Jacques S. Gottlieb

BIOCHEMICAL, PSYCHOLOGICAL, AND BEHAVIORAL RESPONSES TO SLEEP DEPRIVATION

The psychosis of sleep deprivation is one of the more useful models in the study of induced psychopathology in humans. I ts gradual development and comparatively long duration allow for the investigation of a number of response systems. Biochemical changes were not demonstrated in sleep deprivation until Luby et ~ 1 . ~ 3 ~ studied the energy transfer systems. Two subjects reacted to the stress of prolonged yvakefulness by a considerable increase in energy production, as measured by the specific activity of adenosine triphosphate (ATP) in their red cells. Such an increase was followed by a fall a t about 100 hours that continued even after completion of the experiment. Ax and Lubyl investigated the autonomic functioning of 5 subjects who were kept awake for 120 hours and reported that prolonged wakefulness produced a marked decline in central sympathetic responsivity. Decrease in palmar sweating was particularly significant in this respect and the trend was further substantiated by a fall in galvanic skin response (GSR) and a paradoxical drop in diastolic blood pressure to a pain stimulus at 100 hours. Psychopathological changes in sleep deprivation have been extensively described and include irritability, illusions, visual hallucinations, paranoid thinking, and dissociative s t a t e ~ . ~ z ~ ~ Performance on psychological tests has also been thoroughly investigated, particularly by Williams et d.1° Both the psychopathology and the performance deficits in this state have been interpreted by this group within the framework of the “lapse” hypothesis, with a lapse defined as ‘(a period of no response accompanied by extreme drowsiness and a decline in EEG alpha amplitude.” During this lapse period external sensory input is cut off and responses occur only to internal stimuli. Electroencephalographic changes have been highly variable but generally demonstrate a progressive decline in alpha rhythm. After 50 hours, stimuli that normally block alpha rhythm were found to elicit it; the so-called paradoxical alpha.I0 E. Rodin and E. D. Luby (unpublished data) recently found that in certain subjects paroxysmal activity was evoked early in the course of sleep deprivation, disappearing at 48 to 72 hours. This would suggest initial stimulation of energy production in brain, followed by depletion. Bliss et aZ.2 found that some acute schizophrenic reactions were seemingly precipitated by sleep loss and that sleep-deprived subjects were more sensitive to the hallucinogenic effects of lysergic acid diethylamide. These observations suggest that metabolic changes in this state may afford a biological setting favorable to the development of psychosis. Koranyi and Lehman5 provide additional evidence for this hypothesis in an experiment in which they sleepdeprived 6 schizophrenic patients. Progressive deterioration occurred after 72 hours, and 5 of the 6 subjects again manifested their acute psychotic picture “as it had been observed a t the time of their admission to the hospital.”

THE ISOLATION OF AN ACTIVE FACTOR FROM SERUM OF SCHIZOPHRENIC PATIENTS

Previous work done in this laboratory suggests that a defect exists in the metabolism of blood cells of schizophrenic s u b j e c t ~ . ~ ~ ~ J Administration of regular insulin 30 min. before a blood sample was drawn caused a n increase in the rate of irz vitro incorporation of phosphorus into adenosine triphosphate (ATI) and fructose-1,6-diphosphate (Fl, 6P) by cells from whole blood of the control subject. Insulin did not increase the rate of incorporation into these compounds in blood from chronic schizophrenic subjects. The effect of insulin on the rate of incorporation of phosphorus into ATP did not differentiate the acute from the chronic schizophrenic nor the nonschizophrenic subjects. Instead, this effect seems to be connected with the chronicity of the illness rather than simply with its occurrence.4 On the other hand, the rate of incorporation of phosphorus into F1, 6P appears to be related to the primary symptoms of schizophrenia as defined by Bleuler, and it does appear to differentiate both acute and chronic schizophrenic from nonschizophrenic subjects: Since carbohydrate metabolism then seems to be more closely involved in this phenomenon than energy metabolism, the metabolism of glucose by means of the hexose monophosphate shunt and the Emden Meyerhof scheme was examined more closely. Data from studies involving the rate of conversion of the 1-carbon and the 6-carbon of glucose to CO2 by whole blood from schizophrenic and nonschizophrenic subjects before and after insulin stress suggest that in blood from a control subject insulin causes a shift from the hexose monophosphate shunt of the Emden Meyerhof scheme. The shift does not occur in blood from schizophrenic subject^.^,^ The results obtained by placing erythrocytes from control subjects in plasma from schizophrenic subjects and erythrocytes from schizophrenic subjects in plasma from control subjects and repeating the previous experiment demonstrated that the observed defect was the result of some factor contained in the plasma itself, rather than one caused by some dysfunction of the cellular enzyme system. To confirm this observation, chicken erythrocytes were substituted for human red cells. The results were identical. Insulin caused a shift from the hexose monophosphate shunt to the Emden Meyerhof scheme in chicken cells incubated in control serum but did not affect the chicken cells incubated in schizophrenic serum.s,6 I t was discovered that schizophrenic serum had still another effect on the metabolism of glucose by chicken erythrocytes. It stimulated the cell to increase lactic acid production and to decrease pyruvic acid production, thereby increasing the ratio of lactic acid to pyruvic acid. It is not necessary to use insulin stress to detect this increase in the 1actate:pyruvate (T,/P) ratio. Re* The work tlescribed in this articlc was assisted by grants-in-aid from the Scottish Rite Committee on Research in Schizophrenia, Detroit, Mich., and the National Association lor Mental Health, Puhlic Health Service, Bethesda, Md.

