, 1953. 31. Himwich, H., and Rinaldi, F.: Effect of Drugs on Reticular System, in Brain Mechanism and Drug Action, edited by W. S. Fields, Springﬁeld, Ill., Charles C Thomas, Publisher, 1957. Fink 32. Stoll, 'W. A.: Lysergsaure—Diathylamid, ein Phantastikum aus der Mutterkorngruppe, Schweiz. Arch. Neurol. u. Psychiat. 60:279—323, 1947. 33. Beringer, K.: Der Meskalinrausch, Seine Geschichte und Berlin, Erscheinungsweise, Springer—Verlag, 1927. 34. Wikler, A.: Clinical and Electroencephalographic Studies on the Effects of Mescaline, N— Allylnormorphine and Morphine in Man, J. Nerv. & Ment. Dis. 120:157—175, 1954. 35. D‘enber, H., and Merlis, S.: Studies on Mescaline: I. Action in Schizophrenic Patients, Psychiat. Quart. 29:421-429, 1955. 36. Gastaut, H.; Ferrer, S., and Castells, C.: Action de la diéthylamide de l’acide d—lysergique (LSD 25) sur les fonctions psychiques et l’électroencéplhalogramme, Conﬁnia neurol. 13:102— 120, 1953. 37. Rinkel, M.; DeShon, H. J.; Hyde, R. W., and Solomon, H. C.: Experimental Schizophrenialike Symptoms, Am. J. Psychiat. 108:572—578, 1953. 38. Merlis, S., and Hunter, W.: Studies on Merscaline: II. Electro—Encephalogram in Schizophr‘enics, Psychiat. Quart. 29:430—432, 1955. 39. Fink, M.: A Uniﬁed Theory of the Action of Physiodynamic Therapies, J. Hillside Hosp. 6: 197—206, 1957. 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I; 5' 47.5'rﬁ Bulaefﬂuq J’ a 352.6% 9 / g 5/ LSD r ﬂ'f/JXQIWLJ “,3 j in U 9'5. . A m, 4., « 20.3”]; 2.2.00; 4.474 As“. (1 ��Effect of Anticholinergic Compounds on Post Convulsive EEG and Behavior In 1956 Ulett and Johnson (1) reported to this society that large doses of atropine or scopolamine blocked the appearance of the high voltage delta activity usually induced by convulsive therapy. They also noted that the dose of atropine necessary to affect the EEG-was such as to be associated with unpleasant systemic effects. The reports describing diethazine as an anticholinergic by Jenkner and Lechner (2) compound with potent neurologic but minimal systemic effects led us to undertake studies similar to those of Ulett and Jehnson; and these observations, in turn led to an investigation of other similar agents. clinical and EEG It is correlations the purpose of this report to describe the on the intravenous administration of various hallucinogens and anticholinergic agents in psychiatric patients it various stages of convulsive therapy; and to relate these observations to the recently expressed neurophysiologic-adaptive hypothesis of the mode of action of convulsive therapy and of hallucinogens. Subject and Mathod: Our subjects were consecutive referrals for convulsive therapy in an open ward voluntary psychiatric hospital. Patients have various stages of therapy, with observations being in the 17 EEG laboratory. Following a standard leads using needle electrodes, the intravenously at a made been studied in acute experiments 8 channel EEG compound under at recording from study was administered set rate per minute, until clinical behavioral or �electrographic changes diethazine, were observed. Win 2299*, LSD-25, benactyzine, Diethazine was administered at 25 mgm;'Win-2299 and benactyzine at 10 gamma per minute per minute for 1.2-3.6 mgm. at 0.5 for 50-150 studied The compounds JB—318* and JB-336.* per minute, for a mgm gamma; have been total per minute for 2-5 of 175-250 mgm; LSD-25 and JB~318 and JB-336 at 0.h mgm mgm. Observations: the administration of diethazine, in 15 patients prior to convulsive therapy, there was a decrease in voltage and a desynchronization of all On frequencies. Prevailing rhythmic patterns some instances, symmetric prominent in the was not hy frontal altered, but the became low voltage 6-? cps and less prominent. In activity appeared, most anterior temporal leads. in voltage build—up The alpha frequency and slower frequencies induced hyperventilation was blocked (Fig. 1, 2). In 17 patients during convulsive therapy, with varying degrees of induced high voltage delta activity, there was a significant decrease both in voltage and in per cent time of slow wave activity. From an average per cent time delta of h5% in the fronto-occipital leads, there was a reduction to a mean of 20%. Both random and burst delta activity diminished voltage alpha and beta frequencies became prominent. response was no longer apparent. hyperventilation electrographic effects persisted for is 2-diethy1aminoethyl cyclopentyl (2-thienyl) ggycolateg is n-ethyl-B-piperidylbenzilateg JB-336 is memethyl-3-piperidy1benzilate. ”'Win-2299 JB-313 These The and low �one to five hours (Fig. 3, h). Concurrent with these Patients changes. EEG became more effects, we observed irritable and distinctive behavioral restless and complained of sensations of unreality with dysesthesias of the extremities. Visual illusory phenomena and delusional thoughts about their illness, the setting of the test procedure or the examiner's identity were described. Their language patterns were characteristically altered in a fashion opposite to that previously described for amobarbital (3), so that verbal denial, minimization, cliches, third person mode and past tense became less prominent. The These changes were concurrent with maximum electrographic change. behavioral observations with diethazine led to a review of the effects of hallucinogens on EEG activity. In 1955 Denber and Merlis (h) had reported that mescaline altered EEG delta activity induced by electroshock, in a fashion similar to diethazine. They described a marked reduction in amplitude and per cent time of high voltage symmetric slow wave bursts with an increase in alpha per cent time and in low voltage, random leW'wave activity. Reports by fennes (5) that an experimental compound, Win-2299 manifested both potent anticholinergic activity and induced hallucinations in to our study of this compound. The effects were (Fig. 5). led similar to that observed in the diethazine group. In patients pre-convulsive therapy, desynchronization and decrease in voltages of man all frequencies EEG were induced In eleven patients with high voltage delta activity there was a decrease in amplitude and per cent time of slow wave activity with an increase in alpha and beta frequencies. activity dropped from 50% to 23% The mean per cent time delta in these subjects. Associated with these �-helectrographic effects and hallucinatory and clinical patterns of restlessness, excitement, illusory activity (Fig. 6). As the hallucinogenic were activity of LSD-25 was well established, these studies were next repeated with this compound. Here, too, the behavioral and electroencephalogrgphic effects, was a administration, on intravenous were similar to diethazine. There difference in the time constant in that the behavioral effects occurred 1% to 2 after hours drug administration, but the electrographic changes were concurrent with the behavioral change. While there was desynchronization with Mean LSD, less the delta activity was significantly repressed. fell per cent time delta activity in five subjects from h7% to 16% (Fie- 7, 8, 9). Recalling reports that benactyzine, a potent anticholinergic compound, induced EEG desynchronization next administered this we compound intravenously in eleven subjects, and again observed similar clinical and electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, desynchronization was prompt. Delta activity decreased from a subjects (Fig. 10, ll).’ clinical restlessness same per cent time of electrographic patterns 39% to 17% we in 8 were accompanied by and excitement. While we did not observe hallucinatory activity, in the These mean illusory or did note that the language patterns were altered fashion as with the other agents tested. Lately, following reports by Abood (6) that various piperidylbenzilates had potent anticholinergic properties and induced activity, we patterns were tested two of these, clinical hallucinogenic JB~318 and JB-336. identical to those of Win-2299 and The electrographic in each instance in which desynchronization was observed, clinical restlessness and hallucinatory �~5- activity for l to (Fig. 12, 13). was noted 3 The hallucinatory activity persisted hours, and during this period, electrcgraphic alteration was prominent. Thus, six compounds have been shown to have similar electrographic and behavioral effects. Each has definitive anticholinergic activity. Each induces hallucinogenic or excitatory activity; and these behavioral changes are accompanied by desynchronizaticn. compounds have a vamine EEG Furthermore, these similar chemical structure (Fig. 1h). The tertiary in a substituted diethylaminethanol is prominent, corroborating the recent reports by Denber (7) on the hallucinogenic activity of tertiary amines, and amplifying his studies by the common concurrent electrographic patterns. These observations amplify our understanding of the convulsive therapy process. In earlier studies high voltage slow wave activity we indicated that the development of was the neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical years, studies improvement (8). During the past ten by Bernstein, Tower and MeEachern, ward, Sachs, Bugs and others have noted similarities in the