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Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer’s disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations.

Aims Benzodiazepine receptor agonists (BZ‐RAs) are frequently prescribed to treat insomnia; however, their long‐term use is not recommended. To introduce an appropriate pharmaco‐therapy, the current state and background factors of BZ‐RAs' dependence must be elucidated. In this study, we developed a Japanese version of the Benzodiazepine Dependence Self‐Report Questionnaire (Bendep‐SRQ‐J) and conducted a study of BZ‐RAs' use disorder. Methods The Bendep‐SRQ‐J was created with permission from the original developer. Subjects were inpatients and outpatients receiving BZ‐RAs between 2012 and 2013. Clinical data collected were Bendep‐SRQ‐J scores, sleep disorders for which BZ‐RAs were prescribed, physical comorbidities, psychotropic drugs, and lifestyle factors. Logistic analysis was performed to extract factors associated with severe symptoms. Results Of the 707 patients prescribed BZ‐RAs, 324 had voluntarily tapered or discontinued their drugs. Logistic analysis showed that the total number of drugs administered in the last 6 months correlated with both worsening of symptoms or conditions. This was more notable among younger patients, and the proportion of patients with severe symptoms or conditions increased with the increasing number of drugs. Conclusion Using the Bendep‐SRQ‐J, we elucidated the current state of BZ‐RA dependence. Nearly half of the patients were non‐compliant. The proportion of patients with severe symptoms or disease conditions increased with the increase in the number of drugs administered. These findings highlight the need for clinicians to be aware of the likelihood of benzodiazepine dependence, especially in young patients and patients prescribed multiple hypnotics., Using the Bendep‐SRQ‐J, we elucidated the current state of BZ‐RA dependence. Nearly half of the patients were non‐compliant.

Introduction:Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy., Methods:This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG., Results:Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score., Conclusion:Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores.

Delayed sleep–wake phase disorder (DSWPD) is a subtype of circadian rhythm sleep–wake disorders, and is characterized by an inability to fall asleep until late at night and wake up at a socially acceptable time in the morning. The study aim was to identify low-frequency nonsense and missense variants that are associated with DSWPD. Candidate variants in circadian rhythm-related genes were extracted by integration of genetic variation databases and in silico assessment. We narrowed down the candidates to six variants. To examine whether the six variants are associated with DSWPD, we performed an association study in 236 Japanese patients with DSWPD and 1436 controls. A low-frequency missense variant (p.Val1205Met) in PER2 showed a significant association with DSWPD (2.5% in cases and 1.1% in controls, P = 0.026, odds ratio (OR) = 2.32). The variant was also associated with idiopathic hypersomnia known to have a tendency toward phase delay (P = 0.038, OR = 2.07). PER2 forms a heterodimer with CRY, and the heterodimer plays an important role in the regulation of circadian rhythms. Val1205 is located in the CRY-binding domain of PER2 and was hypothesized to interact with CRY. The p.Val1205Met substitution could be a potential genetic marker for DSWPD.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10−9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10−18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Circadian rhythm sleep–wake disorders (CRSWDs) are characterized by disturbed sleep–wake patterns. We genotyped a PER3 variable number tandem repeat (VNTR) in 248 CRSWD individuals and 925 controls and found no significant association between the VNTR and CRSWDs or morningness–eveningness (diurnal) preferences in the Japanese population. Although the VNTR has been associated with circadian and sleep phenotypes in some other populations, the polymorphism may not be a universal genetic marker.

Etiology of narcolepsy–cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P = 1.6 × 10−5, odds ratio [OR] = 1.86). This rs3181077 association was replicated with the independent sample set (P = 0.032, OR = 1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.

Background Sleep disorders are frequently associated with childhood behavioral problems and mental illnesses such as anxiety disorder. To identify promising behavioral targets for pediatric anxiety disorder therapy, we investigated the associations between specific sleep and behavioral problems. Methods We conducted retrospective reviews of 105 patients aged 4–12 years who met the DSM-IV criteria for primary diagnosis of generalized anxiety disorder (n = 33), separation anxiety disorder (n = 23), social phobia (n = 21), or obsessive compulsive disorder (n = 28). Sleep problems were evaluated using the Children's Sleep Habits Questionnaire (CSHQ) and behavioral problems by the Spence Children's Anxiety Scale, Oppositional Defiant Behavior Inventory (ODBI), and Depression Self-Rating Scale for Children. Results Depressive behavior was weakly correlated with CSHQ subscores for sleep onset delay and night waking but not with total sleep disturbance. Anxiety was correlated with bedtime resistance, night waking, and total sleep disturbance score. Oppositional defiance was correlated with bedtime resistance, daytime sleepiness, sleep onset delay, and most strongly with total sleep disturbance. On multiple regression analysis ODBI score had the strongest positive association with total sleep disturbance and the strongest negative association with total sleep duration. Conclusions Sleep problems in children with anxiety disorders are closely related to anxiety and oppositional defiant symptoms.

