Circadian rhythm sleep-wake disorders (CRSWDs) arise from alterations in the circadian timing system or from misalignments between endogenous circadian rhythms and environmental or behavioral demands, leading to sleep disturbances and impaired functioning. Diagnosis remains challenging and largely reliant on subjective assessments, highlighting the need for biologically informed markers. Although genetic and epigenetic factors have been implicated in circadian regulation, their contribution to clinically defined CRSWDs has not previously been systematically evaluated across disorders. This systematic review, registered in PROSPERO (ID: 1117673), examined genetic polymorphisms and epigenetic modifications associated with CRSWDs in studies published up to October 2024. Of 871 articles screened, 38 met the inclusion criteria. Delayed sleep-wake phase disorder was investigated in 18 studies (47 %), shift work disorder in 17 studies (45 %), and non-24-h sleep-wake rhythm disorder in eight studies (21 %). Of these, 27 examined genetic variants, predominantly using candidate-gene approaches targeting core clock genes and circadian-related pathways. Ten studies investigated epigenetic alterations, all limited to DNA methylation and conducted exclusively in the context of shift work disorder. Only one study assessed both genetic and epigenetic variations. The findings suggest that genetic variations, particularly in but not limited to core clock genes, are implicated in an increased susceptibility to CRSWDs. In addition, DNA methylation changes in clock genes and genes as MTNR1B, SIRT1, and SLC6A4 may play a role in modulating circadian adaptation, particularly in the context of shift work. However, substantial heterogeneity in phenotypic definitions, study design, and confounder control limits causal inference and cross-disorder comparison. Only five findings met the review-defined evidentiary standards: the functionally validated PER2 S662G and CSNK1D T44A mutations causing familial advanced sleep phase syndrome (FASPS), the independently replicated PER2 p.Val1205Met and RORC rs3828057 associations with delayed sleep-wake phase disorder (DSWPD), and the MTNR1B rs10830963 × night-shift-work interaction associated with prostate cancer risk. All other reported genetic and epigenetic associations remain exploratory. In conclusion, this review identifies a fragmented and uneven evidence base, with major gaps in epigenetic research and integrative genetic-epigenetic analyses across CRSWDs. Epigenetic studies have been conducted almost exclusively in shift work populations, leaving intrinsic CRSWDs largely unexplored. Future research should prioritize longitudinal, genome-wide, and systematically phenotyped studies involving diverse populations and genetic backgrounds. Expanding epigenetic investigation across CRSWD subtypes will be essential to improve the generalizability of findings and advance biomarker development and personalized approaches in circadian and sleep medicine.
Delirium is a common neuropsychiatric syndrome among hospitalized patients and has been linked to disturbances in sleep and circadian regulation. We conducted a network meta-analysis of randomized controlled trials evaluating sleep-modulating pharmacological interventions for delirium prevention. PubMed, Embase, and Web of Science were searched through August 2025. Thirty-three trials involving 5045 patients were included. In the random-effects model, melatonin and melatonin receptor agonists were associated with a lower risk of delirium compared with non-active control conditions (RR = 0.77, 95% CI: 0.64-0.92). Evidence from suvorexant trials was also associated with a lower delirium risk (RR = 0.51, 95% CI: 0.27-0.95), whereas midazolam-based benzodiazepine evidence did not demonstrate a statistically significant reduction in delirium risk (RR = 1.64, 95% CI: 0.81-3.31). Subgroup analyses suggested that the association for melatonin-based interventions was more evident in non-ICU and surgical populations. The certainty of evidence ranged from low to moderate. Melatonin-based interventions and suvorexant were associated with lower delirium incidence; however, evidence directly comparing different active interventions remains limited, and findings should be interpreted cautiously given the agent-specific evidence base. Further direct comparative trials are needed to clarify the effectiveness and safety of sleep-modulating pharmacological interventions for delirium prevention.