biochemical changes in convulsive therapy to craniocerebral trauma (9). They reported an elevation of free acetylcholine and pseudonholinesterase in the spinal fluid during convulsive therapy. In addition, topical administration of acetylcholine induces high voltage bursts uni spike activity. Ulett and Johnson emphasized the blocking of these cholinergic effects by the anticholinergic activity of atropine and scopolamine. The obsumvaticns on this report on �~6- diethazine, Win-2299, benactyzine and the piperidylbenzilates ISDbZS, support their observations. Each of these compounds has potent anticholinergic clinical behavioral and language effects areqpposite to those described for convulsive therapy. we may thus amplify the earlier conclusion that the neurophysiolegic basis for behavioral change in activity and the convulsive therapy by noting is that this the development of high.voltage slow wave EEG change activity reflects an alteration in the acetylcholine- cholinesterase relations of the nervous system, probably in the direction of increased cholinergic activity. These observations lend themselves to application in studies of craniocerebral trauma. .ward's (10) reports of the efficacy of high doses of atropine in altering the clinical manifestations of head trauma also indicated that effective doses brought with It would more them severe systemic be advisable to repeat these studies, neurologically specific anticholinergic utilizing such effects. more compounds as used potent, in these experiments. Finally, these observations, and our earlier reports significance of EEG on the delta activity in convulsive therapy, support the his report on mescaline, morphine with the comment that: "... regardless observation of Wikler (11) n-allylnormorphine and who concluded of the drug administered, shifts in the pattern of the electroencephalogram in the direction of desynchronization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness." This conclusion, supported by our observations, permit a more meaningful �.7- ._ generalization of the recently expressed neurophysiologicuadaptive twpothesis of the mode of action of somatic therapies in psychiatry. We may infer that agents that synchronize EEG in the beta frequency range frequencies, like barbiturate and and chlorpromazine, promazine and perphenazine in the delta frequency range, tend to while agents that evoke hallucinogenic, as EEG meprobamate be sedative, euphoriant and relaxant; desynchronization tend to be excitant and was noted for diethaaine, mescaline, and the piperidylbenzilates. LSD-25, Win-2299, benactyzine, �~8~ In summary, and the effects of various hallucinogenic we have observed anticholinergic compounds on the electroencephalogram and behavior in psychiatric patients at various stages of convulsive therapy. Behaviorally, these compounds induced increased restlessness, haptic and visual illusory sensations and delusional thoughts about the illness or the examiner's identity. The subject's syntactic language patterns described for convulsive therapy and barbiturate were reversed. Concurrent with these changes were a decrease in voltage and a desynchronization of all freQuencies in the In patients with high voltage delta EEG. activity, the per cent time and voltage of the delta activity were markedly decreased. These observations have been discussed common in the framework of the biochemical structure and anticholinergic properties of these agents with the conclusion that: (a) The biochemical basis for convulsive therapy and for>high alteration in the acetylcholinecholinesterase relation of the nervous system, probably in the direction voltage EEG delta activity may be an of increased cholinergic activity. (b) of the mode The recently expressed neurophysiologic-adaptive hypothesis of action of somatic therapies in psychiatry is amplified to encompass the action of hallucinogens. It is cholinergic more recommended compounds that further studies of the effects of anti- in creniocerebral trauma to neurologically specific Win-2299. compounds be undertaken, utilizing as diethazine, benactyzine and �REFERENCES 1. .2. Ulett, Effect of Atropine and Scopolamine Electroencephalographic Changes Induced by ElectroOlin. Neuro aio . 2; 217-22h, 1957. convulsive Therapy, G.A. and Jehnson,1MJﬂ.: Upon Jenkner, F.L. and Lechner, H.: wig; 19 3. 5. ,6. Effect of Diparcol on the . in Kahn, R.L. and Fink, M.: Changes Therapy, In Grune ,h. The Electroencephalogram in the Normal subject and in Those Cerebral Trauma, EEG Olin. ' NeuropQXSiol. I; 303-305, & EEZOhOEEthOlOEY Stratton, Denber, H. and marlis, N.Y. 19 8. 8.: Studies Language During Eleotroshook of Communication, pp. 126-139, on Nescaline I: Action in Schizophrenic Patients. Eﬁychiat. Quart., g2; h21-h29, 1955. Pennes, H. and Koch, P.: Paychotomimetics, Clinical and Theoretical Considerations, Amer. J. Psychiat. _1_1_;: 887-892, 1957. Abood, L.G., Catfield, A.M. and Biel, J.: A New Group of Psychotomimetic Agents, Proc. Soc. Exp. Biol. Mad. 21: h83‘h861 1958 o 7. Denber, H.C.B.: Drug-Induced States Resembling Naturally Occurring Paychosee, in ggzchotrogic DEEES: eds. Garattini, S. and .8. - , l9 7. Fink, M. and Kahn, R.L.: Relation of EEG Delta Activity to Behavioral Response in Electroehock: Quantitative Serial Studies, A.M.A, Arch. Neurol. & Psychiat. 1Q} 516-525, 1957. Ghetti, V., Elaevier, 9. Fink, M.: Effect of Anti-Cholinergio Agent, Diethazine, on EEG and Behavior: Significance for Theory of Convulsive Therapy, A.M.A. Arch. Neurol. a Psychiat. §Qr W88, 1958. 10. Ward, A.: Atropine in the ”heatinent of Closed 398.).‘02’ 1950. 7: Neurosurg., Head Injury, ,1. Clinical and Electaoencephalographic Studies on the Effects of Mescaline, Nealkylnormorphine and Morphine in ‘Wikler, A.: Man, J. Nerv. Ment. 1318., 120: 157.175, 195h. �Effect of Anti-Cholinergic Agent, Diethazine, on EEG and Behavior: Signiﬁcance for Theory of Omleive merepy Max From LOI.’ Fink, 14.1). the Department of Experimental Psychiatry, Hillside Hospital, NOYI Glen Oaks, in part, by grant M-927 of the National Institute of Mental Health, National Institutes of Health, U.S. Public Health Service. Aided, Read (in part) at the meeting of the Eastern Association of Electroenceplmlo- graphers, N.Y., December 1957. SBP: 3-58 �3-3-58 Effect of Anti-Cholinergic Agent, Diethazine, Significance for Theory on EEG-and Behavior: oi Convulsive Therapy Recent investigations of convulsive therapy have emphasized EEG delta activity as the neuroprxyaaoiogic basis for: the induced behavioral change (l,2,3,h,5). Little study, however, has been given to the biochemical effects of this therapy, except in the course of investigations of head injuries. In investigations of head trauma significance has been ascribed to in the acetylcholine-cholinesterase systems both for the behavioral and the electroencephalographic effects. An increase in free acetylcholine (6) and an alteration of the ratio of cholinesterases (7) in the spinal fluid have been positively correlated with the degree of EEG abnormality changes and degree of neurologic improvement deficit. in clinical status The EEG patterns were "blocked," and was reported following some the administration of atropine (7,8). In convulsive therapy, atropine and scopolamine were observed to block the appearance of delta activity, (9) although the effects of the large doses of these agents were marked. Recent reports (10) noted that EEG and behavioral effects similar to systemic atropine were achieved in patients with head trauma by intravenous diethazine a phenothiazine compound with anticholinergic properties - with minimal systemic effects. In our continuing studies of the role of delta activity in electroshock (3), the effect of diethazine was studied. It is the purpose of this report to describe the effects of diethazine on EEG patterns and on behavior of patients during electroconvulsive therapy; and to relate these observations to the present neurophysiologic-adaptive hypothesis of thexnode of action of convulsive therapy. �SUBJECTS AND METHODS: Forty psychiatric patients, at various stages of electroshock therapy in an open-ward, voluntary psychiatric hospital have been studied. All observations have been made in acute experiments in the EEG laboratory. Following a routine recording, diethazine was administered intravenously per minute, for a total of 175 to 250 mgm, depending the behavioral effect. Dosage varied from 2.8 to h.0 mgm per kilogram at the rate of upon EEG 25 mgm body weight. Diethazine is a soluble phenothiazine compound with pharmacologic properties similar to atropine. In experimental animals, diethazine blocks the bradycardia, bronchospasm, salivatim, fasciculation and seizures induced by acetylcholine, di-isopropyl fluorophosphate and pilocarpine. It suppresses salivation, and induces nwdriasis and hypotension (11). me An ses: Recording was continuous for the duration of the observation period, except during interview periods. Needle electrodes, and an Medcraft instnnnent were used. All records were analyzed delta activity (3) 5 the per cent time the relative amount of fast activity. measured in anterior temporal-vertex, and The and 8 channel for the degree of principal alpha frequency; and alpha and delta activity were parietal-ear lobe lead combinations. Behavior Measures: Prior to drug administration an unstructured psychiatric historical interview and a structured questionnaire period (12) were tape recorded. Following drug administration, periods of recorded interview were alternated �+3- with EEG recording periods, injection pattern on until the EEG had again manifested the pres visual inspection; No estimates sf behavioral effects were used: clinical descriptions by the participants - subject, interviewer and technician - of the changes occurring during the drug period, and language analyses of the recorded interevaluated by a syntactic analysis (12) views, Guanges in language were .