http://exhibits.library.stonybrook.edu/mfp/files/original/547dda87f02e63e10815bbd8bd8b58a3.pdf 2de3623b012b67ce51e9e637220d0b84 PDF Text Text Role of EEG Frequency Shift in Behavioral Effects of Drugs mmmm.* During the past few years we have been interested in the interrelation- ship of changes in various measures of brain function and the behavioral response of psychiatric patients to somatic therapies. were devoted Our initial studies to the changes in tactile perceptual tasks in patients with organic psychoses. This study, carried out at Bellevue Psychiatric Hospital, demonstrated that patients with active organic psychotic reactions made repeated errors in the simple task of reporting two simultaneously applied cutaneous stimuli. The persistence of such‘errors was interpreted as an index to the presence of an "organic mental syndrome." In the initial studies at Hillside Heepital in 1952, the same patterns of errors were observed in patients receiving convulsive therapy. we then became interested in the role of altered brain function in the "improvement" induced by convulsive therapy. we In our first group of patients followed consecutive electroshock referrals with weekly measures of changes in brain function of brain function: and memory clinical interviews. tests, simultaneous we used four indices tactile tests, the amobarbital test for organic brain disease described by Weinstein and Kahn, and the degree of induced delta activity in the EEG. It was soon apparent that neither the memory scales nor the tactile tests were sufficiently sensitive indicators of alteration in brain function to be satisfactory for our purposes. The amobarbital test, however, was a sensitive indicator. In this test, the subject is asked a series of questions regarding his illness the Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, Island, N.Y. Read at the Section of Neurology and Psychiatry, Queens County Medical Society, June 3, 1958. Frcm Long ‘ �.2and orientation for place, date, time and person. Following the administration of intravenous amobarbital until the patient has nystagmns, the questions are repeated. Errors of confabulation and disorientation are scored as "positive" tests, and have been found almost exclusively in subjects with active cerebral dysfunction. In the patients in the electroshock series, a significant relationship was observed between changes in this test and impmvement ratings in convulsive therapy. Amobarbitfl Test EST - Improvement #1 “----‘--- u..---.--—----—--——-we in the also measured the changes in EEG. fine degree of induced delta activity Examination of a series of preliminary records, as well as the description in the literature, demonstrated the early development and ‘persistence of Slow wave activity in the EEG during convulsive therapy. this preliminary information, we obtained weekly records during and ‘We measured of treatment. a after course specified leads for the per-cent time delta, the slowest frequency, highest voltage of delta and the duration With of burst activity. Using these quantitative indices 180 records activity. in The we ranked the initial patients according to the extent of the induced delta upper third were classed as ”high degree delta records," 2h the middle third as "middle or'moderate degree delta" and the lowest third as "low degree delta activity." High, Middle and Low Delta - EST #1 �.3 When we related the development of high degree delta activity to improvement rating, a signifiicant relationship Fig. EEE was again demonstrated. 5 Delta - Improvement - EST #1 ---—-—------ -—------ yo--— --—‘-..- ~- In subsequent months development of high degrees of third to EEG delta activity during the second and ratings. In the next table, these observations in the next Sh patients. weeks of treatment have summarized a predictive study, relating the we embarked on improvement F1 . we 6 Table: Patients High Delta 2nd, 3rd weeks of Treatment EST 2’ 3’ ’4 -_------- ----—----‘u-n-—---------_-----m-‘-----—----By this time we believed that EEG delta activity was related to the behavioral changes in convulsive therapy, and its significance in a control convulsive-subconvulsive study. Of was tested consecutive convulsive therapy referrals, randomly selected patients were subjected to a course of subconvulsive therapy instead of the convulsive therapy. This to the patients or their therapists. 0f the substitution was unknown subjects received convulsive therapy in this series, high degree delta who activity records were observed in of treatment. Of the 27 Subjects 3h during the second who to the fourth h? weeks received subconvulsive therapy, however, none demonstrated either-high or middle degree delta activity �.u. EEG . records during any week of treatment. In concurrent behavioral evaluations, of the h? subjects in the convulsive group h2 behavioral change, while only showed such 3 showed marked of the 27 in the subconvulsive group a change. In clinical improvement ratings, 2h of h? were rated "recovered" and "much improved;" 15 "unimproved or worse." But as "improved" and 8 as of the subconvulsive group,only 3 were "recovered" and "much improved," 5 as "improved" and 19 rated as "unimproved cr'worse." we were now convinced that high degree of EEG delta activity reflected the physiologic changes essential to the behavioral change in convulsive therapy. An alteration in brain function, sufficient induce considerable - and of the kind to activity appeared to be the prerequisite, not sufficient factor - in the convulsive therapy EEG a necessary, flaough slow wave process. Perhaps a similar relationship was observable in other somatic therapies? we next examined insulin activity is induced, hours after gavage. receiving deep or prolonged which Not coma therapy. During each coma, EEG delta usually persists for a few minutes to a few infrequently - in approximately 1/3 of patients insulin therapy in our hospital, seizures, aphasia result. After such events, EEG changes of delta activity coma coma persist for days, The relation ' and in cases of prolonged between prolonged coma, coma, for weeks and months. altered brain function and behavioral response