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Publisher Summary This chapter describes two separate studies dealing with the problem of stability and environmental influence on the 24-hr pattern of the episodic secretion of cortisol in normal subjects. The first study is a comparison of the 24-hr cortisol and growth hormone (GH) secretory patterns during ambulatory functional activity and minimal activity at bed rest. In a second study, a group of 7 healthy male subjects were studied in regard to sleep stages and, 24-hr plasma cortisol and GH patterns during the 4 seasons of the year in an arctic environment. Recent studies have demonstrated that the 24-hr pattern of ACTH (corticotropin)—cortisol secretion consists of a sequence of temporally ordered episodic secretory patterns throughout the entire 24-hr period and that the “circadian” cycle results from the temporal clustering of episodic secretion. To evaluate some of these factors, a study to determine differences in the 24-hr cortisol secretory pattern between a condition of normal ambulatory “activity” and one of minimal activity, “basal” is recently performed.

We studied the effect of flurazepam, a known suppressor of stages 3 and 4 of sleep, on nocturnal sleep patterns and on growth hormone release immediately following sleep onset in normal young adults. Polysomnography and sampling of growth hormone (every 20 min for 26 h) were performed before and after 2 weeks of nightly flurazepam (30 mg, 8 subjects) or placebo (8 subjects) administration. There were no significant changes in growth hormone release in spite of a significant decrease in stage 4 sleep (69%) and total waking time (46%) and an increase in total sleep time (23%) in the drug group. REM sleep was not changed. These results indicate that the normal GH release following sleep onset continues to occur despite stage 4 suppression by pharmacological means.

The acute and chronic effects of alcohol and alcohol withdrawal on sleep patterns and plasma GH and cortisol fluctuations occurring during sleep were studied. Five healthy men, aged 21-26 yr, consumed a placebo drink for 3 baseline nights, alcohol (0.8 g/kg) for 9 nights, and a placebo drink on final withdrawal night. All-night polygraphic sleep recordings and blood samples (every 20 min with a venous catheter) were collected for 1 placebo, 1 acute alcohol, 1 chronic alcohol (night 9), and 1 alcohol withdrawal night. Acute and chronic alcohol consumption reduced rapid eye movement sleep nonsignificantly during the first half of the night, whereas slow wave sleep (stages 3 and 4) was increased significantly after acute alcohol, returning to baseline values on the chronic alcohol night. On the withdrawal night, rapid eye movement sleep and slow wave sleep were not significantly different from placebo sleep. Alcohol significantly suppressed plasma GH values (70-75%) on acute and chronic nights. All measures of GH, including total integral for bedtime hours, mean hourly rate, and peak level, were similarly affected by alcohol. GH returned to placebo values on the withdrawal night. Measures of nighttime plasma cortisol were not significantly altered by alcohol or alcohol withdrawal at this dose level.

It is now well established that all the peptide hormones secreted from the pituitary in man are related to the daily sleep-wake cycle. In addition to a temporal pattern of episodic secretion, the timing of the daily rhythm has been shown to be closely associated with sleep stages (1–6). The field of biological rhythm research has demonstrated that biological organisms have endogenous oscillations and that when these rhythms are no longer entrained to specific daily time cues (zeitgebers) they will develop free-running rhythms with period lengths greater than or less than 24 hours (circadian) (7–15).

An electromyographic study of nonmimetic skeletal muscles was carried out in 8 normal adults and 4 patients with spastic hemiparesis during all stages of sleep for a total of 21 nights. All normal subjects showed absence of tonic electromyographic activity in all nonmimetic skeletal muscles in all stages of sleep. Also, during quiet, relaxed wakefulness, tonic muscle discharges disappeared in the normal subjects. Three patients with upper motor neuron spasticity demonstrated results during sleep similar to those obtained in the normal subjects. In the fourth patient, tonic muscle discharges persisted into stage 2 non-REM sleep, disappeared within 30 to 240 seconds following the onset of stage 2 sleep, and were absent during stages 3 and 4 sleep and REM sleep.

