Sleep

The effects of non-pathogenic cytosine-adenine-guanine (CAG) repeat sizes on sleep remain unclear, although disrupted sleep has been observed in patients with pathogenic CAG expansions in polyglutamine disease-associated genes (PDAGs), particularly in HTT, ATXN3, and CACNA1A. Here, we assessed the associations between CAG repeat sizes of the three genes and self-reported sleep outcomes in the Netherlands Epidemiology of Obesity study (NEO) and the Netherlands Study of Depression and Anxiety (NESDA). Sleep outcomes included excessive daytime sleepiness (EDS) and Pittsburgh Sleep Quality Index (PSQI) in NEO, insomnia score in NESDA, and sleep duration and chronotype in both. We also stratified by sex, menopausal status in women, and questionnaire-based depression score. We observed 31 associations, of which 26 were specific to women. Larger HTT CAG repeat sizes were associated with lower EDS risk and lower PSQI score in premenopausal women, but higher PSQI score in women with depression. CAG repeats in all three PDAGs were associated with sleep duration, with ATXN3 showing U-shaped effects in all population groups except men. CAG repeat size in CACNA1A was primarily associated with chronotype in women. These findings suggest that non-pathogenic CAG repeats in PDAGs affect sleep differentially by sex and depression status.

IntroductionInvestigations of sleep homeostasis often involve tightly controlled experimental sleep deprivation in service of understanding mechanistic physiology. The extent to which the deep sleep response to recent sleep loss occurs in naturalistic settings remains under-studied. We tested the hypothesis that a homeostatic increase in deep sleep occurs on the night following occasional short duration nights that arise in naturalistic settings. MethodsWe analyzed sleep staging data in participants who provided informed consent to participate in the Apple Heart and Movement Study and elected to contribute sleep data. The analysis group included n=44,564 participants with at least 30 nights of sleep staging data from Apple Watch, from November 2022 to May 2023, totaling over 5.3 million nights. ResultsShort nights of sleep that were >=2 hours shorter than each participants median sleep duration occurred at least once in 92.9% of the cohort, most often in isolation (<7% of instances were consecutive short nights), and with a median duration of just over 4 hours. We observed that the amount of deep sleep increased on the subsequent night in proportion to the amount of sleep loss on the preceding short night, in a dose response manner for short night definitions ranging from 30 minutes to >=3 hours below the within-participant median sleep duration. Focusing on short nights that were at least 2 hours below the median duration, we found that 58.8% of participants showed any increase in subsequent deep sleep, with a median increase of 12% (absolute increase of 5 minutes). In addition, the variability in deep sleep after short nights markedly increased in a dose response manner. The deep sleep homeostatic response showed little correlation to sleep duration, timing, consistency, or sleep stages, but was inversely correlated with deep sleep latency (Spearman R = -0.28). ConclusionThe results provide evidence for homeostatic responses in a real-world setting. Although the deep sleep rebound amounts are modest, naturalistic short nights are a milder perturbation compared to experimental deprivation, and reactive behaviors potentially impacting sleep physiology are uncontrolled. The marked increase in variability of deep sleep amount after short nights may reflect unmeasured reactive behaviors such as caffeine or napping, which exert opposing pressures on deep sleep compared to the homeostat. The findings illustrate the utility of longitudinal sleep tracking to assess real-world correlates of sleep phenomenology established in controlled experimental settings.

BackgroundSleep apnea is a common sleep disorder affecting at least ten percent of the population. It is caused by lack of breathing during sleep, typically mediated by obstruction of airways or less frequently by misdirected central signals for breathing. The primary risk factor is a high body mass index (BMI), causing airway obstruction. However, understanding risk factors for sleep apnea in non-obese (BMI < 30) individuals requires further exploration. AimOur goal was to elucidate genetic risk factors for sleep apnea in non-obese individuals. MethodsWe performed genome-wide association testing in individuals with BMI < 30 in FinnGen including 20,413 cases with sleep apnea diagnosis (ICD-10 G47.3 or ICD-9 3472) and 443,463 disease free controls. We replicated our analysis in Estonian Biobank. ResultsWe identified a significant association within the Serotonin receptor 1F (HTR1F) locus (rs1818163, beta = 0.059, se = 0.010, P < 1.58e-8), and replicated the association in Estonian Biobank (beta =0.042, se = 0.021, P = 0.046). The association signal co-localized with HTR1F expression across multiple tissues (posterior probability > 0.8), and single cell sequencing implicated HTR1F expression particularly in neurons. Analysis of eQTL data further supported a possible regulatory role in neurons (beta = -0.03, P = 1.2e-4). Finally, objectively measured sleep-activity data showed association with number awakenings during night (P = 5.6e-8). ConclusionsThe findings indicate association of HTR1F in sleep apnea particularly in the patient population within the non-obese BMI range and provide insight into the growing evidence of serotonin signaling as a factor modulating liability to sleep apnea.