has been discussed by numerous authors. Revitch reported eight cases and concluded that improvement was related to the induction of organic brain damage, similar to lobotomy. Yaeger et a1 �-5. noted a correlation between length of coma, degree of organic confusion, remission of mental symptoms and degree of of prolonged coma. EEG In reviewing our insulin abnormality in 12 cases coma experiences, noted we that our best clinical results have been observed in prolonged coma cases. As a result, it has been the intention of our staff to induce such a state. Persistent coma EEG delta activity has been observed in a small subjects, and only in those with prolonged neurologic signs. Thus, in insulin coma number of our or persistent also, a relation between delta change and behavioral response is indicated. Concurrent with these investigations, We had begun clinical EEG coma investigations with the newer tranquilhers. Initial study of Raudixin in 1953 He were failed to indicate any clinical efficacy. able to administer large doses - up to 10 With mgm. reserpine, however, At these levels, behavioral change become prominent but so also did neurologic complications. Parkinsonism was readily induced, and seizure induction and increased clinical depression became prominent. The EEG changes on chronic administration were small. With our doses, desynchronization was apparent, but at higher dosage hyperSynchrony was also noted. With chlorpromazine, however, we were more fortunate. we had undertaken a control insulin coma-chlorpromazine study, in'which the experimental dosage called for levels sufficient to induce clinical parkinsonism. In three of the thirty patients grand mal seizures were induced. In all patients significant changes were observed in serial EEGs. These consisted of increased modulation, increase in per-cent time alpha, and in twenty patients lOW'voltage theta and delta activity. On hyperventilation, delta �burst activity was observed. In reviewing the experiences of others, noted numerous reports of chlorpremazine inducing seizures; exaggerating seizure activity in epileptics; and activating seizure available for reserpine. EEG we records. Similar reports are review of the electroencephalographic effects of various phreno- A tropics demonstrated that not all newer agents induced Meprobamate, in clinical doses, induces an increase in activity. slow wave EEG fast activity, with increased voltage and Spindling. The records are most similar to barbiturate records. Benactyzine (or suavitil) induced neither slow nor fast activity but desynchronized the record, with flattening of voltages and loss of wave whatever rhythmicity was present. clinical experience we were impressed that chlorprcmazine and reserpine were the most effective modifiers of psychotic behavior, with benactyzine and meprobamate as relatively inefficient agents. It From our seemed appropriate therefore to extend the neurophysiologic adaptive hypothesis of the it was mode of action of convulsive and insulin EEG frequencies to the delta range would active in modifying psychotic behavior; while those that induce a shift to the beta range, or As a corollary it was desynchronize the record would be less effective. suggested that agents that induce no change in brain function or changes so small as not to be reflected in serial have therapies; suggested therefore, that agents that induce a change in brain function reflected by a shift in be most coma little EEGs would behavioral effect. Thus, a classification of newer phrenotropic �-7drugs based on their EEG effects was suggested: (3) Increased slow wave activity with hypersynchrony (b) Desynchronization with voltage and frequency irregularity, .and (0) irregular theta Increased high voltage fast activity In reviewing the available literature reports of promazine and perphenazine would indicate delta range. that these agents induce a shift in the Mepazine has minimal EEG effects, EEG spectrum to the and these are largely desynchronization. Information regarding other newer agents was not available. we EEG have undertaken two studies based on changes to behavior. One is serial EEG this hypothesis relating studies of patients receiving chronic tranquilizer medication at the hospital. a study of the relation acute administration: between the EEG and A now second is the behavioral effects on the data of our chronic administration studies are not yet available, but the acute studies have progressed sufficiently to danonstrate the applicability of the hypothesis. Fbllowing the observations by Denber derivatives, diethazine, elicit some EEG when that one of the phenothiazine administered with chlorpromazine, would activity similar to convulsive therapy, we undertook explorations of this compound. In the EEG laboratory with continuous 31 w wave recording, varying amounts of diethazine from 100 to 250 mg. were administered intravenously over a 10 minute period in psychiatric patients at various stages of the convulsive therapy process. Instead of hyperynchrony, patients who were pretreatment and without EEG delta activity, demonstrated significant desynchronization of the record. �-8Fig. 7, EEG - Diethazine - Pretreatment interesting, however, Most 8 was the effect of diethasine in patients with increased slow wave activity during convulsive therapy. Here, too, desynchronization became manifest, and there was a decrease in the voltage and per-cent time of the induced delta activity. EEG - Diethazine - Delta Activity effects, we observed distinctive behavioral changes. Patients became more irritable and restless; they Concurrent with these complained of sensations of extremities. In some, EEG unreality, visual illusory and of dysesthesias of the phenomena and delusional thoughts their illness, the setting of the test procedures or our identity. There were changes in their language patterns opposite to that previously about described for amobarbital, so that denial, minimization, cliches, third person mode and past tense were less prominent. The duration of these behavioral and language changes was from one to five hours. changes were of similar duration administration and disappearing