Daily melatonin intake resets circadian rhythms of a sighted man with non-24-hour sleep-wake syndrome who lacks the nocturnal melatonin rise

Abstract Effects of daily melatonin intake on the circadian rhythms of sleep and wakefulness, rectal temperature and plasma cortisol were examined in a sighted man who had suffered from the non-24-hour sleep-wake syndrome. The subject lacked the nocturnal melatonin rise in plasma, but showed robust circadian rhythms in rectal temperature and plasma cortisol. The sleep-wake rhythm free-ran with a period longer than 24 hours. Daily melatonin intake at 21:00 h concentrated sleep episodes in the nocturnal period (24:00–8:00 h), and increased the length of the episodes. A single oral dose (3 mg) of melatonin increased plasma melatonin levels to about 1300 pg/mL within one hour and remained at pharmacological levels for approximately 6 hours. The trough of rectal temperature and the circadian rise of plasma cortisol were fixed to the early morning. A higher dose of melatonin (6 mg) did not improve the general feature. After the cessation of melatonin intake, the sleep-wake rhythm began to free-run together with the circadian rhythms in rectal temperature and plasma cortisol. It is concluded that daily intake of melatonin at early night time resets the circadian rhythms in a sighted man who lacked the nocturnal melatonin rise and showed free-running circadian rhythms in routine life.     

A sighted man with non-24-hour sleep-wake syndrome shows damped plasma melatonin rhythm

Abstract Twenty-four-hour profiles of plasma melatonin, cortisol and rectal temperature were measured longitudinally in a sighted man who has been suffering from sleep disorders for more than 10 years. The sleep-wake rhythm of this subject free-ran, despite his routine life, and occasionally showed a sign of internal desyn-chronization, where sleep was lengthened up to 30 h. These states were classified into the non-24-hour sleep-wake syndrome. Plasma melatonin concentrations in the subjective night remained at a low level and showed a damped circadian rhythm. At the same time, robust circadian rhythms were detected in plasma cortisol and rectal temperature, indicating that the circadian pacemaker was intact. The causal relationship between the damping of nocturnal melatonin rise and a failure of entrainment of the sleep-wake cycle is discussed.     

Poor recovery sleep after sleep deprivation in delayed sleep phase syndrome

To clarify disturbances in sleep regulation in patients with delayed sleep phase syndrome (DSPS), we studied three patients with DSPS and seven healthy controls. Sleep propensity and melatonin rhythms after 24-h sleep deprivation were investigated under dim light condition by using the ultra-short sleep-wake schedule. The sleep propensity curves displayed clear differences between DSPS patients and the controls. During the subjective day when melatonin was not produced, recovery sleep after the sleep deprivation did not occur in DSPS patients, while recovery sleep occurred during the subjective day in controls. This suggests that DSPS may involve problems related to the homeostatic regulation of sleep after sleep deprivation.     

African trypanosomiasis in the rat alters melatonin secretion and melatonin receptor binding in the suprachiasmatic nucleus

Rats infected with Trypanosoma brucei brucei, a subspecies of the extracellular parasites that cause African sleeping sickness, were examined for disturbances in the circadian rhythms of melatonin secretion (evaluated by determination of the excretion of melatonin in the urine) and the binding of melatonin to its receptor in the suprachiasmatic nuclei of the anterior hypothalamus. In normal and infected rats, Cosinor analysis showed a significant nocturnal peak. The amplitude of this peak was, however, significantly decreased in the infected rats. The peak of melatonin receptor binding in the suprachiasmatic nuclei showed a 4-h phase advance in the infected rats, compared with the controls (0400 and 0800, respectively). These data point to a disturbance in the circadian rhythm of the melatonin-generating systems in the pathogenesis of African sleeping sickness.     

