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Delayed sleep phase syndrome (DSPS) is a chronic sleep onset insomnia that is caused by a persistent delay of sleep timing. Functional abnormalities of the circadian pacemaker have been assumed to underlie this syndrome, but its detailed pathophysiology has not yet been identified. We studied nine patients with DSPS and 20 healthy controls to compare habitual sleep timings and hormonal rhythms between the groups. Concentrations of serum melatonin, cortisol, and thyroid-stimulating hormone (TSH) were assessed every hour for 26 h under dim light condition. The hormonal rhythms were significantly delayed in patients with DSPS compared with controls, whereas the 24-h amounts of hormonal secretions and the phase relationships between the hormonal rhythms did not differ between the groups. We postulate that sleep-phase delay in patients with DSPS is a consequence of the phase delay of the circadian pacemaker, therefore, suggesting that phase delay in the circadian clock is responsible for this disorder.

The circadian modulation of occurrence of non-rapid-eye-movement sleep (NREM) was investigated in 37 volunteers under dim-light conditions after 24-h total sleep deprivation using a 26-h 10/20-min ultra-short sleep-wake schedule. The propensity of NREM showed rapid increase followed by gradual decrease during the subjective day and nocturnal bouts during the subjective night coinciding with melatonin production. The mean propensity of NREM during the subjective day was smaller than that during the subjective night, even though the sleep debt due to the 24-h sleep deprivation would have enhanced NREM more strongly during the subjective day than that during the subjective night. These results suggest that the occurrence of NREM sleep is modulated by a circadian pacemaker.

Subjective sleep quality has been identified as an important clinical construct in psychiatric disordered patients. The Pittsburgh Sleep Quality Index (PSQI), one of the most widely used standardized measures to assess subjective sleep quality, generates a global score and scores seven components. The present study psychometrically assessed clinical profiles of subjective sleep quality in 82 control and 92 psychiatric disordered subjects (primary insomnia, n=14; major depression, n=30; generalized anxiety disorder, n=24; and schizophrenia, n=24), using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J). The overall reliability coefficient of the PSQI-J was high (Cronbach's alpha=0.77). Correlation coefficients between the PSQI-J global and component scores were statistically significant. The PSQI-J global and component mean scores were significantly higher in psychiatric disordered subjects than control subjects, except for the component of sleep duration. Using a cut-off point of 5.5 in the PSQI-J global score, estimations of sensitivity and specificity provided 85.7 and 86.6% for primary insomnia, 80.0 and 86.6% for major depression, 83.3 and 86.6% for generalized anxiety disorder, and 83.3 and 86.6% for schizophrenia, respectively. The present study supports the utility of the PSQI-J as a reliable and valid measure for subjective sleep quality in clinical practice and research.

Background: The fact that most women experience sleep changes across the menstrual cycle is thought to be associated with changes in circadian rhythms; however, few studies have investigated this relationship. Methods: We applied an ultrashort sleep–wake schedule to eight healthy women and studied diurnal fluctuations in sleep propensity, sleepiness, rectal temperature, and serum concentrations of melatonin, thyroid-stimulating hormone, and cortisol in the follicular and luteal phases. Results: In the luteal phase, amplitude of core body temperature, total melatonin secretions, and amplitudes of TSH and cortisol rhythms were significantly decreased, whereas sleepiness and occurrence of slow-wave sleep during the daytime were significantly increased. Differences in the amount of daytime slow-wave sleep across the menstrual cycle were positively correlated with differences in the daily mean rectal temperature. Conclusions: The findings suggest that the amplitude of circadian oscillation may be dampened in the luteal phase. Increased daytime sleepiness in the luteal phase may be associated with increased daytime slow-wave sleep, due possibly to changes in thermoregulation in the luteal phase.

Changes in the phase relation between sleep timing and the circadian pacemaker are suspected to have an etiological significance in circadian rhythm sleep disorders. Simultaneous recordings of rest-activity and rectal temperature in seven sighted delayed sleep phase syndrome (DSPS) patients, seven sighted non-24-h sleep-wake syndrome (non-24) patients, and 14 healthy controls were made for 10-14 days continuously in the subjects' homes. We found that sleep length and the interval from the body temperature (BT) trough to sleep offset were significantly longer in both non-24 and DSPS patients than in the controls, and that the interval between sleep onset and the BT trough was significantly less in the non-24 patients than in the DSPS patients and the controls. We postulate these alterations in phase relation to be associated with phase changes of the circadian pacemaker via different illumination timings.

