Hypernychthemeral sleep-wake cycle: some hidden regularities

A patient with a sleep-wake cycle greater than 24 h recorded his sleep-onset and wake times for 4 years. During this time the patient found himself unable to maintain a 24-h sleep-wake schedule. The lengths of his sleep-wake periods (subjective days) and his sleep periods were highly variable. Nonetheless, there were certain unexpected regularities in his sleep-wake data, corresponding to fixed clock hours. Across the 4-year period, there were certain clock hours during which sleep onset and waking were likely to occur and certain clock hours that may be considered forbidden zones for sleep, during which the patient rarely either began or ended a sleep period. It is possible that the unexpected regularities resulted from partial entrainment to external cues or from some residual influence of an endogenous ultradian-regulating mechanism.     

Vitamin B12 treatment for sleep-wake rhythm disorders

Vitamin B12 (VB12) was administered to two patients suffering for many years from different sleep-wake rhythm disorders. One patient was a 15-year-old blind girl suffering from a free-running sleep-wake rhythm (hypernychthemeral syndrome) with a period of about 25 h. In spite of repeated trials to entrain her sleep-wake cycle to the environmental 24-h rhythm, her free-running rhythm persisted for about 13 years. When she was 14 years old, administration of VB12 per os was started at the daily dose of 1.5 mg t.i.d. Shortly thereafter, her sleep-wake rhythm was entrained to the environmental 24-h rhythm, and her 24-h sleep-wake rhythm was maintained while she was on the medication. Within 2 months of the withholding of VB12, her free-running sleep-wake rhythm reappeared. The VB12 level in the serum was within the normal range both before and after treatment. The other patient was a 55-year-old man suffering from delayed sleep phase syndrome since 18 years of age. After administration of VB12 at the daily doses of 1.5 mg, his sleep-wake rhythm disorder was improved. The good therapeutic effect lasted for more than 6 months while he was on the medication.     

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.     

Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome

STUDY OBJECTIVES: This study was aimed to clarify phase angle between sleep propensity and the circadian pacemaker in patients with non-24-hour sleep-wake syndrome (Non-24). DESIGN AND SETTING: A case-control study was underaken. PARTICIPANTS: Sighted patient with Non-24 (4 males and 1 female, aged 16 to 39 y), and sex- and age-matched healthy controls (12 males and 3 females, aged 19 to 35 y) participated the study. MEASUREMENT AND INTERVENTION: Following an actigraphic assessment of the sleep-wake cycle in their homes, the participants entered an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation. RESULTS: The period of the sleep-wake cycle observed at home was longer in the Non-24 patients (25.12 hours) than in the controls (24.02 hours, p<0.0001). The interval from sleep propensity (SP) onset to the melatonin midpoint (MLmid) was significantly shorter in the Non-24 patients than in the controls. The interval from the MLmid to the SP offset was significantly longer in the Non-24 patients than in the controls. CONCLUSIONS: It was postulated that Non-24 sufferers' delayed SP onset relative to the circadian pacemaker may accelerate the light-induced phase-delay, leading to sleep-wake cycle that is longer than 24 hours.     

Promoting adjustment of the sleep-wake cycle by chronobiotics

Chronobiotics are substances that adjust the timing of internal biological rhythms. Many classes of drugs have been claimed to possess such properties and arouse growing interest as the circumstances for their use in sleep disturbances caused by circadian rhythms alterations (delayed or advanced sleep-phase syndromes, non-24-h sleep-wake disorders, jet lag, shift work sleep disorders and so on) have become progressively more frequent. Amongst the substances potentially presenting chronobiotic properties, a consensus seems to be reached on the possible use of melatonin or its agonists to shift the phase of the human circadian clock, but optimizing the dose, formulation and especially the time of administration require further studies.     