* and an analysis of the variability in Verbal interaction in the dyad (13.11:) Both measures have been shown induced by changes in the to be sensitive to alterations in behavior central nervous system. * Detailed analyses of these observations Drs. J. Jaffe and R. L. Kahn. will be reported separately by I �OBSERVATIONS: (a) Clinical: Within two to five minutes of the start of the injection, subjects manifested spontaneous coughing followed by a dryness of the anzl a thickness of speech. They reported a feeling of lassitude, mouth and a heaviness and weakness of extremities which was soon succeeded by increased difﬁculty in mintan eyelid closure. Reports of visual and haptic illusory sensations, feelings of unreality distance, and delusional thoughts about their illness, the setting of restlessness and and test procedures or identity were voiced Spontaneously in eighteen subjects in the period between 15 and 60 minutes after drug aduinistration. the our In three instances, increasing agitation and panic led to a cessation of the recording. In two subjects withdrawal and negativism was the prominent behavioral response. Such patterns of behavior were transient and had disappeared in (b) EEG 1% - 14 all subjects. hours in Patterns: Alteration in the EEG patterns was concurrent with the behavioral effects. In all records, changes occurred during drug administration and were sustained, with gradual diminution and restitution of the pre-injection patterns, in one to five hours. The voltage and desynchronization of initial response was a decrease in all frequencies. praninence of prevailing rhytlms. There was a decrease in In patients without delta activity (pm-electroshock), desynchronization and voltage decrease was occasionally activity, symmetric and prominent in frontal and anterior temporal leads (Figure l, 2). The alpha frequency was not altered. accompanied by low voltage 5—7 cps �~5The build-up in voltage and appearance of slower frequencies with hyper- ventilation was blocked. In patients with varying degrees of high voltage delta activity there was a prominent decrease in voltage and desynchronization of the record. burst delta activity diminished or disappeared, and irregular voltage alpha and beta frequencies became prominent (Fig. 3, h). The Both random and low hyperventilation response was no longer apparent. (c) Language Patterns: In previous studies, an intimate relationship betwaen changes in syntactic language patterns and the behavioral response in electroshock had been reported (12). With alteration in brain function, increased use of third person, verbal denial, qualification, displacement and cliches became prominent. These effects could be enhanced by the admirﬁstration of intravenous anobarbital (1h) . In the subjects in the present study, syntactic analyses demonstrated a reversal of the patterns noted in electroshock. Use of third person, qualification and displacement decreased. Explicit verbal denial was modified and replaced by minimization and displacement, or by a complaints of illness. In dyadic analyses, the verbal characterized by a greater diversity of vocabulary and reiteration of interaction was less variability in the diversity scores for 25 word units. qualitative nature of these changes in the language patterns is opposite to that of amobarbital and electroshock. The duration of language changes was concurrent with the changes in the electroencephalogram. The �DISCUSSION: report of Jenkner and Lechner of the effects of diethazine in "normal" subjects (10). Diethazine also alters electroshock induced delta activity in a fashion similar to atropine and These observations confirm.the s cpolamine, as described by Ulett and Johnson (9), with minimal unpleasant symptoms. EEG The effects of intravenous diethszine are immediate, both and behavior, and thus provides a on the useful experimental agent with "anti- aspects of these experimental observations warrant discussion: the role of acetylcholine-cholinesterase in the electrocholinergic" properties. The convulsive therapy progress, and the significance of diethasine "alerting" for concepts of hallucinogenic activity. 1. Biochemical Basis of the Convulsive Therapy Process: While there has been considerable study of the psychologic neurophysiologic aSpects of convulsive therapy, biochemical processes is available. The little and information concerning studies of biochemical changes following head trauma and spontaneous seizures provide some analogic data. Bernstein (6), in a classical experimental study of head trauma in cats, demonstratadthat within a few minutes appeared in the Spinal fluid and after trauma, free acetylcholine persisted for periods up to h8 hours. He further demonstrated a positive relation between the severity of head trauma and the quantity of free acetylcholine, degree of electroencephalographic alteration and graphic records the severity of the behavioral changes. initially showed short periods The electroencephalo- of high voltage fast activity, transient period of flattening of electrical activity, followed by prolonged periods of high amplitude sharp waves in the delta frequencies. Concomitantly, a �.7 - alteration in consciousness, changes in reflexes and post-traumatic seizures were most prominent with highest concentrationsof free acetylcholine and greatest degree of EEG change. Tower and HbEachern (7) confirmed studies in man. In 112 neurologic these observations in clinical patients, free acetylcholine was found in the cerebrospinal fluid only in patients following head trauma grand mal seizures; and the level of free acetylcholine varied the degree of cerebral damage. and recent directly with In addition, these authors assayed the cholin- esterase activity of the spinal fluid, (7, 16). In patients following head trauma, they noted a sharp splitting) and a drop rise in non-specific cholinesterase (benzoylcholine- in the specific cholinesterase (mecholyl-splitting) activity of the spinal fluid. No such inversion was noted in fluids containing free acetylcholine following spontaneous seizures. Electroencephalograms were taken at varying intervals following correlation of the extent of EEG trauma, and demonstrated a direct abnormality and the appearance of free acetylcholine in the spinal fluid. Tower and MbEachern also reported observations in six patients receiving electroconvulsive therapy. In patients after 3-7 induced convulsions, they noted free acetylcholine in the spinal fluid in two, and an increase in non-specific cholinesterase with reversal of the cholinesterase ratio in five of the six. They concluded that the spinal fluid changes in electroshock are more like those of craniocerebral trauma than those found in epilepsy. * patient of the six who failed to show either free acetylcholine or a reversal of the cholinesterase ratio, they noted: "It is interesting that this patient was the only one of the six to Show no response to treatment." * Regarding the one �-8recently, Sachs (17) confirmed the reports of free acetylcholine in the spinal fluid after head trauma and after electroshock. In his studies, Bernstein (6) administered 0.5-1.0 mg/kg atropine More and demonstrated a reversal or a blocking of the EEG effects, and a modification of the behavioral and neurologic signs. Atropine also blocked the EEG and clinical signs induced by intracisternal acetylcholine. Ward (8) applied these observations with varying degrees of head trauma. atropine induced both clinical to the treatment of subjects human Subcutaneous doses of 0.1 mg/kg of improvement and reversal of EEG effects. recently confirmed by Sachs (1?), Huge (18) and these observations, Ulett and Johnson (9) noted the These observations were Hughes (19). Based on in blocking the Em changes of electroshock therapy, without noting the effect on clinical behavior. Concurrently, Jenkner and Lechner (10) reported effects similar to those of Ward, in effect of atropine and scopolamine studies of diethazine in cases of head injury. Another group of investigations complete the available of anticholinesterases, as DFP data. Studies (di-isopropyl fluorophosphate) and (tetraethyl-pyrophosphate), which block the enzymatic TEPP breakdown of acetyl- choline, demonstrate the development of high amplitude rapid frequency EEG patterns similar to status epilepticus as well as lesser degrees of abnormality as noted in post-traumatic states (20, 21, 22, 23). In these studies, atropine blocked both the