Remembering the lost neuroscience of pharmaco‐EEG (2010)

To the electrophysiologist accustomed, in his animal experiments, to probing with his electrode into the nervous system and even into the nerve cell itself, it remains a matter of astonishment that so many of the brain’s secrets escape across the wall of the skull to electrodes fixed to the scalp of man. That they indeed do so is testimony to the fact that the brain’s electrical activity is a most sensitive indicator of its function. In this fact lies the attraction of electroencephalography for its devotees. I am known for my defense of electroconvulsive therapy (ECT) during the decades when professional leaders and the laity denounced and legislated against its use. The worldwide resurrection of ECT in the past decade is a heartening endorsement of those efforts, a story well told by professional historians (2, 3). Researchers are marked by their enthusiasms, and in my life I have followed leads in clinical psychopharmacology, opiates and their antagonists, the physiology and tolerance to cannabis, and for two decades, the psychopathology of catatonia and melancholia. In this essay I relate my 30-year enthusiasm for pharmaco-EEG – the science of the effects of psychoactive substances on brain electrical activity (4–8). After public schooling in New York City and graduation in medicine from the New York University College of Medicine in 1945, I followed a conventional course of internship, military service as an Army physician, residencies in neurology and psychiatry, to certification in neurology (1952), psychoanalysis (1953) and psychiatry (1954). In my fifth year of residency training at Hillside Hospital (a community psychiatric hospital in Long Island, New York) I was introduced to insulin coma (ICT) and ECT and established the hospital’s EEG service to study these treatments. When I introduced chlorpromazine and imipramine to the hospital in the mid-1950s, we were equipped to determine their EEG profiles as well as their clinical effects. Quantifying EEG rhythms was a challenge. It was fortuitous that the digital computer revolution was applied to EEG in 1960 (9) and for three decades my associates and I applied quantitative methods to study the effects of drugs on brain functions in patients and volunteers. This essay describes that experience, mirroring the rise and the fall of pharmaco-EEG, a neuroscience that was discarded well before its full potential was achieved. The hours of encouraging the recollections of the hospitalized mentally ill in psychotherapy sessions, each of 50 min by the clock, stimulated little interest. How often could one listen to strange beliefs and petty thoughts that were repeated again and again, hour after hour, like a well worn phonograph record? Summarizing these stories for a rabbinical teacher-analyst brought little insight and less benefit to the patients. One teacher, Sidney Tarachow proposed a study of a psychoanalytic hypothesis that absence of a parent (by death or divorce) during childhood determined the form of expression of an adult neurosis, whether obsessive (one parent) or hysteric (two parents). A review of the HH records found no support for this fancy (10). A detailed case report about the panic attacks and paranoia of a homosexual man is another marker of this psychoanalytic period. The patient was helped little but the enthusiastic interpretations of the association of paranoia and homosexuality was a cause célèbre in the HH grand rounds schedule (11). By contrast, my patients’ aberrant moods and psychotic thoughts were quickly relieved with ECT, allowing their return to home and work. What occasioned the rapid change in behavior? Brain functions were surely involved, more so than the psychodynamics of the unconscious mind. Electroencephalography was a new science, with less than a quarter century of experience; it promised an objective measure of brain functions. With a fellowship from the National Foundation for Infantile Paralysis I trained in EEG at Mount Sinai Hospital with Hans Strauss, the author of a leading textbook (12). I established the EEG facility with the support of the Dazian Foundation for the equipment and the hospital supported the technician. We quickly confirmed reports that the EEG changed as patients improved with ECT and ICT (13) But could we relate the EEG changes to clinical behavior? A 1954 National Institute of Mental Health research grant (M-927) supported the EEG studies of ECT. Within a few years I received additional support for EEG studies of the newly introduced psychoactive drugs. The central event in each treatment is the induction of a grand mal seizure that is clearly expressed by extensive changes in the scalp recorded EEG. Seizure events are stereotyped so that we are now able to examine the recording of the seizure and decide whether the induction was effective or not. With repeated treatments the inter-seizure recordings change. Frequencies slow, amplitudes increase, and sharp spikes and slow wave bursts and runs appear. Figure 1 shows the patterns with electrical induced seizures, and Fig. 2 shows parallel recordings with seizures induced using the inhalant flurothyl (Indoklon). The sequences are similar but the EEG reflects differences that were explored clinically. Since effective treatments could be induced chemically as well as electrically, we concluded that nothing about the electricity is specific for the treatment benefits. As electric inductions are