ObjectiveInvestigate whether auditory closed-loop stimulation (CLAS) applied during sleep could be beneficial for sleep and declarative memory in individuals with chronic insomnia. MethodsWe performed a randomized crossover sham-controlled study on 27 individuals with chronic insomnia to assess changes in sleep and declarative memory between a night with CLAS (i.e., 2-ON-OFF blocks auditory tones locked to slow wave up-states during NREM) and a SHAM night. We conducted assessments of memory (word paired-associate learning task) and sleep (morning questionnaire, polysomnographic recordings) during both nights. ResultsWe found that applying CLAS in a population of individuals with chronic insomnia led to an acute increase in SO amplitude after auditory stimulation. However, we found no beneficial effect of a single night of CLAS on subjective and objective sleep or declarative overnight memory performance. There was an association between the increase in SO density during CLAS with fewer markers of sleep fragmentation (i.e., sleep fragmentation index, arousals), suggesting interindividual differences in response to CLAS in chronic insomnia. ConclusionsCLAS stimulation applied during NREM sleep in individuals with chronic insomnia is feasible but did not show consistent effects on EEG markers of sleep regulation. A subgroup of individuals with insomnia may be more responsive to the impact of CLAS on sleep maintenance.

RationaleHigh rates of insomnia in older adults lead to widespread benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA) use, even though chronic use has been shown to disrupt sleep regulation and impact cognition. Little is known about sedative-hypnotic effects on NREM slow oscillations (SO) and spindles, including their coupling, which is crucial for memory, especially in the elderly. ObjectivesOur objective was to investigate the effect of chronic sedative-hypnotic use on sleep macro-architecture, EEG relative power, as well as SO and spindle characteristics and coupling. MethodsOne hundred and one individuals (66.05 {+/-} 5.84 years, 73% female) completed a one-night study and were categorized into three groups: good sleepers (GS, n=28), individuals with insomnia (INS, n=26) or individuals with insomnia who chronically use either BZD or BZRA to manage their insomnia difficulties (MED, n=47; dose equivalent in Diazepam: 6.1 {+/-} 3.8 mg/week). We performed a comprehensive comparison of sleep architecture, EEG relative spectrum, and associated brain oscillatory activities, focusing on NREM brain oscillations crucial for sleep-dependent memory consolidation (i.e., SO and spindles) and their temporal coupling. ResultsChronic use of BZD/BZRA worsened sleep architecture and spectral activity compared to older adults with and without insomnia disorder. The use of BZD/BZRAs also altered the characteristics of sleep-related brain oscillations and their synchrony. An exploratory interaction model suggested that BZD use exacerbated sleep alterations compared to BZRA, and higher BZD/BZRA dosage worsened alteration in sleep micro-architecture and EEG spectrum. ConclusionsOur results suggest that chronic use of sedative-hypnotics is detrimental to sleep when compared to drug-free GS and INS. Such alteration of sleep regulation - at the macro and micro-architectural levels - may contribute to the reported association between sedative-hypnotic use and cognitive impairment in older adults. STATEMENT OF SIGNIFICANCEWidespread use of sedative-hypnotics is driven by high insomnia rates among older adults. Chronic use can disrupt sleep and cognitive function, however, its impact on sleep regulation - at the macro and micro-architecture levels - is not well understood. We assessed the effect of chronic sedative-hypnotic use in older adults using a between-group design involving good sleepers, individuals with insomnia disorder who do not take any pharmacological treatment to manage their symptoms and individuals with insomnia disorder who chronically use sedative-hypnotics as a sleep aid. We performed a comprehensive comparison of sleep architecture, EEG relative spectrum, and associated NREM brain oscillations crucial for sleep-dependent memory consolidation (i.e., SO and spindles) and their temporal coupling. We showed that chronic use of sedative-hypnotics is detrimental to sleep regulation - at the macro and micro level - compared to drug-free GS and INS, and this may contribute to the reported link between sedative-hypnotic use and cognitive impairment in older adults.

