Monday, 24.02.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era

Background to An Oral History of the First Fifty Years
Neurophysiology (Volume Two): 1. Early Development
(Bulletin 38)


        In Volume 1 of this series, 22 clinicians and basic scientists reflected on their contributions to the “starting up” of neuropsychopharmacology (NPP). The central theme was the adoption of a behavioral methodology for the detection of psychotropic properties of drugs. In Volume 2 the emphasis shifts to the detection of the action of drugs on the functional activity of the brain. There are two complementary approaches with corresponding methodologies for neurophysiological research in NPP. One is focused on the electrical activity of the brain using electroencephalography (EEG) and the other on cerebral blood flow (CBF) and metabolism using brain imaging.

The bridge between neurophysiological and behavioral (psychiatric) research is the conditional reflex (CR). The origin of the idea that the conditional   (“psychic”  reflex is at the core of mental activity is in Wilhelm Griesinger’s adoption of “reflex activity” as the basis of all brain activity and his introduction of the concept of “psychic reflex” in the mid-1840s (Griesinger 1845, 1845). His notion that mental activity is reflex activity became a feasible proposition by the end of the 19th century after the delineation of the structural underpinning of reflex activity in the brain by Camillo Golgi’s description of “multi-polar cells” in the cerebral cortex; Ramón y Cajal’s recognition of the “neuron” as a structural and functional unit of the nervous system; and Charles Sherrington’s postulation that the “synapse” is the functional site of transmission from one neuron to another(Cajal 1894, 1909; Foster and Sherrington 1897; Garrison 1960; Golgi 1874; Sherrington 1906).

The concept of “psychic reflex” became accessible to scientific study in the early 20th century through Ivan Petrovich Pavlov’s discovery of the CR (Pavlov 1906). His findings that verbal signals could replace sensory signals in CR formation opened a path for research in which mental activity is perceived as CR activity in the second (verbal) signal system and studied with conditioning methods. Pavlov’s postulation that CR formation is based on the opening of formerly non-operating paths in the brain became demonstrable by the 1990s (Ban 1964; Kandei 2006; Pavlov 1928, 1941).  Between the mid-1930s and late 1950s, a series of centrally acting substances, including alcohol,amphetamine,adrenaline and acetylcholine, mescaline, chlorpromazine and reserpine,was studied on CR activity in animals by Horsley Gantt and his associates in the United States (Alpern, Finkelstein and Gantt 1943; Ban 2008; Bridger and Gantt 1956; Freile and Gantt1944; Gantt 1935; Gliedman and Gantt 1958;McGuigan and Ban 1987; Stoff, Bridger and Gantt 1987).

In the 1960s interest shifted from the study of the effect of psychotropic drugs on the CR in animals to the effect of these drugs on the human electroencephalogram. Recognition that electrical activity is a natural property of the living brain dates back to Emil Du Bois-Reymond’s detection of electric currents (action potentials) from the peripheral nerves and brain of frogs with a galvanometer in the late 1840s (Du Bois Reymond 1848; Horanyi 1962).. His discovery that the living brain generates electricity was substantiated independently in the mid-1870s by Richard Caton and Vasilij Jakovlevich Danilevskii who recorded electrical currents and the fluctuations of these currents from the cerebral hemispheres of rabbits, monkeys and dogs (Caton 1875; Danilevskii1875).

It was Hans Berger, in the 1920s, who first recorded electrical activity from the human brain through the intact skull. He introduced the EEG, a technique for recording the electrical activity of the brain and showed that the spontaneous waking EEG was “sensitive to” hypoxia, hypocapnia, barbiturates, bromides, caffeine, cocaine, chloroform, morphine, scopolamine and insulin coma. (Berger 1929; Fink 1978; Gloor1969).

By the time the new psychotropic drugs were introduced in the 1950s, research on the electrical activity of the brain also included “sleep EEG,”with the recognition of rapid eye movement (REM) sleep;“topography”; “functional EEG”; and the study of “evoked (event related) potentials” (ERP) (Aserinsky and Kleitman 1953; Dawson 1947;  Itil 1968;  Lieberson 1945;  Loomis and Harvey1967; Pravdich-Neminsky 1913; Shagass 1968; Shagass and Straumanis 1978;  Shorter 2005; Walter 1963).

In the 1980s research was extended to the study of brain metabolism, as measured by CBF. The roots of this research lie in the assumption frequently held in the 1920s that deficient oxidative processes play an important role in the pathogenesis of mental syndromes and especially of schizophrenia (Freeman 1931). To stimulate oxygen consumption, carbon dioxide inhalation was tried in “catatonic” patients and nitrous oxide inhalation in “psychoses” with equivocal results (Alexander and Himwich 1939; Hinsie,  Barach, Harris, Brand and  McFarland 1934; Lehmann 1993; Loevenhart, Lorenz and Waters 1929).

