Sleep

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.

Trace amine-associated receptor 1 (TAAR1) has gained attention for its roles in modulating neural systems, sleep/wake control, and as a therapeutic target for neuropsychiatric disorders. Although TAARs 2-9 were initially identified as non-canonical olfactory receptors, recent studies have identified extra-nasal receptor distribution of multiple TAARs. To evaluate whether TAARs 2-9 have a role in arousal state regulation, we investigated sleep/wake control in male TAAR2-9 knockout (KO) mice. After determination of baseline sleep/wake patterns, the homeostatic response to sleep deprivation and response to TAAR1 agonists were compared between KO and C57BL/6J mice. Although the EEG of TAAR2-9 KO mice had lower power in the delta and theta bands and higher power in the gamma range, sleep/wake states were readily identified. KO mice had more NREM sleep during the dark phase and more REM sleep during the light phase. Sleep/wake was fragmented in KO mice with shorter Wake and REM bouts during the dark phase and more REM bouts during the light phase. KO mice exhibited more REM sleep during a sleep latency test but the homeostatic response to sleep loss did not differ between the strains. A high dose of the TAAR1 agonist RO5256390 increased Wake and reduced NREM sleep in KO mice whereas RO5256390 and the partial TAAR1 agonist RO5263397 suppressed REM sleep. The number of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was significantly elevated in KO mice. These dopaminergic and sleep/wake alterations in TAAR2-9 KO mice highlight the need for further elucidation of the functions of TAAR2-9.

One in three Americans suffer from chronic sleep disorders, and women are 40% more likely than men to experience sleep disorders. This disparity emerges at puberty and is strongly associated with fluctuations in the ovarian hormone, estrogen (E2), suggesting that E2 and biological sex are a risk factor for sleep disorders. Previous work in the lab has demonstrated that E2 suppresses sleep in female rats, including in sleep deprived rats whose homeostatic need for sleep is increased. However, the specific mechanism for E2 induced decrease in sleep remains unknown. Work in the lab suggests a role for adenosine in mediating E2s sleep suppressive effects; E2 significantly increases Median Preoptic Nucleus (MnPO) extracellular adenosine and attenuates the action of specific agonists on the sleep promoting A2A-Receptor. Astrocytes represent a major source of adenosine in the CNS and have been shown to influence neuronal activity and downstream behaviors. In this project, we tested the hypothesis that astrocytes mediate E2s sleep suppressive effects. We used Gq-linked designer receptors exclusively activated by designer drugs (DREADDs) to evaluate the Gq pathway, which represents a core signaling mechanism in astrocyte activity. We found that, in female rats, activation of Gq signaling in astrocytes decreased sleep and inhibited homeostatic need for sleep. We further expressed the Pleckstrin Homology domain of PLC-like protein (p130PH), which has been shown to attenuate astrocyte activity and functions, in median preoptic nucleus (MnPO) astrocytes. We found that p130PH expression in MnPO astrocytes raised homeostatic sleep pressure to the same extent as 6 hours of sleep deprivation. We further report that inhibiting astrocytic function did not prevent E2s sleep suppressing effects suggesting that astrocytes may not play a role in estrogenic modulation of sleep. However, we did discover that MnPO astrocyte effects on sleep are sex-dependent. p130PH expression in MnPO astrocytes increased sleep and homeostatic sleep drive in female rats but showed a trend towards decreasing sleep and homeostatic sleep need in males. Further, while astrocyte effects on homeostatic sleep need are relegated to the dark phase in female rats, astrocytes appear to influence homeostatic sleep need in both the dark and light phase. To our knowledge, this is the first demonstration of a sex-based difference in astrocyte effects on sleep and homeostatic sleep pressure.

The neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterized by lysosomal storage of fluorescent materials. CLN3 disease, or juvenile Batten disease, is the most common NCL that is caused by mutations in the Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene. Sleep disturbances are among the most common symptoms associated with CLN3 disease, yet this is understudied and has not been delineated in an animal model of the disease. The current study utilized a non-invasive, automated piezoelectric motion sensing system (PiezoSleep) to classify sleep and wakefulness in a Cln3{phi}..ex1-6/{phi}..ex1-6 (Cln3KO) mouse model and age- and sex-matched wild-type (WT) controls. The sleep-wake classification by PiezoSleep was found to be about 90% accurate when validated against simultaneous gold standard polysomnographic recordings including electroencephalography (EEG) and electromyography (EMG) in a small cohort of WT and Cln3KO mice. Our large cohort PiezoSleep study reveals sleep abnormalities during the light period (LP) in male Cln3KO mice compared to WT male, and more subtle differences in Cln3KO female mice throughout the dark period (DP) compared to WT female, recapitulating sleep abnormalities seen in CLN3 disease patients. Our characterization of sleep in a mouse model of CLN3 disease contributes to a better understanding of the sleep disturbances commonly reported for CLN3 disease and other NCLs, which will facilitate the development of new disease treatment and management strategies.

Background and ObjectivesNarcolepsy Type 1 (NT1) is a neurological disorder caused by hypocretin deficiency, leading to excessive daytime sleepiness and cataplexy. This study characterized dynamic functional connectivity (dFC) states in NT1 patients, acute sleep-deprived (SD) individuals, and healthy controls, and explored how these states relate to clinical measures of sleepiness and arousal. MethodsIn this study, resting-state co-fluctuation analysis was employed to identify recurring brain states and compare group differences in state dwell time, transition probabilities, and interaction strength. Associations between dFC properties and clinical metrics (Epworth Sleepiness Scale [ESS] scores, mean sleep latency from MSLT) were also investigated. ResultsFive distinct resting-state co-fluctuation states were identified. NT1 patients showed significantly longer mean dwell time and higher fraction rate in State 3, characterized by synchronized activity between the salience/ventral attention network (SN/VAN) and sensorimotor network (SMN) with antagonistic co-fluctuations to the visual network (VIS), compared to both SD and control groups. They also exhibited increased reciprocal transition probabilities between State 3 and State 5. Group-specific differences in co-fluctuation strength were observed across multiple states, with NT1 showing distinct alterations in interactions involving the striatum, limbic system, and attentional networks. Moreover, the fraction rate of State 5 negatively correlated with ESS scores, while the fraction rate of State 3 negatively correlated with mean sleep latency from MSLT in NT1 patients, indicating that increased occupancy of certain states was associated with less subjective sleepiness and greater arousal instability. ConclusionThese findings highlight the role of chronic hypocretin-mediated arousal failure versus acute homeostatic sleep pressure in shaping network co-fluctuation patterns, characterized by thalamocortical disconnection, cortical dysregulation, and enhanced striatal-limbic connectivity. This state might be specific to hypocretin deficiency and suggests that dFC states may serve as potential biomarkers for sleep-wake disorders.

Study ObjectivesIn older adults, self-reported sleep measures may be inaccurate, but polysomnography (PSG) is burdensome. We assessed the performance of an electroencephalography-measuring headband (HB) or actigraphy (ACT) compared with PSG in older adults with sleep disturbances. MethodsSixty-three adults aged [≥]60 years who reported symptoms of insomnia and/or daytime sleepiness [≥]once/week completed a week-long, home-based protocol during which they wore the HB for seven nights, an actigraph for seven days and nights, and completed a one-night level II unattended PSG. For the current analysis, we compared total sleep time (TST) and wake after sleep onset (WASO) from all three devices on the PSG night. We calculated absolute differences and intraclass correlation coefficients (ICCs) for TST and WASO between HB and ACT, respectively, vs. PSG. We also evaluated the performance of the HB among subgroups of the poorest sleepers according to the presence of sleep apnea, insomnia, poor sleep quality, and periodic limb movements of sleep. Feasibility of the HB was assessed by measures of adherence (i.e., ability to use the HB over seven nights) and usability (i.e., ratings of items from the WEarable Acceptability Range [WEAR] scale). ResultsThe average age was 72.8 [standard deviation 6.6] years, 63.5% were female, and 63.5% identified as non-Hispanic White. On PSG, averages for TST and WASO were 370.1 [93] and 88.9 [63] minutes, respectively. For the HB vs. PSG, mean differences and ICCs were -11.9 minutes and 0.83 [0.74, 0.89] for TST; and -15.5 minutes and 0.65 [0.48, 0.77] for WASO. For ACT vs. PSG, mean differences for TST and WASO were larger, and ICCs showed lower levels of agreement. The HB performed well among the poorest sleepers, with ICCs >0.65 for TST and WASO. On average, participants wore the HB for 6.5 [0.8] nights, and usability was rated highly. ConclusionsThe HB demonstrated good agreement with PSG, outperforming ACT, including among the poorest sleepers. Devices like the HB might provide feasible measures of sleep that are more accurate than ACT and enhance the management of sleep health in older adults with sleep disturbances. Future research should focus on further validation of these devices in habitual sleep environments.