The EEG - appearing during the period of when drug the behavior had apparently reverted to the pretreatment state. The ability of diethazine to activity led to an evaluation of induce other illusory known and hallucinatory hallucinogens. In checking �-9the literature we noted that that mescaline reversed the Denber and Merlis had previously described EEG changes induced by electroshock, in a fashion identical with diethazine. Pennes had observed hallucinogenic activity for another experimental compound Win 2299. We obtained some of this material, and repeated our diethazine studies. Here, too, Win 2299 induced EEG desynchronization associated with clinical patterns of restlessness, excitement, hallucinatory and illusory activity. Fig. 11, Win 2299 We repeated these studies with was a - 12 EEG LSD, and again the same patterns. There difference in the time constant, but concurrent with the behavioral effects we observed EEG changes. Recalling the ability of benactyzine to desynchronize records, this compound intravenously, and again, we observed the same we EEG administered pattern of desynchronization, associated with restlessness and excitement. While not observe the illusory and hallucinatory patterns, kinds of language changes in these patients that we we did note the we did same observed with diethazine. �Fig. 16, 17 Benactyzine The chemistry of these compounds Thus, from each of these agents, - EEG is noted in the next figure: EEG desynchronization was induced, and hallucinogenic or excitatory activity was observed. we can.now amplify our initial hypothesis to encompass hallucinogens. like to refer first to conclusions described in l9Sh by Wikler in a study of the effects of mescaline, n-allylnormorphine In-this regard, I and morphine in would man, in which he stated: ".... regardless of the drug administered, shifts in the pattern of electroencephalogram in the direction of desynchronization occurred in association with anxiety, hallucinations, fantasies, illusions or tremors, and in the direction of synchronbation.with euphoria, relaxation or drowsiness." ‘We would now generalize our observations of EEG changes and behavior to note shift to the delta behavior. Agents that and that agents that induce EEG synchronization range are potent agents in the control of psychotic induce synchronization in the beta range are relaxant, euphoriant and sedative, while agents that desynohronize the record tend to be hallucinogenic. This hypothesis lends itself to a variety of applications. It provides a bases for the understanding of the mode of action of various organic �-11- therapies in psychiatry. EEG analysis may also provide a basis for the assay of new drugs and therapy procedures. Finally, these observations permit a more rational management of the somatic therapies. to explore each application in summary I would like fashion. application of the neurophysiologic adaptive hypothesis - for that is the rubric under which we subsume the relationship between the The in brain function, reflected by the EEG, and the changes in behavior - to insulin coma therapy has already been described. we have changes applied this concept to our studies of phrenotropic agents, and have been able, both It is predictively and retrospectively, to assess new agents. possible to understand lobotomy therapy, and sleep therapy, within this framework. As is for the assay of drugs, our explorations into hallucinogens that each of the potent hallucinogens a biochemical similarity in a common tertiary amine radical connected one example. have new we have recently noted by an ethyl linkage to a large nucleus. compounds with this linkage. One On this basis, we sought for group are known anti-parkinson agents with anti-cholinergic properties as parsidol, artane, kemadrin, panparnit and benadryl. we have not yet tested these compounds for their EEG or clinical effects. Recently, Pfeiffer reported at the Academy of Neurology that these compounds, in trained subjects, were identified most with LSD. In 1956, Gottlieb reported that benadryl desynchronized the patients, much as we saw this evening. available in the literature. shock EEG of electro- Thus, some confinnation is �.12With regard to the third therapies - this hypothesis ammflication may - the management of somatic be of considerable help. In convulsive therapy and in drug therapies, the patient'who responds in a favorable fashion is‘no problem. But what of the patients who responds poorly, or not at all? Could the failure of response be related to inadequate dosage? In electroshock, when a patient manifests paranoid or withdrawal behavior, or no significant change, an If the record we may assume fails to EEG provides a guide to management. demonstrate high voltage slow wave that treatment has been inadequate, activity, then and continue the treatnent course or increase the frequency or alter the convulsant method. If EEG changes are present, then we would assume that other factors - personality, sociologic or interpersonal - are not conducive to "improvement" by electroshock, and other remedies sought. Similar applications are possible for phrenotropic agents. In summary, we believe that somatic therapies in psychiatry exert their effects primarily by altering brain function. Changes in the EEG Spectrum are one reflection of sudatalteration and are useful as a guide to the mode of action, effectiveness and application of somatic therapies. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Research Files and Unpublished Works Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Role of EEG Frequency Shift in Behavioral Effects of Drugs, 1958 Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-03-01-002-12-011 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 <a href="http://id.loc.gov/authorities/subjects/sh85113021">Research Files</a> and Unpublished Works -- Hillside Hospital, Glen Oaks, NY, 1953-1965 Relation A related resource The Max Fink Collection Description An account of the resource Research papers, files, and related correspondence Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. 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