Juda Quastel’s report in 1939 that oxygen uptake in the brain is much greater in vivo than in vitroand the introduction of the first quantitative in vivo measurement of CBF by Dumke and Schmidt in 1943led, in the 1970s, to the introduction of brain imaging techniques suitable for the study of structure-activity relationships in the brain (Dumke and Schmidt 1938; Quastel 1939). Prior to their introduction, information on the living human brain was limited to structural changes revealed by pneumoencephalography and carotid angiography; the only relatively consistent finding relevant to psychiatry was enlarged cerebral ventricles in schizophrenia first reported by Jacobi and Winkler in 1921 (Dandy 1946; Huber 1957; Jacobi and Winkler 1927; Moniz 1927).

Early studies on structure-function relationships, as for example the linking of “motor aphasia” to a lesion of the posterior part of the frontal lobe by Paul Broca in 1861, and of “sensory aphasia” to the posterior part of the temporal lobe by Carl Wernicke in 1874,were based on pathological anatomical findings mainly in stroke patients (Broca 1861; Pichot 1983; Wernicke 1874).

Research from the morgue moved to the study of the living brain of animals with the introduction of electrical stimulation by Fritch and Hitzig in 1870 (Fritch and Hitzig 1879).

Electrical stimulation was adopted in the study of the structure-function relationship in patients undergoing brain surgery by Wilder Penfield in the early 1950s (Andreasen 2001). His findings, that electrical stimulation of certain parts of the temporal lobe (TL) evoked déjà vu experiences and old memories, contributed to the recognition of the role of the TL in memory storage (Penfield and Jaspers 1953).

Introduction of the chronic implanted electrode technique in animals by Walter Rudolf Hess in 1932 and his studies of the diencephalon, thalamus and hypothalamus extended the scope of the use of electrical stimulation in the study of structure-function relationships in the brain (Hess 1956).

In 1954 James Olds and Peter Milner found that rats with metal electrodes implanted in their nucleus accumbens repeatedly pressed a lever controlling the delivery of an electric current, as if they were seeking pleasure by electrical activation of the region (Olds and Millner 1954). The discovery of “a pleasure center” involved in the “reinforcement” of behavior by “reward” provided the key for the identification of the cerebral structures involved in “operant (instrumental) conditioning,” a form of learning, in which a motivational (emotional) factor, i.e., pleasure or punishment, is involved in the acquisition of CR (Iversen and Iversen 1975).

In 1939 James Papez suggested that emotions are processed through a reverberating circuit in the brain – which consists of the cingulate gyrus, hippocampus, amygdala, mammillary bodies, hypothalamus and anterior thalamus – before becoming subjectively-experienced feelings in the cerebral cortex (Kaplan and Saddock 1988; Papez 1937). The “Papez circuit” is also referred to as “limbic lobe” because its site corresponds with Paul Broca’s “great limbic lobe” and “visceral brain” due to its numerous connections with the autonomic nervous system (Broca 1878; MacLean 1949).

The subjective experience of feelings depends on the state of arousal of the cerebral cortex regulated by brain stem structures. In 1949 Moruzzi and Magoun reported that electrical stimulation of the ascending reticular formation in the brain stem of animals produced a generalized activation and desynchronization of the EEG with increased cortical activity, whereas depression of the same structures produced the opposite effect (Moruzzi and Magoun 1949). They suggested that the reticular activating system (RAS) is the structure involved in the regulation of the states of arousal, consciousness, wakefulness and sleep (Lehmann and Ban1994).

In 1949, the same year that Moruzzi and Magoun’s report was published, Herbert Jasper demonstrated that stimulation of the thalamic reticular formation has a similar effect as stimulation of the brain stem reticular formation but with the activation restricted to the region that corresponds with the stimulation (Jasper 1949). Combining Moruzzi and Magoun’s findings with Herbert Jasper’s, Henri Gastaut in the late 1950s formulated a hypothesis about the brain mechanisms involved in acquiring a CR (Gastaut 1957, 1958).

This was the state of art in neurophysiology as relevant to NPP in the 1950s, at the time that the first set of psychotropic drugs was introduced. The findings reviewed in the first part of this Preface provide the background to the research conducted by the interviewees whose transcripts are included in Volume 2.



Alexander FA, Himwich HE. Nitrogen inhalation therapy for schizophrenia. Preliminary report on technique. Am J Psychiatry 1939; 96: 643–55.

Alpern R, Finkelstein N, Gantt WH. Effect of amphetamine (Benzedrine) sulphate upon higher nervous activity. Bull Johns Hopkins Hosp 1943; 73: 287–99.

Andreasen NC. Brave New Brain. Conquering Mental Illness in the Era of the Genome. New York: Oxford University Press; 2001.