electroencephalographic and the clinical toxic effects. Thus, both from experimental and trauma we may assume clinical studies of craniocerebral that (a) the acetylcholine activity of the Spinal �-9- fluid increases; (b) pseudo-cholinesterase activity increases with a reversal of the ratio of cholinesterases; (c) EEG hypersynchrony and slowing agents From parallel these biochemical alterations; may and (d) anticholinergic block both the electroencephalographic and the clinical effects. the data available convulsive therapy it is probable that the biochemical basis is similar to that of craniocerebral trauma. of Convulsive therapy results in free acetylcholine in the spinal fluid (7, 17) and a reversal of cholinesterase ratios (7, 16). The electroencephalographic effects of repeated induced convulsions is the development of high voltage, symmetric Slow wave activity, occasionally with spike activity (3, 2h, 25), which is similar to that previous studies we have observed in severe head trauma (26, 27). In reported the relationship between the degree of activity and behavioral response (3). The studies reported here and that of Ulett and Johnson (9) demonstrate a reversal of the EEG and the behavioral effects of convulsive therapy by anti- induced slow wave cholinergic compounds. In each characteristic, convulsive therapy is thus similar to cerebral trauma. While the acetyloholine-cholinesterase system studies, other enzyme systems may also be altered studies also suggest that convulsive therapy provides an is highlighted (17). These by these excellent experimental method for studies of craniocerebral trauma. Studies of the brain stem activating system by Jasper and DroogleverFortuyn (28) and Lindsley gt|§l. (29) had laid the foundation for the activity has its origin in mesencephalic structures, and that these structures intimately affect the states of "alerting" and "drowsiness." More recently, Rinaldi and prevailing conclusion that symmetric EEG slow'nave �-mrelated the site of action of atropine and cholinergic drugs to this mesodiencephalic activating system. It is also probable that Himwich (30, 31) have these structures may be selectively affected by the convulsive therapy process, and that both the clinical and electrographic effects may be intimately related to changes in this system. 2. Diethazine "Alerting The and Hallucinggenic Activity: behavioral effects of diethazine provide information regarding another aSpect of the convulsive therapy processt. prior convulsive therapy, illusory phenomena and In patients without feelings of unreality were observed. These were similar to the hallucinogenic effects of and mescaline (33). Again analogic data about the of these agents may provide some no change, (31;) noted that the intermittent or continuous increase in alpha frequency. (32) and EG effects information abmt convulsive therapy. In studies of mescaline, Wikler either clinical LSD low voltage EEG demonstrated fast activity or Denber and Merlis (35) noted a similar acceleration of alpha frequency, decrease in per cent time alpha including its disappearance, and non-specific random beta activity. Delta activity did not occur. In patients with delta activity induced by electroshock, Merlis and Hunter (38) noted that in travenous mescaline markedly diminished the amplitude and per cent time delta activity with an increase in per cent time alpha activity. similar. Gastaut gt g. (36) noted an acceleration of alpha frequency of 0.5 to h.0 cps with an accentuatim of beta rhythms. Rinkel 33 al. (37) confirmed this observation and noted, The effects of 151) on EEG are �4L1- in addition, a reduced responsivity to hyperventil‘aﬁon.* In smnmariaing his studies Wikler (3h) concluded that " . . . regardless of the drug administered, shifts in the pattern of electroencephalogram in the direction of desynchnonization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness.“ This generalization provides a meaningful construct may be assessed. Agents that hallucinogenic, and mascaline in which these agents evoke EEG desynchronization tend and 1813 to be are clear examples. Agents that synchronize frequencies, such as barbiturate and meprobamate in the beta frequency range, and chlorpromazine, promazine and pezﬁmaz‘mainthe delta frequency range (39) tend to be sedatives, euphoriants and relaxants. The observations on diethazine reported here are consistent with this hypothesis. In patients without delta activity, the EEG demonstrated desynchronization of frequencies, and this was associated with clinical illusory phenomena. In patients with delta activity desynchronisati.on occurred, and alerting and reversal of the speech patterns induced by electroshock were observed. Electroconvulsive therapy We ~31- have previously noted a Studies are now may also be understood in this framework. direct relationship between clinical evaluations in progress of the effects of LSD, Win-2299, benactyzine other anticholinergic compounds on post-convul sive EEG delta activity. Initial experiments w- ah intravenous LSD (SO-100 gamma) demonstrated marked dinﬁnution in per cent time and amplitude of delta activity. and �of improvement and the degree of Under these conditions, sedation EEG slowing induced by electroshock (3). and euphoria are most prominent and hallucinatory activity diminished. In patients in whom hypersynchrcny is not induced, behayicral change is limited and 'imprcvement' does not occur (hO) . Previously we have concluded therapies is based on the that the mode of action of conVulsive induction of a state of altered cerebral function, in which changes in adaptive interpersonal behavior occur, and are inter» preted as 'hmprovement' (3, h, 39). The present studies amplify two aspects of this neurcphysiologic—adaptive hypothesis. The biochemical substrate of the behavioral change is reflected by an alteration in the acetylchcline-cholinesterase relationships of the central.nervous system. It is also probable that EEG basis of the milieu change hypersynchrony provides the neurophysiologic which is clinically manifest as sedation and euphoria and is evaluated as 'imprcvement.‘ The neurophysiologic-adaptive hypothesis of convulsive therapy has provided a meaningful basis for studies of other physiodynamic therapies (39). In this study, it has been possible to amplify our understanding of neurophysiologic aspects of hallucinogens as well. �SUMMARY: effect of an anticholinergic agent, diethazine, on the behavior and language patterns was observed in to psychiatric patients, 1. EEG, The at various stages in the course of’electroconvulsive treatment. (a) Behavior: Increased restlessness and agitation, haptic and visual illusory sensations, and delusional thoughts about their illness or examiner's identity were observed. (b) pg: Alteration in There was a decrease EEG was concurrent with behavioral changes. in voltage and desynchronization of all frequencies. In patients with delta activity, the per cent time and voltage of delta activity decreased. (c) Language: Syntactic patterns described for convulsive of third person, qualification and displacement decreased. In dyadic analyses, there was a decrease in the coefficient therapy were reversed. Use of variatian. 2. These observations are discussed in the framework of the neuro- physiologic-adaptive hypothesis of the action of convulsive therapy; and it is concluded that: (a) the biochemical basis for convulsive therapy is similar to that of craniocerebral trauma; (b) changes in acetylcholine-cholinesterase metabolism are intimately related to the behavioral effects; (c) EEG desynchronization of hallucinogenic activity; and and sedatidn. EEG may be a and physiologic concomitant hypersynchrony associated with euphoria �.Ih~ REFERENCES 1. Weinstein, E. and Kahn, R.L.: Denial of Illness, C.C. Thomas, Springfield, 111., 1955. 2. Roth, M., Kay, D.W.K., Shaw, J. and Green, J.: Prognosis and Pentcthal Induced Electroencephalographic Changes in Electroconvulsive Treatment, EEG 225-237. 1957. Clin. Neurophysiol. 2: R.L.: Relation of Electroenecephalographic Delta Activity to Behavioral Response in Electromock, AMA. Arch. Neurol. and Psychiat. '_?_8_: 516-525, 1957. 3. Fink, h. 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Gastaut, H. , Ferrer, S. and Castello, 0.: Action de la diethylamide de l'acide d-lysergique (LSD 25) sur lee fonctions psychiques at l'electroencephalogranme, Conf. Neum1., 3;: 102-120, 1953. 36. Pslchiat. , Arch. Mutterkomgruppe, 1-h7, 19m. Monog. §_Q: Neural. Psychiat., 1-315, 37. Rinkel, M., DeShon, H.J., Hyde, R.W. and Solomon, H.C.: Experimental Schizophrenia-Like Symptoms, Am. J. Pszchiat" 108: 572-578, 1953. 38. Merlis, S. and Hunter, W.: Studies on Mescaline II: Electroencephalogram in schizophrenics, Psychiat. Quart., g2: 1.30-1.32, 1955. 