Sleepwalking (SW) is a sleep disorder that belongs to the non-rapid eye movement (NREM) sleep family of parasomnias. Although linkage analyses in large families suggest that some forms of SW may follow a monogenic inheritance pattern, the genetic basis of SW has not been thoroughly investigated. The objective of this study was to investigate the role of rare genetic variants in sleepwalking by performing whole-exome sequencing (WES) in two independent cohorts. WES was performed on a cohort of 254 individuals diagnosed with SW (54.7% female, mean age: 39.1 {+/-} 10.7 years) and 124 control individuals were selected based on age and sex (52.4% female, all aged 18 years or older), from Montreal, Canada and Montpellier, France. To be included in the SW group, probands were required to have a primary complaint of SW, undergone at least one night of video-polysomnography, and to experience at least one parasomnia episode per month. By focusing on rare, potentially deleterious genetic variants, defined as having a minor allele frequency (MAF) [&le;] 5% and a Combined Annotation Dependent Depletion (CADD) pathogenicity score [&ge;] 15, WES allowed us to detect novel contributors to the disorder that might be missed in studies focused on common variants. We first identified 99 genes significantly enriched in patients with SW compared to the control group, with 92 genes overlapping between the two clinical cohorts. By prioritizing genes expressed in the brain, we found a strong genetic overlap between the two populations, with 31 genes carrying rare variants in common, including the top 10 genes with the highest contribution to SW compared to controls: NPIPB13, SRRM2, SIRT1, CANT1, DPYSL5, ABCC10, ELF2, DPP9, RBM28 and MCF2L2. Results were validated using an independent control cohort from the CARTaGENE database, except for MCF2L2. The genes NPIPB13, SRRM2, and SIRT1 displayed the highest contributions in the population, with values of 13.1%, 7.5%, and 5.5%, respectively. This study represents an important step toward understanding the genetic architecture of sleepwalking, particularly the role of rare coding variants, in sleepwalking and opens new avenues for future research into the disorders underlying biological mechanisms.

Sleep benefits episodic memory, which is critical for everyday cognition, future planning and decision-making. Sleep loss, a widespread issue across all ages and a major public health concern, impairs the brains capacity to encode episodic memories. This, in turn, disrupts cognitive functions that rely on episodic memory, such as decision-making based on past experiences, encoding new events, or recalling critical safety protocols posing risks, particularly in safety-sensitive occupations. Cognitive impairment due to sleep loss at such workplaces raises safety concerns and causes accidents. Merely implementing sleep hygiene techniques may not be effective or practical in such settings. Finding cost-effective strategies to preserve episodic memory after sleep loss is critical. We compared the effect of exercise and naps to reduce the impact of sleep loss and investigated mechanisms underlying their potential benefits. Fifty-four healthy young (18-35 years) individuals were subjected to 30 hours of continuously monitored wakefulness after which they were randomized into a 90-minute nap (NAP) (n= 18), 20-minute exercise (EXE) (n= 18) or do nothing (Control: CON) (n= 17, 1 excluded) groups. Following this, all participants were shown images (encoding), and three days later their memory was tested in a Yes-No recognition paradigm by presenting a mix of previously shown images and new ones. Electroencephalography (n= 43) from the encoding session was analyzed for pre-stimulus sleep pressure and fatigue markers: delta/theta spectral power; and episodic memory encoding markers: event-related beta desynchronization (beta-ERD), event-related delta/theta synchronization (SW ERS) and P300 component of event-related potential. Both EXE and NAP groups had higher memory for the encoded images than the CON group (Cohens d 1 and 0.91, respectively; with average improvements of 22% over the CON group), and both intervention groups had similar memory scores. Contrary to the literature in normal wakefulness, beta-ERD and P300 amplitude did not differ significantly between EXE and CON groups, and only in the EXE group these two markers were associated with memory. In the CON group, in contrast, P300 was associated with fatigue. While all the groups showed delta and SW ERS, only in the NAP group were these markers associated with memory. Regression analyses revealed that the best neural predictors of memory performance in the EXE group were P300 and beta-ERD on remembered trials (Rsq. adj. 0.64). In contrast, in the NAP group, memory performance was best predicted by sleep pressure markers and SW ERS on remembered trials (Rsq. adj. 0.77). None of these predictors explained memory performance in the CON group. In summary, we demonstrate that exercise and napping benefit episodic memory performance after sleep loss with equal magnitude, but through different neural contributions within each group. Under a sleep-deprived state, exercise facilitates efficient neural processing while napping makes the brain state conducive to new learning, which contributes to memory encoding. Our mechanistic findings strengthen the principle of neural degeneracy. These results have important societal and policy implications for preserving performance under sleep-deprived conditions.

Background and ObjectivesSleep has been associated with cognition and risk of dementia. However, sleep is a highly complex and multi-dimensional state, and there is uncertainty about which aspects of sleep are most relevant to cognitive performance and dementia risk. We applied a data-driven approach to identify clusters of sleep variables that reflect meaningful sleep composites and examined their association with cognitive performance and dementia risk. MethodsData from the Sleep and Dementia Consortium, consisting of 5 US population-based cohorts were utilized. Participants had methodologically consistent, home-based polysomnography, self-report habitual sleep, neuropsychological assessments, and dementia risk surveillance. The pooled cognitive analysis included 5,958 participants aged [&ge;]45 years, and the incident dementia analysis included 5,471 participants aged [&ge;]60 years. A cluster around latent variables analysis was used to derive 9 latent sleep composites from 44 sleep metrics. Global cognitive composite z-scores were derived from principal component analysis. Linear regression models were used to assess associations between sleep composites and cognitive performance. Cox proportional hazard models assessed associations between sleep composites and incident dementia. ResultsMean (SD) age was 70 {+/-} 11 and 74 {+/-} 12 years for the cognitive and dementia analysis, respectively. There were 1,134 incident dementia cases (median follow-up time of 5-19 years). 9 sleep composites were identified, together explaining 49% of the total variance in the original 44 sleep metrics: Sleep quantity and efficiency, sleep fragmentation, light NREM predominance, N3 predominance, spindle number and duration, REM sleep bouts, respiratory disturbances, slow oscillation-spindle coupling and spindle amplitude. Of these, composites reflecting greater sleep quantity and efficiency (i.e., longer and more consolidated sleep; pooled {beta} per one-unit change in composite, 0.03; 95% CI: 0.004 - 0.06; p=0.033) and stronger slow oscillation-spindle coupling (pooled {beta}, 0.04; 95% CI: 0.003 - 0.07; p=0.039) were associated with better global cognition. However, no significant associations were identified between the 9 sleep composites and dementia risk. DiscussionOur data-driven approach identified longer, more consolidated sleep and stronger slow oscillation-spindle coupling as the composites of sleep most strongly related to cognitive performance. These composites may be useful in guiding further investigations of sleep-brain health relationships.