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.

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.

Study objectivesAdolescence is a period of distinct maturational changes in sleep characteristics. Historically, age trends in sleep physiology have been captured using laboratory-based polysomnography (PSG). However, multiple challenges associated with PSG, including logistical issues, budgetary constraints and ecological validity questions, limit large-scale use. The current study aims to address these challenges by using the Dreem3 headband to measure sleep at home and replicate well-established age-related trends in sleep physiology from late childhood through early adulthood. Methods100 typically developing youth (9-26 years) wore a sleep electroencephalography (EEG) device (Dreem3) for 3-4 consecutive nights at home. Sleep EEG data were processed using the Luna pipeline. We used linear mixed models to estimate age-related trends across 8 macro-architecture and 15 micro-architecture variables previously found to be associated with age, and explored age relationships in 24 additional macro- and micro-architecture variables. ResultsAt-home sleep studies using Dreem3 replicated established age trends in sleep macro- and micro-architecture, including decreases in percent time spent in non-rapid eye movement (NREM) stage 3 (N3%) sleep and decreases in NREM delta power with increasing age. Exploratory analysis revealed age effects in seven other variables, including decreases in integrated slow spindle activity and NREM cycle duration with increasing age. ConclusionSleep EEG wearables may offer an accessible way to characterize sleep physiology development in large cohorts, setting the stage for understanding how deviations from normative age patterns may put young people at risk for adverse outcomes. Statement of SignificanceAdolescence is a dynamic period characterized by changes in sleep physiology and behavior. While polysomnography has long been widely used for capturing age-related trends, it is resource-intensive and laboratory-bound, which limits the ability to track sleep in an accessible, scalable, and ecologically valid manner. Here, we used a sleep EEG headband, the Dreem3, to examine age-related trends in sleep macro- and micro-architecture across late childhood, adolescence, and early adulthood. We assessed sleep features with previously replicated age effects and explored age associations in other macro- and micro-architecture measures. The at-home wearable sleep EEG device replicated many of the age trends seen in traditional polysomnography. Leveraging accessible sleep EEG devices may provide a more scalable and comprehensive understanding of how sleep changes over adolescence.

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.

Sleep disorders affect over 30% of the U.S population and are linked to increased disease risk and mortality. However, the genetic architecture of sleep disorders and the overlap of sleep disorders with habitual sleep quality, quantity, and timing have been poorly characterized. In addition, it is unknown if clinical sleep disorders are extremes of habitual sleep traits. Here, we systematically investigated the genetic basis of seven clinical sleep disorder traits, and sixteen medications used for sleep problems in 1,600,000 individuals. We identified 590 genetic associations for sleep apnea, insomnia, restless legs syndrome, narcolepsy and a combined sleep disorder phenotype, of which 367 were previously unreported. Additionally, we discovered 142 genetic associations with sleep medication use. While overall genetic architecture was shared across sleep traits, we found unique genetic factors for the different sleep disorders that reflect fundamentally different biological mechanisms including for example autoimmune processes with narcolepsy and skeletal morphology in sleep apnea. Furthermore, sleep genetic factors showed a broad multi-omic impact on gene and protein expression levels. These findings suggest that while clinical sleep disorders share genetic architecture with each other and with variation in sleep patterns within the general population, they are not simply extremes of normal sleep variation but involve unique biological mechanisms. These results advance our understanding of sleep disorders and suggest potential novel therapeutic targets.