Aserinsky E, Kleitman N. Regularly occurring periods of eye motility and concomitant phenomena during sleep. Science 1953; 118: 273–4.

Ban TA. Conditioning and Psychiatry. Chicago: Aldine; 1954.

Ban TA. Conditioning Behavior and Psychiatry. New York/London: Aldine; 2008.

Berger H. Über das elektroencephalogramm des menschen. Arch Psychiatr Nervenkr 1929; 87: 527–70.

Bridger WH, Gantt WH. Effect of mescaline on differentiated conditional reflexes. Am J Psychiatry 1956; 113: 352– 60.

Broca PP. Perte de la parole ramolissement chronique et destruction partielle du lobe antérior gauche du cerveau. Bull Soc Anthropologique 1861; 2: 235–8.

Broca P. Anatomie comparée des circonvolutions cérebralés; le grand lobe limbique. Rev Anthropol 1878; 1: 385–498.

Cajal SR. La fine ‘structure` des centres nerveux. Proc R Soc London 1894; 55: 444–67.

Cajal SR. Histologie du Système Nerveux de L’Homme et des Vertébrés. Paris: Maloine; 1909.

Caton R. The electric currents of the brain. Brit Med J 1875; 2: 278–9.

Dandy W. Ventriculography following injection of air into the ventricles. Ann Surgery 1918; 68: 5–11.

Danilevskii VY. Research on the Physiology of the Brain. Moscow: Thesis; 1875.

Dawson CD. Cerebral responses to electrical stimulation of peripheral nerve in man. J Neurol Neurosurg Psychiat 1947; 10: 134–40.

Du Bois-Reymond EH. Untersuchungen űber Tierische Elektrizität. Berlin: G. Remmer; 1848.

Dumke PR, Schmidt CF. Quantitative measurement of cerebral blood flow in the macaque monkey. Am J Physiology 1938; 138: 421–31.

Fink M. Psychoactive drugs and the waking EEG. 1966–1976. In: Lipton MA, DiMascio A, Killam K, editors. Psychopharmacology: A Generation of Progress. New York: Raven Pess; 1978. p.691–8.

Foster M, Sherington CS.Textbook of Physiology. London: McMillan; 1897.

Freeman W. Psychochemistry: Some physicochemical factors in mental disorders. JAMA 1931; 97: 293–6.

Freile M, Gantt WH. Effect of adrenalin and acetylcholine on excitation, inhibition and neuroses. Trans Am Neurol Assoc 1944; 70: 180–1.

Fritsch GT, Hitzig E. Über die elektrische Erregbarkeit des Grosshirns. Arch Anat Physiol Wissentchaftliche Med Leipzig 1870; 37: 300–32.

Gantt WH. Effect of alcohol on cortical and subcortical activity measured by the conditioned reflex method. Bull Johns Hopkins Hosp 1935; 56: 61–83.

Garrison FH. History of Medicine. Philadelphia/London: WB Saunders Company; 1960.

Gastaut H. Etat actuel des connaisances sur l’electroencephalographie du conditionement. Electroencehalogr Clin Neurophysiol 1957; 6 (Suppl): S133–S138.

Gastaut H. Some aspectsof the neurophysiological basis of conditioned reflexes and behavior. In: Wolstenholme GE, O’Connor, editors. Neurophysiological Basis of Behavior. London: Churchill; 1958.

Gliedman L, Gantt WH. The effect of reserpine, chlorpromazine, morphine on the orienting response. In: Gantt WH, editor. Physiological Basis of Psychiatry. Springfield: Charles C. Thomas; 1958. p. 196–206.

Gloor P. The work of Hans Berger and the discovery of the electroencephalogram.  Electroencephalogr Clin Neurophysiol 1969; 28 (Suppl): S1–S36.

Golgi C. Sulla fine struttura dei bulbi olfattorii. Riv Sper Freniatr Med Leg Alienazioni Ment 1874; 1: 405–25.

Griesinger W. Über psychische Reflexactionen. Arch f Physiol Heilk 1843; 2: 76–81.

Griesinger W. Die Pathologie und Therapie der Psychiatrischen Krankheiten. Stuttgart: Krabbe; 1845.

Hess WR. Hypothalamus and Thalamus. Stuttgart: Thieme; 1956.

Hinsie LE, Barach AI, Harris MM, Brand E, McFarland RA. The treatment of dementia praecox by continuous oxygen administration in chambers and oxygen and carbon dioxide inhalations. Psychiatry 1934; 8: 334–71.

Huber G. Pneumoencephalographische und psychopathologische Bilder bei endogenen Psychosen. Berlin: Springer; 1957.

Horányi B. Ideggyogyászat. Budapest: Medicina; 1962.