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.

Background Circadian rhythm sleep disorder, free-running type (FRT), is an intractable sleep disorder in which sleep and wake times progressively delay each day even in normal living environments. This disorder severely affects the social functioning of patients because of periodic nighttime insomnia, excessive daytime sleepiness, and a high rate of comorbid psychiatric disorders. Although abnormal regulation of the biological clock is suspected, the pathophysiology of FRT has yet to be elucidated. In this study, the endogenous circadian period, τ, of FRT patients with normal vision was compared with that of healthy individuals whose circadian rhythms are entrained to a 24-hour cycle. Methods Six FRT patients and 17 healthy individuals (9 intermediate chronotypes and 8 evening chronotypes) were subjected to a 7-day, 28-hour sleep–wake schedule according to the forced desynchrony protocol. Phase shifts in melatonin rhythm were measured under constant routine conditions to calculate τ. Results In FRT patients, τ was significantly longer than in intermediate chronotypes, whereas in evening chronotypes, it ranged widely and was not significantly different from that in FRT patients. Moreover, τ of melatonin rhythm in FRT patients showed no significant correlation with τ of sleep–wake cycles measured before the study. Conclusions The findings suggest that although a prolongation of τ may be involved in the onset mechanism of FRT, a prolonged τ is not the only factor involved. It appears that several factors including abnormal entrainment of circadian rhythms are involved in the onset of FRT in a multilayered manner.

Symmetrical liquid crystalline dimers have been synthesised, composed of rod-like mesogenic units with polar groups and a siloxane core of varying length in the central region. All the dimers containing siloxane units have been shown to exhibit a smectic A phase, confirmed by polarising optical microscopy (POM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Rheological properties under an applied electric field were investigated by rotational rheometer. The influence of the siloxane core length on rheological properties has been investigated, and in addition the behaviour of the liquid crystalline dimers in the smectic A phase under an applied electric field has been observed by POM.

Narcolepsy without cataplexy (NA w/o CA) (narcolepsy type 2) is a lifelong disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, but no cataplexy. In the present study, we examined the human leukocyte antigen HLA-DQB1 in 160 Japanese patients with NA w/o CA and 1,418 control subjects. Frequencies of DQB1*06:02 were significantly higher in patients with NA w/o CA compared with controls (allele frequency: 16.6 vs. 7.8%, P=1.1×10−7, odds ratio (OR)=2.36; carrier frequency: 31.3 vs. 14.7%, P=7.6×10−8, OR=2.64). Distributions of HLA-DQB1 alleles other than DQB1*06:02 were compared between NA w/o CA and narcolepsy with cataplexy (NA-CA) to assess whether the genetic backgrounds of the two diseases have similarities. The distribution of the HLA-DQB1 alleles in DQB1*06:02-negative NA w/o CA was significantly different from that in NA-CA (P=5.8×10−7). On the other hand, the patterns of the HLA-DQB1 alleles were similar between DQB1*06:02-positive NA w/o CA and NA-CA. HLA-DQB1 analysis was also performed in 186 Japanese patients with idiopathic hypersomnia (IHS) with/without long sleep time, but no significant associations were observed.

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.

It has been postulated that time estimation during nocturnal sleep in humans can be explained by an interval timing clock inside the brain. However, no systematic investigations have been carried out with respect to how the human brain perceives the passage of time during sleep. The brain mechanisms of over- or underestimation of time spent in sleep have not yet been clarified. Here, we carried out an experimental study in which 11 healthy volunteers participated in time estimation trials scheduled six times during 9 h nocturnal sleep periods, under carefully controlled conditions. The time estimation ratio (TER: a ratio of subjective passage of time to actual time interval) decreased significantly from the first to the sixth trial. Individual TER was positively correlated with slow wave sleep prior to the trial, while it was negatively correlated with REM sleep. Our results indicate that the human brain has an ability to estimate the passage of time during nocturnal sleep without referring to time cues, and that the accuracy of this function fluctuates from overestimation in the early hours of sleep to underestimation in the last hours of sleep.