LH (luteinizing hormone) secretion in pubertal individuals has been previously reported to be augmented during nocturnal sleep. The present paper attempts to clarify the relationship of this phenomenon to sleep. Two 24-hr periods of blood sampling every 20 min were carried out in each of 4 boys who were 14–15 yr old. The first study was during a normal sleep-wake cycle while the second study was during an acute sleep-wake reversal (or, in one subject, sleep delay). Each blood sample was assayed for LH and sleep was recorded polygraphically. The control study confirmed the association of LH secretory enhancement with nocturnal sleep at puberty while the reversal proved that a rise in LH secretion is also associated with daytime sleep. LH plasma concentrations remained elevated during nocturnal waking, as opposed to daytime waking, showing that acute sleep-wake reversal does not eliminate increased LH secretion at night in pubertal subjects.

Six young men with idiopathic hypogonadotropic hypogonadism had 24-h frequent blood sampling studies for measurement of LH, FSH and testosterone. Five of the patients had LH and FSH measured after administration of 100 mug LH-RH during waking and then during sleep. Four of the patients had testicular biopsies performed. The results of the present studies showed that 4 of the patients had no evidence of episodic LH, FSH, or testosterone secretion. The two patients who showed significant sleep related pulses of LH had the highest 24 h mean testosterone concentrations, the best responses to exogenous LH-RH and the most differentiated testicular biopsies. Sleep had no effect on the release of LH or FSH in response to LH-RH. These sutdies suggest that the clinical and laboratory heterogeneity of idiopathic hypogonadotropic hypogonadism may be the result of differences in the degree of endogenous LH-RH deficiency.

Prepubertal children with major depressive disorder have shown increased growth hormone (GH) secretion during sleep while in a depressive episode. When restudied in a fully recovered state (for at least three months) and drug free (for at least one month), their increased GH secretory pattern during sleep had not changed. Illness-recovery correlations using area under the curve for GH secretion during sleep were highly significant, whereas paired comparisons showed no significant differences. In addition, children who had recovered from major depressive episodes secreted significantly more GH during sleep than did nondepressed neurotic and normal children. No significant differences in delta-sleep were found in the depressed group between ill and recovered states nor among those who had recovered from major depressive episodes or controls. It is concluded that increased GH secretion during sleep is independent of depressive episodes, remains unaltered after full recovery, and may be a true marker of trait for major depressive disorder in prepuberty.

We describe a new syndrome called "delayed sleep phase insomnia." Thirty of 450 patients seen for a primary insomniac complaint had the following characteristics: (1) chronic inability to fall asleep at a desired clock time; (2) when not on a strict schedule, the patients have a normal sleep pattern and after a sleep of normal length awaken spontaneously and feel refreshed; and (3) a long history of unsuccessful attempts to treat the problem. These patients were younger than the general insomniac population and as a group did not have a specific psychiatric disorder. Six patients' histories are described in detail, including the successful nonpharmacological chronotherapy regimen (resetting the patients' biological clock by progressive phase delay). Delayed sleep phase insomnia is proposed to be a disorder of the circadian sleep-wake rhythm in which the "advance" portion of the phase response curve is small.

Human subjects during extended isolation from environmental time cues show complex variations in timing and duration of sleep with a progressive pattern, which eventually results in rest-activity and body temperature rhythms having different average periods. We present a model where temperature and rest-activity are each governed by an oscillator of the van der Pol type, denoted x and y, respectively. The oscillators affect one another through “velocity” type coupling, the effect of x on y being about four times greater than y on x. Periodic zeitgeber, z, is modeled as forcing only on y. We find that the entire pattern sequence can be realistically reproduced by causing only the intrinsic period of the y oscillator to increase while that of x remains stable. Desynchronization between x and y is the result of the intrinsic periods of the two oscillators becoming so disparate that the coupling is no longer able to enforce synchrony. Prior to desynchronization both human subjects and our model exhibit “phase trapping” wherein the relative phase of x and y is slowly modulated although the average x and y periods match. The model phase relations between temperature and both the timing and duration of sleep are, throughout, in good agreement with entrained and free-running human data. Most importantly, the model shows that the dramatic change in the length of the rest-activity cycle when desynchronization occurs is actually due to a relatively small variation in the governing variable, y.

