Max Fink: Remembering: The Forgotten Neuroscience of Pharmaco-EEG
Edited for the INHN Collections, August9, 2018
“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.”
Mary A. B. Brazier (1964)
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 in the past decade is a heartening endorsement of those efforts, a story now well told by professional historians(Dukakis and Tye 2006; Shorter 2007). 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 enthusiasm for pharmaco-EEG – the science of the effects of psychoactive substances on brain electrical activity(Fink 1985, 1993, 2000, 2004; Galderisi and Sannita 2006).
After a common education 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, and successive residencies in neurology and psychiatry. I was certified as a specialist in neurology (1952), psychoanalysis (1953) and psychiatry (1954). In my fifth year of residency training at New York’s Hillside Hospital( a community psychiatric hospital) I was introduced to insulin coma and electroconvulsive therapies (ICT, ECT). In 1953 I established the 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 became a challenge. It was fortuitous that the digital computer revolution was applied to EEG in 1960and for three decades my associates and I applied quantitative methods to study the effects of drugs on brain functions in patients and volunteers (Brazier 1961). 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 explored.
Early research interests
During neurology residency training at Bellevue Psychiatric Hospital, Morris B. Bender and Edwin Weinstein encouraged me to study simple sensory stimulation tests in hundreds of patients. Bender was interested in simultaneous sensory stimulation, the influence of one sensory stimulus on the perception of a second. He developed the Face-Hand Test -- simultaneously touching or pin-pricking two body parts, asking the patients to show where they had been stimulated (Bender 1952). Adults accurately located the stimuli, but brain injured and tumor cases, children before the age of 5, the severe mentally retarded, and the elderly with early dementia erred by failing to perceive one stimulus or misplacing it to another body part or even to outer space. Amobarbital increased the error rate, and I reported the changes before and after ECT (Fink 1962).
As a psychiatric resident at Hillside Hospital (HH) I was assigned patients for psychotherapy, and soon found that the weeks and months of talk therapy did little to relieve their disorders in mood or thought. One teacher, Sidney Tarachow proposed a study of a psychoanalytic hypothesis that absence of a parent during childhood determined the expression of an adult neurosis, whether obsessive (one parent) or hysteric (two parents). A review of the hospital records found no support for this fancy (Tarachow and Fink 1953). A detailed case report about a homosexual man with panic attacks and paranoia is another marker of my psychoanalytic period. The patient was helped little but the case was a cause célèbrein the HH grand rounds schedule (Fink 1953).
By contrast, my patients’ aberrant moods and psychotic thoughts were relieved rapidly with ECT, allowing their quick 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 was trained in EEG at Mount Sinai Hospital with Hans Strauss, and then established the EEG facility at HH. The equipment was supported by the Dazian Foundation and the hospital provided funds for the technician. We quickly confirmed the reports that EEG records changed as patients improved with ECT and ICT. But were the EEG changes related to clinical behavior?
In 1954 a research grant (M-927) from the National Institute of Mental Health supported EEG studies of ECT and within a few years I received additional support to measure the effects of the newly introduced psychoactive drugs.
EEG and the ECT Process
The brain’s electrical rhythms change massively during a grand-mal seizure and with repeated treatments the changes are progressive and persistent. The frequencies of the rhythms slow, amplitudes increase, and sharp spikes and slow wave bursts and runs appear. We systematically recorded the inter-seizure EEG 24-30 hours 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.
EEG records were assessed by rapidly turning pages containing eight (later 16) lines of EEG from different regions of the head and the symmetry, wiggle shapes, and amplitude changes were estimated. These descriptions were little more than Rorschach impressions, of low reliability. To quantify the changes, we measured the width (frequency) and the height (amplitude) of each wave in six artifact-free 10-second epochs using a ruler and calipers. This procedure was very tedious and at best, bracketed degrees of change as “high,” “intermediate” and “low.” Independent clinical assessments rated behavior as “much improved,” “improved” and “unimproved.” When the rhythms slowed and amplitudes increased early in the treatment course, the greater was the behavioral change. Slowing of EEG rhythms was necessary for clinical improvement(Fink 1979; Fink and Kahn 1957).
But not all the referred patients who showed the slowing of rhythms improved clinically. We were convinced that the physiologic changes seen in the EEG were necessary but did not assure recovery. What determinedwho improved and who did not? Our patients were referred for ECT by the residents; for the most part they were deemed unacceptable for psychotherapy or after they had failed months of such treatment. The diagnostic criteria1st edition of the first edition of the Diagnostic and Statistical Manualof the American Psychiatric Association (DSM-I) poorly identified the illnesses and we could not identify those who would improve and those who would not by their diagnoses. Patients with depressive and manic moods, psychosis and catatonia all remitted. We needed a hypothesis to test.
The Denial hypothesis: Edwin Weinstein, a psychoanalyst and neurologist, following the notions of the time, disregarded clinical diagnosis and explained the benefits after ECT by the psychological defense of “denial of illness” (Weinstein and Kahn 1955). Psychiatric patients express symptoms caused by percolating memories of childhood’s traumatic events. These painful memories are out of immediate awareness but by free association of thoughts and discussions of dream reports, the impact of the memories weakens and “understanding” follows. Relief is also achieved through denial, negation that is encouraged by the clouding of immediate awareness and recall. Denial of illness is commonly seen in patients with brain pathology, in post-stroke, brain tumor, or head trauma, especially when consciousness is clouded. Consciousness clouding and denial are enhanced by intravenous amobarbital; after dosing patients deny their symptoms and appear “better.” Similarly, when the EEG shows slowing of frequencies, patients complain less and see themselves as improved. This denial image was proffered as an explanation of the ECT process.