Most women experience sleep changes across the menstrual cycle. We applied the ultra-short sleep-wake schedule to healthy females to compare their 24-h sleep propensity rhythms in the follicular and luteal phases. The daytime (09.00-16.30 h) subjective sleepiness and the number of slow wave sleep-containing nap trials increased in the luteal phase compared to the follicular phase, but the mean sleep propensity did not change. During the periods of 17.00-00.30 h and 01.00-08.30 h there were no differences between the two phases. These results suggest that increased daytime sleepiness in the luteal phase may be related to brain mechanisms controlling slow wave sleep.

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.

The aim of this study was to clarify effects of hormonal and temperature rhythms on circadian fluctuations of sleep propensity. Ten healthy females underwent 24-h sleep deprivation and entered the circadian sleep propensity assessment setting under the ultra-short sleep–wake schedule. During the experiment, sleep propensity rhythm, rectal temperature, and 24-h serum hormone profiles (melatonin, cortisol and thyroid-stimulating hormone) were investigated. The circadian sleep propensity rhythms had two apparent peaks (afternoon and nocturnal peaks) and a trough (nocturnal sleep gate). The timings of the nocturnal sleep gate and the nocturnal peak were correlated exclusively with temperature and melatonin rhythms (P < 0.05), while that of the afternoon peak was significantly correlated with habitual wake time and melatonin rhythm. These results indicate that the circadian sleep propensity rhythm is influenced not only by the circadian pacemaker, but also by sleep habit.

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.

Recent progress in biological clock research has facilitated genetic analysis of circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep–wake syndrome (N-24). We analyzed the human period3 (hPer3) gene, one of the human homologs of the Drosophila clock-gene period (Per), as a possible candidate for rhythm disorder susceptibility. All of the coding exons in the hPer3 gene were screened for polymorphisms by a PCR-based strategy using genomic DNA samples from sleep disorder patients and control subjects. We identified six sequence variations with amino acid changes, of which five were common and predicted four haplotypes of the hPer3 gene. One of the haplotypes was significantly associated with DSPS (Bonferroni’s corrected P = 0.037; odds ratio = 7.79; 95% CI 1.59–38.3) in our study population. Our results suggest that structural polymorphisms in the hPer3 gene may be implicated in the pathogenesis of DSPS.

Nine healthy men (mean age, 22.2 years) participated in two experimental sessions cross-overed randomly in a double blind manner; one with a placebo and the other with 0.125 mg of brotizolam (BTZ) administered in the morning. Resting electroencephalogram and event-related potential under oddball paradigm was recorded before and 1, 2, 4, 6 and 8 h after the administration. Mean 30-msec bin amplitude from 240 msec to 450 msec after the stimulus was compared between placebo and drug sessions in order to observe P300. Brotizolam reduced the amplitude of P300 at 6 h after administration. It was noted that the effects of BTZ were most marked at Fz.

We administered 1-3 mg melatonin to 11 patients (eight men, three women, aged 16-46 years) with circadian rhythm sleep disorders; nine with delayed sleep phase syndrome and two with non-24-hour sleep-wake syndrome. Sleep logs were recorded throughout the study periods and actigraph and rectal temperature were monitored during treatment periods. Melatonin was administered 1-2 h before the desirable bedtime for expected phase-shifting, or 0.5-1 h before habitual bedtime for gradual advance expecting an hypnotic effect of the melatonin. Melatonin treatments were successful in 6/11 patients. Timing and dose of melatonin administration, together with its pharmacological properties for circadian rhythm sleep disorders, should be further studied.

STUDY OBJECTIVES This study examined the prevalence and correlates of sleep problems in Chinese schoolchildren. DESIGN AND SETTING A cross-sectional questionnaire survey was undertaken in Shandong Province, People's Republic of China. PARTICIPANTS A total of 2004 elementary school children (998 boys and 1006 girls) participated in the survey. MEASUREMENTS AND INTERVENTIONS The parents completed a questionnaire that asked about sleep problems, and characteristics of the family and child. Teachers completed a questionnaire that included the Modified Conners Hyperkinesis Index (MCHI), whether the child slept in class, and school achievement. RESULTS Parent-reported sleep problems that occurred "sometimes" or "often" were sleep walking/talking, 14.2%; too little sleep, 14.0%; too much sleep, 12.5%; nightmares, 12.0%; trouble sleeping, 6.1%; and nocturnal enuresis, 4.5%. Teachers reported that 9.4% of children slept in class "sometimes" or "often". Approximately 11% of children were reported to have any sleep problem "often". Children with sleep problems were more frequently reported to be hyperactive, and to have poorer child-parent relations, poorer peer relations, and poorer social competency and school achievement. Multivariate logistic regression analysis indicated that sleep problems were significantly correlated with following factors: poor parental relations, crowded homes, bedwetting cessation after age 4, chronic physical diseases, reported hyperactivity and poor peer relations. CONCLUSIONS Parent-reported sleep problems in Chinese children were less prevalent than those reported in Western countries, and associated with multiple family, prenatal, and child developmental factors. Children with sleep problems were reported to be more hyperactive, and to have social and academic problems more frequently.