much easier to administer, flurothyl was quickly phased out (14) [This experience cautioned me to doubt the recent enthusiasm for TMS, VNS and DBS as replacements for ECT; none elicit seizures more readily than the present method of electric induction and the induction of a seizure is essential to clinical benefits (15)]. (a) Serial interseizure EEG records of a 60-year-old depressed man exhibiting progressive slowing of frequencies, occasional spikes and increased amplitudes during course of ECT. The rhythms return almost to pretreatment levels after 2 weeks, with greater amounts of alpha frequencies. (b) Serial interseizure EEG records of 44-year-old depressed woman treated with flurothyl (Indoklon) induced seizures. The changes in EEG are parallel to patient in 1a, with greater degree of slowing and higher amplitudes. (a) Effect of intravenous LSD-25 on EEG and the reversal by chlorpromazine in a psychotic male patient, age 29. Note frequency analyzer trace. (b) Frequency analysis of the same records. By varying doses of LSD and CPZ we assayed the relative potencies of the agents. We systematically recorded the inter-seizure EEG 24–30 h after a treatment once each week, documenting the changes during the treatment course. The rhythms return to normal within a month after the last seizure. The conventional practice in examining EEG records was to rapidly turn pages containing eight lines of EEG from different regions of the head and to estimate symmetry, wiggle shapes and amplitude changes. These descriptions were little more than Rorschach impressions of low reliability. To quantify the changes, we hand-measured the width (frequency) and the height (amplitude) of each wave in six artifact-free 10-s epochs using a ruler and calipers. This procedure was tedious and at best, bracketed degrees of change as ‘high’, ‘intermediate’ and ‘low’. Independent clinical assessments rated behavior as ‘much improved’, ‘improved’ and ‘unimproved’. Even with this simple quantification, we were able to conclude that the greater the slowing of EEG rhythms, the greater the increase in amplitudes and the earlier their appearance, the greater the induced behavioral change. Slowing of EEG rhythms was necessary for clinical improvement in ECT (16). But not all the patients whose rhythms slowed improved clinically. The physiologic changes in the EEG were necessary but not sufficient to assure recovery. What determined who improved and who did not? The patients were of many psychopathologies, deemed unsuitable for psychotherapy or after they had failed months of such treatment. Their diagnoses (DSM-I) varied widely. The labels were not helpful in predicting who would improve and those who would not, although the older patients were more responsive than the younger. Patients with depressive and manic moods, psychosis and catatonia all remitted. We needed a hypothesis to test. Enthusiasm for psychodynamic thinking was at its peak among American psychiatrists in the 1950s. Edwin Weinstein, a psychoanalyst and neurologist, following the notions of the time, disdained clinical diagnosis and explained the benefits of ECT by the psychological defense of ‘denial of illness’. (17) Psychiatric symptoms resulted from continuing subconscious irritation of memories of childhood’s traumatic events. The memories are out of immediate awareness but dissipate when ‘understanding’ comes with free association of thoughts and discussions of dream reports with a skilled guide. In examining patients brain-damaged by tumor, stroke or trauma, Weinstein found such patients were relieved of their anxieties by the psychologic defense of denial, a defense that was encouraged when consciousness was partially clouded by an injection of amobarbital. Could ‘denial’ explain the improvement seen in patients during a course of ECT? Was the EEG slowing evidence of an obtunded consciousness that enhanced denial and explained the benefit of the treatment? We examined the patients before and after ECT, recording their speech and measuring the extent of denial in the content. We expected denial language to increase with clinical recovery. Although the scores increased with treatments in some patients, we could not relate the denial defense to recovery (16). The denial hypothesis failed. These writings present a child-like image, a religious fervor for psychological explanations of mental illness that pervaded the professions and society. We were so and so to such simple explanations of psychiatric By LSD had a research in psychiatry and among a the the experience as a to We LSD to patients in the ECT when the EEG was with slow and were by the immediate of LSD to the EEG effects of ECT we psychiatry LSD of EEG all and for one in the his as all their experience and encouraged to In my LSD experience my EEG rhythms and changed but I failed the of and insight promised by was in chlorpromazine its EEG and its clinical effects. the for mental in New had studies of chlorpromazine in the research Sidney and newly research at psychiatric in psychosis of and to the with its use. I CPZ to psychotic patients for Within a few weeks, stories of the in and were in the and in the patients for the new treatment. were not as three of the patients a that was at a few The that a from the in was the we that as We at 50 and increased to this we psychosis and in of patients. and in some patients, the of We on as an effective for slowed the EEG by the and the frequencies. Seizure activity was induced at The