Successful treatment of human non-24-hour sleep-wake syndrome

The authors report a case in which a non-24-h (hypernychthemeral) sleep-wake cycle appeared as a late complication of a more fundamental disturbance in the quality of sleep (difficulty falling asleep, frequent awakenings, nonrefreshing sleep). The sleep disturbance began abruptly after a series of stressful events. The patient reported that he extended his hours of bedrest in the morning in order to increase his total sleep time and feel mor rested, and that he gradually extended his hours of activity in the late evening in order to increase his drowsiness and ability to fall asleep. At first this behavior, which was a deliberate attempt to compensate for inefficient nighttime sleep, led to a delayed sleep period, as also occurs in the delayed sleep phase syndrome. After several years in which sleep efficiency progressively deteriorated, this behavior led to a non-24-h free-running sleep-wake cycle. After the patient was treated with thyroxine for borderline hypothyroidism, and then flurazepam and finally vitamin B12, his sleep disturbance progressively improved and his sleep-wake cycle shortened. After B12 treatment he was able to advance the timing of ;his sleep period for the first time in nearly 10 years and to follow a normal 24-h sleep-wake regimen.     

Clinical analyses of sighted patients with non-24-hour sleep-wake syndrome: a study of 57 consecutively diagnosed cases

STUDY OBJECTIVES: The objective of this study was to clarify the clinical features of sighted patients with non-24-hour sleep-wake syndrome. DESIGN: Clinical analyses of consecutive patients suffering from non-24-hour sleep-wake syndrome. SETTING: The sleep disorders clinic at Kohnodai Hospital, National Center of Neurology and Psychiatry, Japan. PATIENTS: Fifty-seven patients who were diagnosed consecutively as having non-24-hour sleep-wake syndrome between 1991 and 2001 were included in the study. MEASUREMENTS AND RESULTS: The clinical features and sleep characteristics of the patients were analyzed. A semistructured psychiatric interview that included the criteria for Axis I or II disorders of Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised was conducted, and relationships between psychiatric problems and non-24-hour sleep-wake syndrome were analyzed. The patient cohort included 41 (72%) men and 16 (28%) women. The onset of non-24-hour sleep-wake syndrome had occurred during the teenage years in 63% of the cohort, and the mean ( +/-SD) period of the sleep-wake cycle was 24.9 +/- 0.4 hours (range 24.4-26.5 hours). The mean sleep length of the patients was 9.3 +/- 1.3 hours, and 44% of them had a sleep length of between 9 and 10 hours. Psychiatric disorders had preceded the onset of non-24-hour sleep-wake syndrome in 16 patients (28%); of the remaining 41 patients, 14 (34%) developed major depression after the onset of non-24-hour sleep-wake syndrome. CONCLUSIONS: These results represent the first detailed clinical review of a relatively large number of sighted patients with non-24-hour sleep-wake syndrome.     

Plasma melatonin rhythms in young and older humans during sleep, sleep deprivation, and wake

STUDY OBJECTIVES: To determine the effects of sleep and sleep deprivation on plasma melatonin concentrations in humans and whether these effects are age-dependent. DESIGN: At least 2 weeks of regular at-home, sleep/wake schedule followed by 3 baseline days in the laboratory and at least one constant routine (sleep deprivation). SETTING: General Clinical Research Center (GCRC), Brigham and Women's Hospital, Boston, MA. PARTICIPANTS: In Study 1, one group (<10 lux when awake) of 19 young men (18-30 y) plus a second group (<2 lux when awake) of 15 young men (20-28 y) and 10 young women (19-27 y); in Study 2, 90 young men (18-30 y), 18 older women (65-81 y), and 11 older men (64-75 y). All participants were in good health, as determined by medical and psychological screening. INTERVENTIONS: One to three constant routines with interspersed inversion of the sleep/wake cycle in those with multiple constant routines. MEASUREMENTS AND RESULTS: Examination of plasma melatonin concentrations and core body temperature. Study 1. There was a small, but significant effect of sleep deprivation of up to 50 hours on melatonin concentrations (increase of 9.81 +/- 3.73%, P <0.05, compared to normally timed melatonin). There was also an effect of circadian phase angle with the prior sleep episode, such that if melatonin onset occurred <8 hours after wake time, the amplitude was significantly lower (22.4% +/- 4.79%, P <0.001). Study 2. In comparing melatonin concentrations during sleep to the same hours during constant wakefulness, in young men, melatonin amplitude was 6.7% +/- 2.1% higher(P <0.001) during the sleep episode. In older men, melatonin amplitude was 37.0% +/- 12.5% lower (P <0.05) during the sleep episode and in older women, melatonin amplitude was non-significantly 10.9% +/- 8.38% lower (P = 0.13) during the sleep episode. CONCLUSIONS: Both sleep and sleep deprivation likely influence melatonin amplitude, and the effect of sleep on melatonin appears to be age dependent.     