Sleep disorders are increasingly understood as systems-level conditions in which the brain and body reweight sensory evidence from the external world and internal milieu. We systematically reviewed human evidence for sensory and multisensory dysfunction across sleep disorders and experimental sleep loss. Searches identified 25,777 records; after removal of 7235 duplicates, 18,542 records were screened, 4452 full records were assessed for eligibility, and 377 studies met inclusion criteria. Evidence was organised across 31 sensory modalities in seven domains: olfaction, gustation, vision, audition, somatosensation/nociception, vestibular-proprioceptive function, and interoception/autonomic function, with higher-order perceptual outcomes analysed separately. Using a prespecified conservative criterion requiring a non-null direction of effect with at least moderate certainty, 23 of 31 modalities were altered in at least one sleep disorder or experimental sleep-loss category (74.2%). The evidence clustered in specific disorder-domain pairs. Moderate-certainty signals identified clinically meaningful hyposmia in isolated rapid eye movement sleep behaviour disorder and obstructive sleep apnoea, heightened pain sensitivity in chronic insomnia, altered chronoception after experimental sleep loss, and obstructive sleep apnoea-associated hearing-threshold impairment. Central auditory-processing, visual, gustatory, and vestibular-proprioceptive findings were more heterogeneous or lower certainty. Across disorders, the emerging map is consistent with state-dependent disturbances in sensory gain, gating, salience, and interoceptive control. These findings position sensory profiling as a clinically tractable strategy for phenotyping and for prospective evaluation of risk and treatment response in selected sleep disorders. Longitudinal and interventional studies should now test whether sensory measures predict disease course, sleep stability, and clinical outcomes, and whether targeted sensory or interoceptive modulation can improve sleep-related symptoms.
Numerous brief events, known as phasic activities, have been observed in terms of rapid eye movements (REMs), muscle activity, and autonomic nervous system activity during REM sleep. This occurs against the backdrop of sustained muscle atonia and vagal tone. The first part of this review was dedicated to REMs and skeletal muscle phasic activities. The second part, here, provides a list of phasic autonomic changes in the human body. Considerably stronger evidence exists for pupillary, respiratory, cardiovascular, and reproductive phasic activity than for gastrointestinal and urinary phasic activity. In addition to tonic miosis of the pupil, brief mydriasis occurs during REM sleep. The cardiovascular system exhibits phasic events such as spikes in blood pressure, tachycardia, and vasoconstriction alongside REMs. Phasic bradycardia episodes also occur during REM sleep without REMs. The respiratory system exhibits rapid and shallow breathing, as well as transient phasic hypoventilation, alongside REMs. The rate of spontaneous contractions in the esophagus and stomach increased during REM sleep compared to NREM sleep. In the reproductive system, phasic activity has been observed in the penis (although tonic activity is predominant), vagina and uterus during REM sleep. The review also examines how REMs, muscle twitches and autonomic phasic activities cluster together.
Obstructive sleep apnoea (OSA) diagnosis and severity classification is typically determined from a single-night sleep study. However, high night-to-night variability (N2NV) in OSA severity is associated with adverse health outcomes and complicates diagnosis and treatment. While the contributions of the four main OSA endotypes (i.e., anatomical compromise, unstable ventilatory control, low arousal threshold, and poor upper-airway muscle function) on OSA severity are relatively well established, the extent to which specific mechanistic contributors to N2NV in OSA severity is poorly understood. This narrative review collates evidence-based and theoretically plausible contributors to high N2NV. We consider a plethora of physiological, behavioural, and environmental factors which are known to, or hypothetically contribute to variable OSA severity. How a single-night evaluation may fail to capture key mechanistic contributors to OSA and its variability is also highlighted. Understanding the complexity and interactive nature of these mechanisms may help inform diagnosis, risk stratification, and treatment selection for OSA via a more holistic, precision-medicine approach. Studies that include multi-night in-laboratory and at-home assessments combined with wearable/nearable sleep sensors are required to better understand the underlying mechanisms that contribute to high N2NV in OSA severity and its associated adverse consequences.
Obstructive sleep apnea (OSA) is a prevalent sleep-related breathing disorder that increases the risk of chronic diseases and negatively affects quality of life. Although polysomnography (PSG) remains the gold standard for diagnosis, its high cost, labor-intensive and time-consuming procedures highlight the need for alternative diagnostic tools. Advances in machine learning and consumer sleep technologies have accelerated the possibilities of early screening and risk assessments for various medical conditions, including OSA. The aim of this systematic review was to review the evidence for the detection of OSA via audio signals (smartphone, microphone) in adults. Of 122 papers identified, 15 were included. Whilst some studies demonstrated the trade-off between high sensitivity vs low specificity (or vice versa), six studies showed both high-to-very high sensitivity and specificity (≥80%). These results suggest detecting the risk of moderate-to-severe OSA from audio signals is plausible and sufficiently accurate. We review factors that may guide future research to increase the odds of training and testing algorithms to screen for OSA.
