A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

Genome-wide association study of idiopathic hypersomnia in a Japanese population.

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-021-00349-2.

Effects of Cognitive Behavioral Therapy for Insomnia on Subjective-Objective Sleep Discrepancy in Patients with Primary Insomnia: a Small-Scale Cohort Pilot Study.

BACKGROUND: Cognitive behavioral therapy for insomnia (CBT-I) is a first-line therapy for insomnia disorders. We assessed changes in discrepancies between subjective and objective sleep measures and correlations between discrepancy changes and clinical insomnia severity for CBT-I in patients with primary insomnia METHODS: Fifty-two outpatients (mean age, 60.3 years; 26 women) with primary insomnia were treated by individual CBT-I (50 min, maximum six sessions, once every 1-2 weeks). One week before and after CBT-I, patients recorded a sleep log and wore an actigraphy device. Subjective and objective time in bed (TIB), total sleep time (TST), sleep-onset latency (SOL), wake time after sleep onset (WASO), and sleep efficiency (SE) were evaluated by averaging 1-week records. Relative values of sleep discrepancy in TIB, TST, SOL, WASO, and SE were calculated for estimating effects of CBT-I. The therapeutic effects were also evaluated using psychological scales before and after CBT-I. RESULTS: Subjective and objective discrepancies in sleep measures decreased by 36, 25, and 37 min in TST, SOL, and WASO, respectively, and 7% in SE (all P < 0.001) after CBT-I. Seven patients transitioned from underestimating SE before CBT-I to overestimating SE after CBT-I. Although CBT-I improved relative values of discrepancy in WASO and SE, alongside ISI, the improvement in insomnia severity only correlated with SOL discrepancy. CONCLUSIONS: CBT-I may reduce the discrepancy between subjective and objective sleep measures in patients with primary insomnia. However, a greater therapeutic effect of CBT-I was observed in reducing the ISI, which was slightly influenced by improvements in sleep discrepancies.

Prevalence and associated factors of circadian rhythm sleep-wake disorders and insomnia among visually impaired Japanese individuals.

BACKGROUND: Although earlier studies have demonstrated that circadian rhythm sleep-wake disorders (CRSWD) are more prevalent in visually impaired individuals, the actual prevalence of CRSWD and insomnia among the visually impaired Japanese population remains unclear. The aim of this cross-sectional, telephone-based study was to estimate the prevalence of CRSWD and insomnia, and explore factors associated with CRSWD and insomnia among visually impaired Japanese individuals. METHODS: A nationwide telephone survey was conducted among visually-impaired individuals through local branches of the Japan Federation of the Blind. In total, 157 visually impaired individuals were eligible for this study. Demographic information and information about visual impairments, lifestyle, and sleep patterns were assessed using questionnaires and subsequent telephone interviews. CRSWD and insomnia were defined according to the International Classification of Sleep Disorders-Third Edition criteria. RESULTS: The prevalence of CRSWD in visually impaired individuals was 33.1%. Among those with CRSWD, a non-24-h/irregular sleep-wake rhythm type was the most frequently observed (26.8%), followed by an advanced sleep-wake phase type and a delayed sleep-wake phase type (3.8 and 2.5%, respectively). Furthermore, 28.7% of the visually impaired individuals were found to have insomnia. In the visually impaired individuals, the absence of light perception, unemployment, living alone, and use of hypnotics were significantly associated with CRSWD, whereas only the use of hypnotics was extracted as a marginally associated factor of insomnia. CONCLUSIONS: CRSWD and insomnia were highly prevalent in visually impaired Japanese individuals. The presence of CRSWD among the visually impaired individuals was associated with a lack of light perception and/or social zeitgebers.

A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia.

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.

A Nationwide Cross-Sectional Survey of Sleep-Related Problems in Japanese Visually Impaired Patients: Prevalence and Association with Health-Related Quality of Life.