BackgroundWe aimed to identify metabolites and create risk scores for insomnia symptoms in U.S. Hispanic/Latino adults. MethodsWe analyzed data from 6,107 participants in the Hispanic Community Health Study/Study of Latinos, split into discovery (n=3,932) and replication datasets (n=2,175). Serum metabolites and the Womens Health Initiative Insomnia Rating Scale (WHIIRS) were collected at baseline. We examined the relationships between 768 metabolites and insomnia symptoms and suspected insomnia (WHIIRS[&ge;]9) using the discovery dataset, followed by replication. Metabolite risk scores (MRSs) were generated with LASSO regression and evaluated for replication. We assessed the relationships of replicated metabolite measures and MRS with sleep, cognitive, and psychological traits (cross-phenotypes). FindingsNine metabolites were associated with insomnia symptoms in the discovery study, with two of these being replicated. Lower levels of hydrocinnamate and indolepropionate correlated with increased insomnia symptoms. We developed MRS for insomnia symptoms with replication. Various associations were observed between the two metabolites, 2 MRS, and cross-phenotypes. For instance, the WHIIRS MRS was associated with a higher risk of mild cognitive impairment (MCI) seven years later (OR:1.58, 95%CI:1.43-1.74 per 1 SD increase in MRS). InterpretationThe metabolomic profile associated with insomnia symptoms encompasses diet and gut microbiome metabolites. This study identified specific metabolites linked to insomnia that are also related to comorbidities, such as a higher risk of developing MCI during follow-up, suggesting a shared mechanism. FundingGrants from various National Institutes of Health and the JLH Foundation supported the work. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSInsomnia affects 30-36% of individuals, with clinical insomnia estimated at 6-10%, and it is more severe among Hispanics, who also face higher risks for cognitive decline and cardiovascular disease. While previous metabolomics studies have investigated sleep disorders, most have focused on sleep apnea or sleep duration, not insomnia. The few studies that focus on insomnia were limited by small sample sizes or co-occurring psychiatric conditions. Only two large-scale studies linked insomnia symptoms to specific metabolites, but neither examined these associations in Hispanics or their connection to cognitive decline--gaps this study aims to address using data from the HCHS/SOL cohort. Added value of this studyWe identified nine metabolites related to insomnia symptoms, with two--hydrocinnamate and indolepropionate--being replicated. We also created and validated metabolite risk scores (MRS), which predicted a higher likelihood of developing mild cognitive impairment (MCI) seven years later. These results provide new insights into the metabolic pathways connecting insomnia and cognitive decline in a high-risk Hispanic population. Implications of all the available evidenceOur findings indicate that insomnia symptoms are linked to specific metabolic changes, some of which may also play a role in cognitive decline. Identifying metabolites related to diet and the gut microbiome points to biological pathways that could be modified through lifestyle or therapeutic interventions. The metabolite risk scores (MRS) developed in this study showed links with mild cognitive impairment (MCI) over time, suggesting their potential usefulness in understanding long-term health risks associated with sleep disturbances. These results encourage further research into the role of metabolomics in sleep and cognitive health, especially in high-risk populations like Hispanics.