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 denial scores increased with treatments in some patients, we could not relate the change in denial language to recovery. The denial hypothesis failed.
The psychologic and social writings of that time present a child-like image, a religious fervor for psychological explanations of mental illness that pervaded the professions and society. We were so innocent and so naïve to accept such simple explanations of psychiatric illnesses!
Anticholinergic agents and ECT: Like dogs on a foxhunt, we next followed the spoor of brain chemistry. Hans Berger first recorded the brain’s electrical rhythms from the intact skull of man in 1929. In his third report (1931) he described the effects of atropine, morphine, scopolamine, and cocaine on the EEG rhythms when they altered behavior. Within minutes of an intravenous injection, the rhythms respond with specific and predictable changes in frequency, pattern, and amplitude. Martin Roth enhanced the post-ECT slowing with intravenous Pentothal in 1952, suggesting that the slowing of the rhythms predicted behavioral recovery with ECT (an observation that we confirmed) (Roth 1951, 1952).
By 1953 LSD had become a popular research tool, as microgram quantities affected mood and imagery in normal subjects. Such potency must have significance as others and we administered 50µg to 100µg lysegic acid diethylamide (LSD) intravenously. The mood of depressed patients heightened and some illusory experiences were elicited. In experiments in our patients with LSD administered late in the ECT course, when the recorded EEG was filled with slow waves, these were blocked in a dose related fashion. Although the patient’s mood and expressed thoughts changed, these observations did not extend our understanding of ECT as the chemistry of LSD was poorly defined(Fink and Itil 1968a).
We offered our psychiatry residents LSD experiences under conditions of EEG recording. Almost all volunteered and except for one paranoid response in which the subject refused his lunch as “poisoned,” all “enjoyed” their experience and encouraged others to volunteer. My personal LSD experience was trivial, for other than decreases in EEG alpha frequencies and increased heart rate, I failed the nirvana of imagery and insight promised by hippie enthusiasts. I cannot say that the illusions would have appeared spontaneously as we strongly encouraged the subjects to report any effects. Our experience with LSD did not anticipate the hyper-enthusiasm that developed in the hippie culture of the 1960s.
Seeking other agents that might influence the EEG rhythms after ECT, we turned to anti-cholinergic drugs. We examined atropine and some experimental anticholinergic deliriants being investigated in Parkinsonism (Fink 1958, 1960). Diethazine was one such experimental agent introduced by Herman Denber. Before ECT, in normal subjects, diethazine increased EEG amplitudes and both slow-wave and fast-wave activity. The patterns differed from those induced by LSD. (In later studies we separately classified LSD as a hallucinogen, diethazine and other anticholinergic agents as deliriants.) In post ECT patients who were no longer depressed, the high-voltage EEG slow-waves induced by the treatment were quickly replaced with low voltage fast frequencies. Simultaneously the patients complained of un-ease, sadness, guilt and paranoia. This dramatic switch in behavior lasted for one to three hours and as post-ECT slowing returned, so did the relief in behavior.
Could increased release of acetylcholine (ACh) be the basis for the post-seizure EEG changes? In experimental studies of head trauma in cats Murray Bornstein at New York’s Mount Sinai Hospital reported that acetylcholine and acetylcholinesterase activity in the CSF increased with increases in EEG slow wave activity. The EEG changes were very similar to those induced by seizures. Excited by the possibility that increased ACh might explain EEG slowing, we replicated the Bornstein assay using the clam heart preparation. The assay was messy and difficult. After more or less developing skill in the method, we obtained CSF from our patients before and late in the ECT process. CSF ACh levels rose during ECT. It was a time of great interest in neurotransmitters and our observations that ACh and cholinesterase increase during ECT, and the blockade of EEG effects and reversal of behavior by anticholinergic agents, made increased release of acetylcholine in the CSF a challenging hypothesis that I published in 1966 (Fink 1966). By that time I had moved on from ECT to interest in psychoactive drugs. I did not study this hypothesis further. In retrospect it has much to commend it. I had learned, however, that laboratory experiments were no nirvana; animal based studies were as full of loopholes and difficulties as were human trials, with the added burden of species specificity in brain physiology.
Hillside Hospital’s Clinical Psychopharmacology Studies
Hillside Hospital was a unique setting for clinical research. The hospital’s leadership flaunted the banner of psychodynamic psychotherapy, proudly offering daily individual and frequent group therapy sessions for each patient. An orthodox accredited psychoanalyst supervised each resident. In the training hierarchy, young, attractive, and intelligent patients were prized as learning opportunities while psychotic, aggressive, and the elderly were shunted to the ECT service. When chlorpromazine was introduced in the fall of 1954, it was considered an experimental “biological” treatment, of little interest to the trainees or their teachers, thus allowing the members of the Department of Experimental Psychiatry to control the experimental treatments. This attitude encouraged unique clinical and experimental trials.
New psychotropic drug clinical trials: A New York Times report of experiments with Rauwolfia alkaloids in India stimulated my interest in 1953 (As it did that of Nathan Kline) (Kaempffert 1953). Clinical trials were encouraged when the Swiss pharmaceutical company Ciba produced purified extracts of reserpine. I was having little success in treating a severely psychotic young woman with ICT and after I described the reports to her industrialist father with connections in Europe, he returned with a box of 25 ampoules, 5mg each. Reserpine neither helped his daughter nor reduced anxiety but it did elicit severe dystonia (Wachspress, Fink, Blumberg and Miller 1956).