STUDY OBJECTIVES: This questionnaire-based cross-sectional study was conducted (1) to estimate the prevalence of sleep-related problems, and (2) to explore factors associated with lower physical/mental quality of life (QOL), particularly addressing sleep-related problems among Japanese visually impaired people. METHODS: This nationwide questionnaire-based survey was administered to visually impaired individuals through the Japan Federation of the Blind. Visually impaired individuals without light perception (LP) (n = 311), those with LP (n = 287), and age-matched and gender-matched controls (n = 615) were eligible for this study. Study questionnaires elicited demographic information, and information about visual impairment status, sleep-related problems, and health-related quality of life. RESULTS: Visually impaired individuals with and without LP showed higher prevalence rates of irregular sleep-wake patterns and difficulty maintaining sleep than controls (34.7% and 29.4% vs. 15.8%, 60.1% and 46.7% vs. 26.8%, respectively; p < 0.001). These sleep-related problems were observed more frequently in visually impaired individuals without LP than in those with LP. Non-restorative sleep or excessive daytime sleepiness was associated with lower mental/physical QOL in visually impaired individuals with LP and in control subjects. However, visually impaired individuals without LP showed irregular sleep-wake pattern or difficulty waking up at the desired time, which was associated with lower mental/physical QOL. CONCLUSIONS: Sleep-related problems were observed more frequently in visually impaired individuals than in controls. Moreover, the rates of difficulties were higher among subjects without LP. Sleep-related problems, especially circadian rhythm-related ones, can be associated with lower mental/physical QOL in visually impaired individuals without LP.

Obstructive sleep apnea in preschool-aged Japanese children - efficiency of screening using lateral neck radiography.

Conclusions The prevalence of obstructive sleep apnea (OSA) in preschool-aged children diagnosed by the International Classification of Sleep Disorders (ICSD) version 3 criteria was relatively higher than that diagnosed by ICSD-2. Although the assessment of the upper airway by lateral neck radiography was effective for detecting OSA in this age group, this assessment is not recommended for all children as a screening method because of parental concern related to radiation exposure. Objective This study investigated the prevalence of OSA and the screening capacity of lateral neck radiography in community-based preschool-aged children. Methods Parents of 211 children aged 3-6 years were requested to complete the sleep-related questionnaire. Subjects who agreed to further investigations were invited to undergo home type 3 portable monitoring and clinical examination, including radiography. We estimated the prevalence of OSA and evaluated the detection power of radiography for predicting OSA. Results One hundred and eighty-eight (89.1%) subjects completed the questionnaire and 67 (31.8%) agreed to further examinations. The weighted prevalence was 7.3% and 12.8% by ICSD-2 and 3, respectively. Area under the receiver operator curve for the adenoidal/nasopharyngeal and tonsil/pharyngeal ratios measured using radiography was slightly larger than that for tonsil size graded by visual inspection.

[Bright light therapy for elderly].

Bright light therapy (BLT) holds considerable promise for sleep problems in the elderly. BLT for community-dwelling patients with Alzheimer's disease showed significant improvement in sleep parameters. In the institutional setting, BLT was effective in reducing daytime nap duration. Morning BLT was found to advance the peak circadian rhythm and increase activity level in daytime and melatonin level at night. Light therapy could be used in combination with other nonpharmacological methods such as social activities, outside walking, physical exercises, which showed greater effects than independent BLT on sleep and cognitive function. BLT treatment strategy was proposed in the present paper. We should pay more attentions to BLT in community setting for mental and physical well-being.

A polymorphism in CCR1/CCR3 is associated with narcolepsy.

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.

An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population.

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.

New susceptibility variants to narcolepsy identified in HLA class II region.

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.

The melatonin receptor agonist is effective for free-running type circadian rhythm sleep disorder: case report on two sighted patients.

