Sleep

INTRODUCTIONAgitation is a common and burdensome neuropsychiatric symptom in dementia that fluctuates from day to day, but objective tools for short-term risk stratification are limited. We examined whether nocturnal physiological signals from unobtrusive under-mattress sensors predict next-day daytime agitation and whether associations differ for agitation occurrence versus severity. METHODSWe extracted cardiorespiratory, movement, and sleep-proxy features from two long-term care cohorts (N=55; 333 nights) and one external home-monitoring cohort (N=18; 803 nights). A two-part mixed-effects framework was used to model next-day agitation episodes. RESULTSLower nocturnal respiratory rate and greater activity instability independently predicted higher odds of next-day agitation occurrence. Associations were stronger for motor than verbal agitation. Respiration-related predictors were validated externally. Conversely, no nocturnal features significantly predicted agitation severity. DISCUSSIONPassive sleep monitoring identified reproducible, physiologically interpretable markers of next-day agitation occurrence, supporting the potential of under-mattress sensing for short-term risk stratification and more proactive dementia care.

Background: Sleep architecture fragmentation is common in Long COVID and dysautonomia, yet the relationship between block-level deep sleep consolidation and next-day functional wellbeing has not been characterized longitudinally in this population. We tested the hypothesis that block-level deep sleep architecture predicts next-day wellness better than aggregate stage duration. Methods: A prospective N-of-1 longitudinal study was conducted across 78 nights between January 1 and March 25, 2026 using a consumer wearable (Garmin Index Sleep Monitor). Next-day wellbeing was assessed using the Overall Feeling Score (OFS; 0-10 scale). A five-tier Architecture Group (AG) classification operationalized consolidation quality. A custom predictive model (Pendulum v5.2) quantified consolidation through block-level weighting and contextual penalties. Space weather metrics (Kp index, daily electron fluence, Load Score) were correlated with sleep architecture and OFS across same-day and lagged alignments. A secondary hierarchical regression examined illness as an independent covariate across the full dataset. Results: Architecture Group explained 56.7% of next-day OFS variance (r = 0.753, p < 0.001), compared with 17.0% for total deep sleep duration (r = 0.412) and 4.8% for the Garmin Sleep Score (r = 0.220). Pendulum v5.2 explained 43.0% of variance (r = 0.656). The deep sleep fragmentation phenotype occurred on 25.6% of nights despite adequate total deep sleep. Space weather explained 14.2% of OFS variance through architecture degradation; Load Score at 1-day lag was the strongest space weather predictor (r = -0.328, p = 0.004). A binary illness indicator explained an additional 5.7% of OFS variance beyond architecture and space weather (full-model R{superscript 2} = 55.2%), with a mean illness-night residual of -0.56 (SD = 0.36; 95% CI [-0.72, -0.40]), consistent with immune/viral flares reducing OFS through pathways independent of sleep architecture. Conclusions: Block-level deep sleep consolidation quality is a substantially stronger predictor of next-day wellbeing than total stage duration in Long COVID with dysautonomia. Space weather constitutes a measurable environmental modifier operating through architecture degradation. Immune and viral flares constitute a significant architecture-independent confound consistent with direct neuroinflammatory effects on functional capacity. This framework may be applicable across conditions where sleep architecture fragmentation plays a pathophysiological role.

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.

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 [&ge;]60 years who reported symptoms of insomnia and/or daytime sleepiness [&ge;]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.

Study ObjectivesSleep interventions targeting slow-wave activity (SWA) show heterogeneous effects across individuals. We investigated whether pre-sleep brain states predict responsiveness to auditory stimulation and associated cognitive benefits. MethodsTwenty-eight healthy adults (19-40 years) completed three overnight laboratory visits under mild sleep restriction. Pre-sleep EEG recordings captured spectral band power before each night. Participants received auditory stimulation or sham on two randomized nights with polysomnography monitoring. Memory recall and sustained attention were assessed at multiple timepoints the following day. Machine learning models using normalized EEG features and transfer learning with pre-trained sleep architectures (SleepNet, DeepSleepNet, TinySleepNet) predicted responsiveness. ResultsAuditory stimulation significantly enhanced SWA (p < 0.01) in over 90% of participants. Pre-sleep alpha and theta power correlated with SWA enhancement (alpha: r = 0.436; theta: r = 0.329; both p < 0.01), as did sleep onset latency (r = 0.429, p < 0.01). Temporal embeddings derived from 8 minutes of pre-sleep EEG before lights off predicted individual responsiveness to auditory stimulation with 80% accuracy (AUC = 0.93). ConclusionsPre-sleep brain state determines responsiveness to auditory stimulation, with individuals exhibiting longer sleep onset latency showing greater SWA enhancement. Tailoring pre-sleep interventions based on these predictive features may optimize brain receptivity to auditory stimulation during sleep.