Phase-dependent treatment of delayed sleep phase syndrome with melatonin

STUDY OBJECTIVE: Delayed sleep phase syndrome (DSPS) is a circadian-rhythm sleep disorder characterized by abnormally late sleep and wake times. Melatonin, taken in the evening, advances sleep and circadian phase in patients with DSPS. However, little is known about the most effective dose or time of administration. In the present study, we tested the effectiveness of melatonin to advance the timing of sleep and circadian phase in individuals with DSPS. DESIGN: Following baseline assessment of sleep and circadian phase, subjects were randomly assigned to 1 of 3 treatment groups. The administration of melatonin (0.3 or 3.0 mg) or placebo was double-blinded. SETTING: All procedures were conducted on an outpatient basis. PARTICIPANTS: Thirteen subjects with DSPS, recruited via flyers, advertisements, and referrals from the Sleep Clinic, completed this study. INTERVENTIONS: Melatonin (0.3 or 3.0 mg) or placebo was administered between 1.5 and 6.5 hours prior to dim light melatonin onset for a 4-week period. MEASUREMENTS AND RESULTS: Both doses of melatonin advanced the circadian phase of endogenous melatonin. The magnitude of phase advance in dim-light melatonin onset correlated strongly with the time of melatonin administration, with earlier times being more effective (r2 = 0.94, P < .0001). Similar, though weaker, relationships were obtained between the timing of melatonin administration and changes in sleep time. CONCLUSIONS: These results indicate that melatonin advances the circadian clock and sleep in patients with DSPS in a phase-dependent manner. This is the first study that reports a relationship between timing of melatonin administration and phase changes in patients with DSPS.     

Menstrual changes in sleep, rectal temperature and melatonin rhythms in a subject with premenstrual syndrome

We studied a sighted woman with premenstrual syndrome who showed menstrual changes in circadian rhythms. She showed alternative phase shifts in the sleep rhythm in the menstrual cycle: progressive phase advances in the follicular phase and phase delays in the luteal phase. Rectal temperature rhythm also showed similar menstrual changes, but the phase advance and delay started a few days earlier than changes in sleep-wake rhythm so that the two rhythms were dissociated around ovulation and menstruation. These results suggest that her circadian rhythms in sleep and temperature are under the control of ovarian steroid hormones and that these two rhythms have different sensitivity to the hormones.     

Effects of nocturnal bright light on saliva melatonin, core body temperature and sleep propensity rhythms in human subjects

Nine healthy male volunteers (mean age of 24) participated in two experimental sessions of random crossover design: a bright light (5000 lux for 5 h from 00:00 to 05:00 h) session and a dim light (10 lux for 5 h from 00:00 to 05:00 h) session. Subsequently participants entered an ultra-short sleep-wake schedule for 26 h, in which a sleep-wake cycle consisting of 10-min sleep EEG recording on a bed and 20-min resting awake on a semi-upright chair were repeated. Saliva melatonin level and core body temperature was measured throughout the experiment. Bright light significantly delayed rhythms of melatonin secretion (01:58 h), core body temperature (01:12 h) and sleep propensity (02:00 h), compared as dim light session. Significant positive correlation was found between bright light-induced phase change in core body temperature and that in sleep propensity rhythm. Light-induced melatonin suppression significantly positively correlated with the phase change in core body temperature and that in sleep propensity rhythm. Assuming that light-induced melatonin suppression represents an acute impact of light on the circadian pacemaker, our results suggest that such an impact may be directly reflected in phase changes of sleep propensity and core body temperature rhythms rather than in melatonin rhythm.     

Inducing a 6-hour phase advance in the elderly: effects on sleep and temperature rhythms

The aim of this experiment was to study the effects on sleep and temperature rhythms of a 6-hour (h) phase advance of the sleep/wake cycle in healthy elderly subjects. Twenty-five subjects (77–91 y.o.) lived in a time-isolation apartment on an experimenter-controlled routine for 15 days. The experiment started with five baseline days. The wake time on the 6th night was phase advanced by 6-h and the routine for the remaining nine days was held constant to the new phase position. After the phase shift, temperature circadian rhythms showed rapid phase adjustment leading to a small (1.1 h) phase angle disturbance. Sleep efficiency decreased and showed little evidence of recovery back to baseline following the phase shift. The amount of wakefulness in the first two hours of sleep increased after the phase shift while no effect was found for the amount of wakefulness in the last two hours of sleep. The 6-h phase shift did not change the percentages of REM and SWS. Early night sleep propensity appeared to be very sensitive to a small phase angle disturbance of the circadian oscillator in this healthy elderly sample. The phase angle disturbance induced in this study did not seem to be large enough to have a systematic effect on sleep propensity at the end of the night or on REM sleep parameters, suggesting that these variables are less sensitive to an altered phase relationship with the circadian oscillator than early night sleep propensity. These results indicate that there might be a variable phase tolerance for different sleep parameters in older subjects.     