Along with urbanization of the living environment, the number of patients with circadian rhythm sleep disorder (CRSD) has been increasing. There are several treatment candidates for CRSD, such as light therapy, drugs (melatonin and vitamin B12), and sleep hygiene education. However, successful treatment method has not been established. In free-running type (FRT) CRSD, the endogenous circadian rhythm cannot be entrained to the 24-h light-dark cycle, resulting in free running on a cycle 0.5-2.5 h longer than the 24-h period. This condition is relatively common in blind individuals and is unusual in sighted individuals. Here we report two sighted patients with FRT, successfully treated with a melatonin receptor agonist, ramelteon. Patient 1 (36-year-old female) had suffered from FRT for nearly 4 months after resigning her job. She was given sleep hygiene education together with ramelteon at first and the free-running cycle stopped after treatment day 15. Triazolam was added from the day 25 to promote earlier sleep onset. And the sleep-wake schedule was normalized by the day 34. Patient 2 (33-year-old male) had suffered from FRT for nearly 8 months after starting to take a leave of absence from his job. He was given sleep hygiene education and was treated with ramelteon and methylcobalamin. His sleep-wake schedule was normalized from the first treatment day. By the combined treatment with ramelteon, both patients have maintained favorable sleep-wake schedules. The agonist action of ramelteon at the melatonin 2 receptor may have primarily contributed to the cessation of the free-running cycle in these patients.

Screening of clock gene polymorphisms demonstrates association of a PER3 polymorphism with morningness-eveningness preference and circadian rhythm sleep disorder.

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.

Type I Chiari malformation presenting central sleep apnea.

Sleep apnea is a rare but a well-known clinical feature of type I Chiari malformation. It may be obstructive or central in nature. Sleep apnea in patients with type I Chiari malformation rarely presents without accompanying neurological signs or symptoms. We here report a case of a 10-year-old girl who presented with central sleep apnea without any other neurological signs but was ultimately diagnosed with type I Chiari malformation. The patient initially showed mild improvement in symptoms after administration of an acetazolamide. Finally, posterior fossa decompression dramatically improved her respiratory status during sleep, both clinically and on polysomnography. This case suggests that type I Chiari malformation should be considered in the differential diagnoses of central apneas in children, even if there are no other neurological signs and symptoms. Furthermore, sagittal craniocervical magnetic resonance imaging may be necessary for a definitive diagnosis.

Prevalence of obstructive sleep apnea syndrome in Japanese elementary school children aged 6-8 years.

PURPOSE: We aimed to determine the prevalence of and the risk factors for obstructive sleep apnea syndrome (OSAS) in Japanese children aged 6-8 years. METHODS: The parents of 202 children aged 6-8 years who attended a single elementary school in Shiga, Japan, were requested to complete the Child and Adolescent Sleep Checklist (CASC) and perform home Type 3 portable monitoring of their children. By using the CASC data and monitor recordings, we estimated the prevalence of pediatric OSAS with the help of different diagnostic criteria and identified the risk factors associated with OSAS. RESULTS: Complete data were obtained from 170 of the 194 children whose parents participated in the study. The mean total apnea-hypopnea index and obstructive apnea hypopnea index were 1.4 ± 1.3 and 0.4 ± 0.6 h(-1), respectively, and central apnea was the most prevalent type of respiratory event, accounting for 70.4% of all events. The overall prevalence of OSAS ranged from 0.6% to 43.5%, depending on the cutoff value used, and was 3.5% when using International Criteria of Sleep Disorders version II (ICSD II) diagnostic criteria. The presence of tonsillar hypertrophy was the only parameter whose prevalence was significantly elevated in children with OSAS across all diagnostic criteria. CONCLUSIONS: The prevalence of pediatric OSAS varies according to the diagnostic criteria used, indicating the need for further research focusing on outcomes to define a clinically significant diagnostic threshold. The presence of tonsillar hypertrophy is an important risk factor in the development of pediatric OSAS.

Pilot study on the effects of a 1-day sleep education program: influence on sleep of stopping alcohol intake at bedtime.