Henry Brill, the commissioner for mental health in New York, had launched studies of chlorpromazine in each of the state’s mental hospitals. In 1954 he organized a public conference at Creedmoor Psychiatric Center of the first experiences by Herman Denber, Anthony Sainz, Sidney Merlis, and Nathan Kline, newly appointed research directors at various state psychiatric hospitals. They reported reductions in psychosis rating scale scores, numbers of broken windows, fire-setting, and harm to the staff with its use.
We offered CPZ to psychotic patients referred for ICT. Within a few weeks, stories of the reduction in agitation, excitement, and delusions were whispered in the halls and then shouted in the dining rooms. Nurses enthusiastically recommended patients for the new experimental treatment. Our first experiences were not without difficulty, however, as three of the first seven patients developed jaundice, a finding that was experienced at a few other centers. The sponsors suggested that a contamination from the batch made in South America was the culprit; we accepted that conclusion as reports of jaundice disappeared.
Our clinical dosing trials began at 50, 100, then 300 up to 1200 mg/day. At 1200 mg/day, we estimated that we effectively reduced psychosis and motor excitement in 80% of our patients. Rigidity, posturing, and tremors occurred in some patients, marking the upper limit of dosing. We also settled on procyclidine (Kemadrin) as an effective prophylactic for motor rigidity.
Chlorpromazine-insulin coma randomized clinical trial (RCT): The rapid efficacy of CPZ stimulated our random controlled trial of ICT referred patients to either 50 comas or 3 months of daily oral dosing with CPZ (combined with procyclidine). Dosing of both treatments were optimized by a research clinician. In 60 patients we reported equivalent efficacy for CPZ with ICT in the discharge improvement ratings and the incidence and severity of complications. Seizures were induced in 15% of the ICT and 9% of the CPZ treatment groups. Prolonged coma occurred in 10% of the ICT group. We concluded that CPZ was safer, easier to administer, at much less cost with similar outcomes to ICT and that “ . . . neither treatment altered the basic schizophrenic process, nor is there any evidence that there is a greater specificity of either form of therapy for schizophrenic illnesses” (Fink, Shaw, Gross and Coleman 1958). The HH Medical Board closed the ICT facility in 1959.
Years later I was asked to consult in the film A Beautiful Mind, the story of the treatment of the 1994 Nobel Economics prizewinner John Nash. Reviewing the literature on ICT led me to re-assess its mode of action. Since 20% of patients developed grand mal seizures, it was parsimonious to consider that the induction of seizures was the essential therapeutic element, and not any inherent characteristic of insulin (Fink 2003). I concluded that ICT is an inefficient method of seizure induction. At the same time, I mentored a Harvard College student Deborah Doroshow in her history of science thesis. She described the impact of ICT in encouraging more humane environments in psychiatric facilities (Doroshow 2007).
Imipramine (IMI): The EEG profile of IMI and its effect on the interseizure EEG were very similar to that induced by diethazine and atropine, with dry mouth and faster heart rates as additional consistent findings. We concluded IMI was anticholinergic in the CNS. At a meeting in Montreal in 1959 this interpretation was challenged as inconsistent with the pre-clinical studies that did not show anti-cholinergic activity (Fink 1959). In time the anticholinergic effects of IMI was supported; indeed, these effects are the principal basis for its clinical discard.
This early failure of animal studies to predict the effects in man seeded doubts that were strengthened by similar experiences with other proposed new psychoactive entities. Predictions from preclinical pharmacology for human trials were hazardous.
Chlorpromazine, imipramine, placebo RCT: By 1958 we were puzzled for whom the different new agents might be useful. Donald Klein had joined our clinicians and at one point Max Hamilton visited us. He believed he could identify populations for these treatments on clinical criteria alone, and challenged our inability to use psychiatric diagnosis for treatment selection. After he had seen our patients, he agreed that the DSM diagnoses were unreliable. But was there a better way?
We planned another RCT assigning patients regardless of their clinical diagnosis to 6-week courses of either CPZ (with procyclidine), IMI, or placebo. Dosing was according to fixed schedules up to 1200 mg/day for CPZ and 300 mg/day for IMI. In a sample of more than 150 patients we confirmed the antipsychotic benefits of CPZ and the antidepressant benefits of IMI. We recorded an antidepressant benefit for CPZ (Fink, Klein and Kramer 1965). Phobias in adolescents were relieved by IMI while psychotic adolescents became more aggressive (Klein and Fink 1962a;b). Treatment response offered a pharmacologic dissection of clinical states, a finding that became the basis for verification of clinical diagnoses in later reports by Richard Abrams and Michael Taylorand by Donald Klein (Abrams and Taylor 1980, 1983; Klein 1989; Taylor and Abrams 1973, 1980). Decades later, Taylor and I used treatment response to validate our arguments for the independent classification of catatonia (Taylor and Fink 2003) and of melancholia (Fink and Taylor 2002, 2008; Taylor and Fink 2003, 2006, 2008)..
Our research group included five psychologists and we carried out extensive neuropsychologic tests. Social attitude (California F Scale), figure-ground embedded figures, Rorschach, tachistoscopic presentation of ambiguous figures, and simultaneous tactile and auditory tests were explored, finding different effects for CPZ and IMI, and both different from the similar tests in patients treated with ECT (Fink 1979). Although CPZ and IMI had similar chemical structures, they were distinguishable by their effects in EEG, neuropsychology as well as behavior.