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.

IntroductionDisrupted sleep is common in individuals with Alzheimers disease (AD) and may be a marker for AD risk. The timing of sleep or chronotype affects sleep-wake activity and is also associated with AD, but little is known about links between sleep and chronotype in older adults. In this study, we tested if different measures of sleep and chronotype are associated among older adults even after adjusting for multiple potentially confounding variables. MethodsParticipants (N=243) with a mean age of 74 underwent standardized cognitive assessments, measurement of CSF AD biomarkers, and sleep monitoring via single-channel EEG, actigraphy, and self-reported sleep logs. Chronotype was defined as the midpoint of sleep measured by actigraphy. ResultsLater mid-point of sleep (i.e., late chronotype) was associated with African American race and greater night-to-night variability in the sleep mid-point. After controlling for age, race, sex, cognitive status, AD biomarkers, and sleep disorders, a later mid-point of sleep was associated with longer rapid eye movement (REM) onset latency, decreased REM sleep time, lower sleep efficiency, increased sleep onset latency, and more awakenings at night. Late chronotype was also associated with increased <2 Hz non-REM slow-wave activity. ConclusionsTo identify individuals at risk for cognitive impairment before symptoms onset, non-invasive in vivo markers of brain function, such as sleep, are needed to track both future risk of cognitive impairment and response to interventions. Chronotype is a potential modifiable AD risk factor and should also be taken into account when using sleep as a marker for AD risk.

The Circadia Study (Circadia) is a novel "direct to participant" research study investigating the genetics of circadian rhythm disorders. The long-term goals of this study are to better understand the genetics of circadian rhythm disorders, investigate the efficacy and accessibility of an at-home, self-directed DLMO collection, to improve health outcomes in the future for patients with circadian rhythm disorders, and to address the specific needs of the circadian rhythm disorder patient population. In this manuscript, we briefly outline the standard methods of both circadian biology research protocols and circadian rhythm disorder diagnostic procedures. We describe some of the inherent limitations of current circadian research and diagnostic methods, which motivated our development of and informed the design of the Circadia Study. We discuss the main goals of the Circadia Study, and we outline key features of our study design that build upon current study methods and address limitations. Finally, we describe specific aspects of the Circadia Study, including our study population, data collection methods, and standard operating procedures so that others may replicate aspects of the study design. The Circadia Study is approved for human subject research by the Mass General Brigham Institutional Review Board, Protocol # 2020P002779.

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.

Sleep disturbances are common features of neurodegenerative disorders including Huntingtons disease (HD). The sleep and circadian disruptions are recapitulated in animal models, and these models provide the opportunity to evaluate whether circadian interventions can be effective countermeasures for neurodegenerative disease. Time restricted feeding (TRF) interventions successfully improve activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits of scheduled feeding extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in adult mice (six mo-old) under TRF and ad lib feeding (ALF). With each diet, both male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) mice were evaluated. Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and non-rapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding. The treatment did impact the power spectral curves during the day in male but not female mice. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases.