Itil TM. Invited discussion of Dr. M. Fink’s paper (Human psychopharmacology and functional electroencephalography.) In: Efron DH, Cole JO, Levine J, Wittenborn JR, editors.  Psychopharmacology. A Review of Progress. 1957–1967. Washington: Public Health Service Publications No 1836. Superintendent of Documents Government Printing Office; 1968. p. 509–22.

Iversen SD, Iversen LL. Behavioral Pharmacology. Oxford: Oxford University Press; 1975.

Jacobi W, Winkler H. Encephalograhische studien am chronische schizophrenen. Arch Psychiatr Nervenkr 1927; 81: 299–332.

Jasper HH. Diffuse projection system: the integrative action of the thalamic reticular system. Electroencephalogr Clin Neurophysiol 1949; 1: 405–19.

Kandel ER. In Search of Memory. The Emergence of a New Science of Mind. New York: W.W. Norton & Company; 2006. p.165–318.

Kaplan HI, Saddock BJ. Synopsis of Psychiatry, Behavioral Sciences, Clinical Psychiatry. Fifth ed. Baltimore: Williams & Wilkins; 1988.

Lehmann HE. Before they called it psychopharmacology Neuropsychopharmacology 1993; 8: 291–303.

Lehmann HE, Ban TA. Psychiatric research in America. In: Oldham JM, Riba MB, editors. Review of Psychiatry. Volume 13. Washington/London; 1994. p. 27–54.

Lieberson WT. Functional electroencephalography in mental disorders. Dis Nerv Syst 1945; 5: 1–2.

Loevenhart AS, Lorenz W, Waters RM. Cerebral stimulation. JAMA 1929; 92: 880–3.

Loomis AL, Harvey EN, Hobart GA. Cerebral states during sleep as studied by human brain potentials. J Exp Psychol 1937; 21: 127–44.

MacLean PD. Psychosomatic disease and the “visceral brain.” Recent developments bearing on the Papez Theory of Emotions. Psychosom Med 1949; 11: 338–53.

McGuigan FJ, Ban TA, editors. Critical Issues in Psychology, Psychiatry and Physiology. A Memorial to W. Horsley Gantt. New York/London: Gordon and Breach Science Publishers; 1987.

Moniz E. Injections intracarotidiennes et substances opaques. Presse méd 1927; 35: 969–71.

Moruzzi G, Magoun HW. Brainstem reticular formation and the activation of the EEG. Electroencephalogr Clin Neurophysiol 1949; 1: 455-73.

Olds J, Millner P. Positive reinforcement produced by electrical stimulation of the septal area and other regions of rat brain. J Compr Physiol Psychiatry 1954; 47: 419–27.

Papez W. A proposed mechanism of emotions. Arch Neurol Psychiatry 1937; 38: 725–43.

Pavlov IP. The scientific investigation of the psychical faculties or processes of higher animals. Science 1906; 24: 613-9.

Pavlov IP. Conditioned Reflexes. Translated by GV Anrep. Oxford: Oxford University Press; 1928.

Pavlov IP. Conditioned Reflexes and Psychiatry. Translated by WH Horsley Gantt. Chicago: International Publishers; 1941.

Penfield W, Jaspers H.Temporal Lobe Epilepsy and the Functional Anatomy of the Brain.  New York: Little, Brown and Company; 1953.

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Pravdich-Neminsky W. Ein Versuch der Registrierung der elektrischen Gehirnerscheinungen. Zbl Physiol 1913; 27: 951–60.

Quastel JH. Metabolism of brain and nerve. Ann Rev Biochem 1939; 8: 435–62.

Shagass Ch. Pharmacology of evoked potentials in man.  In: Efron DH, Cole JO, Levine J, Wittenborn JR, editors. Psychopharmacology A Review of Progress. 1957–1967. Washington: Public Health Service Publications No 1836. Superintendent of Documents. Government Printing Office; 1968. p. 483–92.

Shagass C, Straumanis JJ. Drugs in human sensory evoked potentials. In: Lipton MA, DiMascio A, Killam KF, editors. Psychopharmacology: A Generation of Progress. New York: Raven Pess; 1978. p. 699–710.

Sherrington CS.The Integrative Action of the Nervous System. London: Scribner; 1906.

Shorter E. A Historical Dictionary of Psychiatry. New York: Oxford University Press; 2005.

Stoff DM, Bridger WH, Gantt WH. The first American psychopharmacologist. In: McGuigan FJ, Ban TA, editors. Critical Issues in Psychology, Psychiatry and Physiology. A Memorial to W. Horsley Gantt. New York/London: Gordon and Breach Science Publishers; 1987. p. 177–87.

Walter W. The Living Brain. New York: W.W. Norton; 1963.

Wernicke C. DerAphasische Symptomencomplex. Bresalu: Cohn & Weigert; 1874.


October 4, 2018