Effect of ambient temperature on the 24-hour sleep-wake cycle in normal and capsaicin-treated rats

The 24-hour sleep-wake cycle of untreated, normal rats and of capsaicin-treated rats was continuously recorded by telemetry. Recordings were made on two baseline days at 22 degrees C, two days at 29 degrees C, and two final days at 22 degrees C. In untreated animals the daily amount of waking was reduced by the elevated ambient temperature and nonREM sleep was enhanced. This effect was mainly due to the frequent interruption of the dark-time waking episodes by sleep. In capsaicin-treated animals, raising the ambient temperature did not significantly enhance sleep. However, in both groups of rats the slow wave sleep (SWS) fraction of nonREM sleep was increased after elevating the temperature to 29 degrees C. REM sleep showed a minor increase which was significant only for the capsaicin-treated group. The results suggest that a moderate increase of ambient temperature has two effects: (1) It causes an enhancement of sleep by a reduction in the duration of waking episodes, an effect that may represent a heat-defense response. The attenuation of this response in capsaicin-treated rats may be a consequence of the impairment of warm-receptors. (2) It favors the occurrence of SWS and REM sleep.     

Sleep propensity free-runs with the temperature, melatonin and cortisol rhythms in a totally blind person.

In previous studies, we found that many totally blind people have free-running melatonin rhythms, but that free-running melatonin rhythms were not necessarily associated with periodic insomnia and daytime sleepiness. Thus, it was not clear if the circadian sleep propensity rhythm was free-running with the other circadian rhythms. In the present study, we report that the sleep propensity rhythm (as defined by an ultrashort sleep-wake schedule) free-ran with the melatonin, temperature and cortisol rhythms in a 44-year-old totally blind man even though he maintained a conventional sleep schedule and did not complain of clinically significant insomnia or excessive daytime sleepiness.     

Diurnal preference, sleep habits, circadian sleep propensity and melatonin rhythm in healthy human subjects

After 24-h sleep deprivation, 33 healthy young subjects entered the 10/20 min ultra-short sleep–wake schedule for 26 h. Melatonin rhythm was hourly assessed simultaneously. Results indicated that morning preference was significantly correlated with habitual sleep onset (r=−0.41, P=0.04), habitual sleep offset (r=−0.52, P=0.002), melatonin peak time (r=−0.36, P=0.04), and sleep propensity onset time (r=−0.36, P=0.04). The intervals between habitual sleep mid-point and melatonin peak time and between habitual sleep mid-point and sleep propensity onset time were significantly longer in morning-preference subjects than in evening-preference subjects (P<0.05). These findings suggest that the variance of diurnal preference may be related to differences in phase relations between habitual sleep timing and the circadian pacemaker.     

Diurnal preference, sleep habits, circadian sleep propensity and melatonin rhythm in healthy human subjects

We studied the in vitro effects of ethanol (25, 50 and 100 mM) on pyroglutamyl aminopeptidase activity (pGluAP), which has been reported as thyrotrophin-releasing-hormone-degrading activity. pGluAP was measured in presence or absence of calcium, under basal and K(+)-stimulated conditions, in synaptosomes and their incubation supernatant, using pyroglutamyl-beta-naphthylamide as substrate. In basal conditions, in synaptosomes, pGluAP was inhibited by ethanol in a calcium-independent way. In the supernatant, the response differed depending on the concentration of ethanol. Depolarization with K(+) modified pGluAP in synaptosomes and supernatant depending on the presence or not of calcium. In synaptosomes, in absence of calcium, the activity was inhibited at the highest concentrations of ethanol. In contrast, in the supernatant, under depolarizing conditions, ethanol increases pGluAP in absence of calcium. These changes may be in part responsible of the behavioural changes associated to alcohol intake.     

Effects of exogenous melatonin on sleep and circadian rhythms in women with premenstrual dysphoric disorder

We previously found normal polysomnographic (PSG) sleep efficiency, increased slow-wave sleep (SWS), and a blunted melatonin secretion in women with premenstrual dysphoric disorder (PMDD) compared to controls. Here, we investigated the effects of exogenous melatonin in five patients previously studied. They took 2 mg of slow-release melatonin 1 h before bedtime during their luteal phase (LP) for three menstrual cycles. At baseline, patients spent every third night throughout one menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analog scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM), and ovarian plasma hormones. Participants also underwent two 24-hour intensive physiological monitoring (during the follicular phase and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. In the intervention condition compared to baseline, we found increased urinary aMt6 (p < 0.001), reduced objective sleep onset latency (p = 0.01), reduced SWS (p < 0.001), and increased Stage 2 sleep (p < 0.001). Increased urinary aMt6 was correlated with reduced SWS (r = −0.51, p < 0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p = 0.01). Ovarian hormones were comparable between the conditions (p ≥ 0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p = 0.02) and the PRISM (p < 0.001). These findings support a role for disturbed melatonergic system in PMDD that can be partially corrected by exogenous melatonin.     