Sex differences in sleep and wakefulness are well documented in humans but remain inconsistent in rodent studies, suggesting strong sensitivity to experimental context. In prior work, we observed no sex differences in sleep-wake architecture under relatively bright daytime light, raising the possibility that daytime illumination is a critical but underappreciated variable shaping sex-dependent sleep regulation. Here, we tested the hypothesis that daytime light intensity modulates sex differences in sleep-wake architecture and vulnerability to dim light at night (DLaN). Male and female C57BL/6J mice were exposed to acute (one night) or chronic (two weeks) DLaN (10 lux) under three daytime light intensities (50, 100, 300 lux). Sleep was assessed using electroencephalographic-based measures of vigilance states and slow wave activity (SWA). Dim daytime light (50 lux) unmasked robust sex differences in dark-phase sleep-wake architecture that were absent under brighter daytime light (300 lux). Acute DLaN reduced early-night wakefulness in both sexes under low daytime light but had minimal effect under bright daytime conditions. Following chronic DLaN, males exhibited reduced dim light-phase wakefulness and dampened rhythm amplitude, whereas females showed pronounced phase shifts, rhythm attenuation, and altered timing of SWA under 50 and 100 lux. These changes were largely prevented under bright daytime light. Together, these findings identify daytime light intensity as a critical contextual factor governing sex-specific regulation of sleep and vulnerability to nighttime light, providing a unifying framework to reconcile inconsistencies in the rodent sleep literature. HighlightsO_LIDaytime light intensity shapes sex differences in sleep-wake architecture C_LIO_LIAcute and chronic nighttime light elicit distinct sex-specific sleep responses C_LIO_LIFemales exhibit greater circadian and slow-wave vulnerability to nighttime light C_LIO_LIBrighter daytime light buffers sleep and circadian disruption C_LI

Sleep architecture and microstructures alter with aging and sleep disorder-led accelerated aging. We proposed a sleep electroencephalogram (EEG) based brain age prediction model using convolutional neural networks. We then associated the estimated brain age index (BAI) with brain structural aging features, sleep disorders and various sleep parameters. Our model also showed a higher BAI (predicted brain age minus chronological age) is associated with cortical thinning in various functional areas. We found a higher BAI for sleep disorder groups compared to healthy sleepers, as well as significant differences in the spectral pattern of EEG among different sleep disorders (lower power in slow and{vartheta} waves for sleep apnea vs. higher power in {beta} and{sigma} for insomnia), suggesting sleep disorder-dependent pathomechanisms of aging. Our results demonstrate that the new EEG-BAI can be a biomarker reflecting brain health in normal and various sleep disorder subjects, and may be used to assess treatment efficacy.

Study ObjectivesSleep is a complex phenomenon regulated by various factors, including sensory input. Anecdotal observations have suggested that gentle rocking helps babies fall asleep, and experimental studies have verified that rocking promotes sleep in both humans and mice. Recent studies have expanded this understanding, demonstrating that gentle vibration also induces sleep in Drosophila. Natural sleep serves multiple functions, including learning and memory, synaptic downscaling, and clearance of harmful substances associated with neurodegenerative diseases. Here, we investigated whether vibration-induced sleep provides similar cognitive and health benefits in Drosophila. MethodsWe administered gentle vibration to flies that slept very little due to a forced activation of wake-promoting neurons and investigated how the vibration influenced learning and memory in the courtship conditioning paradigm. Additionally, we examined the effects of VIS on synaptic downscaling by counting synapse numbers of select neurons. Finally, we determined whether vibration could induce sleep in Drosophila models of Alzheimers disease (AD) and promote the clearance of Amyloid {beta} (A{beta}) and Tubulin Associated Unit (TAU). ResultsVibration-induced sleep enhanced performance in a courtship conditioning paradigm and reduced the number of synapses in select neurons. Moreover, vibration improved sleep in Drosophila models of AD, promoting the clearance of A{beta} and TAU. ConclusionsMechanosensory stimulation offers a promising non-invasive avenue for enhancing sleep, potentially providing associated cognitive and health benefits. Significance StatementSleep is critical for a healthy mind and body, and sleep disturbances are commonly associated with neurodegenerative diseases such as Alzheimers disease. Sleep is influenced by sensory input, and mechanical stimulation, such as gentle rocking and vibration, has been shown to promote sleep in various species, including humans, mice, and fruit flies. This study demonstrates that gentle vibration not only helps flies sleep better but also improves their performance in a learning and memory task and makes their brains more efficient in clearing harmful substances. Notably, vibration can facilitate the clearance of Amyloid {beta} and the TAU proteins, which accumulate in Alzheimers disease. These results highlight the potential for gentle mechanosensory stimulation to promote sleep and cognitive health.

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.