IMI withdrawal syndrome: At the end of six weeks of treatment, both CPZ and IMI dosing stopped. Within 48 hours, the IMI patients complained of malaise, nausea, vomiting, anorexia, and diffuse aches and pains. They were afebrile. The syndrome was relieved with IMI dosing, an early example of tolerance development and withdrawal signs in TCA agents (Kramer, Klein and Fink 1961).
EEG in Psychopharmacology
Drug Effects by EEG Criteria: We lacked adequate clinical criteria for selection of treatments for individual patients. Nor did we have useful methods to measure the effects of the treatments on behavior or physiology. Salivary and pupillary measures, the blood pressure response to Mecholyl and epinephrine (Funkenstein Test), time to induced nystagmus after intravenous amobarbital (Shagass sedation threshold), hand writing analyses and reaction time tests for motor function, and an array of neuropsychological tests were all studied to determine differences in drug effects and as predictors for treatment selection and outcome verification. An even greater array of animal trial measures filled a burgeoning literature. Turan Itil and I contributed to this cacophony by classifying psychoactive agents by the differences in their EEG patterns in man (Fink 1968, 1969; Fink and Itil 1968a, b)..
In 1961, participants in a symposium on EEG and behavior at the Third World Congress of Psychiatry in Montreal asked: Was there a predictable relationship between the changes in EEG patterns and the behaviors altered by psychoactive drugs? Three themes emerged. Patients who failed to show their characteristic EEG changes showed poor clinical responses despite seemingly adequate doses of medication; psychotropic drugs affected the EEG in characteristic ways in responsive patients; and frequency analysis accurately reflected the subtle effects of these agents(Fink 1963). We concluded that the human EEG reflected changes in brain chemistry and physiology that were relevant to changes in mood and thought.
At first we thought drug patterns were unique to each compound. With better quantitative methods we separated antipsychotic, antidepressant, anxiolytic, psychostimulant, hallucinogenic, and deliriant drug classes by their EEG criteria. These analyses, first done in patients and later in normal adult volunteers, predicted whether the agents were psychoactive, their clinical targets, and effective dosing schedules. This model became the basis for an international collaboration and biennial meetings of the International Pharmaco-EEG Group (IPEG) in which the investigators shared their methods and experiences. Our studies of doxepin, mianserin, flutroline, and 6-azamianserin are examples of our experience.
Doxepin. Pre-clinical pharmacologic data suggested that doxepin (Sinequan) would have anxiolytic properties and it was recommended to the clinic to compete with meprobamate and barbiturates. It was a poor anxiolytic, however, and marketing efforts failed. At a Pfizer-sponsored investigators’ meeting Herman Denber, Turan Itil and I examined available human EEG recordings. We agreed that the patterns were similar to those of TCA antidepressants and not to the known anxiolytics. We challenged the managers to undertake clinical trials in depressed patients. They did, found doxepin to be an active antidepressant, and embarked on marketing that was successful for many years. Our study of doxepin confirmed its antidepressant EEG profile (Simeon, Spero and Fink 1969).
Mianserin. By 1970, Organon pharmacologists supported quantitative EEG methods in phase-2 clinical assessments of their new psychotropic drugs. Both Itil in St. Louis and I in New York studied different putative compounds made by their chemists. Itil found the EEG patterns of GB-94 (mianserin) to be similar to those of amitriptyline, predicted its antidepressant potential, and recommended clinical trials (Itil, Polvan and Hsu 1972).
Organon pharmacologists and neuroscientists scoffed at his prediction. They found GB-94 an active serotonin and histamine antagonist and predicted anti-asthmatic and anti-migraine activity. But Jack Vossenaar, director of medical research, gambled on Itil’s prediction and supported clinical trials. These trials quickly demonstrated mianserin to be an active clinical antidepressant. Its effective dosage was 1/5 that of known tricyclic antidepressant drugs, with less cardiotoxicity, making it valuable in the clinic (Pinder and Fink 1982). It was successfully marketed as an antidepressant in Europe.
Flutroline. Pharmacologic studies in the dog reported that a single 1-mg dose of flutroline inhibited the vomiting induced by apomorphine for as long as one week. Extrapolated to man, pharmacologists enthused that flutroline would be an ideal antipsychotic, requiring a single oral dose each week. Alas, our clinical trials failed to elicit an antipsychotic effect, even at multiple dosing schedules. Nor did the EEG measures show any measurable change. The preclinical prediction of small doses being effective for days or weeks was untenable and studies of the drug ended (Fink and Irwin 1981).
6-azamianserin (mirtazapine). Like mianserin, mirtazapine is a racemic mixture. In preclinical studies, the dextro-enantiomer was considered active and the leavo- not. In our EEG trials of the mixture and its two enantiomers we recorded equal EEG changes with both enantiomers in a pattern that replicated the mianserin profile (Fink and Irwin 1982a). Clinical trials for each enantiomer found both to be “clinically effective” although neither differed from placebo at the doses tested. The racemic mixture was marketed as an antidepressant in the mid-1990s.
Extended studies: Over the two decades of our activity, we determined the EEG profiles of many agents – of the sedative drugs triflubazam, bromazepam, brontizalam; putative antihistaminics, psychostimulants and phenytoin; and assorted peptides. In a study of acetylsalicylic acid (Aspirin) single doses less than 3.0 grams were inactive; those higher than 3.6 grams elicited EEG and behavior changes characteristic of soporifics (Fink and Irwin 1982b). Phenytoin elicited patterns that mimicked those of antidepressant drugs (Fink, Irwin, Sannita, Papakostas and Green 1979).