Melatonin circadian rhythm in anorexia nervosa and obesity

The mean 24-hour secretion and circadian rhythm of melatonin were studied in 12 female subjects with anorexia nervosa (AN), 13 massively obese (OB) women, and 9 normal weight healthy volunteers to investigate the relationship between type of feeding behavior and hormonal secretory pattern. Blood samples for melatonin were drawn every 4 hours from 0400 h to 2400 h and every 2 hours from 2400 h to 0400 h. Mean 24-hour melatonin secretion was significantly higher in AN than in OB patients and controls. Melatonin circadian rhythms were disrupted in 8 of the 12 AN patients and in 9 of the 13 OB subjects, with phase-advanced nocturnal rises, abnormal diurnal peaks, or no nocturnal rises. The population mean cosinor analysis validated the existence of a significant circadian rhythm of the hormone in AN but not in OB subjects. No significant correlation between mean 24-hour secretion or type of circadian alterations and degree of weight deficit or excess was observed. The circadian alterations of melatonin in AN and OB may be linked to impaired secretory tonus of noradrenalin in the central nervous system, possibly unrelated to feeding patterns.     

Melatonin,cortisol and body temperature rhythms in Lennox-Gastaut patients with or without circadian rhythm sleep disorders

The daily rhythms of melatonin, cortisol and body temperature were studied in 16 institutionalized subjects with the Lennox-Gastaut syndrome. The results of 9 subjects with normal daily rhythms of sleep and wakefulness (group 1) were compared with those of 7 subjects with disordered sleep (group 2). Salivary samples were collected and axillary temperature was measured every 2 h during two or three separate 26-h periods. The hormones were measured by radioimmunoassays. The rhythms were characterized with single cosinor analysis. Two subjects in group 1 and six subjects in group 2 had abnormalities in their rhythms of temperature, cortisol or melatonin. All three rhythms were disrupted in two subjects of group 2. These two subjects were the only ones with disrupted cortisol rhythm. The diversity of rhythm pathologies suggested partly separate regulatory mechanisms for each rhythm. The co-occurrence of circadian rhythm sleep disorders with the deteriorated melatonin rhythm raised the question as to whether the sleep disorders of these subjects, like those of subjects with healthy brains, could be relieved by the induction of normal melatonin rhythm.     

Role of melatonin in the regulation of human circadian rhythms and sleep

The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep "facilitator" in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.     

Sleep in normal aging]

Sleep in the elderly is characterized by a decrease in the ability to stay asleep resulting in a more fragmented sleep. Spindles are less frequent and less ample, shorter, without an increase during the night contrary young subjects. Delta activity in slow wave sleep is decreased in the 0.5-2 Hz frequency band only. REM sleep occurs earlier the first REM period duration increases. The REM sleep appearance is almost uniform during the night. REMs density does not increase toward the end of the sleeping period. The sleep-wake circadian rhythm is advanced (bedtime and morning awakening occur earlier). The temperature rhythm is also advanced. The rise in temperature after the nadir begins earlier for females and the initial ascent is more rapid. This explains why women wake up earlier and sleep for shorter durations than men. The nocturnal and diurnal mean plasmatic norepinephrine values increase. The rhythm of cortisol secretion is advanced. The GH and melatonin peaks of secretion are decreased. The acrophase of melatonin rhythm is occurring later in the elderly. These results suggest a weakening of circadian structure in the course of aging and an altered relationship between the pacemakers driving melatonin and cortisol circadian rhythms.     

Rhythms of plasma noradrenaline in man

Fluctuations in plasma noradrenaline were investigated in normal volunteers sampled over 24 hr. A significant circadian rhythm was demonstrable, with a trough occurring during the nocturnal period in those subjects on a normal sleep-wake cycle. Spectral analysis failed to provide any evidence for significant ultradian rhythms in plasma noradrenaline.     