39. Fink, M.: ho. Fink, A Unified Theory of the Action of mysiodynamic Therapies, J. Hillside M. Hosp. , é: 197-206, 1957. and Green, M.A.: Electroencephalographic Electroshock Process (in preparation). Correlates of the ��j: q-»-\’X mm or mumma manganese» w Panama“ m and Behavior 4" tho abmﬁm at W Fm;black-d the W mek, m mathem- diam!” induced «synchronization of ma fmquamisa and in ”mums. In ptﬁent! with dais: activity, voltage ﬂowed, nativity diuppeumd. muﬁms, m, amt mm mm function. ath an was amt alpha and beta and bdnvioral changes Wynn in mm“ therapy. the behavioral wager? airﬂow}: 11:01:16.6 mm o! the language patterns indicative psychotonmotio nativity nf 2299, um mm frame“: increased WV Mutton and withdrawal, immaod asthma, in maintaining eyelid closure, of 1115”“ and W muuhdmrgic comm, amine. tine of delta nativity and burnt. “W that «It: w’dﬂty .méucad by convulsiw mum, studies mm max-tutu: with a and Jamie»: 419mm led 1» may of Mme sum or cmlsive for ml: of mu W: In recordings of compounds 1:: tbs dons matreutmt, each MOW. m amt induced memmauon at can record with momma in beta “unity, mm, par-1103.06 mm md 1n fmuemy and per-cent time at alpha. m nativity, both the mug. and ppm meat. was “at Imam" mm, nativity. In ”cards with 01w was of thin: activity and ﬁlm alpha Wan}. Bombwnt of mm: W58 APR 2 :5: tummy immacd. (many: new concurrent with than ehctmgnphic manages, use both mm inhibited by Pram the mm, mtmm WW mummsim. Psychiatry, Hillside Kama, Cam Oaks, LL, NJ“. �nﬁa‘ m alumna” are Mar ta thwa of Dunbar a}. 3;. tor Winn. Wt Michalimmio prawn", and signiﬁcanaa structurally, each contain: 1 mm nitrogen linkage. Each of theme compounds have The 01’ than ﬁanrapy of amatima far the theazy of ﬁlm made of nation at convulsiw mama‘s. as will u tor the wommbmr and Wing $.13 1:311qu 1:111 b0 discusud. K �new cat Antichollnergle Game at mmmm me and Bob-71w * 3mm the observations 2: 217, 1957) by cumin ergie (W. ﬁle“ and Johnson um. atropine and 309130le blocked the delta wtiuty induced than”, dMlar studies were undemken with another madmanof diet-henna. Prenloe’oroehock, dietbuine induced demahrmiution tuuuaned.“ end a decrease/1n voltages. In peasants with delta. activity, compound, of ER; voltage md pennant time of delta emvity hemmed, frequencies increased and burst activity diuppeared. dam all” end beta . Concurrent behavioral mum, illusory maid ideetion and withdrawal, increased restlessness, difficulty in maintaining eyelid closure, and reversal of the language patterns «scouted with altered eerebml function after canvulsive changes included therapy (m amt. tholog 9; Gomniggtion, _ The Gram a: Sure/atom, pg. 126, 1958) psychotoulmtle aunt}; of diethuim led to the study at hear-ac and diethyhﬂde, Win 2299 and bemtysim in voluntary momma patients at venous stages of convulsive ﬁrm-aw. These antichaunerglo compounds were Metered intmenously in amounts! of 50-150 gm, 2 to S m and 1.5 m respectively, dung“ mder continuous and language mum-es mutmtmt, nah compound EEG mm. ‘For «ch compound the behavioral peremled those of diethuine. In ma meanings induced EEG demchmieeuon with an increase in beta activity and in the alpha fmqueney. In renews with slow wave activity, both the voltage and pop-neat time of this activity decreased, pement time feet rmuemlea manned, and the alpha frequency increased. Behavioral ahmgea mm concurrent with these ehctrographlc changes, and both were inhibited by intravenous uhlorpmmine. A it Fm: the 61.1}. m. Amos Mia/SB ﬂuent of Experimnbal Psychiatry, Hillside Hospital, .1. NW York. �«a. 3mm ahauntim for muslin. we boon reported by Dunbar. We and (W. W want]. the 33: m. 1955). of postoonvulain Em and bah-uric: pattoma by these potent “mallow «unwound: “was“ a naumphyuiologic but: for comma“ thorupy. Purim 39mm acted that. the clinical ropoma to manned comm m «peach; m the dmlemﬁt af Wain hiya voltnga aim: we nativity (W. my than be 19,: 516.. mmiaud with ma 1957). An 1mm in ahalinorgic nativity Wchrazv and clinical sedation and whom. SWy. a decrease in choumrgia activity may bu associated with EEG «syncing-am mum and 6111:1031 psychotmuc nativity. as therapy or the mad. or whim of amulaiu ”exam and tho mou- phyamlogic «ﬂoat: of mﬁebalmergic command- will be dismantled. �\\ "v Mint: of Ant-1011mm: W311: Minimums on Wm E39 and neopolmim blocked the dclta activity induced by convulsive therapy, studies are Wart-ken with moflar mama“ 0136th dinthuim «cram in voltages. induced compound, diothuine. m. «mm-m on of frequencioa and In putianta with delta activity, volﬁge and pen-mt m of delta nativity acct-cu», tramway immune and law“ activity disappears. Concurrent behavioral chanson: 11:01am imam and withdrawal, illusory sensations, paranoid incmaod ”ﬂatleusnass, difficulty in maintaining mud. of the ham patterns indicative of altered The apparent. hallucinogenic activity m to any of eyelid cio'sum, and «mm. ﬂirtation. various Wu inoluang The of hmetysim LSD. Win 2299, bohuvionl changes in the dam dawns. In m6 Hoarding intizm at the record with an employed were mutmhaant, «eh mousse in '58" parallel to those agent indmd «manom- an fmuemiu, max-cue in alpha Inquency, and alpha voltaga tad para-mt 601%: and masculine. tins. In records mm activity, both the valtagc md pox-«mt tins of delta. activity duel-sand, �duh 4..., par-43m tine fut {maintains Manama, Behavioral (changes were ugd both wm inhibited by and. alpha Inquancy increased. emmnt with than electramphie mung», intramm «human-um. 00de hm patent mticholimrgic properties a wall as n W tertiary W W... Wm“ or them absent»Each at then The um 29:: thus timery :5 of thg an“ a: nation or combs.” therapy in payments, all «a fur the mumphysialogy and pinmcology of hallumogana 61mm. 11.111 be �Effect of Anticholinergic * Compounds an Post—Convulsive EEG and Behavior Following the observations of Ulett and Johnson (EEG Clin. Neurophysiol. 2; 217, 1957) that atropine and scopolamine blocked the delta by convulsive therapy, similar studies were undertaken with ergic of compound, EEG activity induced snail-l anticholin- diethazine. Pre-electroShock, diethazine induced desynchronization frequencies and a decrease in voltages. In patients with delta activity, voltage and per-cent time of delta activity decreased, donﬁnant alpha and beta frequencies increased and burst activity disappeared. Concurrent behavioral illusory sensations, paranoid ideation and withdrawal, increased restlessness, difficulty in maintaining eyelid closure, and reversal of the language patterns associated with altered cerebral function after convulsive changes included therapy. The apparent psychotomimetic activity of diethazine led to the study of lysergicl;:dudiethylamide, benactyzine in voluntary psychiatric Win 2299 and patients at various stages of convulsive therapy. were administered intravenously mgm in reSpectively, under continuous These anticholinergic amounts of 50-150 gamma, EEG recording. 2 EEG 5 mgm and 1:5 For each compound the behavioral changes and language measures paralleled those of diethazine. pre—treatment, each compound induced to compounds In EEG recordings desynchronization with an increase in in the alpha frequency. In records with slow wave activity, both the voltage and per—cent time of this activity decreased, per~cent time fast frequencies increased, and the alpha frequency increased. Behavioral beta activity and changes were concurrent with these electrographic changes, and both were inhibited by intravenous chlorpromazine. % From the Department Glen Oaks, AEEG: L.I. u/3/58 New of Experimental Peychiatry, Hillside Hospital, York. ' . H.“ as... �a-2-n Similar observations for mscaline have been reported by Denber, Merlis and Hunter . w» “inhuman“. ﬁJ/A‘revious reportstzgoted that the clinical response to induced convulsions the development of extensive high voltage was dependent upon slow wave,activity.QAaH7k7~Aznh.aNauroi7v9SyChtat?"j§7"516?“t959}n The reversal of postconvulsive cholinergic compounds suggcrests and euphoria ’ WC ﬁes G The EEG and behavior “patterns thatEEmersynchrony by these potent and anti- [clinical sedation {increase in cholinergic acti@ desynchronization and clinical psvchotomimetic activity,ere 4:. decrease in cholinergic activl$291 5M7 Wild relation of these observations to studies of head trauma, and to the neurophysiologic-adaptive hypothesis of the convulsive therapy will be discussed. mode of action of �Effect of Anti cholingeric Compounds on Post Convulsive EEG and Behavior , In 1956 Ulett and Johnsgon repcrted to this society that large doses (jig of atropine erscopolamine blocked the appearance of high voltage delta ,. Its-their—smdyzhey noted 6? activity usually induced by convulsive therapy. that the dose! of atropine necessary to affect the W" ' with“ carried m unpleasant W5 mic ”We effects. ‘ ' Jenkner and Lechner M compound. It is m were these-sthet—else— Following. £23 reports by Modiethazine 4 a—peten-‘t (Mf‘iam facts aw cw. anticholinergic compound with minimal systemic 9 those of Ulett and Johnson EEG W. 1' Mi! W XMMA‘.