changes were from those of ECT, LSD and amobarbital. The of these psychoactive were clearly seen in the EEG changes. Figure shows the of LSD and the of this by Fig. shows the recording and the frequency analyzer trace. The EEG of imipramine and its on the interseizure EEG from that of CPZ and increased the of the and the and the of the alpha frequencies. In patients with EEG the slow and enhanced the an that the effects of the and The clinical effects of from I the with CPZ and at the in on the same with from 3). We the same effects and we were to that we could to present each The science of pharmaco-EEG was that and association was for more than years the EEG of drugs by EEG and and – each on to pharmaco-EEG The EEG and clinical patterns of the effects of the and and were additional We concluded was in the a on the of imipramine in in this was by whose studies did not activity In the effects of was these effects are the for its clinical In studies we its In a of at the of of treatment. Within the patients of and and were The was relieved with an of in Hillside Hospital was a for clinical and EEG The hospital’s the of psychodynamic and therapy for each psychoanalyst each In the training and patients were as and the were to the ECT When chlorpromazine was introduced in the fall of it was an of little to the or their allowing the of the of to the treatments. This encouraged clinical and A New York report of with in stimulated my and that of I was little in a psychotic woman with ICT and after I the reports and the that was a to with in with a of of helped his in patients but they did elicit and to clinical The rapid of CPZ stimulated of patients for ICT to 50 or months of with of treatments were by a research After experience with patients we in the improvement and the and of were induced in of the ICT and of the CPZ treatment coma in of the ICT We concluded that CPZ was easier to administer, at much less with similar to ICT and that treatment the is evidence that is a greater of form of therapy for The HH the ICT facility in I was to for the A the story of the treatment with ICT of the the ICT me to its of Since of patients grand mal seizures, it is to that the induction of seizures is the essential and not of insulin or coma ICT is an method of seizure the same time, I the College in of science the of ICT as encouraging more in psychiatric By we were for the different new be had research and at one could these treatments on clinical and and to psychiatric diagnosis for treatment After had seen patients, we that the diagnoses were Was a We an of patients for of their clinical Patients were to of CPZ or was to fixed to for CPZ and for In a of patients we confirmed the benefits of CPZ and the benefits of We recorded an benefit for CPZ in were relieved by psychotic more We treatment as a of clinical a that was by and and by to clinical and I treatment to for the of catatonia and of HH research and we out extensive of of speech and and were different effects for CPZ and that from similar in patients treated with ECT Although CPZ and had similar they were by their effects in and that the EEG rhythms after ECT, we to drugs. We examined and in was one such introduced by ECT, increased EEG amplitudes and and that the induced The patterns from those induced by studies we LSD as a and as In patients who were no the EEG induced by the treatment were quickly with low frequencies. the patients of and This in behavior for one to h and as slowing so did the in behavior EEG activity induced by ECT is by injection of the The same effects were found with and the and of the These encouraged the hypothesis of the of ECT. of and animal physiology are the of But of psychoactive substances in their effects in man. The effects of psychoactive as the for their psychoactive are in but the are not in and animal the pharmaco-EEG studies in the when to EEG and behavior for known psychoactive that the EEG effects were from the behavioral effects. In studies of drugs in records with activity when the were with The same were in and of the same found a association of the EEG changes with in a and at a of the in drugs in and man. The EEG shows slowing and frequencies, and in and man the is clouded and The are not and their EEG is from that of normal by the of and of are able to out normal to their to man although often with EEG methods had not applied in the animal The of EEG and behavior by resulted from their of – of behavior to functions and the EEG to of the the EEG of normal to that in Their were by their of in the that in are of the effects in are not. We clinical for of treatments for patients. did we have methods to measure the effects of the treatments on behavior or and the to and to induced after intravenous and for and an of were all to determine differences in effects and as for treatment and even greater of animal a and I to this by psychoactive by the differences in their EEG patterns in man In in a on EEG and behavior at the of in Was a the changes in EEG patterns and by psychoactive Patients who failed to their EEG changes clinical doses of drugs the EEG in in responsive and frequency analysis the effects of these The EEG changes in brain and physiology that were to changes in and the for the hypothesis of the association of EEG and behavior in man. we patterns were specific to each With quantitative methods we and by their EEG These in patients and in normal adult whether the were their clinical and effective This the for and of the