Background This review investigated the impact of Obstructive Sleep Apnea (OSA) on sleep architecture and cognition. Methods Fifty-six entries identified from more than 11,000 records were synthesized into five sections: sleep macroarchitecture, sleep microstructure, comorbid insomnia and sleep apnea (COMISA), REM-related OSA (REM-OSA), and Continuous Positive Airway Pressure (CPAP) treatment. Results A shift toward lighter sleep and reduced Slow-Wave and REM sleep were associated with deficits in attention, memory, and executive functions. Severe OSA patients reported subjective cognitive complaints despite normal objective screening scores, highlighting a critical window for early assessment. Specific high-risk phenotypes emerged: COMISA, characterized by hyperarousal and reduced total sleep time; and REM-OSA, associated with poorer verbal memory and cognitive vulnerability in APOE ε4 carriers. Neuroimaging studies showed hippocampal disconnection and Default Mode Network dysregulation linked to REM deprivation and hypoxia-related white matter abnormalities. CPAP treatment was associated with improvements in sleep architecture and cognitive performance, although recovery appears incomplete and variable across individuals. Conclusion Polysomnography-based assessment provides clinically relevant information beyond the apnea-hypopnea index, helping identify OSA patients at greatest risk of cognitive impairment. CPAP is associated with partial restoration of sleep architecture and improvement in selected cognitive domains, reinforcing the importance of sustained treatment adherence.
Continuous positive airway pressure (CPAP) remains the cornerstone of obstructive sleep apnoea (OSA) treatment and can provide rapid symptomatic relief. However, long-term adherence is often suboptimal, and a device-focused model may overlook upstream lifestyle and metabolic drivers. Increasing evidence shows that OSA commonly coexists with, and is partly driven by, modifiable factors such as poor diet quality, physical inactivity, alcohol use, circadian disruption, and adiposity. Emerging anti-obesity pharmacotherapies further support the concept that modifying mechanical and metabolic control can markedly reduce OSA severity. Framing OSA within a lifestyle-metabolic paradigm may therefore improve both symptom control and long-term cardiometabolic outcomes. In this perspective with targeted evidence synthesis, we argue for integration of structured lifestyle and behavioural interventions into routine OSA care and outline a pragmatic multidisciplinary model for implementation. Randomised controlled trials consistently show that healthy dietary patterns, structured physical activity, alcohol reduction, and interdisciplinary lifestyle programmes can reduce OSA severity, daytime sleepiness, and cardiometabolic risk markers. Some benefits appear to occur without substantial weight loss, suggesting additional mechanisms such as improved ventilatory stability, reduced rostral fluid shift, enhanced upper-airway neuromuscular responsiveness, and lower systemic inflammation. We therefore propose expansion, rather than replacement, of the current disease model by pairing airway therapies with structured lifestyle and metabolic risk modification from the time of diagnosis. This integrated, whole-person approach has the potential to improve quality of life, enhance treatment durability, and reduce long-term cardiovascular and metabolic complications. Aligning funding models, implementation pathways, and research priorities with this framework could help shift OSA care from device dependent nocturnal symptom control toward sustained health gains across the life course.
Aging causes dramatic alterations in bodily functions. Among them, sleep quality declines with age, particularly in individuals with neurodegenerative diseases. In this review, we first describe alterations in sleep-wake architecture and discuss potential mechanisms underlying sleep disorders that arise with age. We discuss evidence linking sleep disorders with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) syndrome. Even though the causes of AD, PD, PSP, and HD are diverse, several shared symptoms including difficulty falling asleep, fragmented sleep, and disrupted circadian rhythm collectively suggest their pathologies disrupt sleep-wake control. Hyperexcitability of implicated neurons is commonly observed prior to neurodegeneration. Upregulated neuronal excitability in the early phase of these diseases appears as a potential shared mechanism among neurodegenerative diseases. Abnormal protein accumulation and aggregation in these diseases exacerbate neuronal circuit hyperactivity by increasing neurons' intrinsic excitability or dampening inhibitory inputs to neurons controlling sleep-wake cycles. A better understanding of the mechanisms underlying sleep disorders that emerge with age may greatly benefit the development of novel preventative and therapeutic strategies for neurodegenerative diseases, and therefore improve the life quality of older adults.
Workers in physically and operationally demanding (POD) occupations (e.g. military personnel, emergency responders, law enforcement) experience disrupted sleep due to irregular schedules and high-stress work environments. Given the importance of sleep for physical and cognitive performance, interventions to improve sleep in POD occupations are crucial yet remain under-researched. To investigate the effectiveness of sleep hygiene interventions in improving sleep quality and quantity outcomes for POD occupations, a systematic review was conducted across five databases (PubMed, CINAHL, SPORTDiscus, PsycINFO, Web of Science) in September 2024. Eligible studies involved workers in POD occupations where a sleep hygiene intervention was compared against a waitlist or passive control. Ten studies were included, eight randomised controlled trials (RCTs) and two non-randomised controlled trials (NRCTs). Narrative synthesis identified Structured Training Programs (n = 7), Phone Assistance Programs (n = 2), and Single Lecture Interventions (n = 1). Evidence certainty ranged from Very Low to Moderate, converging towards Low quality due to imprecision, risk of bias, and indirectness. Structured Training Programs showed moderate improvements in sleep quality and small-to-moderate effects on sleep duration. Phone Assistance Programs had minimal effects, and Single Lecture Interventions had negligible impact. Higher-quality research is urgently needed to assess sleep hygiene interventions in POD occupations.