Combined sernyl and sensory deprivation

Summary When Sernyl was combined with sensory deprivation, considerable damping of psychotomimetic effects was noted. The subjects remained calm, felt more in control, and experienced a state comparable to utter nothingness or emptiness. It is hypothesized that exteroceptive input is required to produce the severe psychotomimetic changes associated with Sernyl.

Postnatal effect of antidepressant drugs administered during gestation.

In a previous study, iproniazid administered to rats during the second trimester of gestation resulted in 100 per cent neonatal mortality. This report compares the effects of iproniazid and isocarboxazid administered prenatally on neonatal mortality and susceptibility to audiogenic seizures. Gravid albino rats of the Sprague-Dawley strain were randomly divided into a control and two drug groups. In every group, the treatment was administered intraperitoneally during one trimester of gestation on days 5 through 8, 11 through 14, or 17 through 20. The control group received 0.5 ml distilled water while the drug groups received either iproniazid (Marsilid, Hoffman-LaRoche) at 8.0, 4.0, or 2.0 mg/kg, or isocarboxazid (Marplan, Hoffman-LaRoche) at 4.0, 2.0, or 1.0 mg/kg. A total of 1047 offspring were born. Neonatal mortality was evaluated daily from birth through 30 days of age. At 45 and 47 days of age respectively, audiogenic seizure stimuli were administered under two conditions of threshold testing. Iproniazid was found to be significantly more toxic to neonatal survival than isocarboxazid or distilled water. Iproniazids effect was uniform throughout all trimesters of gestation, while isocarboxazid was most toxic in the first trimester. Distilled water administered as a control was found to be extremely toxic in the third trimester. Findings were independent of level of dosage. Offspring of both drug groups gave significantly fewer seizure responses than control offspring. The prenatal administration of these antidepressant drugs had a profound effect on neonatal mortality and susceptibility to audiogenic seizures.

PSYCHOPHYSIOLOGICAL DATA RETRIEVAL AND UTILIZATION.

Psychophysiology may be considered as the extension of observation to subtle aspects of behavior. The responses of the skin, the heart, the blood vessels, the blood itself, the gastrointestinal tract, the glands as well as covert responses of the skeletal muscles can provide information valuable for the diagnosis of deasese, for the analysis of personality, and for the objective description of temporary states of emotion, motivation and stress. Because of the interdependency of these physiological systems, several variables must be simultaneously observed. Thus, arises the need for multichannel recorders and high speed data processing. We agree with the philosophy expressed by Josiah Macy, that one should abstract from ones data only those aspects which are essential for the purposes of the study, but always with an eye for serendipity. One method of emphasizing the essential aspect of a variable is the judicious selection of narrow band pass transducers and their associated amplifier and conditioning circuitry which can efficiently increase the specificity of the variable, and at the same time greatly decrease the required frequency of digital sampling, thus achieving an optimum reduction of data. The approach we are presenting focuses on curve analysis at the digital stage of computing by utilizing the response as the primary entity. Arbitrary samples are used only to identify the responses; subsequently, only the major parameters of the physiologic responses are considered. Our recorded outputs rapidly decrease in amount as we progress through stages of computing. One reel of one-inch, 14 channel analog tape fits into one-third reel of one-half-inch digital tape. The final digital printed output may be reduced to any desired size, depending on degree of summarization. Because of space limitations, we shall have to neglect many important aspects of data processing such as human and machine editing, curve smoothing, verified checking at every step, and interpretation of psychophysiological data. In order to avoid misunderstanding, we wish to state clearly that our approach was not designed for the detailed analysis of physiological systems as a physiologist needs to know them. Rather it seeks to detect, abstract and display in objective, quantitative units physiological indices that may be useful for the characterization or diagnosis of psychological states and