The aim of this pilot study was to evaluate whether sleep was improved by a 1-day sleep education program in an occupational setting and whether stopping alcohol intake at bedtime might influence sleep. Subjects were 40 high school employees. The sleep education program lasted 4.5 hours and consisted of sleep science information, and sleep hygiene education including the risk of sleep related breathing disorder resulting from alcohol intake. Sleep conditions were evaluated by self-administered questionnaires at baseline and approximately 1 month later. The mean the Epworth Sleepiness Scale (ESS) score was significantly decreased by 1.2 points (P = 0.04), while the mean sleep duration was significantly decreased by 10 minutes (P = 0.02). Shortened sleep duration coincided with a decrease in sleepiness. This may indicate an improvement in sleep quality. The percentage of habitual alcohol intake at bedtime was significantly decreased (from 38.5% (15/39) to 20.5% (8/39), P = 0.04). Subjects who stopped alcohol intake at bedtime (n = 8) received the most benefit, with decreased scores of ESS and Insomnia Severity Index (ISI), although the reductions were not significant. This education program offers the possibility of improving sleep conditions among the general population, especially in those who cease habitual alcohol intake at bedtime. Further larger, randomized, controlled studies are warranted.

A new modification of uvulopalatopharyngoplasty for the treatment of obstructive sleep apnea syndrome.

OBJECTIVE: To evaluate objective and subjective improvement after applying a new surgical technique, two-piece palatopharyngoplasty (Two-P4), to the treatment of obstructive sleep apnea syndrome (OSAS). METHODS: Twenty-four patients with mild to severe OSAS underwent Two-P4 between January 2002 and November 2007. Polysomnography and Epworth Sleepiness Scale (ESS) score were used to evaluate surgical results. RESULTS: Mean apnea-hypopnea index (AHI) improved from 50.9 to 10.7 after Two-P4. Mean ESS score decreased significantly from 13.0 to 7.7. Body mass index was unchanged after surgery. Objective success as evaluated by a 50% reduction in AHI and by AHI <20 was obtained in 22 of 24 patients (91.7%). Mean reduction in AHI was 76.9% for all 24 patients, 86.2% for patients with Friedman's anatomical stage I, 78.9% for stage II, and 54.5% for stage III. CONCLUSION: Two-P4 is a novel surgical treatment for OSAS patients with a high success rate (91.7%) as evaluated by reductions in AHI. Two-P4 keeps the middle soft palate intact to form independent scars on both sides, which constrict to stretch the soft palate and widen the pharyngeal space.

A before and after comparison of the effects of forest walking on the sleep of a community-based sample of people with sleep complaints.

BACKGROUND: Sleep disturbance is a major health issue in Japan. This before-after study aimed to evaluate the immediate effects of forest walking in a community-based population with sleep complaints. METHODS: Participants were 71 healthy volunteers (43 men and 28 women). Two-hour forest-walking sessions were conducted on 8 different weekend days from September through December 2005. Sleep conditions were compared between the nights before and after walking in a forest by self-administered questionnaire and actigraphy data. RESULTS: Two hours of forest walking improved sleep characteristics; impacting actual sleep time, immobile minutes, self-rated depth of sleep, and sleep quality. Mean actual sleep time estimated by actigraphy on the night after forest walking was 419.8 ± 128.7 (S.D.) minutes whereas that the night before was 365.9 ± 89.4 minutes (n = 42). Forest walking in the afternoon improved actual sleep time and immobile minutes compared with forest walking in the forenoon. Mean actual sleep times did not increase after forenoon walks (n = 26) (the night before and after forenoon walks, 380.0 ± 99.6 and 385.6 ± 101.7 minutes, respectively), whereas afternoon walks (n = 16) increased mean actual sleep times from 342.9 ± 66.2 to 475.4 ± 150.5 minutes. The trend of mean immobile minutes was similar to the abovementioned trend of mean actual sleep times. CONCLUSIONS: Forest walking improved nocturnal sleep conditions for individuals with sleep complaints, possibly as a result of exercise and emotional improvement. Furthermore, extension of sleep duration was greater after an afternoon walk compared to a forenoon walk. Further study of a forest-walking program in a randomized controlled trial is warranted to clarify its effect on people with insomnia.