Study ObjectivesIdiopathic hypersomnia (IH) is a central nervous system hypersomnia frequently accompanied by autonomic symptoms, yet objective physiological data are limited. We sought to characterize autonomic nervous system (ANS) dysfunction in IH using nocturnal heart rate variability (HRV) and diurnal autonomic reflex testing (ART), compared to individuals with type 1 narcolepsy (NT1) and healthy controls (HCs). MethodsTwenty-four adults with IH, 10 with NT1, and 14 HCs underwent overnight video polysomnography with HRV analyses in time and frequency domains during stable slow-wave sleep and REM sleep. Comprehensive ART included sympathetic adrenergic (head-up tilt (HUT), Valsalva BP responses), parasympathetic cardiovagal (HRV to deep breathing, Valsalva ratio), and sudomotor (Q-Sweat) measures. ResultsIH participants were predominantly female, with over half reporting long sleep duration. Compared to NT1 and HC, participants with IH demonstrated a greater magnitude of orthostatic tachycardia on tilt ({Delta}HR 41.0 {+/-} 16.3 vs. 26.3 {+/-} 9.3 vs. 30.8 {+/-} 9.3 bpm, p = 0.0086), as well as frequent sudomotor dysfunction (64.3%). IH participants demonstrated greater nocturnal and REM HR with reduced parasympathetic indices during REM, indicating diminished vagal modulation compared with HCs ConclusionsIH is characterized by a distinct pattern of autonomic dysfunction, including pronounced orthostatic tachycardia, frequent sudomotor abnormalities, and reduced parasympathetic activity during sleep. These findings provide objective physiological evidence of ANS involvement in IH and delineate features that distinguish IH from NT1 and HCs.

Study objectivesPoor sleep may play a role in the risk of dementia. However, few studies have investigated the association between polysomnography (PSG)-derived sleep architecture and dementia incidence. We examined the relationship between sleep macro-architecture and dementia incidence across five US-based cohort studies from the Sleep and Dementia Consortium (SDC). MethodsPercent of time spent in stages of sleep (N1, N2, N3, REM sleep), wake after sleep onset and sleep maintenance efficiency were derived from a single night home-based PSG. Dementia was ascertained in each cohort using its cohort-specific criteria. Each cohort performed Cox proportional hazard regressions for each sleep exposure and incident dementia, adjusting for age, sex, body mass index, anti-depressant use, sedative use, and APOE e4 status. Results were then pooled in random effects meta-analyses. ResultsThe pooled sample comprised 4,657 participants (30% women) aged [&ge;]60 years (mean age was 74 years at sleep assessment). There were 998 (21.4%) dementia cases (median follow-up time of 5 to 19 years). Pooled effects of the five cohorts showed no association between sleep architecture and incident dementia. When meta-analyses were restricted to the three cohorts which had dementia case ascertainment based on DSM-IV/V criteria (n=2,374), higher N3% was marginally associated with an increased risk of dementia (HR: 1.06; 95%CI: 1.00-1.12, per percent increase N3, p=0.050). ConclusionsThere were no consistent associations between sleep macro-architecture measured and the risk of incident dementia. Implementing more nuanced sleep metrics remains an important next step for uncovering more about sleep-dementia associations. STATEMENT OF SIGNIFICANCEPoor sleep may represent a potential lifestyle risk factor for dementia. Sleep is thought to be important for the clearance of toxic Alzheimers disease proteins, but whether sleep is associated with dementia risk remains unclear. In the largest study of its kind, utilizing overnight polysomnographic assessment of sleep and data from 5 large U.S cohort studies, we examined the association between sleep macro-architecture and dementia risk. Meta-analysis revealed no clear associations between sleep measures and dementia risk, though there was a suggestion that a higher proportion of N3 sleep may be associated with greater dementia risk. Further exploration of sleep patterns across time, latent sleep traits across metrics, and sleep micro-architecture remain as important next steps for understanding sleep-dementia associations.

Type 1 narcolepsy (NT1), a disorder caused by the loss of hypocretin/orexin transmission, is characterized by daytime sleepiness and symptoms where Rapid Eye Movement (REM) sleep, a state normally occurring from middle to late in the night, can intermingle with wakefulness. This results in cataplexy and sleep paralysis, episodes of muscle paralysis when awake, or in the generation of dream-like hallucinations and vivid dreaming, periods of visual imagery or sensory experiences that occur while awake, notably when falling asleep (hypnagogic hallucinations) or lingering dreams with over-realistic recall. Using deep learning of nocturnal sleep polysomnography (PSG) signals (EEG, EMG and EOG) applied to sleep stage scoring, we found that NT1 shows abnormally short wake to REM sleep transitions and occurrences of abnormal sleep stages probabilities of wake, REM sleep and N1 (very light NREM) sleep abnormally co-occurs (sleep stage mixing). Interestingly, although presence of these during sleep enables NT1 diagnosis with performances similar to gold standard diagnostic procedure, the multiple sleep latency test (MSLT), the cortical localization of these dissociations remains unclear. In this work, we used electrode specific predictions of sleep stages to explore if these are global or observed at the local cortical level. Surprisingly, although sleep stage mixing was preeminent between REM sleep, N1 and wake across all electrodes, it was found to fluctuate across locations, with stronger fluctuations found in frontal and central locations, notably in the dominant (left) hemisphere. The strongest single discriminator for NT1 was N1-REM stage mixing across central electrodes (C3-C4), showing 4.3-fold higher dissociation in NT1 patients (Cohens d = 0.61). Analysis of sleep stage dissociations across varying time scales revealed that windows lasting several minutes were most predictive of NT1 status, aligning with the duration of clinically reported symptoms of dissociated REM sleep in narcolepsy. Local N1-W-REM sleep dissociations correlated with CSF orexin/hypocretin levels and severity as measured using MSLT. The predominance of stage mixing in frontal and central regions, areas typically associated with executive and motor control, may contribute to the partial preservation of awareness during dissociated REM phenomena. Further, self-reports of hypnagogic hallucinations correlated best with dissociations involving occipital locations, in agreement with its usual visual content. Coherence analysis was also conducted but did not reveal additional insight. These results suggest that orexin deficiency destabilizes REM sleep organization across cortical projection area contributing both to REM sleep dissociation and to abnormal state transitions observed in NT1.