in the their methods and (a) the EEG in (b) of The pharmaco-EEG profiles of almost all new psychoactive were in many the using patients for the assessments and normal We to their clinical and of and are of that would have and it was to the to with and It was a and were a and I examined EEG We found the patterns similar to those of and not to the known We the to clinical in depressed patients. found to be an and on the that was for many EEG study of confirmed its By supported quantitative EEG methods in clinical assessments of their new drugs. in and I in New York different by their found the EEG patterns of to be similar to those of its and clinical at his found an and and and But of on and supported clinical These quickly to be an clinical effective was that of known with less it in the It was as an in the by chemically to is a In the was found to be and the We examined the EEG profiles of and recorded EEG changes that were most similar to the for each found to be although from at the doses The was as an in studies in the that a of the induced by for as as 1 to that would be an a each clinical failed to elicit an even at did the EEG change. The of doses effective for or was and studies of the the three decades of we determined the EEG profiles of many – of the drugs and and In a study of doses less than were those higher than EEG and behavior changes of patterns those of drugs The effects of and their were and their The physiology and behavior effects of at in were to those of the of drugs to and clinical and were the effects of a male and the effects of an The of pharmaco-EEG methods the Health in to a of in to for these assessments and their A in pharmaco-EEG studies was to measure the induced effects. recordings on each of the are min in pages to be and are quickly for a of of EEG and and differences or and head are at the of the are In my at of the EEG in ECT I each wave using a ruler and for the of one of of free recording and the degree of change. But such was by and In I of an frequency analyzer that could by in on by of the had the analyzer to measure the of head of during the and his to such a for With this at HH in Although and each for a it more objective of effects in Fig. with and when was by the of to the mental hospital a newly on the of the Hospital for a research the of my in New me by the to a new research with free in an with and a was a and skilled my with We in in and the year equipped the research and by we were well on the with and clinical support from of the supported in clinical and encouraged in EEG The was the on to head the of followed quickly by from and from The who the digital computer that the of The digital computer analysis of an EEG was by at a at in 1960 I this of the Brain Institute and this report encouraged me to the computer at University to these new methods to We an digital computer for in and had computer for and The were to of but by the of epochs using the more The science of pharmaco-EEG is on this quantitative EEG recording and analysis system established at New York College in and to in EEG analysis system and computer analysis system of recorded was my and from to By the we had examined a of psychoactive in a quantitative on in patients and in normal volunteers. A of EEG and the of the But methods were and and in patients Patients were to after many whose effects for and after their Hospital were allowing little to dissipate these effects. of from and the patients We we had the by normal volunteers. How much was needed to in How much could be before the an Could and the for studies with substances with to psychoactive and and and one such before a time, research were enthusiastic about pharmaco-EEG studies as these to clinical These as studies more animal for EEG studies but these on and the in in research were by whose were on those studies that would support from the in each and not on of the of the agents. at and were enthusiastic with much The rapid of to than research this for The was the to the system of that my research studies in pharmaco-EEG by in ECT. The ECT research at New York College that in electrode and treatments. on the of ECT in my in ECT The to ECT in the American Psychiatric to a on ECT in I the report but I was by the of that were on than on As a I my and in to my of was known (16). I the known and my extensive The encouraged my report on ECT and the of the studies of treatments that my from to In I for the ECT at University Hospital at me the to clinical research the in was another The in ECT the to pharmaco-EEG research and I my EEG in in psychopathology was during my clinical service at I was by a clinical to the diagnosis of But many patients did not they to and to ECT, two treatments not for With we out to the of catatonia and to that it was an and that a home of its in the psychiatric A review of catatonia to be seen as a of A few years we examined and again that this readily and a home of its in the indeed among The enthusiasm for this quantitative science is in a few as the of and are the This is pharmaco-EEG is a quantitative science that of and brain events that are to It is a the changes in brain and It be for hours to the and equipment are and readily we of the changes in electrical rhythms about physiology and we do with the in and that are of to and It is a science that much to about psychiatric illness and treatment of the mentally I found the study and am with memories of experiments, and a community of enthusiastic to the brain and