Charles E. Frohman

sleep Deprivation: Effects on Behavior, Thinking, Motor Performance, and Biological Energy Transfer Systems

&NA; The effect of sleep deprivation on behavior, thinking, motor performance, and biological energy transfer systems was studied in a single subject who remained awake without drugs for 220 hours. Behavioral changes included irritability, paranoid thinking, expansiveness, grandiosity, hypnagogic states, visual hallucinations, and episodic rage. Deficits in thinking and visual‐motor performance occurred cyclically across days of wakefulness, with gradual deterioration finally resulting in virtual untestability on the ninth day. Energy transfer systems responded to sleep deprivation as a stressor with a marked increase in the specific activities of ATP, AMP, and F‐1,6‐P; this was eviden on the fourth day. For the first time in out laboratories, radioactive phosphorus was observed in AMP, a reflection of increased synthesis of this substance from adenine ribose‐I‐phosphate, and phosphate. This emergency energy mobilization began to fail by the seventh day, when the specific activities of all the adenylic phosphates fell appreciably. Conceivably the energy transfer system respond to a stressor in a manner similar to the pituitary adrenal axis, passing through stages of alarm, resistance, and exhaustion. The relationship of disturbances in these systems (associated with the most fundamental cellular processes) to various disease mechanisms is under investigation in our laboratories.

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.”

Subunits of the extracellular hemoglobin of Tubifex tubifex

The molecular weight of the extracellular hemoglobin of Tubifex tubifex determined by equilibrium sedimentation is 3.0 +/- 0.2 . 10(6). Polyacrylamide gel electrophoresis in sodium dodecyl sulfate showed that the hemoglobin dissociated into four subunits: 13 000 (subunit 1), 21 000 (subunit 2), 23 000 (subunit 3) and 47 000 (subunit 4); in the presence of mercaptoethanol two subunits were observed, 13 000 +/- 1000 (subunit I) accounting for 70--80% of the whole molecule, and 26 000 (subunit II). Electrophoresis of the subunits obtained in the absence of mercaptoethanol showed that subunit I originated from subunits 1 and 4, while subunit II originated from subunits 2 and 3. These relationships were supported by N-terminal group determinations. Gel filtration in 6 M guanidine hydrochloride showed that the molecular weight of subunit I is 17 500 and that of subunit II, 36 000. Tubifex hemoglobin appears to consist of at least seven polypeptide chains.

A New Metabolic Pathway for N,N-Dimethyltryptamine

N,N-Dimethyltryptamine (DMT) undergoes a major structural alteration when added to whole human blood or its red blood cells in vitro. A new high-pressure liquid chromatography (HPLC) peak is present in extracts of these treated tissues. The compound responsible for this peak has been identified by ultraviolet spectrophotometry and by mass spectrometry as dimethylkynuramine (DMK). The enzyme responsible for this appears to be different from tryptophan 2,3-dioxygenase and also from indoleamine 2,3-dioxygenase.

Biologic responsiveness to environmental stimuli in schizophrenia

Summary Evidence has previously been presented that a plasma factor, measured by the chicken-cell lactate-pyruvate ratio method, is at a higher level in the blood of schizophrenic subjects than control subjects after exercise. The present study examined the question of whether this difference was also present after a cold pressor test or 80 reaction time trials. It was found that after each of these two stress situations the groups could be significantly distinguished (p An explanatory hypothesis is presented which considers the schizophrenic subject as more sensitive than control subjects to the unfamiliar and new in his environment. This maladaptive sensitivity makes him unpredictably responsive to relatively minor environmental stimulation. Studies are now underway to discover the specific biologic mechanism responsible for this response.

Differential Effect of Carbidopa on the Concentration of Rat Pineal and Hypothalamic Indoleamines

Carbidopa, an aromatic acid decarboxylase inhibitor, has been shown to significantly decrease the pineal concentration of melatonin, N‐acetyl serotonin (NAS), serotonin (5‐HT), and 5‐hydroxyindoleacetic acid (5‐HIAA) but not the hypothalamic concentrations of these indoles. Increased levels of 5‐hydroxytryptophan (5‐HTP) indicate that carbidopa directly inhibits 5‐HTP decarboxylation, thus limiting 5‐HT production. Possible practical implications of selective inhibition of pineal indoleamines by carbidopa are discussed.

The Effect of Plasma from Psychotic Children on Tryptophan Uptake in Chicken Erythrocytes

Ten children diagnosed as psychotic by the DeMeyer-Churchill guidelines were matched for age and sex with ten non-psychotic but emotionally disturbed children. Six of the ten pairs were medication free. In four of the ten pairs, at least one member was medicated at the time of testing. The plasma of the children diagnosed as psychotic caused a significantly (p less than 0.025) greater uptake of tryptophan by chicken red blood cells than did the serum of their control group. This is the same effect on tryptophan uptake as found when the plasma of adult patients with process schizophrenia is incubated with chicken erythrocytes and tryptophan. This finding lends support to the possibility that there is a subgroup of childhood psychotic patients who have a biological disturbance similar to that found in adult process schizophrenia patients.

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.