Sleep-wake patterns and sleep disturbance among Hong Kong Chinese adolescents

STUDY OBJECTIVES: To determine sleep-wake patterns and evaluate sleep disturbance in Hong Kong adolescents; to identify factors that are associated with sleep disturbance; and to examine the relationship of sleep-wake variables and academic performance. DESIGN AND SETTING: A school-based cross-sectional survey. PARTICIPANTS: Sample included 1629 adolescents aged 12 to 19 years. MEASUREMENTS AND RESULTS: Self-report questionnaires, including sleep-wake habit questionnaire, Sleep Quality Index, Morningness/ Eveningness scale, Epworth Sleepiness Scale, Perceived Stress Scale, academic performance, and personal data were administered. The average school-night bedtime was 23:24, and total sleep time was 7.3 hr. During weekends, the average bedtime and rise time was delayed by 64 min and 195 min, respectively. The prevalence of sleep disturbances occurring > or = 3 days per week in the preceding 3 months were: difficulty falling asleep (5.6%), waking up during the night (7.2%), and waking up too early in the morning (10.4%). The prevalence of > or = 1 of these three symptoms was 19.1%. Stepwise regression analyses revealed that circadian phase preference was the most significant predictor for school night bedtime, weekend oversleep, and daytime sleepiness. Perceived stress was the most significant risk factor for sleep disturbance. Students with marginal academic performance reported later bedtimes and shorter sleep during school nights, greater weekend delays in bedtime, and more daytime sleepiness than those with better grades. CONCLUSION: The prevalence of sleep deprivation and sleep disturbance among Hong Kong adolescents is comparable to those found in other countries. An intervention program for sleep problems in adolescents should be considered.     

Time of day effects in, and the relationship between, sleep quality and movement

The study aimed to measure the effects of a 27-h 'day' sleep-wake regime on actigraphic and subjective sleep variables, and to examine the relationships between these variables. Nine subjects spent 30 days and nights in the laboratory. After sleeping 8 h for each of 8 nights, the subjects had an imposed 27-h 'day', for 18 'days', remaining in bed for 9 h on each sleep period. Sleep periods therefore started 3 h later each day, although subjects' circadian rhythms stayed entrained to 24 h, because subjects were not isolated from the natural light-dark cycle. Time asleep, subjective sleep efficiency and subjective sleep quality, but not movement during sleep, were found to be significantly affected by time of going to bed. There were significant decreases in movement during recovery sleeps following each of two episodes of 26 h sleep deprivation. Over the study there were significant within-subject correlations between subjective sleep quality and subjective sleep efficiency (r_av=0.65), movement during sleep and subjective sleep efficiency (r_av=−0.48), and movement during sleep and subjective sleep quality (r_av=–0.26). We conclude that sleep movement, despite its low within-and between-subjects variability, is nevertheless a statistically reliable, but weak, indicator of subjective sleep efficiency and quality.     

Association between delayed sleep phase and hypernyctohemeral syndromes: a case study

STUDY OBJECTIVE: We investigated whether the hypernyctohemeral syndrome (non-24-hour sleep-wake syndrome) may show a clinical association with the delayed sleep phase syndrome (DSPS) in a 39-year-old woman who developed sleep disturbances following a traumatic brain injury. MEASUREMENTS AND RESULTS: Sleep-wake log documentation and wrist-activity recordings for more than 6 consecutive months confirmed the patient's tendency to live on longer-than-24-hour "days." Episodes of relative coordination to the 24-hour day were also noted, suggesting that the patient was transiently in and out of phase with environmental synchronizers too weak to fully entrain her to the geophysical environment. Interestingly, we noted a tendency to initiate sleep between 3:00 am and 5:00 am and wake up from sleep between noon and 1:00 pm. CONCLUSIONS: These results support an association between the hypernyctohemeral syndrome and the DSPS. This association may carry implications for the treatment of circadian rhythms disorders.     

Practice parameters for the use of light therapy in the treatment of sleep disorders. Standards of Practice Committee, American Academy of Sleep Medicine.

These clinical guidelines were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. The guidelines provide recommendations for the practice of sleep medicine in North America regarding the use of light therapy for treatment of various sleep disorders. This paper is based on a series of articles in the Journal of Biological Rhythms and also includes evidence tables from an updated Medline review covering the period January 1994 to December 1997. Evidence is presented by grade and level. Recommendations are identified as standards, guidelines, or options. Recommendations are provided for delayed sleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS), non-24-hour sleep-wake syndrome, jet lag, shift work, dementia, and sleep complaints in the healthy elderly. Light therapy appears generally safe if used within recommended intensity and time limits. Light therapy can be useful in treatment of DSPS and ASPS. Benefits of light therapy are less clear and treatment is an option in jet lag, shift work, and non-24-hour sleep-wake syndrome in some blind patients.     