‘ ”ﬁr/félcm studies to similar W Our observations with led to an investigation of other anticholinergic this. the purpose of this report to describe the clinical and EG correlations on intravenous A administration of LSD-25, Win-2299, benactyzine and diethazine . n Z; in pSychiatric patients at various stages of convulsive therapy; and relate and these observations to thekneurophysiolog'c-adapative hypothesis of the mode of action of convulsive therapy and of hallucinogens. Subject and Method: Our km subjects ass consecutive referrals for convulsive therapy in an open ward voluntary I psychiatric hospital. Patients have been studied at �.2— [ll observations mg: made in acute is? laborah'y. Following a standardﬁrecording from experimnts in the W 17 leads, the compound under study #8 administered intravenously at a W various stages of therapy, EEG 1-: rate per minute , until clinical behavioral or electrographic changes m I observed. The compounds studied have been diethazine, Win-2299, LSD-25 p and benactyzine . Fig. I- Diethazine was administered at Win-2299 and benactyzine mgm; 10 gamma Chemistry structure 25 mgn. per minute, at 0.5 per minute for 50-150 mgm for a total of 175-250 per mimte for 2—; men; and )5atI LSD gamna. Observations: ‘ low If; patients (Q Wm ' there decrease in voltage and a desynchronization of rhythmic patterns became less prominent. In all frequencies. Prevailing some voltage 6-7 cps activity appeared, most prominent temporal leads. m The alpha frequency was not 993 $9321; Wm was a instances, symmetric in low the frontal and anterior a; altered, and? the build-up an by hyperventilation was blocked, �-u-u— -- .— --- —-.— --—--- Fig. 2’ \‘V 93 \. W; Diethazine - EEG - g Pre-Cenvulsive Treatment vi; .........._.-- __ W , /7 “I at! 3 InApatients during convulsive therapy, with varying degrees ofﬂhigh ,5 (V significant decreaseA in voltage and in We}? ‘1‘! a W K%W W aways... Flusucu/ISlow per-cent time of delta activity. Both random and burst delta activity is voltage delta activity, there M a M 4 V - ~ I 0’3 diminished and low voltage alpha and beta frequencies The hyperventilation respoxaewas — no Fig. Diethazine --—---- .- EEG - Patients ’4, S Convulsive Treatment EEG effects, “wwwwww for irritable Mdysesthesias 1:3» and patterns were ‘ ,m to five hours. I Me dest-tive restless behavioral and complained of of the extremities. W. Visual illusory their illness, the setting of the test W1 46M! procedure; or the examiner's identity were MAM Myopposite one we observed phenomena and delusional thoughts about ‘ / #‘X became more sensations of unreality prominent. longer apparent. @hctrographic effects persisted changes. been .— Concurrent with these . l4» "— ' Their language L w to that previously described for amobarbital) 5 �- 80 W thatkdehial, minimization, cliches, third person were of 4:mode and less prominent. These behaVioral changes were pun-at. during the period 46W W W W W M maximum EG- chani gs. We: led to i. :qs's’ diethazine of other-imam hallucinogens Aru— m Denber and Merlis had W W mmdhﬁmmndm They WAWWM t-L similar to diethazine. «mt ﬁche-high voltage symmetric slow wave time and in w ”Mutant low voltage, ‘9” WW W wand M ”ma,”led to ‘x ’ril' ‘ ~ MWMJ MIM‘M? - MAM“? Fﬁfﬁw' W this compound. study ELIZA; —— 51/ bursts were-diminished WW activity. random slow wave //{/,{r_,,"" fa. etagrm with an increase in alpha per/cent ”.WMM @ports by Pennes and anticholinergic altered mescaline . it: EEG changes“induced by electroshock in a fashion The past tense M. ‘ x-Jyx'yﬂ effects were similar to that: in the diethazine group. Inpatients pres convulsive therapy, 4,.v‘. I EEG .4 ‘ '7 .“-' ’ ' , I desynchronizationéwas induced. Fig. Win 2299 - 6 Pm-Cpnvulsive Treatment .I‘.\ In patients with high voltage slow wave activity induced by convulsive therapy, �.5. P, . \B ‘2‘ 9 \C . there was of slow wave adecrease in amplitude and per-cent time " OLE, & WA. LC— "1L” . ”I , ‘ r '1‘.“ I activity ' with an increase in alpha and beta frequencies. AA‘ssociated with these electrographic effects were clinical patterns of restlessness, excitement, / _.__ , Win 2299 and hallucinatory and - Post Fig. 7 Convulsive Treatment We ﬁremeﬁkwawAﬂ illusory activity. . I, Th? studies yore7/"repeated with intravenous -' 4 LSD {if/(MW isWM inMcbwLW W MAL/”3‘ W. l /.I ( V W A’M/[F There m behavioral effects] W €265 a difference In the time constant bee—names In line/- M electrographio changes-.ﬂkhh 144. ’1» A—‘nﬁlvj 5—6796 mi there me less desynchronization 2-bit the delta activity WrepressedmMkw M “(p/7L “79% M7 miﬂlméw} __ (5‘; a I/L-v ‘ I, . Wﬁ‘ﬁ’Wxﬁi Mose-Al} Recalling the- reports that benactyzine induced l . “Mﬂx I)?“ ‘ EEG W '3 desy‘nchmnization 5 we / adninistered the- ccmpound intravenously: and again! observed similar clinical and is electrographic patterns. In the well modulated alpha record, desynchronization prcmpt. In the record with high voltage delta activity, desynchronization �~6- ' MWMKL Wdelta I790: V13. activity 3903+} __ Fig. 11,’ 12 Bemctyzine WWW These pattems were accompanied by While we did not observe - EEG clinical restlessness and excitement. illusory or hallucinatory activity, mguagew m and Mo diethazine, ‘éu-e ”,ij Cl w w IL: cc te-theé-r EEG M M M3 a: W desmchrmizWeWw, thﬁcue M compounds , an, Malt/71,) aaﬂwf/‘04 WM have In: W11 chemical structure W Jaw/554m these did note the Am to have similar electrographictand behavioral effects. minced I”) we Win-2299 and LSD. Thus, four compounds shown M awfﬁijfj d‘u a M M “by; have been {m W’MM 0’}; Ag,“ écfmmnmé’ é; 444-“ my 1“.” “In diethyl-anﬁno-ethyl organization. ' 7544.. (5y --------m-- ---~Repeat Fig __________________ WM”; WWWtK’L/océeuﬁﬂﬁnféawhhmva\ «a �. ' I I I These observations therapy process. In high voltage slow a; i Ii . site amplify our understanding of the convulsive earlier studies wave activity was . we indicated that the development of the neurophysiologic correlate of behavioral change in convulsive therapy, and a necessary, though not sufficient, condition for clinical improvement. During the past ten years, studies by Bornstein, Tower and McEachern, Ward, Sachs, Bugs and I“.— of convulsive therapy have noted similarities in the biochemical to craniocerebral trauma. acetylcholins They reported thatqguring convu Sl and pseudocholinesterase others erap free are-eiouated in the Spinal fluid. In addition, topical administration of acetyicholine induces high voltage burst and Spike activity. Ulstt and cholinergic effects ‘ The by the Johnson emphasized anticholinergic the blocking of these i::;::§§s;7:;ropine and 5v . . observation in this report on dietha21ne,‘Win-2299, support their observations. Each of these activity and the clinical behavioral 6 AldAbév‘ that the neurophvsiologic eerreiate compounds has and language thfse described for convulsive therapy. LSD-25 and thus scopolamine. benactyzine potent anticholinergic effects are apposite to we may/amplify the earlier conclusion behavioral changes in convulsive therapy �.5- is the development of high voltage slow wave activity, by this EEG tag—ion that reflects an alteration.in the acetylcholine-cholinesterase change "L”! J‘ relation of the basin, probably in the direction of increased cholinergic activity} [Tl' These observations lend themselves to application in studies of cranio- h9,41;r17§ cerebral trauma. The-repeat—ef Ward ll“ e clinical efficacy of high doses of atropine in altering the clinical manifestations of head trauma/also noted that effective doses brought with be advisable them severe peripheral effects. to repeat these studies, utilizing such neurologically Specific anticholinergic more potent, It would more compounds as Win-2299, diethazine or benactyzine. Finally, these observations, of EEG (l95h) and our earlier reports on the significance delta activity in convulsive therapy, support the observation of Wikler who concluded with the comment his report that: ".... on mascaline, n-allylnormorphine and morphine regardless of the drug administered, shifts in m the pattern.ofnelectroencephalogram.in the direction of desynchronization occurred in association with anxiety, hallucinations, fantasies, illusions or �tremors, and in the direction of synchronization with euphoria, relaxation M or drowsiness." This conclusion, supported by these observations, permit a more near meaningful generalization of the recently expressed neurophysiologic - adaptive hypothesis of the We may mode of action of somatic therapies in psychiatry. infer that agents that Synchronize frequencies, like barbiturate ”ﬂ . and meprobamate phenazine EEG in the in the be r ge and chlorpromazine , promazine and deltm; tend to be sedativel, while agents that evoke EEG euphoriant and relaxantl; desynchmnization tend to be excitant and halluc- inogenic, as was noted for diethazine, In smmnary, per- we have observed pf 161), Win- 2299, benactyzine and meccaline. the effects of various compounds as diethazine, ,x/ Win~2299, LSD, benactyzine and mescaline on the electroencephalogran and behavior? in psychiatric patients at various stages of convulsive therapy. Behaviorally, these compounds induced increased restlessness, haptic and visual illusory sensations and delusional thoughts about the subject's illness or the examiner' 5 identity. The syntactic language patterns described for Wham/C convulsive therapy were reversed. Concurrent with these changes were a decrease in voltage and a desynchronization of all frequencies in the EEG. In patients with high voltage delta activity, the per-cent time and voltage �.10.. of the delta activity were marhedly decreased. These observations have been discussed in the framework of the common biochemical structure - that of a substituted diethylanimoethanol thééIanticholinergic properties with