Recent studies suggest that melatonin 1b (Mel1b) receptor, as well as melatonin 1a (Mel1a) receptor, is involved in the modulation of circadian rhythms in mammals. Mutational analysis was performed in the entire coding region of the human Mel1b receptor gene using genomic DNA from sleep disorder subjects. We have identified two missense mutations, G24E and L66F. However, neither is likely to be associated with sleep disorders in our study population. One of the subjects with non-24-h sleep-wake syndrome carries missense mutations in both the Mel1a and Mel1b receptor genes.

There are few epidemiological studies on sleep loss and daytime sleepiness in the general adult population of Japan. A total of 4000 adult people, aged 20 and over, were randomly drawn from five areas of Japan, and 3030 individuals were interviewed and completed a questionnaire including information about sleep duration and sleep problems. Overall, 29% slept less than 6 h at night, 23% reported having insufficient sleep, and 6% took sleep enhancing medications. The prevalence rates were 21% for symptoms of insomnia and 15% for excessive daytime sleepiness. Symptoms of insomnia were more prevalent in the elderly, whereas young people were more likely to report short sleep duration, subjective insufficient sleep and excessive daytime sleepiness. A multiple logistic regression model revealed that excessive daytime sleepiness had significant associations with young people, short sleep duration, insomnia symptoms, subjective insufficient sleep and sleep enhancing medication use. Short sleep duration was the strongest predictor of excessive daytime sleepiness. The findings indicate that sleep loss and excessive daytime sleepiness in the Japanese adult population are common, and comparable to those reported in Western countries. Excessive daytime sleepiness in the general adult population seems more likely to be attributed to short sleep duration.

In this study, we investigated the association between dopamine receptor D4 (DRD4) exon III polymorphism and novelty seeking in 69 Japanese women. The group of subjects with long allele (≥5 repeats) exhibited significantly elevated novelty seeking scores in comparison with subjects lacking the long allele. By contrast, the scores for harm avoidance, reward dependence, and persistence were statistically indistinguishable in the two group of subjects. With regard to the subscales of novelty seeking, the scores for exploratory excitability and extravagance were significantly higher in subjects with the long allele than in subjects lacking the long allele. However, no significant associations with impulsiveness or disorderliness were recognized. Our results suggest that although long alleles of the polymorphic exon III repeats are low in the Japanese population, there is an association between long alleles of DRD4 exon III polymorphism and novelty seeking. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:469–471, 1999. © 1999 Wiley-Liss, Inc.

The human melatonin 1a (hMella) receptor gene was screened for mutations using genomic DNA samples from patients with circadian rhythm sleep disorders and control subjects by single strand conformational polymorphism analysis (SSCP). We found seven mutations, two of which predict amino acid changes R54W and A157V, respectively. The prevalence of the R54W variant and that of the A157V variant were several times more common in non-24-h sleep-wake syndrome subjects than among control subjects, although the incidence was not significant in our study group. When expressed in COS-7 cells, the R54W mutant receptor exhibited significantly reduced B(max) and slightly enhanced affinity (reduced K(d)) compared to the wild type receptor, while the A157V variant receptor showed similar binding characteristics to the wild type. The identification of variants in the hMella receptor will provide a useful tool for analyzing genetic predisposition toward various diseases related to melatonin function and to clarify the physiological role of melatonin receptors in humans.

To clarify the effects of daily stress, habitual exercise, drinking and smoking on the prevalence of sleep disorders, we selected 4000 residents (or =20 years) in Japan by stratified random sampling and carried out structured interviews (response rate 75.8%). Frequencies of sleep disorders (difficulty initiating sleep: DIS; difficulty maintaining sleep: DMS; early morning awakening and hypnotic medication use) were treated as dependent variables. Significant effects of stress were prevalent in all sleep disorders. Habitual exercise had significant negative association with DIS and DMS. Drinking and smoking did not affect sleep disorders.