To the Editor. —We read with interest the two recent articles by Kales et al on narcolepsy (Archives1982;39:164-168, 169-171). The authors stated that the presence of cataplexy allows the physician to proceed with treatment "solely on the basis of the clinical picture, without sleep laboratory evaluation." We agree that a skilled clinician can easily and accurately diagnose narcolepsy when the symptoms are classic. However, it has been our experience that recording sleep patterns in the clinical sleep laboratory is important for several reasons other than just diagnosis. First, the clinical diagnosis of narcolepsy is based on the patient's subjective symptoms and is a subjective conclusion by the clinician, as there are no objective clinical signs. Although the clinician may be confident in making the assessment, the patient recognizes that the clinician is not infallible and frequently desires objective documentation of the disorder. We have studied many patients with narcolepsy

The concentration of PRL was measured every 20 min for 24 h in six prepubertal and three adolescent boys. In both groups, PRL secretory episodes occurred throughout the 24-h period. In all subjects, the mean concentration of PRL was significantly higher during sleep than during wakefulness; the mean concentration during the entire 24-h period, during sleep or during wakefulness, was not different between the prepubertal subjects and the adolescents. These data suggest the absence of an ontogenetic change for PRL secretion in boys. During acute sleep-wake reversal, two of three pubertal boys showed significantly higher PRL during daytime sleep than during nocturnal wakefulness. This suggests that PRL release in adolescent boys is linked with sleep, rather than with clock time.

After 1 week of a normal control (baseline) period, 7 healthy young adult subjects were subjected to a 3-hr sleep-wake schedule, (ultradian) which was adhered to for 10 days. They were allowed eight 1 hr sleep times, equally spaced throughout each 24 hr period. They were then allowed a normal nocturnal 8-hr sleep time for 7 days. During all lights-out sleep periods, poly-graphic definition of sleep stages and waking time was made. On the sixth 24-hr period of the first week (baseline) and on the eighth 24-hr period of the ultradian period, sequential 20-min plasma samples were obtained by means of an indwelling intravenous catheter. Rectal temperature was obtained at regularly spaced frequent intervals. Despite significant sleep deprivation, a circadian pattern of total sleep time persisted throughout the 10-day ultradian condition. The distribution and amount of REM sleep time was most affected with stages 3–4 sleep least affected. The time of maximum sleep was delayed by approximately 6 hr. The...

Interest in the effect of phase-shifting of the sleep-waking rhythm in man has been accelerated because of the recent demonstration of important relationships between sleep, sleep stages, and hypothalamic-pituitary neuroendocrine function (Weitzman and Hellman 1974). The past history of studies concerned with the effect of altering the sleep-waking pattern has emphasized biochemical and physiological changes occurring when the individual was subject to either a 180-degree inversion, partial phase shift, or change in the length of the “day” (Mills 1966, Halberg 1969, Elliott et al. 1972). The use of such experimental manipulations of defined circadian rhythmic processes has led to several general principles regarding differing modes of response patterns to such cyclic shifts. It is clear that a number of circadian rhythmic processes are quite resistant to shift, requiring several weeks for the establishment of an inverted rhythm. The body temperature cycle, urinary potassium rhythm, and the 24-hour adrenocorticotropic hormone (ACTH)-cortisol secretory pattern are examples of such resistant rhythms (Sharp 1960; Sharp, Slorach, and Vipond 1961; Weitzman et al. 1968; Aschoff 1969; Elliott et al. 1972). Other measured functions have been shown to be rapidly inverted or shifted. These functions include urinary phosphates, water excretion, and the 24-hour pattern of plasma growth hormone (Sassin, Parker, and Johnson 1969), prolactin (Sassin et al. 1973), and luteinizing hormones in pubertal children (Boyar et al. 1972a).