Sundowning and circadian rhythms in Alzheimer's disease

OBJECTIVE: The goal of this study was to determine changes of circadian rhythms induced by Alzheimer's disease and to explore relationships among rhythm disturbances, sundowning, and sleep disturbances in patients with Alzheimer's disease. "Sundowning" is the occurrence or exacerbation of behavioral symptoms of Alzheimer's disease in the afternoon and evening. METHOD: Circadian rhythms of core body temperature and motor activity were measured in 25 patients with diagnoses of probable Alzheimer's disease and in nine healthy individuals. The subjects with Alzheimer's disease were divided according to the occurrence of sundowning as determined by staff reports. RESULTS: The subjects with Alzheimer's disease had less diurnal motor activity, a higher percentage of nocturnal activity, lower interdaily stability of motor activity, and a later activity acrophase (time of peak) than did the healthy individuals. They also had a higher mesor (fitted mean) temperature, higher amplitude of the fitted cosine temperature curve, and later temperature acrophase than did the healthy subjects. The severity of sundowning was associated with later acrophase of temperature, less correlation of circadian temperature rhythm with a 24-hour cycle, and lower amplitude of temperature curve. CONCLUSIONS: These data indicate that Alzheimer's disease causes disturbances of circadian rhythms and that sundowning is related to a phase delay of body temperature caused by Alzheimer's disease.     

The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders

Normal circadian rhythms are synchronized to a regular 24 h environmental light-dark cycle, and the suprachiasmatic nucleus and the hormone melatonin have important roles in this process. Desynchronization of circadian rhythms, as occurs in chronobiological disorders, can produce severe disturbances in sleep patterns. According to the International Classification of Sleep Disorders, circadian rhythm sleep disorders (CRSDs) include delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 h sleep-wake disorder, jet lag and shift-work sleep disorder. Disturbances in the circadian phase position of plasma melatonin levels have been documented in all of these disorders. There is compelling evidence to implicate endogenous melatonin as an important mediator in CRSD pathophysiology, although further research involving large numbers of patients will be required to clarify whether the disruption of melatonin secretion is a causal factor in CRSDs. In this Review, we focus on the use of exogenous melatonin and light therapy to treat the disturbed sleep-wake rhythms seen in CRSDs.     

Temporal organization of the 24-h corticosterone rhythm in the diurnal murid rodent Arvicanthis ansorgei Thomas 1910

Arvicanthis ansorgei is a diurnal murid rodent from sub-Saharan Africa. The present study reports on the temporal organization of one of the major hormonal rhythms, i.e. the adrenal steroid hormone corticosterone, in an attempt to characterize further the diurnal nature of this species. The data were obtained by means of two different physiological methods: blood sampling and intracerebral microdialysis. The results show a 12-h rhythm of corticosterone release with peak values close to the light-dark (ZT10) and dark-light transition (ZT22-24), which is clearly different from that in a nocturnal animal. Both corticosterone peaks are closely correlated with the occurrence of two major bouts of running wheel activity. As far as we are aware, this is the first demonstration of a hormonal rhythm with a clear crepuscular appearance (peak values around dusk and dawn). In conclusion, these data show that also in a rodent with a diurnal/crepuscular activity pattern, the tight association between the daily corticosterone peak and the onset of activity is maintained. In addition, intracerebral microdialysis is a suitable technique to measure hormonal rhythms when repeated blood sampling is not possible.     