the conclusion that: (a) The // - and £74kfzitiég‘ biochemical basis for convulsive therapy;may be an alteration in the acetylcholine-dholinesterase relation of the nyrvous system, probably in the direction of increased cholinergic (b) The (Z? encompass the activity. recently expressed neurophysiologic adaptive hypothesis of the mode of action of somatic therapies action of hallucinogens; studies of the effects of anticholinergic trauma be undertaken, utilizing more in psychiatry is amplified to t is recommended that further compounds in craniocerebral neurologically Specific as diethazine, benactyzine and Winr2299. lﬁfﬁg’ compounds �Effect of Antichelinergic Hallucinogen: on Post Convaleive EEG _and Behavior * tron the Department of Experimental Psychiatry, Hillside Hospital, GlQn OIkB, L010, 3.1. part, by grant H—927 and HI~2092 of the National Institute of Hental Health, National Institutes of Health, 0.8. Public Health Aided, in Service. Read at the v1: 1/59 ~ American EEG. EEG Society neeting, Atlantic City, June, 1958, �Effect of Anticholinergic Hellocinogens on Poet Convnleive EEG and Behavior In 1956 Ulett and Johnson ( ) reported that atropine and ecopolanino blocked the appearance of the high voltage delta activity usually induced by convulsive therapy. They that the dose of atropine necessary to affect the also noted EEG was each as to be associated with unpleasant systemic effects. Reports by Jenkner conponnd us 90 this J Leehner (r) describing diethaeine as an antioholinergic bet minimal eyatenic effects led vith potent neurologic endertake studies similar to those of Ulett and Johnson using compound ( )y and these observations, in turn, led to an investigation of other experiaental enticholinergic agents. is the purpose of this report to describe clinical and It electro~ encephalographic observations on the intravenous administration of various anticholinergic agents in psychiatric patients at various stages of convulsive therapy and to relate these obeervationa to hypotheses concerning the node of action of convulsive therapy and the physiology o: hallucinogens ( ). ( ) �-2SUBJECTS AND METHOD: Our subjects were consecutive referrals for convulsive therapy in an open ward voluntary psychiatric hospital. numbers of While varying subjects have been studied for each compound, Ages ranged from 18 in 10k eXperinents have been assayed. subjects 86 to 67 years, and diagnoses include schizophrenic reactions, manic-depressive and involutional depressive psychoses. Patients have been studied at various stages of the treatment process. observations were The laboratory. 1 standard 8 made channel EEG in acute experiments in the EEG recorder and needle electrodes applied in 17 lead placements following Strauss 22.2; ( ) were In each experiment, the compound under study was edninistered used. intravenously at a set rate per minute, until clinical behavioral or electrographic changes were observed. The compounds studied have been diethasine, Win-2299, benaetyaine, Each is a potent JB~318, JB-336, and atropine. anticholinergic agent in vitrc. Diethasine (diethylaaineethyl~n~dibensoparathiasine), for example, induces mydriesis and hypotension, suppresses salivatien and blocks the �-5. bradycardia, aalivation and soizuros cf acctylchcline and fluorophosphatc ). ( Win-2299 (2-diotylaminoothy1 cycloponty1—2-thieny1~ 1 (2-diethy1aninoathyl benzilato) are similar to atropine pcgﬂLt central offocts synthetic anticholinorgic agents/but with glycolatc) and minimal and benactyzino : peripheral effects ( , ). JBo318 and JB-336 (N~ethy1o3-piperidy1bensilate, H-nethyl~3-piperidy1bonsilato) , . are two at a rccant series or synthetic anticholinergic 33:3: coupounda of high ( ). Diathazino total or minute central potency was 2 to 5 hallucinogenic activity adminiatcrod at 25 ngn. per minute for a 175—250 ngn; Win—2299 for and high ngn.3 and anqbonactynine at 0.5 nan. par JB—BIB) ngnt per minute for 1.2 to h.o ngn. JB-336, and atropine at O.h �OBSERVATIOHS: (a) Diethezine: A: previously reported administration or diethezine in 15 ), the ( patients prior to convulsive ron therepy resulted in a decrease ib volteges and a deeychnnnization or all frequencies. Prevailing rhythmic patterns became lees In some inetences, symmetric low voltage 6-7 ope prominent. activity appeared, nest proninent in the frontal temporal leads. The and anterior elphe frequency was not altered, but the build-up in voltage and the slower frequencies induced by hyper- ventilation vere blocked (fig. 1). acetone-ounces- In 25 petiente during convulsive therapy, with varying degrees of induced high voltage delta activity significant decrease both in voltage slow wave activity. From an and in ( ) there was a per cent time or everage per cent tine delta or hSI in the £ronte~occipita1 lends, there was 1 reduction to e neen per cent tine of 201. Both random and burnt delte �-5- activity diminished became proninent. and low increase in degree of slow The hyperventilation was on effects persisted for voltage alpha and bets frequencies longer apparent. no one activity wave These electrographic to five hours (Fig. 2). ﬁ-‘-¢’---‘ Fig. 2 --‘------Concurrent with these electrographic effects, distinctive behavioral changes. Patients and restless and conplained of we observed irritable became more sensations of unreality and or dysthesias of the extremities; Visual illusory phenomena and delusional thoughts about their illness, the setting or the test procedure or the examiner’s identity were reported. syntactic language patterns a ( were Their . characteristically altered in fashion opposite to that previously described for snobarbital ), so that verbal denial, minimisation, cliches, third person node and past tense hsaanaﬂhax becane less prominent. changes were concurrent with maximum These electrographic change. �«6» (b) Win-2299: Reports by Pennee compound, Win 229?, manifested both and induced compound. excitetory etatee in The ( ) that an eXperimental potent anticholinergic actiity nan led to our study or this observations were einilar to those observed with diethazino. In five patients without slow wave activity, deeynchronisation of frequencies and decrease in voltages of all frequencies were noted in tour (Fig. 3). nooﬁﬂﬂ‘vw Pig. 3 ”------In 11 patients with high voltage delta activity there was a decrease in amplitude and per cent tine of slow wave activity with an increaee in alpha and beta frequencieec The mean per cent tine delta activity dropped from 50% to 23% (Fig. h). Fiz.\h -‘-‘---“ Associated with these electrographio effects were clinical patterne of reatleaeneea and and excitenent. Patients became fearful tenee. Visual seneatione were reported and in three subjects, delusional elaboraticne about their hospital experience were �-7. proninentdheee behavioral changee appeared during drug administrau tion or within ten minutes, ' levels, within to Reports that benactycine induced (c) Benactzaine: diethazine and disappeared, at these dosage tea three hours. two deeynchronization and ( its structural similarity both to and ) Win~2299 EEG led to our testing of this coupoond. Intravenous administration in 12 oubjecto elicited oiuilar clinical and electrographic patterns. Both in the well modulated alpha record and in the record with high voltage delta activity, deeynchroniaation was prompt. Delta activity decreaeed from a mean per cent tire of to 171 in 391 ‘--“‘-C“--“ PigS. 5’ 8 cuhjecte (Figs. 5, 6). 6 ﬁ“-~--‘---These electrographic patterns were accompanied by clinical reetleeeoeee, irritability was more difficult. dittaanxt The thoughts econ with the dosage levels. In and excitement. Artifact-free recording illusory sensations initial compounds were and delusional not noted at these patients with manifest dieorientation language changee associated with convulsive therapy ( and ), however, �‘8‘ there wee en alerting and e revereal or the language patterns. (d) Piperiqzibenziletee: Abood ( ) that various piperidylbenziletea both manifested entioholinergic activity subjects, The Following recent reports by we tested and induced two or these, hallucinations in psychiatric JB-318 and JB—336 in 2b subjects. electrographio patterne were identicel to those other deeynohronination was during - Onset of inaynshxlaxxntx experimental oonponnde. injection or within 15 ninntee and persisted for one to four hours (Fig. 7, 8). -“Q.*.‘..--‘U.Figs. 7, 8 -nﬂ-~ﬁ--.‘-‘--animation was observed, In each instance in whioh deeynchrntxixx clinical restlessness activity changes. were and exoitenent, illusory and hallucinatory noted, and were concurrent with the electrographio In two inetanoee the behavioral changes were halted by the subsequent intravenous adninietration of chlorpronaaine. �(e) Atrozine: Continuing our etudy or enticholinergic compounds, we edniuietered atropine intraveneuely in 12 subjects, in dosages of 0.8 to h.0ngn. Systemic erreeta were prenineut during the injection with increased respiratory rate, puller, dial dry akin and dry mouth, preeorttxxx cenpleinte and eerked teehy~ eerdie (Figs. 9, 10). und.~¢...mnd.¢Figs. 9, 10 ‘b.-’~.