Documented observations of a 5-week-old infant during a "near miss" for a Sudden Infant Death Syndrome (SIDS) episode by a physician were carried out during an in-hospital physiological recording of respiratory and cardiac activity. This "near miss" event occurred during quiet sleep and was characterized by a prolonged apneic attack with marked bradycardia, cyanosis and limpness which required immediate vigorous resuscitative efforts by a physician and trained nurse. Parental descriptions of similar events parallel these documented sudden unexpected changes in cardiorespiratory parameters. Objective polygraphic data were obtained immediately following the episode and at later ages during 24 and 48 hour continuous recordings of respiration, heart rate, sleep/wake and behavioral activity. The data show that numerous apneic episodes occurred following the "near miss" event, many accompanied by marked bradycardia. The moderately severe hypoxemia noted during these sleep-related apneas indicate that immediate intervention is required to prevent significant hypoxia and central depression in such infants.

A group of 7 healthy male subjects was studied in regard to sleep stages and 24 h plasma cortisol and growth hormone patterns during the 4 seasons of the year in an Arctic environment (Tromsø, Norway). No difference in total sleep or sleep stage per cents was found for any of the yearly seasons. A small but statistical significant increase in mean plasma cortisol concentration and amount secreted for 24 h was found for the autumn-winter seasons, as compared with the spring and summer. However, no difference in the circadian curve of cortisol hormonal pattern was found. All subjects secreted growth hormone shortly after sleep onset at night and no difference was found as a function of season of the year.

Publisher Summary This chapter discusses the 24-hr patterns of luteinizing hormone secretion in humans. Much progress is made in recent years in understanding factors controlling gonadotropin secretion in humans. This progress is made possible primarily by three technical advances: (1) the development of sensitive and specific assays for LH (luteinizing hormone) and FSH (follicle-stimulating hormone), especially radio immunoassay; (2) frequent blood sampling by techniques that interfere as little as possible with the subject's waking and sleeping activity; and (3) polygraphic recording of the EEG (electroencephalogram), EOG (electrooculogram), and EMG (electromyogram) during sleep so that sleep onset and offset can be precisely determined and correlations can be made with sleep stages. Using the methods enumerated in the foregoing paragraph, we will describe findings from this laboratory which deal with 24-hr LH secretory patterns in men and women from childhood to adulthood. The twenty-four-hour patterns of LH (luteinizing hormone) secretion are characterized by major changes with ontogenetic development and by marked gender differences. Thus, sleeping activity is distinguished during puberty by an augmentation of LH secretion while, conversely, LH secretion decreases during the sleep of adult women. Adult men do not show such sleep-related changes in LH secretion.

Periodic movements in sleep (PMS) are stereotyped, repetitive, nonepileptiform movements of the lower extremities. A total of 409 sleep disorder patients were studied with all-night polysomnogram recording, and 53 (13%) had PMS. Such movements occurred in a wide variety of sleep-wake disorders in addition to insomnia. The prevalence and magnitude of PMS were not statistically greater in patients with insomniac disorders than in those with syndromes of excessive daytime sleepiness or other sleep-wake disorders. The results suggest that although PMS is responsible for disturbed sleep in relatively few patients, chronic sleep-wake disturbance is associated with PMS and may lead to the development of these movements.

Publisher Summary This chapter reviews the major new observations made regarding the temporal organization of the 24-hour pattern of hypothalamic-pituitary function in regard to sleepwaking function. It discusses the recent application of these results to certain clinical disorders. All the pituitary hormones studied with the technique of frequent plasma sampling have been found to be secreted in an episodic manner throughout the 24-hour day. These hormones have important temporal secretory pattern relationships with the sleepwaking 24-hour cycle. In addition, the sleep stage cyclic pattern during nocturnal sleep is closely related to the timing of several pituitary hormones indicating state control by the central nervous system (CNS) over the timing and amount of secretion under normal physiological conditions. Each system appears to have its own temporal organization and response to manipulations of the sleepwaking cycle, and no single principle or mechanism can be invoked to explain these differing patterns. The concept that a homesotatic steady state or basal level is present for any extended time period of the 24-hour day is clearly not the case. The data suggest that a major mechanism of control takes place by CNS 24-hour temporal programs that initiate secretion independent of existing plasma concentrations under normal stable conditions.