Reciprocal interactions between sleep,circadian rhythms and Alzheimer's disease: Focus on the role of hypocretin and melatonin

AD, sleep and circadian rhythm physiology display an intricate relationship. On the one hand, AD pathology leads to sleep and circadian disturbances, with a clear negative influence on quality of life. On the other hand, there is increasing evidence that both sleep and circadian regulating systems exert an influence on AD pathology. In this review we describe the impairments of both sleep regulating systems and circadian rhythms in AD and their link to clinical symptoms, as this may increase knowledge on appropriate diagnosis and adequate treatment of sleep problems in AD. Furthermore we discuss how sleep regulating systems, and especially neurotransmitters such as melatonin and hypocretin, may affect AD pathophysiology, as this may provide a role for lack of sleep and circadian rhythm deterioration in the onset of AD.     

Differences in sleep-wake habits and EEG sleep variables between active morning and evening subjects

This article is a survey study, followed by an experimental study, examining the differences of sleep-wake habits and sleep electroencephalographic (EEG) variables between morning and evening type subjects (Ss). In the survey study, the Japanese version of the Horne and Ostberg Morningness-Eveningness Questionnaire and Life Habits Inventory (LHI) were administered to approximately 1,500 university students. The survey results showed that the two types were significantly different from each other in terms of retiring and arising time, sleep latency, mood on arising, nap, adequate amount of sleep, number of times of staying awake all night, and variability in bedtime, arising time, and sleep length. These results suggested that evening type Ss had more irregular and/or flexible sleep-wake habits than morning type Ss. In the experimental study, 10 morning and 11 evening type Ss were selected from the population included in the survey study, and polysomnograms were obtained. The results showed that only in rapid eye movement (REM) latency did morning type Ss significantly differ from evening type Ss. REM latency might be related to personality factors, particularly to neuroticism and anxiety.     

Home dim light melatonin onsets with measures of compliance in delayed sleep phase disorder

The dim light melatonin onset (DLMO) assists with the diagnosis and treatment of circadian rhythm sleep disorders. Home DLMOs are attractive for cost savings and convenience, but can be confounded by home lighting and sample timing errors. We developed a home saliva collection kit with objective measures of light exposure and sample timing. We report on our first test of the kit in a clinical population. Thirty‐two participants with delayed sleep phase disorder (DSPD; 17 women, aged 18–52 years) participated in two back‐to‐back home and laboratory phase assessments. Most participants (66%) received at least one 30‐s epoch of light >50 lux during the home phase assessments, but for only 1.5% of the time. Most participants (56%) collected every saliva sample within 5 min of the scheduled time. Eighty‐three per cent of home DLMOs were not affected by light or sampling errors. The home DLMOs occurred, on average, 10.2 min before the laboratory DLMOs, and were correlated highly with the laboratory DLMOs (r = 0.93, P < 0.001). These results indicate that home saliva sampling with objective measures of light exposure and sample timing, can assist in identifying accurate home DLMOs.     

Resynchronization of hormonal rhythms after an eastbound flight in humans: effects of slow-release caffeine and melatonin

The aim of this work was to investigate the potential chronobiotic properties of slow-release caffeine, in comparison with melatonin, on resynchronization of endogenous melatonin and cortisol secretions after an eastbound flight by jet incurring a time loss of 7 h. A group of 27 reservists of the US Air Force received either slow-release caffeine (300 mg), melatonin (5 mg) or placebo before, during and/or after the transmeridian flight. Saliva and urine were sampled before the flight in the United States (from day –2 to day 0) and after the flight in France (from day 1 to day 10). Saliva was collected once a day on waking to determine saliva melatonin and cortisol concentrations. In addition, concentrations of caffeine in saliva were determined three times a day and of 6-sulphatoxymelatonin in urine collected overnight to check that the treatment regimes had been complied with. From day 3 to day 5, post-flight saliva melatonin concentrations were significantly different from control values in the placebo group only. During treatment with melatonin, the mean urinary 6-sulphatoxymelatonin concentration in the melatonin group was more than twice as high as in the two other groups. In the slow-release caffeine group and the melatonin group, mean saliva cortisol concentrations were significantly lower than control from day 2 to day 5, whereas the placebo group had a mean saliva cortisol concentration significantly lower than the control value from day 2 to day 9. In conclusion, these results indicate that administration of slow-release caffeine, as well as of melatonin, allows a faster resynchronization of hormone rhythms during the 4 days following an eastbound flight incurring the loss of 7 h. Electronic Publication