Psychophysiological Patterns in Chronic Schizophrenia

This study was done at the Lafayette Clinic, Detroit, where the chief research activity is the interdisciplinary study of schizophrenia. There have been reports of previous studies on carbohydrate metabolism in schizophrenia [1] and on the use of a psychiatric coding system to correlate clinical and biological data [2.] Now our psychophysiology laboratory is completing a series of studies of which this is the second to be reported [3]. As with the previous studies mentioned, there have been many measurements made on the same subjects (often simultaneously) by techniques of biochemistry, physiology, psychology, and psychiatry. In this report we shall deal exclusively with the autonomic responses to three experimental stressors—pain apprehension, the psychodynamic stress interview, and insulin injection.

Childhood schizophrenia--what is it?

Diagnostic criteria and follow-up findings on groups of children diagnosed by various investigators as childhood schizophrenic, autistic, or atypical are presented. Patients diagnosed by strict criteria believed to be indicative of severe disturbance by the originators of those criteria were, with few exceptions, severely disturbed at the time of follow-up. Those diagnosed by broader criteria showed a much greater variability in their social adjustment at the time of follow-up. Also presented are the results of studies attempting to find common physiologic abnormalities between childhood schizophrenics and a group of adult “process” schizophrenics. It is stated that to date no common physiologic abnormality has been found. The heterogeneity of the children found under the diagnosis of childhood schizophrenia and the need for a “marker” either physiologic or psychologic as a means of delimiting a more homogeneous group for study are stressed.

The depressive illnesses: Their diagnosis and treatment

0 NE of the most ubiquitous phenomena of man’s affective experiences is the disorder of mood called depression. Depression is a normal emotional response to a loss, such as a loss of a close interpersonal relationship, of prestige and position, of finances, or similar experiences. In addition depression is probably the most common of psychiatric symptoms, being associated with many psychiatric conditions and various types of physical disease. The symptom of depression can occur at any age, although it is difficult to recognize this during infancy and childhood. Definite depressive illnesses occurring in adolescence, adulthood, and during the senium have been described and are the subject of this presentation. The primary symptom of depressive illness is the generally depressed affect of the individual. This varies considerably with the type of depressive illness, the personality make-up of the patient, his emotional defense patterns, and the nature of the precipitating factors. Often mild depressive symptoms are not overtly expressed by the individual in that his depressive preoccupations are suppressed from others, and therefore may be difficult to detect. However, indications of the depression are usually manifest in some patterns of behavior such as a general pessimistic attitude, hopelessness about the future, vague somatic complaints, fatigue, loss of sleep, appetite, and weight, difficulty in concentration, and disturbed psychomotor activity, such as either retardation or agitation. These symptoms may develop acutely and persist for a short time or occur in chronic form. The thoughts of the individual dwell on feelings of self-blame, worthlessness, self-abnegation, and frequently suicide. Associated physiologic phenomena are often of considerable significance and include such things as blurring of vision, dryness of the mouth, anorexia, constipation, general fatigue, and sometimes such symptoms as amenorrhea in women or failure of potency in men.

Biologic effects of infantile restriction in chimpanzees

Summary Previous clinical and animal studies have indicated that monotony in the rearing environment may relate to biologic maladaptation of the type found in schizophrenia. Laboratory-born chimpanzees who had spent their first two years in a controlled environment of monotony and restriction were compared with African-born animals captured as infants. The results indicated that the laboratory-born animals reared under the more restricted conditions showed some tendency towards biologic maladaptation; the less restricted group did not. The African-born animals also showed evidence of biologic disturbance, but since their early environment was far from “normal” (e.g., the capture) and for other reasons it is difficult to evaluate the significance of this finding. It is concluded that the results provide some support to the hypothesis but that small numbers and the unsatisfactory control group prevent this support from being clear-cut.