It has been postulated that the sudden infant death syndrome (s.i.d.s.) may sometimes be due to abnormal maturation or injury to the brain stem centres that regulate respiration. This functional abnormality of the brain stem respiratory centres may result in the interruption of the automatic inspiratory/expiratory cycle by recurrent periods of apnoea. There is a subgroup of infants known as ‘near-miss’ for s.i.d.s., who survived a prolonged apnoeic episode during sleep which may have resulted in death. In a number of recent studies, the near-miss infant has been clearly identified as an infant at high risk for s.i.d.s. Clinical studies conducted by using polygraphic and behavioural monitoring of near-miss infants have revealed numerous apnoeic episodes during sleep. Consequently, the clinical necessity of monitoring these babies in a paediatric care unit has become well established both for diagnostic purposes and for subsequent outpatient care. In view of these findings, it has become increasingly more important to develop advanced sophisticated computer methods for the on-line detection and processing of apnoeas during in-hospital monitoring of infants. This paper describes a digital computer method of on-line apnoea processing for application during the in-hospital monitoring of infants. The method is based on the application of Walsh transformations to the expired CO2 signal measured in infants using a Beckman CO2 analyser.

Publisher Summary This chapter discusses the regularity in the patterns of unsynchronized circadian rhythms in man. When activity–rest and body temperature cycles become unsynchronized in man, large variations in sleep duration and timing occur. Both these cycles have become unsynchronized (NS) in every subject free-running longer than 2 months. The average period of activity–rest typically lengthened during the free-run whereas sleep duration varied predictably with body temperature at sleep onset, even in subjects with activity-rest cycles of 24 hrs. The rate of rapid eye movement (REM) sleep accumulation varied with the phase of body temperature, as did plasma cortisol and subjective assessments of alterness.

The relationship of luteinizing hormone (LH) secretion to sleep in adult women was investigated in two ways: an acute 180 degrees sleep-wake cycle reversal in a group of six women and a schedule in which a young woman engaged in a three hour sleep-wake cycle (two hours awake, one hour allowed for sleep continuously for ten days--the study was carried out on the eighth day). Each subject in the reversal study had a baseline period during which plasma samples were collected every twenty minutes for twenty-four hours and nocturnal sleep was monitored electrophysiologically during the early follicular phase of the menstrual cycle. During a succeeding cycle, the study was repeated after sleep-wake reversal. LH secretory patterns were analyzed by comparing the 24-hour mean plasma LH concentration with the hourly averages in percentage terms, using Stage 2 sleep onset as the zero point. LH secretion was depressed to approximately the same degree in both the baseline and reversal studies. The average hourly percentage difference from the 24-hour mean for the four-hour period following sleep onset was -13.4% and -13.1% for the baseline and reversal, respectively. These percentage deviations represented practically the entire negative deviation for the 24-hour period in both studies. The difference between the first four-hour period after sleep onset and the second was significant. The subject on a three-hour cycle had a baseline in which a large decrease in LH secretion occurred after sleep onset (-52.2% during the third hour). Her LH secretory pattern during the three-hour sleep-wake schedule was characterized by a fall during sleep periods, particularly when slow wave sleep (SWS) predominated. However, no correlation was found between specific sleep stages and LH secretion in the six women of the reversal study. These results confirm a relationship of LH secretion to sleep in adult women, one which is different from that described during puberty.