Effects of light exposure and sleep displacement on dim light melatonin onset

The purpose of the study was to induce in two different ways, a phase-angle difference between the circadian pacemaker and the imposed sleep-wake cycle in humans, we intended to: (i) shift the circadian pacemaker by exposure to bright light and keep the timing of the sleep-wake cycle fixed; and (ii) keep the timing of the circadian pacemaker fixed by a constant light-dark cycle and displace sleep. We monitored dim light melatonin onset (DLMO), core body temperature and sleep. DLMO was delayed significantly after 3 days of a 3-h delayed sleep-phase when compared with 3 days of sleep at a normal or 3-h advanced sleep-phase. The shifts in DLMO were not accompanied by shifts in body temperature, changes in waking-up time or by a change in the duration of the first rapid eye movement (REM) sleep episode. Three days of light exposure in the morning or evening resulted in shifts in DLMO of similar magnitude, but this was accompanied by shifts in the rhythm of body temperature, changes in waking-up time and in the duration of the first REM sleep episode. We conclude that the changes observed after light exposure reflect shifts in the circadian pacemaker. In contrast, we propose that the changes observed in DLMO after sleep displacement are not mediated by the circadian pacemaker. These results raise some doubts about the reliability of DLMO as a marker of circadian phase in cases of sleep disturbances. Finally, we initiate a search for changes in sleep that might be responsible for the unexpected effects on DLMO.     

Non-24: eine unterschätzte zirkadiane Schlafstörung bei Blinden

The non-24-hour sleep-wake disorder (Non-24) is a very rare circadian rhythm disorder but present in the majority of totally blind people due to the lack of the photic time cue to reset their circadian pacemaker, the master clock. Up to70?% of totally blind people have to live with their intrinsic circadian rhythm not aligned to the environmental 24-hour day. Due to social and professional demands, most of them attempt to live on a regular 24-hour schedule, although their intrinsic circadian rhythm of sleep and wakefulness follows a non-24-hour cycle. This may result in sleep disturbances and excessive sleepiness during the day. Since the phases of the environmental 24-hour day and of their endogenous circadian rhythm cyclically run in and out of synchrony with each other, symptoms also cyclically increase and decrease. The clinical picture is an intermittent sleep disorder. The characteristics of a cyclic sleep disorder, caused by a Non-24 rhythm, often are not even known to sleep specialists. Diagnosis of Non-24 includes a detailed sleep history, a specific questionnaire, a sleep diary kept over at least 2 weeks, preferably actigraphy and, possibly, polysomnography for differential diagnosis. Currently, symptomatic treatment of insomnia is often centered on prescribing hypnotics or psychopharmaceuticals while stimulants are used to address daytime sleepiness. Melatonin may be a treatment option but is not labelled for synchronization of the sleep-wake rhythm in Germany. Recently, tasimelteon, a melatonin receptor agonist, has received EU approval and provides a causal therapy for Non-24 in totally blind people. Treatment with tasimelteon is able to entrain the non-synchronized endogenous circadian sleep-wake rhythm to the 24-hour day.     

Schlafregulation

Circadian rhythmicity and sleep homeostasis both contribute to sleep timing and sleep structure in animals and humans. The circadian process and the sleep homeostat interact to consolidate the sleep-wake cycle and, thus, establish wakefulness and sleep. The circadian process generates a sleep-wake propensity rhythm that is timed to oppose homeostatic changes in sleep drive. Disruption of this fined-tuned interaction can lead to performance decrements, daytime sleepiness, and sleep problems, which are often found in shift workers, jet lag, in older people, and patients suffering from delayed or advanced sleep phase syndrome. Recent progress in molecular biology and cell physiology has led to the following conclusions regarding these two processes and their impact on the neurobiology of sleep: The suprachiasmatic nuclei (SCN), located in the anterior hypothalamus, represent the master circadian pacemaker. There is a feedback to the SCN via the neurohormone melatonin. The ventrolateral preoptic area (VLPO) is particularly important for the initiation of sleep. Adenosine triggers the VLPO. An ultradian oscillator located in the mesopontine brainstem region controls the regular cycling between non-REM and REM sleep. The sleep-wake cycle and the NREM-REM sleep cycle induce regularly occurring neuromodulatory changes in forebrain structures.     