Baseline and post-deprivation recovery sleep in SCN-lesioned rats

In humans, advancing age alters sleep patterns, reducing high voltage NREM sleep, sleep bout length, and delta power during NREM sleep. Although the mechanism by which these alterations occur is unknown, age-related changes in normal circadian processes may play a role. Increased age produces histological and functional changes in the suprachiasmatic nucleus (SCN), and alters the amplitude and phase of circadian rhythms. To examine the relationship between SCN function and age-related changes in sleep, we produced radiofrequency (RF) lesions of the SCN in rats of different ages and examined sleep behavior before and after sleep deprivation. Three-, 12- and 18-month-old rats received RF or sham lesions of the SCN. After verifying loss of circadian rhythm, 24-h EEG/EMG/temperature recordings were made in dim light before and after 24 h of sleep deprivation using the disk-over-water method. Age-related changes in NREM sleep, sleep bout length, and delta EEG power persisted despite SCN lesions. SCN lesions in all age groups increased baseline NREM sleep by 4% and NREM delta power by 15%, and decreased REM sleep by 10%. Although SCN lesions initially produced more REM and NREM sleep during recovery, 24-h values did not differ. Deteriorating SCN function is unlikely to cause the characteristic changes in sleep that occur with age. Our data also imply that an intact SCN slightly inhibits NREM sleep in the rat. Changes in NREM sleep and delta EEG power during recovery in lesioned rats suggest that the SCN may influence homeostatic regulation.     

Melatonin: Generation and Modulation of Avian Circadian Rhythms

The pineal organ and its hormone melatonin are significant components of avian circadian pacemaking systems. In songbirds, pinealectomy results in the abolition or destabilization of overt circadian rhythms such as the rhythm of locomotor activity, feeding, or body temperature. A stable rhythmicity can be restored either by reimplanting a pineal organ, by periodic injections or infusions of melatonin, or by applying melatonin rhythmically through the drinking water. Several results suggest that the pineal melatonin rhythm acts on at least one other oscillator within the circadian pacemaking system, presumably the SCN, which in turn, feeds back to the pineal. As described by the “Neuroendocrine Loop” and “Internal Resonance” models, overall pacemaker output thus depends on the relative strengths of the oscillations in the pineal and the SCN. Investigations on migratory birds have shown that the amplitude of the 24-h plasma melatonin rhythm is reduced during the migratory seasons compared with the nonmigratory seasons. According to the models mentioned above, such a reduced melatonin amplitude should result in a reduction in the degree of self-sustainment of the pacemaker as a whole. This, in turn, should facilitate adjustment to the altered Zeitgeber conditions encountered by these birds as a result of their own migratory flights. A seasonal reduction in melatonin amplitude also occurs in some high-latitude birds during midsummer and midwinter. Under such conditions a less self-sustained circadian pacemaker may enhance entrainability to weak zeitgeber conditions. These examples suggest that the properties of the circadian system may be adjusted to match the changing requirements for synchronization, and that this is achieved by altering the melatonin amplitude.     

Increased skin temperature in Alzheimer’s disease is associated with sleepiness

The 24-h rhythms in sleep and temperature both change in Alzheimer's disease (AD). Characteristic changes consist of a more fragmented diurnal sleep profile with frequent nocturnal awakenings and daytime sleepiness, as well as a reduction in the amplitude of the 24-h rhythm in core body temperature (CBT). Although the 24-h rhythm in CBT is to a large extent the result of a 24-h rhythm in heat loss from the skin caused by pronounced changes in skin blood flow and consequently skin temperature (Ts), changes in the diurnal skin temperature profile in AD as compared to normal aging have remained unexplored. Because recent work indicates a causal contribution of fluctuations in skin temperature to daytime sleepiness and nocturnal sleep depth, the present study aimed to investigate the skin temperature rhythm in AD and its association with daytime sleepiness and nocturnal sleep. Ambulatory recorders were used to estimate sleep and 24-h rhythms in skin temperature in 55 AD patients and 26 matched non-demented elderly controls. Subjective sleep and daytime sleepiness were obtained using questionnaires. The results indicate that AD patients had a significantly higher daytime proximal skin temperature (PST) than elderly controls. In both AD patients and elderly controls, an elevated daytime PST was associated with more daytime sleepiness. The findings suggest a deficient downregulation of daytime proximal skin blood flow that might contribute to daytime sleepiness. Because daytime sleepiness contributes to cognitive dysfunction in AD, further research into the underlying mechanisms and possible reversibility is warranted.     