Study ObjectivesTo test the feasibility of a novel at-home salivary Dim Light Melatonin Onset (DLMO) assessment protocol to measure the endogenous circadian phase of 10 individuals (1 Advanced Sleep-Wake Phase Disorder patient (ASWPD), 4 Delayed Sleep-Wake Phase Disorder patients (DSWPD), and 5 controls). MethodsThe study involved 10 participants (sex at birth: females = 9; male= 1), who ranged between 27 to 63 years old, with an average age of 38 years old. Our study population consisted of 7 individuals who identified as white and 3 who identified as Asian. Our participants were diverse in gender identity (woman = 7, male = 1, transgender = 1, nonbinary = 1, none = 1).The study tracked the sleep and activity patterns of 10 individuals over a 5-6 week period using self-reported online sleep diaries and objective actigraphy data. Participants completed two self-directed DLMO assessments, approximately one week apart, adhering to objective compliance measures. Participants completed the study entirely remotely: they completed all sleep diaries and other evaluations online and were mailed a kit with all materials needed to perform the actigraphy and at-home sample collections. ResultsSalivary DLMO times were calculated for 8/10 participants using the Hockeystick method. DLMO times were on average 3 hours and 18 minutes earlier than self-reported sleep onset times (DSPD: 12:04 AM, controls: 9:55 PM.) Among the 6 participants for whom we calculated two separate DLMO times, DLMOs 1 and 2 were 96% correlated (p<0.0005.) ConclusionsOur results indicate that self-directed, at-home DLMO assessments are feasible and accurate. The current protocol may serve as a framework to reliably assess circadian phase in both clinical and general populations.

Behavioural responses to COVID-19 lockdown will define the long-term impact of psychological stressors on sleep and brain health. Here we tease apart factors that help protect against sleep disturbance. We capitalise on the unique restrictions during COVID-19 to understand how time of day of daylight exposure and outside exercise interact with chronotype and sleep quality. 3474 people from the UK (median age 62, range 18-91) completed our online SleepQuest Study between 29th April and 13th May 2020 - a set of validated questionnaires probing sleep quality, depression, anxiety and attitudes to sleep alongside bespoke questions on the effect of COVID-19 lockdown on sleep, time spent outside and exercising and self-help sleep measures. Significantly more people (n=1252) reported worsened than improved sleep (n=562) during lockdown (p<0.0001). Factors significantly associated with worsened sleep included low mood (p<0.001), anxiety (p<0.001) and suspected, proven or at risk of COVID-19 symptoms (all p<0.03). Sleep improvement was related to the increased length of time spent outside (P<0.01). Older peoples sleep quality was less affected than younger people by COVID lockdown (p<0.001). Better sleep quality was associated with going outside and exercising earlier, rather than later, in the day. However, the benefit of being outside early is driven by improved sleep in owl (p=0.0002) and not lark (p=0.27) chronotype, whereas, the benefit of early exercise (inside or outside) did not depend on chronotype. Defining the interaction between chronotype, mental health and behaviour will be critical for targeted lifestyle adaptations to protect brain health through current and future crises.