In a previous publication, this group reported a dissociation between multiple sleep complaints and polysomnographic abnormalities in prepubertal major depressive children. Spindle activity has been thought by some to be a correlate of restorative sleep. On this basis, it was hypothesized that prepubertal depressives might exhibit differences in sleep spindle characteristics when compared with normal and psychiatric control groups, and with their former state during sustained recovery in a drug-free state. Further, it was thought that clinical complaints of disrupted sleep might be related to differences in spindle characteristics. Spindle frequency (Hz) was the only significant finding among the groups, but it was not specific to depressive disorder, since all psychiatric groups presented higher frequencies than did normal children. As expected, significant differences across halves of the sleep period time (SPT) were also found for the number of spindles, frequency (Hz), duration (ms), spindle density (rate), and the amount of stage 2 sleep (min). The presence or absence of sleep complaints had no bearing on spindle characteristics, thus indicating a lack of apparent relationship between the two. Upon recovery the depressives exhibited no changes across clinical state, and a cross-sectional comparison of the recovered data with the original control data gave results essentially identical to the first (active illness) comparisons. It is suggested that high spindle frequency may be a nonspecific correlate of emotional disorders in prepuberty, which, at least in depressives, does not change with clinical state.

We report here the development of a brief drug-free rescheduling treatment ("chronotherapy") for Delayed Sleep Phase (DSP) insomnia, a syndrome characterized by sleep-onset insomnia with difficulty in morning awakening. We postulated that patients with DSP insomnia had an inadequate capacity to achieve phase advance shifts of the circadian pacemaker which times the sleep-wake cycle. Chronotherapy was therefore designed to reset these patients' biological clocks by the phase delay route. This single 5-6 day treatment was tested in 5 patients with a 4-15 year history of DSP insomnia. All 5 patients reported a lasting resolution of their symptoms substantiated by systematic long-term self-reports and objective polygraphic recording before and after treatment (average follow-up of 260 days; range, 42-910 days). The average sleep onset advanced from 4:50 a.m. before treatment to 12:20 a.m. afterwards, and wake times advanced from 1:00 p.m. to 755 a.m. (for both, p less than 0.001), with no reduction in sleep efficiency. As a result, all 5 patients were able to end their chronic dependence on hypnotic medications.

A portable temperature data logger was used for prolonged rectal temperature monitoring in an ambulatory subject with a longer than 24 hr (hypernychthemeral) sleep-wake cycle. The mean period of the sleep-wake and circadian temperature cycles was 24.8 hr. However, the period of the sleep-wake cycle fluctuated considerably, being less than 24.8 hr when he slept during the socially desirable sleep hours and more than 24.8 hr when he slept during the day. In the first instance, the daily temperature fall occurred later than, and in the second earlier than, sleep onset. During the times of desynchronization of the two cycles, he complained of insomnia, fatigue, and reduced performance. We postulate that his hypernychthemeral cycles were the result of either a primary defect in the mechanism of entrainment or "weakened" social zeitgebers due to a personality disorder. These concepts are supported by a sleep-wake pattern resembling that of relative coordination. We therefore raise the possibility that 24 hr was beyond the range of entrainment of the subject's circadian temperature cycle during the study.

In 4 studies in a normal man it was demonstrated that dehydroisoandrosterone (DHA) was secreted episodically and synchronously with cortisol. The studies were done at 20-min intervals in the early morning (0340–0720 hr) and in the late afternoon (1540–1920 hr). A double isotope derivative method was developed for measurement of the low concentrations of DHA in plasma. DHA never reached zero concentration in plasma, whereas cortisol did. This is explained by the contribution to DHA by hydrolysis of the relatively abundant circulating DHA sulfate. Because of the low plasma concentration a high degree of biological activity can be implied for DHA, the function of which is at present unknown.

Human prolactin was measured in plasma by radioimmunoassay at 20 minute intervals for a 24-hour period in each of six normal adults, whose sleep-wake cycles were monitored polygraphically. A marked diurnal variation in plasma concentrations was demonstrated, with highest values during sleep; periods of episodic release occurred throughout the 24 hours.