Recent studies have shown that functional variations in clock genes, which generate circadian rhythms through interactive positive/negative feedback loops, contribute to the development of circadian rhythm sleep disorders in humans. Another potential candidate for rhythm disorder susceptibility is casein kinase I epsilon (CKIepsilon), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIepsilon induce vulnerability to human circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24), we analyzed all of the coding exons of the human CKIepsilon gene. One of the variants identified encoded an amino-acid substitution S408N, eliminating one of the putative autophosphorylation sites in the carboxyl-terminal extension of CKIepsilon. The N408 allele was less common in both DSPS (p = 0.028) and N-24 patients (p = 0.035) compared to controls. When DSPS and N-24 subjects were combined, based on an a priori prediction of a common mechanism underlying both DSPS and N-24, the inverse association between the N408 allele and rhythm disorders was highly significant (p = 0.0067, odds ratio = 0.42, 95% confidence interval: 0.22-0.79). In vitro kinase assay revealed that CKIepsilon with the S408N variation was approximately 1.8-fold more active than wild-type CKIepsilon. These results indicate that the N408 allele in CKIepsilon plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.

To clarify the sleep habits, and predictors thereof, in Japanese high-school students, a community study was conducted. A total of 3833 students were selected randomly from the 34 full-time high schools in two suburban cities in Japan. The response rate was 90.7% (n = 3478). The students completed the Japanese version of the Pittsburgh Sleep Questionnaire Index (PSQI-J), the Japanese version of the 12-item General Health Questionnaire (GHQ12-J), and a questionnaire on sociodemographic characteristics, daily life, domestic situations, and perceived physical health. Mean bed and rise times were found to be 00:03 and 06:33 h, respectively, resulting in a sleep duration of 380.0 min. A multivariate logistic regression analysis revealed that a short sleep duration (i.e. less than 6 h; prevalence: 25.6%) was significantly associated with a later bedtime, a higher global PSQI-J score, an earlier rise time, being female, a longer study duration outside school hours, and a longer commuting duration, but not with a higher GHQ12-J score. Short sleep duration in Japanese high-school students is associated with their lifestyle as well as sleep problems, but not with psychosomatic problems.

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.

Eight healthy young male volunteers entered a 20-40 min ultrashort sleep-wake schedule for 78 h in the time-isolation facility. Rectal temperature was continuously recorded. Sleep electroencephalograms (EEGs) obtained during 20 min nap trials were stored in the computer and later analyzed by fast Fourier transform. A two-way repeated-measures ANOVA (with day and time-of-day as the repeated measures) revealed significant circadian rhythms in the powers of sigma and delta sleep EEGs, and in rectal temperature. These results obtained under conditions in which behavioral confounding factors of retiring and rising were experimentally minimized suggest that the circadian pacemaker contributes to determining the hours of day when one can sleep deeply.

Previous studies suggested that various psychophysiological factors have influences on human time perception. In particular, working memory loads, time of day, body temperature, and mood were known as important modifiers of time perception. The purpose of this study is to elucidate factors affecting the short-term time perception under controlled condition. Fourteen healthy young male adults participated in this study. Time perception sessions (TPS) were conducted 4 times at 0900, 1300, 1700 and 2100 h. The TPS consisted of five 10-s time production trials under five different conditions (control trial, those with reward, and 3 different dual-load working memory tasks). Subjective status was assessed using visual analogue scales (VAS). To verify a participant's vigilance state, an alpha attenuation coefficient (AAC) was calculated. Two-way repeated measures ANOVA for produced time revealed a significant main effect of session, but no effect of task or interaction. Although produced time was not correlated with AACs or VAS scores, there was a significant negative correlation between produced time and core body temperature. These results suggest that human short-term time perception may be more influenced by circadian rhythm than working memory load or psychophysiological status.

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.

Sleep disorders are frequently associated with childhood behavioral problems and mental illnesses such as anxiety disorder. To identify promising behavioral targets for pediatric anxiety disorder therapy, we investigated the associations between specific sleep and behavioral problems.We conducted retrospective reviews of 105 patients aged 4-12 years who met the DSM-IV criteria for primary diagnosis of generalized anxiety disorder (n = 33), separation anxiety disorder (n = 23), social phobia (n = 21), or obsessive compulsive disorder (n = 28). Sleep problems were evaluated using the Children's Sleep Habits Questionnaire (CSHQ) and behavioral problems by the Spence Children's Anxiety Scale, Oppositional Defiant Behavior Inventory (ODBI), and Depression Self-Rating Scale for Children.Depressive behavior was weakly correlated with CSHQ subscores for sleep onset delay and night waking but not with total sleep disturbance. Anxiety was correlated with bedtime resistance, night waking, and total sleep disturbance score. Oppositional defiance was correlated with bedtime resistance, daytime sleepiness, sleep onset delay, and most strongly with total sleep disturbance. On multiple regression analysis ODBI score had the strongest positive association with total sleep disturbance and the strongest negative association with total sleep duration.Sleep problems in children with anxiety disorders are closely related to anxiety and oppositional defiant symptoms.