ObjectivesOur objective was to assess the effect of cognitive-behavioral therapy for insomnia (CBTi) on subjective and objective sleep quality (including sleep spindles) and cognition during a sedative-hypnotics withdrawal program in older adults with insomnia disorder. MethodsWe performed a two-arm randomised controlled trial (RCT) of a sedative-hypnotic withdrawal plan alone (WPo group) or combined with CBTi (WP+CBTi group) in 47 older adults with insomnia disorder over a sixteen-week period. Our primary outcomes were change in self-reported insomnia severity (Insomnia Severity Index (ISI)), sleep efficiency (SE) from sleep diaries, and change in SE and spindle density from polysomnographic (PSG) recordings collected at baseline and at post-intervention (16 weeks). Secondary outcomes included other sleep changes from PSG, actigraphy and sleep diaries, sleep and mood questionnaires and neuropsychological assessments (manual dexterity, attention/concentration, verbal inhibition, visuo-spatial abilities). ResultsThe withdrawal program was effective in achieving discontinuation and reducing insomnia severity, with similar success with and without CBTi. The combined intervention additionally improved subjective sleep quality and prevented the decrease in subjective sleep duration induced by sedative-hypnotic discontinuation. Neither intervention significantly impacted objective sleep architecture or cognitive performance. Furthermore, reduction in sleep spindle density was observed with combined CBTi and withdrawal, but not with withdrawal alone. ConclusionsBoth withdrawal alone and sedative-hypnotic withdrawal combined with CBTi effectively facilitated discontinuation and reduced insomnia severity, with the combined intervention further enhancing subjective sleep quality and preserving sleep duration. Although neither approach significantly impacted objective sleep architecture or cognitive performance, the potential reduction in sleep spindle density linked to the combined intervention warrants further investigation. STATEMENT OF SIGNIFICANCEThis study evaluated the combined effects of CBTi and sedative-hypnotic withdrawal on both subjective and objective sleep outcomes, such as sleep spindle density, as well as cognitive performance, in older adults with insomnia disorder. Findings reveal that CBTi, when combined to sedative-hypnotic withdrawal program, not only supports withdrawal success and reduces insomnia severity but also enhances subjective sleep quality and maintains sleep duration, which may be compromised by withdrawal alone. The observed reduction in sleep spindle density, linked to the combined intervention, needs further investigation. These results provide valuable insights into optimizing sedative-hypnotic discontinuation strategies for older adults experiencing chronic insomnia.

Idiopathic hypersomnia (IH) is a rare and heterogeneous sleep disorder characterized by excessive daytime sleepiness. We aimed to stratify IH patients based on polygenic risk scores (PRSs) for sleep-related traits and explored the underlying genetic predispositions. Genome-wide single-nucleotide polymorphism data from 303 Japanese IH patients and 2,918 controls were analyzed. PRSs were calculated for chronotype (morningness/eveningness), daytime napping, sleep duration, and insomnia using publicly available base data. Patients in the extreme PRS tails were examined for clinical phenotypes. Causal inference was evaluated via Mendelian randomization (MR). IH patients were significantly enriched in the top PRS percentiles for eveningness (top 0.5%: odds ratio [OR] = 3.40, P = 3.9x10-5; top 1%: OR = 2.48, P = 1.9x10-4) and daytime napping (top 0.5%: OR = 3.80; P = 1.6x10-5), with substantially elevated ORs. Patients with high morningness PRS exhibited increased slow-wave sleep near wake time, frequently observed in patients with IH. MR analysis supported a causal relationship between eveningness and IH (inverse-variance weighted, UK Biobank: P = 1.3x10-3; replicated in 23andMe P = 0.037). This causal association was consistently observed even among a subgroup of IH patients who showed [&ge;]660 minutes of total sleep time in 24-hour polysomnography. PRS analysis identified significant associations between IH and sleep traits such as eveningness and daytime napping, with notably large effect sizes. Importantly, MR analysis further suggested a causal role for eveningness in IH pathogenesis. These findings highlight distinct genetic subtypes within IH and reinforce the relevance of circadian misalignment in its pathophysiology.

Obstructive sleep apnea (OSA) is a multifactorial sleep disorder characterized by a strong genetic basis. Excessive daytime sleepiness (EDS) is a symptom that is reported by a subset of OSA patients, persisting even after treatment with continuous positive airway pressure (CPAP). It is recognized as a clinical subtype underlying OSA carrying alarming heightened cardiovascular risk. Thus, conceptualizing EDS as an exposure variable, we sought to investigate EDSs influence on genetic variation linked to apnea-hypopnea index (AHI), a diagnostic measure of OSA severity. This study serves as the first large-scale genome-wide gene x environment interaction analysis for AHI, investigating the interplay between its genetic markers and EDS across and within specific sex. Our work pools together whole genome sequencing data from seven cohorts, enabling a diverse dataset (four population backgrounds) of over 11,500 samples. Among the total 16 discovered genetic targets with interaction evidence with EDS, eight are previously unreported for OSA, including CCDC3, MARCHF1, and MED31 identified in all sexes; TMEM26, CPSF4L, and PI4K2B identified in males; and RAP1GAP and YY1 identified in females. We discuss connections to insulin resistance, thiamine deficiency, and resveratrol use that may be worthy of therapeutic consideration for excessively sleepy OSA patients.