Introduction RECENT observations have demonstrated in adult man a basic physiologic periodicity during sleep of 80-90 minutes, 1-3 in the adult cat 20-25 minutes 4-6 and in the adult rat 13 minutes. 7 These cycles consist of alternation of a high voltage slow wave stage with a low voltage fast frequency cortical electroencephalographic sleep stage, the latter occupying 15%-25% of sleep time. Characteristic alterations in a number of autonomic and somatic motor functions have been found to correlate with the EEG pattern. 8,9 In this study observations of the periodic EEG and behavioral sleep patterns of Macaca mulatta are reported. Method Five M mulatta monkeys, (5-8 lb) had cortical and subcortical electrodes implanted under anesthesia for chronic recordings. The cortical electrodes (three-eighth inch silver discs) were placed on the dura mater through burr holes in the skull and cemented in place with acrylic central cement. Bipolar stainless steel electrodes

The pattern of cortisol secretion was studied in a patient with Cushing's syndrome before and during treatment with o,p'-DDD. Plasma samples were obtained every 20 min throughout the 24 hr day and analyzed for cortisol by competitive protein binding. It was found that the numbers of cortisol secretory episodes were roughly comparable in the treated and untreated state despite a 60 day interval between the studies. Under the influence of the drug the adrenals were producing cortisol almost constantly during the 24 hr day. This was proved for a 3 hr period in the early afternoon after a tracer amount of cortisol-4-14C was injected. The specific activity of the plasma cortisol diminished progressively at different rates even though the plasma cortisol concentration rose and fell during this time. It is concluded that the system: central nervous system-corticosteroid releasing factor—ACTH, was intact, hyperfunctioning and similarly programmed in both the treated and untreated stages of the disease. D...

Serial plasma growth hormone (GH) concentrations were measured every 20 min for 24 hr before and after the administration of clomiphene citrate (100 mg/day for 7 days) to four healthy young adult male subjects. The number of GH secretory episodes and the magnitude of the peak plasma concentrations during both wakefulness and sleep were decreased after the clomiphene treatment periods.

The pattern of cortisol secretory activity of four patients with severe spontaneous hyperthyroidism were studied by sampling plasma every 20 min around the 24 hr clock and measurement of cortisol by competitive protein binding. Estimates of cortisol secretion rate were made employing the equation of Hellman, Nakada, Curti, Weitzman, Kream, Roffwarg, Ellman, Fukushima and Gallagher (J Clin Endocrinol Metab 30: 411, 1970). In addition, the secretion rate in certain patients was measured by the rinary metabolite(s) method. It was demonstrated that: 1) there were more cortisol secretory episodes than normal; 2) more of the 24-hr day was spent in adrenal secretory activity; 3) there was increased production of cortisol in conjunction with a very much shortened half-life of plasma cortisol; 4) there was an almost certain increased functional adrenal capacity to nearly double normal as evident from greater cortisol production per unit time; and 5) there was retention of the normal post-midnight concentration of ...

Six normal adult subjects were studied during all stages of sleep for a total of 14 nights to determine whether nystagmus could be elicited by vestibular stimulation, particularly during the rapid eye movement (REM) sleep stage. Perrotatory vestibular stimulation was induced by means of a constant angle torsion swing. At no time during REM sleep was nystagmus evoked by vestibular stimulation. In addition, no clear nystagmic responses were elicited during non-REM stages 2, 3, and 4. In all stages of sleep, rotation of the torsion swing always produced slow, compensatory conjugate eye movements. With the onset of rotational stimulation during the REM sleep stage, REM bursts were suppressed but emerged immediately following termination of stimulation; phasic activity of the chin muscles was unaffected, however, during REM sleep by rotational stimulation.

Dural, orbital, and depth electrodes were chronically implanted in five monkeys, and 473 brain stem stimulations were given during 80 hr of EEG recording on 14 nights of sleep. Although occasional rapid eye movement sleep periods occurred soon after stimulations, no parameters or loci of stimulation consistently provoked REMPs, occurred. Statistical analyses did not demonstrate any precipitation of REMPs, and it is probable that only spontaneous REMPs occurred. When compared with previous reports, these findings emphasize the importance of statistical controls in neurophysiological studies of REMP origin.