ﬁ-‘----Subjects beenne reetleee end feertul (as did the obeervergp) end Seekxxxnptenxxunxnxpxenixentxlxxte recording became difficult. Within ten minutes these symptoms subsided and the subjects became drowsy and relaxed. In subjects without delta activity in the initial record, to leeeitude by decreased slowing (Fig. little be followed during change was seen the period at voltages, desychrenization and increased 9). Fig. 9 In subject: with delte activity, there wee en initial decreeee in voltage and per eent time or such activity during the period or �~10... reatlonancaa, following by an increaao during tho period of quiotudc (Fig. 10). --ﬁ---.-‘&-ﬂw Fig. 10 “.Q‘....‘.‘.‘ �-11DISGUSSIOH: i Various compound: with measurable anticholinorgic activity have that been effects. Thoco shown to have similar oloctrographic and bohovioralw oxporinontal compounds oxhibiting the greater facility in altoring cloctrcgraphic patterns structure oach containing a have a cannon tortiory nitrogen with linkage to varying roota (Fig. ll); a diothyl whilo atropine, rolativoly inpotont in altering oloctrcgraphic patterns contains a quaternary nitrogen. Bohaviorolly each compound induces stimulating, excitatcry and illusory and hallucinatory activity. Electro- graphically each induces dcaynchronication of frequencioa, and docroaac in voltages, most prominent in anhycta with delta activity c 7 following thoropcntically induced convulsions. (a) Convulsive theragy process: Those observations amplify our understanding of the convulsive therapy process and at the induced activity. In earlier studios or high voltoho slow wave ccrroloto or bohoviordl we slow wave indicated that the development activitr chango EEG woo tho nonraphyaiologic in convulsive therapy, and a �-12- - heceslary, though not sufficient, condition for clinical improvement ( ). During the past ten years, .1ncluding Bernstein, have reported numerous Tower and HoEachern, Ward, similarities in the biochednicsl authors Sachs, Rugs changes or the central nervous system in convulsive therapy to that seen in craniocerebral trauma ( ). They observed an inorease in cholnerzic activity as manifest by an elevation of tree acetylcholine and pseudocholinestereses in the spinal fluid. In addition, the direct increase in central nervous system acetyloholine activity by topical administration or eoetyloholine induced high voltage bursts and spike activity. Ulett and Johnson ( enphesised the blocking of the behevioral and electrographic effects by the antioholinergic activity of strapine The observations in this report on end scopolenine. dietheziue, Win-2299, benectysine and the piperidylbenziletes support their observations. The potent enticholinergic activity of such of these compounds (with apparent predoninant locus of activity in the central nervous system) expliries the suggestion that the beechenical basis for the induced slow wave activity of oonvulsivei therapy results from �an increased lova4tf control acetylcholine-cho1inesterase activity. Support for such a hypothesis considerable degrees of slow adniniotrotion of DE? wave is also seen in the activity observed after the (di-ioopropylrlnorophoophote) - a potent oholinootoraoo blocking agent. Uhilo these observations demonstrate that anticholinorgic compounds or. affective in reducing slow wovo activity,.roporto of othor compounds with similar effectihavo also appeared. ‘Anphotanino (Bonaodrino) ( acid diothylonido and diphenhydronino (Bonodryl) ( ) ), moocalino ), lyoorgic ( ( have been reported as rodncing post-convulsive slow wave These compounds ) activity. are primarily described as oymphthominotio and ontihiatoninio in phornncologio activity, yet each has exoitotory ond stimulating effoﬁoto on bahnvior ( , , , ). The relations or those observations to than. soon in this report are possibly boat assessed in relation to synaptic activity. In t study of tho effects or vorioua agonta on the EEG and behavior of unanosthotizod cats with chronic inpltnted electrodes, �-1hBradley and Elkee ( ) postulated the exietence of two, or pcesibly three, types of interacting chemoreaponeive receptors within the central nervous system: cholinergic, non~cholinergie eheeeptible to amphetamine, and nonecholinergic susceptible to LSD and tryptaminie derivatives. Marezei and Hart ( ) exploring intercortical-(transcollosel) partwaye in the cat, described the effects of various compounds on direct electrical stimulation. They on the evoked potentials postulated the presence of two chenoreeeptive potentialities of the synapse - cholinergic and adrenergic ~ with Opposing stimulatory and inhibitory aetien. In both constructs, the administration at antifcholinergie agents, or at eympatheniaetic agenta, results in equivalent eynaptic .electrieal effects. LSD Thus adrenaiine, amphetamine, meecaline inhibit the electrical activity recorded afcreee and a synapse. in ddentieal effect is achieved with atropine. In the light or these suggestions, the present experiments permit a.mere specific hypothesis regarding the pharmacologic baeie of the convulsive therapy preceee. Repeated induced convulsions leads to an increase in synaptic eheliaergie activity with an �-15- increase in the level at electrical activity of the central nerveue system, which 1e recorded by surface electrodes es augmented high voltage slow wave activity. Adainietratien of entieholinergic agents reduces the leveﬂef synaptic activity, resulting in a decrease in tbe manifest cortical electrical activity to pre-convulsive levels. The administration of ayapathomimetic agente, however, also achieve: the seme etiolate, not by altering the by increasing the aloe EEG uni“ chelinergic ectivity but level of adrenergic activity. activity, wave so preninent and so or the poet-seizure state electrical ( The manifest persistent in the ) may waking thus be related to a pereiatent alteration in synaptic transmission activity of large numbers of The delicate thin balance is seen in the ready reversibility with a! Venture or alerting calls at the centre‘rerveee system. ( ), tine agents neted hare. ( ) and the wide variety or pharmacologie Repeated induced convuleione nay thus be described an a device to creete bioeheaieal changes in the brain �.16. for their resulting behavioral effects. fornuletion is Such a consistent with the view that convulsive therapy is therapeutic process non~apecitic ). ( initial suggestion The a ( ) for the convulsive therapy process may that the pharmacologio basis lie in alteration in an acetylcholine-cholinaeteraeo relationships, can, thus on be focused the alteration in the level of synaptic activity. 11:? regard, the observation that diphonkydranine anti~hystaninic agent, also reduces slow convulciono amount of ), ( and wave Innzyknhni In this primarily an , activity of induced the observations by Sacha ( ) that increased cerotinin appear in the spinal fluid otter convulsion: cuggeet that this image of synaptic activity in convulsive therapy is oversimplified. Nevertheless, further animal studies or the effects of various drugs on the poat~seizure electrical activity are warranted. (b) Neurophysiologz;pf hallucinogenic activitz: These observations of anticholinergic compounds delta activity also nay activity. be on EEG related to concepts of hallucinogenic Each of the compounds studied induced excitatory �-17behavior including illusory and hallucinatory phenomena.* Here, - too, synaptic models nescaline, may be useful. Sympathomimetie agetts, as amphetamine, and LSD, and entieholinergie agents es those described here, are equally potent hellucinogene, The neurophermacologic basis for such behavior may be characterized ee en alteration in synaptic balance in the direction of increased inhibition (decreeeed.trenenieeion) of stimuli. clinical efficacy of convulsive therapy in The hallucinatory ectivity.ney the: lie in biochemical level. known alteration at this Equally eignifieent are the effects of other cin entiehellunuiogene, ee chlorpromezine end reserpine, electrical activity. in an modifying men ( nedceline ), block the ( ), and Both compounds induce EEG EEG on hypersynohrony deeynehronieing effects of LSC.end in animal studies, block behavioral and electrogrephic effects ( ,). LSD and mesoeline The nonospecific nature of the neurophysiologic basis of orperimental hallucinatory activity ia thus emphasized. In the doses need, hellucinetory phenomene were not observed for benectyeine. A report of such activity was reported at higher doeege ( ). � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Effect of anticholinergic agent, diethazine, on EEG and behavior; significance for theory of convulsive therapy. AMA Arch Neurol Psychiatry. 1958 Sep;80(3):380-7 Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-002-29b-005 Date A point or period of time associated with an event in the lifecycle of the resource 1958 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource 6 items. 1: Experimental Studies of Convulsive and Drug Therapies in Psychiatry: Theoretic Implications (one page). 2: Small graphs. 3: [preprint]. 4: Draft. 5: Reprint from the A. M. A. Archives of Neurology and Psychiatry September 1958, Vol. 80, pp. 380—387. 3: File copy. 4: Handwritten notes. 5: 8 drafts. 6: [preprint]. 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