Influence of sleep disturbance on steroid 5alpha-reductase mRNA levels in rat brain

Sleep deprivation has been shown to affect the production of steroid hormones in peripheral steroidogenic organs, but little is known about the influence of sleep disturbance on the metabolism of steroid hormones in the brain. To elucidate a possible association of the sleep-wake cycle with brain neurosteroid metabolism, the influence of short-term sleep disturbance on the expression of mRNA encoding steroid 5alpha-reductase, the enzyme converting progesterone and other steroid hormones to their neuroactive 5alpha-reduced metabolites, was investigated. Rats were first subjected to non-selective disturbance of the sleep-wake cycle, and the expression of steroid 5alpha-reductase mRNA in rat hippocampus and brainstem was determined using a semi-quantitative one-step RT-PCR technique. Non-selective disturbance of the sleep-wake cycle resulted in the elevation of 5alpha-reductase mRNA levels in the brainstem, but not in the hippocampus, and the elevated mRNA expression returned to the basal levels after a short period of the sleep recovery. Further studies showed that selective REM sleep deprivation significantly elevated 5alpha-reductase mRNA levels in both hippocampus and brainstem, thus proposing the possibility that REM sleep reduction may largely contribute to the elevation of steroid 5alpha-reductase mRNA levels observed during short-term disturbance of the sleep-wake cycle.Since the enhancement of steroid 5alpha-reductase gene expression may result in the elevation of neuroactive 5alpha-reduced steroid production in the brainstem, the findings presented here provide further evidence for suggesting that neuroactive steroids may play a physiologically important role in the neuronal network for REM sleep initiation and maintenance.     

Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12).

Two adolescent patients suffering from persistent sleep-wake schedule disorders appear to have responded to treatment with vitamin B12 (methylcobalamin). A 15-year-old girl with delayed sleep phase syndrome (DSPS) and a 17-year-old boy with hypernychthemeral syndrome complained of not being able to attend school despite many trials of medication. The improvement of the sleep-wake rhythm disorders appeared immediately after the administration of high doses (3,000 micrograms/day) of methylcobalamin. Neither patient showed any laboratory or clinical evidence of vitamin B12 deficiency or hypothyroidism (which can cause B12 deficiency). Serum concentrations of vitamin B12 during treatment were in the high range of normal or above normal. The duration of the sleep period of the DSPS patient decreased gradually from 10 hours to 7 hours, and the time of sleep onset advanced from 2 a.m. to midnight. The period of the sleep-wake cycle of the hypernychthemeral patient was 24.6 hours before treatment and 24.0 hours after treatment. The relationship between the circadian basis of these disorders and vitamin B12 and its metabolites is discussed.     

Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod

Heart rate (HR) and heart rate variability (HRV) undergo marked fluctuations over the 24-h day. Although controversial, this 24-h rhythm is thought to be driven by the sleep-wake/rest-activity cycle as well as by endogenous circadian rhythmicity. We quantified the endogenous circadian rhythm of HR and HRV and investigated whether this rhythm can be shifted by repeated melatonin administration while exposed to an altered photoperiod. Eight healthy males (age 24.4 +/- 4.4 years) participated in a double-blind cross-over design study. In both conditions, volunteers were scheduled to 16 h-8 h rest : wake and dark : light cycles for nine consecutive days preceded and followed by 29-h constant routines (CR) for assessment of endogenous circadian rhythmicity. Melatonin (1.5 mg) or placebo was administered at the beginning of the extended sleep opportunities. For all polysomnographically verified wakefulness periods of the CR, we calculated the high- (HF) and low- (LF) frequency bands of the power spectrum of the R-R interval, the standard deviation of the normal-to-normal (NN) intervals (SDNN) and the square root of the mean-squared difference of successive NN intervals (rMSSD). HR and HRV variables revealed robust endogenous circadian rhythms with fitted maxima, respectively, in the afternoon (16:36 hours) and in the early morning (between 05:00 and 06:59 hours). Melatonin treatment phase-advanced HR, HF, SDNN and rMSSD, and these shifts were significantly greater than after placebo treatment. We conclude that endogenous circadian rhythmicity influences autonomic control of HR and that the timing of these endogenous rhythms can be altered by extended sleep/rest episodes and associated changes in photoperiod as well as by melatonin treatment.     