The effects of opioids and their antagonists were catalogued and their interactions described (Volavka, Levine, Feldstein and Fink 1974). The EEG, physiology and behavior effects of cannabis produced at government farms in Mississippi were compared to those of Greek produced hashish (Volavka, Fink and Panayiotopoulos 1977). Itil expanded the list of identified drugs to hormones and cognitive enhancers. Of particular clinical and theoretic interest were the antidepressant effects of a synthetic male hormone and the anxiolytic effects of an anti-male hormone (Itil, Cora, Akpinar, Herrmann and Patterson 1974). The widespread use of pharmaco-EEG methods led the Federal Health Office in Germany to convene a special panel of experts in 1979 to set guidelines for these assessments and their reporting (Stille, Herrmann, Bente, Fink et al. 1982).
Electroencephalographers commonly scan multi-channel recordings on printout pages, each page showing 10-seconds of the ongoing rhythms. Recordings are usually 20 minutes in length offering 180-200 pages to be visually scanned and interpreted. Pages are quickly turned for a kaleidoscope image of waveforms (bursts, runs, spikes, symmetry), estimates of dominant EEG frequencies and amplitudes, and focal differences or asymmetries. Eye and head movement artifacts are de-selected at the whim of the reviewer. Such visual estimates are neither reliable nor quantitative. In my first attempts at quantification of the EEG in ECT I measured each wave using a ruler and calipers for the record of one channel of 60-seconds of artifact free recording and coded as to degree of change. But such work was tedious, made imprecise by fatigue and boredom.
In 1957, I read of an electronic analog frequency analyzer that could replace hand measurements, built by George Ulett in St. Louis on designs made by Grey Walter of the UK Burden Neurological Institute. Walter had designed the analyzer to measure the severity of head injuries of British soldiers during the war. Ulett and his engineer Robert Loeffel agreed to build such a device for us. With NIMH funding, this device arrived in 1959. Although unstable, requiring delicate nursing and calibration each day, for a time it offered more objective measures of drug effects.
My friendship with Ulett continued and when he was asked by the Governor of Missouri to re-organize the Missouri state mental hospital system, he obtained a newly developed building on the grounds of the St. Louis State Hospital for a research institute. Over the Christmas holidays of 1961 he visited my family in New York, seducing me by the opportunity to start a new research center, with free rein in appointment, an affiliation with Washington University, and a good state budget. George was a master story-teller and skilled magician, captivating my children with sleight-of-hand tricks. We arrived in St. Louis in July 1962 and over the next year equipped the building, appointed scientists, developed research protocols and by early 1963 we were well on the way with both laboratory and clinical studies. Much support came from Jonathan O. Cole of the NIMH Psychopharmacology Center. He supported our programs in clinical psychopharmacology and encouraged our interest in EEG quantification. The first appointee was the Librarian Nina Matheson (who went on to head the Welch Library of Johns Hopkins University), followed quickly by Turan Itil from Germany and Sam Gershon from Australia. The WU Computer Center sent us Donald M. Shapiro who developed the digital computer programs that became the centerpiece of pharmaco-EEG.
The first digital computer analysis of an EEG sample was demonstrated by MIT scientists at a meeting at UCLA in 1960 (Brazier 1961). I attended this inauguration of the UCLA Brain Research Institute and this report encouraged me to ask the computer scientists at Washington University to help us apply these new methods to our studies. We first used an IBM 1710 digital computer (with card reader, card punch for data entry) in 1964 and soon had Fortran computer programs for amplitude, period, and power spectrum analyses. The first data analyses were limited to minutes of recording, but by the 1970s, continuous quantification of epochs became feasible using the more sophisticated IBM 1800 system. The science of pharmaco-EEG was founded on this quantitative technology.
Studies of the physiology of animals are the bedrock of medical science. But examinations of psychoactive substances in animals are poorly predictive of their effects in man. The neurotransmitter effects of psychoactive agents are measured in animal pharmacology with almost no verification in human studies. Similar discrepancies mark the pharmaco-EEG studies in the 1960s when pharmacologists, unable to find associations between EEG measures and behavior for known psychoactive agents, claimed that the EEG effects were dissociated from the behavioral effects. In studies of anticholinergic drugs in dogs Abraham Wikler reported “sleep EEG” records with high voltage burst activity when the animals were restless with running motor movements (Wikler 1952, 1954). The same findings were reported in rabbits, cats, and monkeys. Yet, human trials of the same agents found a remarkable association of the EEG changes with human behavior. An explanation appeared in a dialogue between pharmacologists and electrophysiologists at a 1966 meeting of the CINP in Washington (Bradley and Fink 1968).
With anticholinergic drugs animals and man develop a delirium, a confused and excited state. The EEG shows high voltage slowing and very fast frequencies, and in both animals and man the sensorium is clouded and motor movements appear purposeless. The subjects are not “asleep” and their EEG is distinguished from that of normal sleep by the preponderance of fast frequencies and lack of patterned sleep stages. Animals are neither able to carry out normal commands nor to make their usual responses to sensory cues, while man does respond, often with errors. Quantitative EEG methods had not been applied in the animal studies. The dissociation reported by pharmacologists resulted from their limited range of observations - limiting measures of behavior to motor functions, and limiting the EEG to visual measures of the superficial similarity between the EEG of normal sleep to that occurring in delirium.