Circadian rhythm sleep disorders: lessons from the blind

As totally blind people cannot perceive the light-dark cycle (the major synchroniser of the circadian pacemaker) their circadian rhythms often "free run" on a cycle slightly longer than 24 h. When the free-running sleep propensity rhythm passes out of phase with the desired time for sleep, night-time insomnia and daytime sleepiness result. It has recently been shown that daily melatonin administration can entrain the circadian pacemaker, thereby correcting this burdensome circadian sleep disorder. The primary purpose of this review is to elevate awareness of circadian sleep disorders in totally blind people (especially free-running rhythms) and to provide some guidance for clinical management. An additional goal is to show how research on sleep and circadian rhythms in the totally blind can contribute insights into the scientific understanding of the human circadian system. 2001 Harcourt Publishers Ltd     

Effect of melatonin replacement on serum hormone rhythms in a patient lacking endogenous melatonin.

A potentially confounding variable inherent in studies designed to examine the effect of melatonin administration in humans is the presence of an endogenous melatonin rhythm in the experimental subjects. The effects of exogenous melatonin administration on serum hormone rhythms was recently examined in a male patient who lacked detectable circulating levels of endogenous melatonin. The patient's pineal gland had been destroyed five years previously in the course of treatment for a pineal astrocytoma. On three separate occasions, over approximately a one-year period, the patient was given daily oral melatonin replacement (2 mg/day, 1 mg/day and 0.5 mg/day). These experiments were designed to assess the effects of exogenous melatonin on serum growth hormone, prolactin, cortisol and testosterone rhythms. Analysis of blood samples collected every 2-4 hours periods both before and during melatonin replacement revealed that the exogenous melatonin rhythm was associated with improvements in self-reported sleep and mood ratings. Melatonin administration produced robust nocturnal peaks in serum growth hormone and prolactin levels immediately following ingestion of the hormone, while serum cortisol and testosterone rhythms were not influenced. These results suggest that melatonin may modulate the coordination and enhancement of selected biological rhythms in man.     

Free-running circadian rhythm of melatonin in a sighted man despite a 24-hour sleep pattern: A non-24-hour circadian syndrome

Abstract Sleep and plasma melatonin rhythms were measured longitudinally in a sighted young man (21 years old) under a day-night environment. At each measurement, the responsiveness of the melatonin rhythm to a single light pulse was examined in addition to the 24-hour profile. In experiment 1, the timing of sleep was decided by the subject himself. Although most sleep episodes were observed between 21:02 h and 10:55 h, the plasma melatonin rhythm free-ran for a period of 24.18 h. In experiment 2, the sleep-wake schedule of the subject was strictly fixed. The subject was instructed to go to bed at 24:00 h and wake up, at the latest, before 8:00 h for 40 days. The melatonin rhythm, however, continued to free-run for a period of 24.12 h. Nocturnal melatonin level could not be suppressed by a 3-hour light pulse of 500 lx, but was suppressed by a pulse of 1000 lx. It is concluded that internal desynchronization occurred in this particular sighted subject where the sleep-wake rhythm was entrained by the 24-hour day-night environment, whereas the plasma melatonin rhythm free ran, and that a forced sleep schedule did not act as a strong zeitgeber.     

Twenty-four hour profiles of four hormones under constant routine

Abstract We studied the circadian features of melatonin, cortisol, thyroid stimulating hormone (TSH), and growth hormone (GH) together with rectal temperature during 36 h continuous forced wakefulness without physical exercise under dim light condition (constant routine). Subjects consisted of four healthy men aged 22–24 years. Blood sampling was conducted hourly, and food and water were supplied bi-hourly during the constant routine. Melatonin, TSH and cortisol displayed clear circadian rhythms under constant routine condition. While GH secretion was unlikely to be driven solely by the circadian pacemaker, its suppression round BT nadir may indicate that GH secretion was modulated to some extent by circadian rhythm.