5-Hydroxytryptophan, but not L-tryptophan, alters sleep and brain temperature in rats

The precise role of serotonin (5-hydroxytryptamine) in the regulation of sleep is not fully understood. To further clarify this role for 5-hydroxytryptamine, the 5-hydroxytryptamine precursors L-tryptophan (40 and 80 mg/kg) and L-5-hydroxytryptophan (25-, 50-, 75-, 100 mg/kg) were injected intraperitoneally into freely behaving rats 15 min prior to dark onset, and subsequent effects on sleep-wake activity and cortical brain temperature were determined. L-5-hydroxytryptophan, but not L-tryptophan, induced dose-dependent changes in sleep-wake activity. During the 12-h dark period, non-rapid eye movement sleep was inhibited in post-injection hours 1-2 by the two lowest L-5-hydroxytryptophan doses tested, while the two highest doses induced a delayed increase in non-rapid eye movement sleep in post-injection hours 3-12. These highest doses inhibited non-rapid eye movement sleep during the subsequent 12-h light period. The finding that L-5-hydroxytryptophan, but not L-tryptophan, induced a dose-dependent and long-lasting decrease in cortical brain temperature regardless of whether or not non-rapid eye movement sleep was suppressed or enhanced contributes to a growing list of conditions showing that sleep-wake activity and thermoregulation, although normally tightly coupled, may be dissociated. The initial non-rapid eye movement sleep inhibition observed following low doses of L-5-hydroxytryptophan may be attributable to increased serotonergic activity since 5-hydroxytryptamine may promote wakefulness per se, whereas the delayed non-rapid eye movement sleep enhancement after higher doses may be due to the induction by 5-hydroxytryptamine of sleep-inducing factor(s), as previously hypothesized. The period of non-rapid eye movement sleep inhibition beginning 12 h after administration of L-5-hydroxytryptophan doses that increase non-rapid eye movement sleep is characteristic of physiological manipulations in which non-rapid eye movement sleep is enhanced. The results of the present study suggest that the complex effects of 5-HT on sleep depend on the degree and time course of activation of the serotonergic system such that 5-HT may directly inhibit sleep, yet induce a cascade of physiological processes that enhance subsequent sleep.     

The 24-h growth hormone rhythm in men: sleep and circadian influences questioned

The 24-h rhythm of growth hormone (GH) is thought to be controlled primarily by sleep processes with a weak circadian component. This concept has been recently questioned in sleep-deprived persons. To test the notion of a high sleep-dependency of GH release, we established simultaneous 24-h rhythms of GH and melatonin, a circadian marker, in night workers who form a model for challenging sleep and circadian processes. Ten day-active subjects and 11 night workers were studied during their usual sleep-wake schedule, with sleep from 23:00 to 07:00 hours and 07:00 to 15:00 hours, respectively. Experiments were conducted in sleep rooms under continuous nutrition, bed rest, and dim light. Melatonin and GH were measured every 10 min over 24 h. In day-active subjects, melatonin and GH showed the well-known 24-h profiles, with a major sleep-related GH pulse accounting for 52.8 +/- 3.5% of the 24-h GH production and the onset of the melatonin surge occurring at 21:53 hours +/- 18 min. In night workers, melatonin showed variable circadian adaptation, with the onset of secretion varying between 21:45 and 05:05 hours. The sleep-related GH pulse was lowered, but the reduction was compensated for by the emergence of large individual pulses occurring unpredictably during waking periods, so that the total amount of GH secreted during the 24 h was constant. One cannot predict the degree of GH adaptation from the highly variable melatonin shift. These results argue against the concept that sleep processes exert a predominant influence on GH release whatever the conditions. When sleep and circadian processes are misaligned, the blunting of the sleep-related GH pulse is counteracted, as in sleep-deprived persons, by a compensatory mechanism promoting GH pulses during wakefulness.     

The circadian rhythm of temperature in humans during a 26-hr sleep-wake schedule

The effect of non-24-hr zeitgebers on human circadian rhythms is usually studied in temporal isolation units. In this study, subjects tried to adhere to a 26-hr sleep-wake schedule while living at home exposed to the conflicting natural 24-hr zeitgebers. Temperature was continuously measured with a rectal probe. Daily sleep logs provided subjective estimates of sleep and wake times. After a baseline period on a 24-hr schedule, the subjects followed the 26-hr schedule for 12-13 consecutive days. The circadian rhythm of temperature appeared entrained to the 26-hr schedule for two of the subjects (the adapters), but was definitely not entrained for the other two subjects (the non-adapters). For the non-adapters a 24-hr component persisted in the temperature rhythm. Sleep time conformed more closely to the planned schedule for the adapters than for the non-adapters. These results show that a 26-hr sleep-wake schedule can be a more powerful zeitgeber than the natural 24-hr zeitgebers. Factors that might determine whether an individual will entrain to the 26-hr schedule are discussed.     

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.