A suggested solution to the hazards of species specificity in using animals for pre-clinical studies was to use primates. Such studies were attempted but they were unsuccessful since primates maintained in restrictive environments were very sensitive to infection and mortality. With Alexander Pope, I concluded “the proper study of Mankind is Man” (Bredvold, McKillap and Whitney 1956).
End of my pharmaco-EEG studies
By the 1970s we had examined a long list of psychoactive compounds in a well-designed quantitative methodology. A catalog of EEG and drug correlations showed the predictive merits of the system. But our methods were expensive and time-consuming and increasingly met ethical hurdles.
Studies in patients became difficult. Patients were admitted to hospitals after having taken many medications whose effects persisted for days and weeks after their prescription ended. Hospital length-of-stays were shortened, allowing little chance to dissipate these medication effects. Questions of “voluntary consent” became increasingly strident, both from administrators and the patients themselves.
We thought we had solved the subject problem by studying normal human volunteers. How much pre-clinical information was needed to justify human experiments, especially in volunteers? How much could volunteers be paid before the fair price became an unethical challenge? Could prisoners, children, and the elderly “volunteer” for studies with substances with unknown effects? While subjects agreed to resist taking psychoactive substances, including common foodstuffs (caffeine and theobromine) and smoking (nicotine and cannabis), how does one patrol such use before laboratory experiments?
For a time, pharmaceutical company research directors were enthusiastic about pharmaco-EEG studies as these offered valuable guides to clinical trials. These interests waned as human studies became more expensive. Some companies developed in-house animal laboratories for EEG studies but these faltered, mainly on species-specificity issues and the risks in maintaining primates in laboratory settings. Physician research directors were replaced by marketing executives whose interests were focused on those studies that would support marketing approval from the government’s licensing authority in each country and not on better understanding of the pharmacology of the agents.
At first, presentations at national and international meetings were enthusiastic affairs with much active interchange. The rapid shift of programs to industry sponsored infomercials rather than academic research experiences removed this stimulus for continued research. The final blow was the NIMH decision to end the ECDEU system of evaluation (Fink 2000).
Renewed interest in convulsive therapy and psychopathology
My personal interest in pharmaco-EEG faltered by competing interests in ECT. The ECT research program at New York Medical College that began in 1968 successfully answered questions regarding electrode placement and multiple treatments. An NIMH sponsored conference on the psychobiology of ECT in 1972 rekindled my interest in ECT mechanism (Fink, Kety and McGaugh 1974). The 1974 legislative mandate to prohibit ECT in California led the American Psychiatric Association to establish a Task Force on ECT in 1975 (American Psychiatric Association 1978). I signed the commission’s report but I was chagrined by the number of recommendations that were based on majority opinions rather than on reliable evidence. As a response, I published my text on ECT in 1979 to offer my image of what was known (Fink 1979). The recommendations were based on the known data and the missing information became the basis for my subsequent report on continuation ECT (Fink, Abrams, Bailine and Jaffe 1996). In 1980 I assumed responsibility for the ECT Service at University Hospital at Stony Brook, giving me the opportunity to answer clinical research questions (Fink 2002, 2009). Establishing the quarterly journal Convulsive Therapy in 1985 was another distraction. The competing interest in ECT trumped the struggles to continue pharmaco-EEG research and I closed my EEG laboratory in 1985.
My interest in psychopathology was aroused during my clinical service at Stony Brook. I was intrigued by catatonia, a clinical syndrome tied to the diagnosis of schizophrenia. But many patients did not meet schizophrenia criteria. Also, they responded to benzodiazepines and to ECT, two treatments not recommended for schizophrenia. With Michael Taylor, we set out to document the broad nature of catatonia and to recommend that it was an identifiable and treatable syndrome that warranted a home of its own in the psychiatric classification (Fink and Taylor 2003; Taylor and Fink 2003). A historical review of how catatonia came to be seen as a type of schizophrenia documented Kraepelin’s fallacy (Fink, Shorter and Taylor 2010). A few years later we examined “melancholia” and again urged that this readily identifiable and treatable syndrome deserved a home of its own in the classification (Fink and Taylor 2008; Taylor and Fink 2006, 2008)..
Pharmaco-EEG, indeed electroencephalography, now has limited interest among neuroscientists. The enthusiasm for this quantitative science is muted, surviving in a few isolated centers, as the promises of genetics and other forms of brain-imaging are the dominant enthusiasms. This shift is sad, since pharmaco-EEG is a quantitative science that yields direct images of ongoing biochemical and neurophysiologic brain events that are intimately connected to human behavior. It is non-invasive, reflecting the moment-to-moment changes in brain function and vigilance. While we lack understanding of what the changes in electrical rhythms tell us about cellular physiology and biochemistry, we do see relationships with the aberrances in mood, thought, and recollection that are of interest to neurologists and psychiatrists. It is a valuable science that has much to teach us about psychiatric illness and treatment of the severe mentally ill. I found the study rewarding and am left with memories of exciting experiments, dedicated co-workers, and a large community of enthusiastic scientists seeking to better understand the relation between brain and behavior.
Abrams R, Taylor MA. A comparison of unipolar and bipolar depressive illness. Am J Psychiatry 1980;137:1084‑7.
Abrams R, Taylor MA: The importance of mood-incongruent psychotic symptoms in melancholia. J Affect Disord 1983;5:179-81.
American Psychiatric Association.Electroconvulsive therapy. Task Force Report #14. Washington, DC: American Psychiatric Association; 1978. (200 pp.).