A system of self-sustained biological clocks controls the 24-h rhythms of behavioral and physiological processes such as the sleep-wake cycle. The circadian clock system is regulated by transcriptional and translational negative feedback loops of multiple clock genes. Polymorphisms in circadian clock genes have been associated with morningness-eveningness (diurnal) preference, familial advanced sleep phase type (ASPT), and delayed sleep phase type (DSPT). We genotyped single-nucleotide polymorphisms in circadian clock genes in 182 DSPT individuals, 67 free-running type (FRT) individuals, and 925 controls. The clock gene polymorphisms were tested for associations with diurnal preference and circadian rhythm sleep disorder (CRSD) phenotypes. The PER3 polymorphism (rs228697) was significantly associated with diurnal preference and the FRT phenotype. The minor allele of rs228697 was more prevalent in evening types than in morning types (sex-adjusted odds ratio (OR), 2.483, Bonferroni-corrected P = 0.012) and in FRT individuals compared with the controls (age- and sex-adjusted OR, 2.021, permutated P = 0.017). Our findings support the notion that PER3 polymorphisms could be a potential genetic marker for an individual's circadian and sleep phenotypes.

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.

Objective Delayed sleep phase syndrome (DSPS) is a condition in which the patient is unable to reset or phase-advance his/her sleep timing properly after transient sleep delay and consequently shows persistent sleep phase delay. Prior studies suggested that DSPS is associated with a phase delay in the circadian pacemaker, but there was no evidence to explain the patient's inability to reset sleep phase. Subjects and methods We used an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation to allow the differential observation of diurnal sleep propensity fluctuation both from circadian and homeostatic aspects in 11 patients with DSPS (17-37 years; 8 men, 3 women) and 15 healthy controls (19-32 years; 8 men, 7 women). Setting NA. Patients or participants NA. Interventions NA. Results DSPS patients showed less ability to compensate for previous sleep loss during their circadian day and first hours of their circadian nighttime determined by dim light melatonin onset compared with controls, while controls compensated for previous sleep loss at most circadian times. Though shapes of dim light melatonin rhythm did not differ between the groups, phase angle between melatonin and sleep propensity rhythms was wider in DSPS patients than in controls. Conclusions These findings suggest that poor compensatory function for sleep loss predisposes DSPS patients to failure to reset their sleep phase. Our results provide implications for understanding not only the pathophysiology of DSPS but also the biological basis for why some people can change their sleep schedule easily according to personal or social demands while others cannot.

Evaluation of circadian phenotypes is crucial for understanding the pathophysiology of diseases associated with disturbed biological rhythms such as circadian rhythm sleep disorders (CRSDs). We measured clock gene expression in fibroblasts from individual subjects and observed circadian rhythms in the cells (in vitro rhythms). Period length of the in vitro rhythm (in vitro period) was compared with the intrinsic circadian period, τ, measured under a forced desynchrony protocol (in vivo period) and circadian/sleep parameters evaluated by questionnaires, sleep log, and actigraphy. Although no significant correlation was observed between the in vitro and in vivo periods, the in vitro period was correlated with chronotype, habitual sleep time, and preferred sleep time. Our data demonstrate that the in vitro period is significantly correlated with circadian/sleep preference. The findings suggest that fibroblasts from individual patients can be utilized for in vitro screening of therapeutic agents to provide personalized therapeutic regimens for CRSD patients.

Although evening preference has recently been identified as a risk factor for depression, it has not been substantiated whether evening preference is a direct risk factor for depressive states, or if it is associated secondarily through other factors, such as delayed sleep timing and shortened sleep duration. The objective of this study is to investigate associations in Japanese adult subjects between evening preference and incidence of depressive states, adjusting for various sleep parameters related to depressive states. The Morningness-Eveningness Questionnaire (MEQ), the Pittsburgh Sleep Quality Index (PSQI), and the Center for Epidemiologic Studies Depression Scale (CES-D) were administered to 1170 individuals (493 males/677 females; mean and range 38.5 and 20–59 yrs) to assess their diurnal preferences, sleeping states, and presence of depression symptoms. Subjects were classified into five chronotypes based on MEQ scores. Evening preference was associated with delayed sleep timing, shortened sleep duration, deteriorated subjective sleep quality, and worsened daytime sleepiness. Logistic regression analysis demonstrated that the extreme evening type (odds ratio [OR] =1.926, p=.018) was associated with increased incidence of depressive states and that the extreme morning type (OR=0.342, p=.038) was associated with the decreased incidence of depressive states, independent of sleep parameters, such as nocturnal awakening (OR=1.844, p