ObjectiveSleep and cancer are intricately interconnected. We used a nationally representative sample to study the effect of sleep duration on cancer incidence and prognosis, aiming to propose an optimal sleep duration and generalize it to community populations. MethodsData from participants aged [&ge;]18 years in the National Health and Nutrition Examination Survey (NHANES, 2005-2018) were analyzed (n=37,338). Self-reported sleep duration was analyzed alongside mortality data from the National Death Index as of 12/31/2019. Primary outcomes included all-cause mortality, cancer-specific mortality, and non-cancer mortality. Odds ratios (OR), hazard ratios (HR), and corresponding 95% confidence intervals (CI) were calculated using logistic regression and Cox proportional hazards regression, respectively. Restricted cubic spline (RCS) analysis was used to explore potential non-linear associations. ResultsThe prevalence of cancer was 10.12%. After adjusting for confounders, >7 hours of sleep was strongly associated with an increased OR for cancer incidence (1.18 (1.04,1.33) for (7-8] and 1.54 (1.28,1.86) for (8-14.5]). During a median follow-up of 6.1 years, 341 cancer-related deaths and 661 non-cancer-related deaths occurred. fully adjusted models, compared with 7 hours of sleep, >7 hours of sleep significantly increased the HR of all-cause mortality (1.40 (1.06,1.84) for (7-8] and 1.90 (1.42,2.54) for (8-14.5]); cancer mortality (1.20 (0.77,1.87) for (7-8] and 1.70 (1.05,2.73) for (8- 14.5], 1.70 (1.05,2.73)) and non-cancer mortality (1.50 (1.07,2.12) for (7-8], 2.03 (1.42,2.90) for (8-14.5]). Stratified analysis, RCS analysis and sensitivity analysis yielded consistent results. ConclusionsThis study suggests that the optimal sleep duration should be 7 hours, as excessive sleep may increase cancer risk and mortality risk in cancer survivors. Our findings should be useful for health education and promotion in primary care and clinical practice.

Individuals with comorbid REM sleep behavior disorder (RBD) and neurotrauma (defined by traumatic brain injury and post-traumatic stress disorder) have an earlier age of RBD symptom onset, increased RBD-related symptom severity and more neurological features indicative of prodromal synucleinopathy compared to RBD only. An early sign of neurodegenerative condition is autonomic dysfunction, which we sought to evaluate by examining heart rate variability during sleep. Participants with overnight polysomnography were recruited from the VA Portland Health Care System. Veterans without neurotrauma or RBD (controls; n=19), with RBD only (RBD, n=14), and with RBD and neurotrauma (RBD+NT, n=19) were evaluated. Eligible 5-minute NREM and REM epochs without apneas/hypopneas, microarousals, and ectopic beats were analyzed for frequency and time domain (e.g. low frequency power, LF; high frequency power, HF; root mean square of successive RR intervals, RMSSD; % of RR intervals that vary [&ge;]50 ms, pNN50) heart rate variability outcomes. Heart rate did not significantly differ between groups in any sleep stage. Time domain and frequency domain variables (e.g., LF power, HF power, RMSSD, and pNN50) were significantly reduced in the RBD and RBD+NT groups compared to controls and RBD only during NREM sleep. There were no group differences detected during REM sleep. These data suggest significant reductions in heart rate variability during NREM sleep in RBD+NT participants, suggesting greater autonomic dysfunction compared to controls or RBD alone. Heart rate variability during sleep may be an early, promising biomarker, yielding mechanistic insight for diagnosis and prognosis of early neurodegeneration in this vulnerable population. STATEMENT OF SIGNIFICANCEComorbid REM sleep behavior disorder (RBD) and neurotrauma (NT, traumatic brain injury + post-traumatic stress disorder; RBD+NT) is associated with increased neurodegenerative symptom burden and worsened health. Sleep and autonomic function are integrally and bidirectionally related to neurodegenerative processes. In the current study, we sought to determine if early signs of autonomic dysfunction, measured via heart rate variability (HRV), were present during sleep in comorbid RBD+NT compared to RBD only and controls. Our data show reduced time and frequency domain HRV during NREM sleep in RBD+NT Veterans compared to RBD only and controls. These data contribute evidence that participants with RBD and comorbid NT demonstrate significantly worse autonomic dysfunction compared to age/sex matched participants with RBD alone.

ObjectiveTo explore potential genetic and/or causal associations between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder. MethodsWe conducted polygenic risk score, genetic correlation, and Mendelian randomization analyses using the latest genome-wide association studies summary statistics and individual genotyping data. Next, a blinded observer examined dopamine transporter imaging binding status--a marker of neurodegeneration--in patients with isolated/idiopathic rapid-eye movement sleep behavior disorder, with (N = 6) and without Post-Traumatic Stress Disorder (N = 32). ResultsPolygenic risk scores for Post-Traumatic Stress Disorder were associated with isolated/idiopathic rapid-eye-movement sleep behavior disorder, with each standard deviation increase linked to 14.7% higher odds (odds ratio = 1.15, 95% confidence interval: 1.04 to 1.26, p = 0.005). However, genetic correlation was weak, and Mendelian randomization did not support a potential causal relationship. The proportion of individuals with abnormal dopamine transporter imaging binding status was significantly higher in the Post-Traumatic Stress Disorder group compared to those without the disorder (p=0.01, X2 = 6.62). InterpretationPolygenic risk scores analysis identified an association between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder, consistent with the result from the small exploratory substudy. The lack of strong genetic correlation or causation may reflect limited sample size. Further research with larger and more diverse cohorts is crucial to clarify the genetic, biological and physiological mechanisms underlying this association.