Sleep disruption is common in Alzheimers disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type mice. Female 5XFAD (n=16) and wild-type (WT) littermates (n=14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG), electromyography (EMG), temperature, and activity continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD mice had more time in NREM1 than WT controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, which is analogous to daytime drowsiness in humans. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment exacerbated NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.

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.

The effects of diet quality and timing on sleep quality remain poorly understood, particularly at the level of sleep microarchitecture. Traditional visual scoring captures only coarse sleep stages, overlooking the marked heterogeneity of electroencephalographic (EEG) patterns in non-rapid eye movement (NREM) sleep of mice. Here, we apply a pipeline that combines EEG feature extraction with unsupervised machine-learning-based clustering to resolve discrete NREM substates and ask how a high-fat diet (HFD) and time- restricted feeding (TRF) affect sleep microarchitectures. HFD increases sleep latency and sleep fragmentation; both abnormalities were ameliorated by active phase TRF. Clustering of 10s epochs identified two high-amplitude NREM substates sensitive to TRF: Cluster 1, enriched in low-delta power and peaking early in the light phase (ZT 0-6), consistent with canonical slow-wave sleep, and Cluster 6, characterized by elevated alpha, sigma, and beta power and peaking in the latter half of the light phase (ZT6-12). TRF increases the frequency of both NREM substates, particularly within longer uninterrupted sleep episodes during the light phases. These findings introduce an objective framework for quantifying murine sleep microarchitecture and show that aligning caloric intake with the circadian active window mitigates HFD-induced macro-level sleep disruption while selectively enhancing two physiologically distinct NREM substates. Significance StatementTime-restricted eating - targeting food intake to a defined window during the circadian active phase - confers well-established metabolic benefits, but its impact on sleep is largely underexplored. Using continuous EEG/EMG recordings, we show that an active- phase eating window mitigates high-fat-diet-induced sleep disruption in mice. We employed a novel machine-learning pipeline, further revealing that timed eating selectively increases distinct NREM substates, demonstrating that "when we eat" fine-tunes the macro- and microarchitecture of sleep. These insights lay the foundation for future translational studies and clinical trials aimed at harnessing timed eating to enhance both metabolic and sleep health.

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.

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.

ObjectivesChronic insomnia (INS) is particularly prevalent in older adults and females. Sex-and age-related differences in neurophysiological markers of sleep quality (sleep spindles and slow-wave activity [SWA]) may underlie differential vulnerability to INS. This study investigated the effects of sex and insomnia on spindle and SWA beyond aging, to better understand the mechanistic differences contributing to the higher prevalence of INS in females. MethodsAfter a habituation night, one night of sleep assessed with polysomnography was analyzed in 222 adults (aged 18-82) including 119 INS (71% female) and 103 healthy sleepers (HS; 61% female). Spindle density, slow oscillation (SO) density, relative sigma power and SWA were derived during NREM sleep. Age, group, sex, and group-by-sex interactions were examined, with age as a covariate. ResultsAge, insomnia, and sex each contributed uniquely to NREM oscillatory activity. INS primarily reduced spindle and SO density, while sex accounted for differences in SWA. While SWA was higher in females overall, sex differences were not significant within the INS or HS groups. Female INS reported highest rates of insomnia severity as well as lower sigma power than males in the INS group. Spindle and SO density deficits were also present in female INS relative to female HS, as well as male INS relative to male HS. ConclusionsThe combination of reduced sigma power in females with insomnia relative to their male counterparts, as well as less spindle and SO density compared to female healthy sleepers may contribute to greater insomnia severity in females. Statement of SignificanceInsomnia is a growing public health concern that is more commonly reported in females, yet the neural mechanisms underlying this sex difference remain poorly understood. Our findings suggest that specific markers of sleep quality are disproportionately disrupted in females with insomnia, potentially contributing to greater vulnerability and symptom severity. These results provide new insight into how sex influences the neurophysiology of insomnia disorder and identify oscillatory markers that could serve as targets for personalized interventions. Future research should investigate whether these alterations represent persistent dysfunction or reversible changes, which could advance understanding of the biological basis of insomnia and inform strategies to improve sleep health in at-risk populations.

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.

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.