Bright light is a treatment of choice for seasonal affective disorder. Other indications for bright light therapy have also been tested. These include circadian rhythm sleep disorders, early-morning awakening or sleep-maintenance insomnia in elders and behavioral disturbance or insomnia in organic dementia. In these sleep disorders, the pattern of sleep-wake is misaligned with the patient's circadian system or the external environment, resulting in insomnia. Appropriately-timed exposure to bright light can shift the sleep-wake cycle to earlier or later times, in order to correct for misalignment between the circadian system and the desired sleep-wake schedule. Evidence of the efficacy of bright light was so limited. Further research is needed to determine guidelines for the appropriate timing and safe use of bright light therapy.

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.

Background To respond to the rapid surge in the incidence of suicide in Japan, which appears to be an ongoing trend, the Japanese Multimodal Intervention Trials for Suicide Prevention (J-MISP) have launched a multimodal community-based suicide prevention program, NOCOMIT-J. The primary aim of this study is to examine whether NOCOMIT-J is effective in reducing suicidal behavior in the community. Methods/DesignThis study is a community intervention trial involving seven intervention regions with accompanying control regions, all with populations of statistically sufficient size. The program focuses on building social support networks in the public health system for suicide prevention and mental health promotion, intending to reinforce human relationships in the community. The intervention program components includes a primary prevention measures of awareness campaign for the public and key personnel, secondary prevention measures for screening of, and assisting, high-risk individuals, after-care for individuals bereaved by suicide, and other measures. The intervention started in July 2006, and will continue for 3.5 years. Participants are Japanese and foreign residents living in the intervention and control regions (a total of population of 2,120,000 individuals). Discussion The present study is designed to evaluate the effectiveness of the community-based suicide prevention program in the seven participating areas. Trial registration UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000460.

Previous studies have reported that time perception in humans fluctuates over a 24-h period. Behavioral changes seem to affect human time perception, so that the fluctuation in human time perception may be the result of such changes due to self-determined activities. Recently, we carried out a study in which a healthy human cohort was asked to perform simultaneously loaded cognitive tasks under controlled conditions, and found that time perception decreased linearly from morning to evening. In addition, the variations in time perception were not a consequence of behavioral changes. It remains to be elucidated whether diurnal variations in time perception are a consequence of circadian rhythm or of some homeostatic changes that are attributable to accumulated wake time. The effects of circadian rhythm on time perception were investigated in eight healthy young male volunteers by conducting 10-s time production tasks under 30-h constant-routine conditions. Core body temperature and serum melatonin and cortisol levels were measured during the course of the study. Produced time exhibited a diurnal variation and was strongly correlated with circadian variations in core body temperature and serum melatonin levels. These results suggest that human short-term time perception is under the influence of the circadian pacemaker.

Study Objectives: There is a long-standing controversy surrounding the existence of dream experiences during non-rapid eye movement (NREM) sleep. Previous studies have not answered the question whether this “NREM dream” originates from the NREM sleep mechanism because the subject might simply be recalling experiences from the preceding rapid eye movement (REM) sleep. Methods: We scheduled 11 healthy men to repeat 20-minute nap trials separated by 40-minute periods of enforced wakefulness across a period of 3 days. At the end of the nap trial, each participant answered questions regarding the formal aspects of his dream experiences during the nap trial, using the structured interviews. Results: We obtained a total of 172 dream reports after naps containing REM sleep (REM naps) and 563 after naps consisting of only NREM sleep (NREM naps). Dream reports from NREM naps were less remarkable in quantity, vividness, and emotion than those from REM naps and were obtained more frequently during the morning hours when the occurrences of REM sleep were highest. Conclusions: These results suggest that the polysomnographic manifestations of REM sleep are not required for dream experiences but that the mechanisms driving REM sleep alter experiences during NREM sleep in the morning. A subcortical activation similar to REM sleep may occur in human NREM sleep during the morning when REM sleep is most likely to occur, resulting in dream experiences during NREM sleep.

Study objectives: This study was aimed to clarify phase angle between sleep propensity and the circadian pacemaker in patients with non-24hour sleep-wake syndrome (Non-24). Design and Setting: A case-control study was undertaken. 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 ultrashort 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

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.

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.

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.

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.