Bender MB. Disorders in Perception. Springfield IL: C.C Thomas; 1952.
Bradley P, Fink M. (Eds): Anticholinergic Drugs and Brain Functions in Animals and Man. Prog Brain Res 1968; 28: 1 – 184..
Brazier MAB (Ed): Computer Techniques in EEG Analysis. EEG Journal 1961; Supplement 20, 1-98.
Brazier MAB. The effect of drugs on the electroencephalogram of man. Clin Pharmacol Ther 1964; 5:102-16.
Doroshow DB. Performing a cure for schizophrenia: Insulin coma therapy on the wards. J Hist Med Allied Sci 2007; 62:213-43.
Dukakis K, Tye L. Shock. The Healing Power of Electroconvulsive Therapy. New York: Penguin Group; 2006.
Fink M. Homosexuality with panic and paranoid states. J Hillside Hosp 1953; 2:164-90.
Fink M. Electroshock: Restoring the Mind. New York: Oxford University Press; 1999.
Fink M. Effect of anticholinergic agent, diethazine, on EEG and behavior: Significance for theory of convulsive therapy. Arch Neurol Psychiatry 1958; 80:380-7.
Fink M. Electroencephalographic and behavioral effects of Tofranil. Canad Psychiat Assoc J, 1959; 4 (suppl): 166-71.
Fink M. Effects of anticholinergic compounds on post convulsive EEG and behavior of psychiatric patients. EEG clin Neurophysiol. 1960; 12:359-69.
Fink M. Disordered perception of simultaneous stimulation of face and hand: A review and theory. In: J. Wortis (Ed.): Biological Psychiatry 1962; 4:362-9.
Fink M. EEG and human psychopharmacology. (Abstracts of proceedings of symposium at third World Congress of Psychiatry, Montreal, 1961) Electroenceph clin Neurophysiol 1963; 15:133-7.
Fink M. EEG classification of psychoactive compounds in man: Review and theory of behavioral association. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967. Washington D.C.: U.S.G.P.O; 1968, 497-507.
Fink M. EEG and human psychopharmacology. Ann Rev Pharmacol 1969; 9 :241-58.
Fink M. Convulsive Therapy: Theory and Practice. New York: Raven Press; 1979.
Fink M. Pharmaco-electroencephalography: A note on its history. Neuropsychobiology. 1985; 12: 173-8.
Fink M. Electroshock: Restoring the Mind. New York: Oxford University Press; 1999.
Fink M. EEG and behavior: Association or dissociation in man? Integrative Psychiatry 1993; 9:108-123.
Fink M. A clinician-researcher and ECDEU: 1959-1980. In: T. Ban, D. Healy, E. Shorter (Eds.): The Triumph of Psychopharmacology and the Story of the CINP. Budapest: Animula; 2000, p 82-96.
Fink M.Electroshock Healing Mental Ilness. (Fink M. Electroshock: Restoring the Mind. New York: Oxford University Press;1999 re-issued) New York: Oxford University Press; 2002.
Fink M. A Beautiful Mind and insulin coma: Social constraints on psychiatric diagnosis and treatment. Harvard Review of Psychiatry 2003; 11:284-90.
Fink M. Pharmaco-Electroencephalography: A Selective History of the Study of Brain Responses to Psychoactive Drugs. In: Ban TA, Healy D, Shorter (Eds.), Refelectionss on Twentieth Century Psychopharmacology. Budapdsg: Animula; 2004, p.661-72.
Fink M. Cholinergic aspects of convulsive therapy. J Nerv Ment Dis 1966; 142:475-84.
Fink M. Electroconvulsive Therapy: A Guide for Practitioners & Their Patients. 2nd Edition. New York: Oxford University Press;2009.
Fink M, Abrams R, Bailine S, Jaffe R. Ambulatory Electroconvulsive Therapy. Task Force Report of the Association for Convulsive Therapy. Convulsive Ther. 1996; 12: 42-55.
Fink M, Irwin P. EEG and behavioral profile of flutroline (CP-36,584), a novel antipsychotic drug. Psychopharmacology 1981; 72: 67-71.
Fink M, Irwin P. Pharmaco-EEG study of 6-azamianserin (ORG-3770): Dissociation of EEG and pharmacologic predictors of antidepressant activity. Psychopharmacology 1982a; 78: 44-8.
Fink M, Irwin P. CNS effects of acetylsalicylic acid (Aspirin). Clin Pharm Therap 1982b; 32:362-5.
Fink M, Irwin P, Sannita W, Papakostas Y, Green MA. Phenytoin: EEG effects and plasma levels in volunteers. Therap Drug Monitoring 1979; 1: 93-104.
Fink M, Itil T. Neurophysiology of the phantastica: EEG and behavioral relations in man. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967. Washington D.C.: U.S.G.P.O; 1968a, p.231-9.
Fink M, Itil T. EEG and human psychopharmacology: IV: Clinical antidepressants. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967. Washington: U.S.G.P.O: 1968b, p. 671-82.
Fink M, Kahn RL. Relation of EEG delta activity to behavioral response in electroshock: Quantitative serial studies. Arch Neurol & Psychiatry 1957; 78:516-25.
Fink M, Kety S, McGaugh J (Eds.): Psychobiology of Convulsive Therapy. Washington DC: VH Winston & Sons; 1974.
Fink M, Klein DF, Kramer J. Clinical efficacy of chlorpromazine-procyclidine combination, imipramine and placebo in depressive disorders. Psychopharmacologia 1965; 7:27-36.