Luteinizing hormone (LH) was measured in plasma every 20 minutes for 24 hours in 14 children and adolescents in different stages of sexual maturation and in five adult men. Polygraphic monitoring of nocturnal sleep was carried out simultaneously to identify sleep onset, wakefulness and sleep stages precisely. Prepubertal children and adult men showed no consistent significant difference between mean LH concentrations with subjects asleep and awake. In all pubertal subjects, an increase in LH secretion was associated with sleep that resulted in significantly higher mean LH concentrations than with the subject awake. By experimental delay in sleep onset, synchronization of this LH secretory "program" with actual sleep was clearly demonstrated. The number of LH secretory episodes during night or day sleep corresponded to the number of sleep cycles of rapid and nonrapid eye movements. This finding of a sleep-associated increase in LH secretory activity provides a biologic index for the identification...

Responses to auditory stimuli can be recorded from the scalp of man in all stages of sleep. At the vertex, the mean peak latency of the first positive deflection (P1) occurs at 50 msec after stimulation; N1, at 100 msec; P2, at 175 msec; N2, at 325 msec; and P3 at 800 msec. The amplitude and latency of the components of longer latency (N2 and P3) increase during stages 2 through 4 sleep. The amplitude of the summed auditory evoked responses during the REM stage is considerably smaller than in the other stages and generally is of similar configuration to that of the awake state. Our results support the concept that the auditory evoked response during sleep represents summed K complexes.

Plasma luteinizing hormone (LH) was measured by radioimmunoassay at 20-min intervals around the clock for 24 hr in 5 normal adult men. During the nocturnal S-hr sleep period, polygraphic monitoring of sleep stages was carried out. All 5 subjects showed episodic secretion of LH characterized by rapid rises and the declining slopes approximated the half-life of LH. Calculation of LH “half-life” from the declining phase of the LH secretory episodes gave variable estimates within subjects and between subjects (65–114 min). The longer T1/2 estimates calculated by this method, contrasted with previous studies where LH half-life was determined directly by the measurement of LH disappearance, is probably the result of small amounts of LH being secreted during the declining phase of the LH secretory episode. This study failed to show a 24-hr LH rhythm or relationship of LH secretory activity to the sleep-wake cycle. The marked temporal variability of the LH system throughout the 24-hr period clearly demon...

Further evidence that there is a relationship between prolactin rise and sleep is offered by this study that delayed sleep onset and inverted the normal sleep-waking cycle in 4 normal patients (3 women and 1 man). The inversion schedule lasted 3 weeks, and at its conclusion a final 12-hour laboratory study was carried out measuring the plasma levels of human prolactin and growth hormone by radioimmunoassay. In the first female subject, mean prolactin levels (ng/ml) were, for baseline and after shift, 7 and 8.3; for case 2 (female) the values were 7.3 and 5.9; for case 3 (male) the levels were 6.1 and 6.1; and for the last case, the levels were 4.7 and 4.3, respectively. Values for growth hormone were (ng/ml) 1.5 and 1.5 for Case 1 for baseline and after shift, respectively; 1.1 and 2.5 for Case 2, respectively; 1.8 and 1.1 for Case 3, respectively; and 7.3 and 5.2 for Case 4, respectively. Prolactin release shifted immediately and completely with shifts of sleep onset of 3, 6, and 12 hours. Thus, it is concluded that the nocturnal rise is dependent on the occurrence of sleep, not on the inherent rhythm related to time of day.

Human cortisol intermittent secretion during early morning sleep and sleep-wake cycle, examining adrenal activity

A behavioral method is described in which increasing intensities of electric shocks were applied to the gasserian ganglia of alert monkeys. The animals were trained to press a lever to regulate the shock level. "Pain thresholds" were thereby obtained, and these thresholds were modified by varying the shock duration and by administration of morphine.