Elliot D. Luby

The electroencephalogram during prolonged experimental sleep deprivation

Abstract 1. 1. Sixteen healthy, volunteer, male student subjects were deprived of sleep up to 120 h. 2. 2. The EEGs showed marked evidence of drowsiness from the 24 and 48 h period on. 3. 3. When the subjects were kept alert the EEGs showed a desynchronized pattern, when the subjects were allowed to relax they dropped off to sleep immediately. 4. 4. Five subjects showed high voltage paroxysmal activity during the first 48 h of sleeplessness. This activity was quite similar to the paroxysms seen in some patients with convulsive disorders of “deep level” origin. 5. 5. The subjects who developed paroxysms during sleep deprivation had also low thresholds for intravenous megimide. 6. 6. The results of the study suggest that prolonged loss of sleep is associated initially with increased cerebral irritability which may result in epileptic-like manifestations in certain predisposed individuals. 7. 7. This increase in cerebral electrical excitability appears to be limited for the most part to the first 48 h of sleep loss.

An auto‐addiction opioid model of chronic anorexia nervosa

The phenomenology of chronic anorexia nervosa is compared with that of addictive states. A model is proposed in which brain opioids mediate the elation, neuroendocrine changes, and down-regulation of metabolism that occur in adaptation to dieting. The physiology of opioids is reviewed, and clinical and animal data are marshalled to support an auto-addictive model. Opiate blockade together with therapeutic approaches used in the addictions may prove helpful in this stubborn disorder.

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.

Phencyclidine/Schizophrenia: One View Toward the Past, The Other to the Future

The history of the chemical synthesis and animal/human pharmacology of phencyclidine is documented. From its early use as a general anesthetic, chemical model of schizophrenia, and drug of abuse, phencyclidine has had a checkered history. Research with this agent and its chemical derivatives like ketamine have provided a solid foundation for just a beginning to understanding the neuropathology of schizophrenia.

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.”

Endogenous codeine and morphine in anorexia and bulimia nervosa

The endogenous plasma alkaloids codeine and morphine were shown to be elevated in patients with anorexia nervosa and bulimia nervosa compared to control subjects. The role of these opioids in the pathophysiology of these eating disorders is discussed in relation to an auto-addiction opioid model. This model proposes that endogenous opioids are released during an initial period of dieting and reinforce a state of starvation dependence [1,2].

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.

The Neurobiology of Anorexia Nervosa: An Auto-Addiction?

Anorexia nervosa (AN) is a disorder in which patients refuse to eat, as a result of a morbid fear of obesity. They believe themselves to be “fat and ugly” despite severe emaciation and an appearance shocking to others. They lose weight through caloric restriction, ritualistic exercising, and abuse of laxatives and diuretics. Some patients become involved in bulimic binging and purging cycles in which they transiently lose control of disciplined dieting but avoid weight gain through vomiting. A related eating disorder is bulimia in which the binge-purge cycle occurs without caloric restriction and normal body weight is maintained. The incidence of eating disorders is highest between the ages of 15 and 30 years and is 10–20 times greater in females than males (1). In women, amenorrhea also occurs. The prevalence is highest in middle class Caucasian families. The patients are typically perfectionist and model children until the onset of the disorder which may be triggered by a spectrum of psychosocial stressors. Prevalence of the disorder has been reported as high as 1 in 200 adolescent girls in British schools (2) and the rate is rising. It can be a lethal disorder. A mortality rate of close to 20% was found in two populations of AN patients over approximately a 20-year period (3,4). Suicide is a prominent factor in mortality.

CNS Opiate Systems and Eating Disorders

Anorexia nervosa resembles drug dependence because of the apparent pattern of starvation abuse. The self-starvation behavior of anorexic subjects is compulsive, self-gratifying, and persistent, despite life-threatening consequences. Opioid systems are activated by food deprivation and may induce the euphoria of self-starvation. Opioids act upon μ-receptors, resulting in a hedonic response, which can be powerfully reinforcing. Opiate blockade using naltrexone was shown to be effective in some anorexic and bulimic subjects. Research utilizing more powerful opioid blockers might show promise in the treatment of this resistant and potentially lethal disorder.

Adrenocortical, anterior pituitary and gonadal activity in an extremely obese male

It has been suggested that excretion levels of 17-ketosteroids and 17-hydroxyeorticosteroids are related to body weight. Adrenal overactivity as measured by 17-hydroxycorticosteroids has been ascribed to obesity. In this case the urinary 17-hydroxycorticosteriods, 17-ketosteroids, and gonadotropins were estimated in a 525 pounds, young, apparently well male. The mean values of the urinary 17-hydroxycorticosteroids (15.4 mg./24 hr.) indicated some degree of adrenal overactivity, and the mean values for the 17-ketosteroids and gona-dotropins (14.3 mg./24 hr. and 28MU/ 24 hr., respectively) indicated that there was no evidence of hypogonadotropic or hypogonadal function. It is concluded that while there was evidence of some adrenal overactivity as measured by 17-hydroxycorticosteroids, the magnitude of this steroid production did not exceed that of far less obese subjects as reported by others 7 . Thus there appears to be no correspondence between steroid excretion levels and absolute body weight.