Fink M, Shaw R, Gross G, Coleman FS. Comparative study of chlorpromazine and insulin coma in the therapy of psychosis. JAMA 1958; 166:1846-50.
Fink M, Shorter E, Taylor MA. Catatonia is not schizophrenia: Kraepelin’s Error and the need to recognize catatonia as an independent syndrome in medical nomenclature. Schizophrenia Bulletin 2010:36:314-20.
Fink M, Taylor MA. The medical evidence-based model to identify psychiatric syndroes: Return to a classical paradigm. Acta psychiatr scand. 2008; 87:81-84.
Fink M, Taylor MA. Irvin A. Clinician’s Guide to Diagnosis and Treatment. New York:: Cambridge University Press; 2003.
Galderisi S, Sannita WG. Pharmaco-EEG: A history of progress and missed opportunity. Clinical EEG and Neuroscience 2006; 37:61-5.
Itil TM, Cora R, Akpinar S, Herrmann WH, Patterson CJ. "Psychotropic" action of sex hormones: Computerized EEG in establishing the immediate CNS effects of steroid hormones. Curr Therapeutic Res 1974; 16:1147-70.
Itil TM, Polvan N, Hsu W. Clinical and EEG effects of GB-94, a tetracyclic antidepressant: EEG model in the discovery of a new psychotropic drug. Curr Ther Res 1972; 14:395-413.
Kaempffert W. Indian drugs for mental diseases. New York Times May 31, 1953, pg 1.
Klein DF, Fink M. Psychiatric reaction patterns to imipramine. Am J Psychiatry 1962a;119:432-8.
Klein DF, Fink M. Behavioral reaction patterns with phenothiazines. Arch Gen Psychiatry 1962b;7:449-59.
Klein DF. The pharmacological validation of psychiatric diagnosis. In: Robins LN, Barrett JE (eds): The Validity of Psychiatric Diagnosis. New York, Raven Press, 1989, p. 177-201.
Kramer JC, Klein DF, Fink M. Withdrawal symptoms following discontinuation of imipramine therapy. Am J Psychiatry 1961; 118:549-50.
Pinder R, Fink M. Mianserin. In: H. Lehmann (Ed.): Non-MAOI and Non-Tricyclic Antidepressants. Basel: S. Karger. Mod Probl Pharmacopsychiatry 18.Basel: Karger; 1982, p. 70-101.
Pope A. Essay on man. Epistle II. In: Bredvold LI, McKillap AD, Whitney SL (Eds): Eighteenth Century Poetry & Prose. New York: Ronald Press; 1956, p. 1732-4.
Roth MA. Changes in the EEG under barbiturate anesthesia produced by electro-convulsive treatment and their significance for ECT action. Electroenceph Clin Neurophysiol 1951; 3:261-80.
Roth MA. A theory of E.C.T. action and its bearing on the biological significance of epilepsy. J Ment Sci 1952; 98:44-59.
Shorter E, Healy D. Shock Therapy: A History of Electroconvulsive Treatment in Mental Illness. New Brunswick NJ: Rutgers University Press; 2007.
Simeon J, Spero M, Fink M. Clinical and EEG studies of doxepin. Psychosomatics 1969; 10:14-7.
Stille G, Herrmann W, Bente D, Fink M, Itil T, Koella WP, Kubicki S, Künkel H, Kugler J, Matejcek M, Petsche H. Guidelines for pharmaco-EEG studies in man. Pharmacopsychiatry 1982; 15:107-8.
Tarachow S, Fink M. A statistical study of am psychoanalytic hypothesis: Absence of a parent as a specific factor determining choice of neurosis. J Hillside Hosp 1953; 2:67-71.
Taylor MA, Abrams R. The phenomenology of mania: a new look at some old patients. Arch Gen Psychiatry 1973;29:520-2.
Taylor MA, Abrams R. Reassessing the bipolar-unipolar dichotomy. J Affect Disord 1980;2:195-217.
Taylor MA, Fink M. Catatonia in psychiatric classification: A home of its own. Am J Psychiatry 2003;160:1233-41.
Taylor MA, Fink M. Melancholia: The Diagnosis, Pathophysiology and Treatment of Depressive Illness. Cambridge University Press, 2006.
Taylor MA, Fink M. Restoring melancholia in the classification of mood disorders. Jrl Affective Disorders 2008; 105: 1-14.
Volavka J, Fink M, Panayiotopoulos CP. Acute EEG effects of cannabis preparations in long-term users. In: C. Stefanis, R. Dornbush, M Fink (Eds): Hashish- A Study of Long-Term Use. NY: Raven Press;1977.
Volavka J, Levine R, Feldstein S, Fink M. Short-term effects of heroin in man. Arch Gen Psychiatry 1974; 30:677-84.
Wachspress M, Fink M, Blumberg AG, Miller JSA. Evaluation of high dose reserpine therapy for the relief of anxiety. J Hillside Hosp 1956; 5:67-77.
Weinstein EA, Kahn RL. Denial of Illness. Springfield IL: C. C Thomas; 1955.
Wikler A. Pharmacologic dissociation of behavior and EEG 'sleep patterns' in dogs: Morphine, n-allynormorphine and atropine. Proc Soc exp Biol 1952; 79:261-4.
Wikler A. Clinical and electroencephalographic studies on the effect of mescaline, n-allyInormorphine and morphine in man. J nerv ment Dis 1954; 120:157-75.
August 9, 2018