Insomnia disorder (ID) is the most common sleep disorder and among the most prevalent neuropsychiatric conditions, affecting ∼9-20% of adults with substantial burden. Chronic ID is linked to cardiometabolic and psychiatric morbidity, cognitive impairment, and accelerated neurodegeneration. Although behavioral and pharmacologic therapies help, relapse is common, suggesting a pathophysiology not simply of "too little sleep" but a persistent bias toward wakefulness. Current models converge on ID as a disorder of hyperarousal, yet the circuit, cellular, and synaptic mechanisms by which stress produces a durable wake-biased state remain unclear. Here we synthesize clinical and mechanistic evidence that stress-responsive hubs, particularly the paraventricular nucleus of the hypothalamus (PVN) and bed nucleus of the stria terminalis (BNST), interact with hypothalamic sleep-wake effectors, including lateral hypothalamic (LH) arousal systems (orexin and LHGABA) and sleep-promoting circuitry in the ventrolateral preoptic area (VLPO), to destabilize state control. We propose that acute stress recruits PVN-BNST pathways to promote vigilance, whereas chronic stress induces plastic changes that recalibrates circuit gain and weakens inhibitory "brakes," stabilizing hyperarousal and fragmenting sleep. In this framework, insomnia reflects a failure of state regulation in which PVN-BNST networks reset arousal systems, converting adaptive vigilance into chronic wakefulness and pointing toward mechanism-based, durable therapies.
Adversities in childhood and adolescence (ACA) can disrupt biological, developmental, and behavioral processes, potentially contributing to poorer sleep in adulthood. However, the certainty of the evidence of this association remains unclear. To synthesize and evaluate evidence of associations between ACA and adult sleep health (≥18 years) across World Health Organization regions while considering benevolent and risk factors, we conducted an overview of systematic reviews/meta-analyses. Using a predefined protocol, we systematically reviewed records published from database (n = 5) inception to February 2026, synthesized results, and performed quality and bias appraisal using validated tools, which allowed for assessment of the overall certainty of evidence. Twelve systematic reviews, including one relevant meta-analysis, were identified. ACA exposure was consistently associated with poorer sleep (e.g., insomnia symptoms, nightmares, higher arousals) in adulthood. Confidence in findings was generally critically low, and risk of bias was high, resulting in low certainty, overall. Evidence was concentrated in Regions of the Americas and Europe, with no representation from low-income countries. Reviews broadly summarized ACA-sleep associations, limiting synthesis of potential moderation by benevolent and risk factors. ACAs appear associated with poorer sleep health in adulthood; however, certainty remains low. More research across global populations is needed.
Cardiac rehabilitation (CR) aims to enhance cardiovascular health and quality of life, as well as survival through structured exercise training, lifestyle education, cardiovascular risk factor management, and psychosocial support. Despite growing evidence linking sleep disorders, poor sleep health, and circadian rhythm disruption to impaired cardiac recovery, reduced exercise adherence, and increased adverse cardiovascular events, systematic assessment and management of sleep and circadian health remain underutilized in CR programs. In this narrative review, we aim to explore and characterize the gap and address the potential benefits of incorporating sleep and circadian rhythm assessment into CR practice. Sleep disorders commonly encountered in patients undergoing CR, including obstructive sleep apnea, central sleep apnea, and insomnia, may adversely affect CR participation, functional recovery, and cardiovascular prognosis. Practical strategies include routine sleep screening with validated assessment tools, selective use of objective sleep assessments, sleep hygiene education, chronotype-informed exercise scheduling, and referral pathways to sleep medicine specialists. Integrating sleep-circadian considerations into CR may enhance cardiac recovery, improve exercise tolerance and adherence, and support more comprehensive, personalized secondary prevention strategies. Artificial intelligence may further support early detection of sleep disturbances, individualized exercise prescription, remote monitoring, and precision CR approaches integrating sleep and circadian health.
REM sleep is a state in which powerful inhibitory and excitatory mechanisms coexist. Numerous short-lived activities, known as phasic events, occur against a backdrop of sustained muscle atonia and vagal tone during REM sleep. Pioneering research in this area dates back to 1953, with renewed interest periodically emerging in the context of diseases such as depression, erectile dysfunction, sleep-related breathing disorders, and REM sleep behavior disorder. This review in two parts provides a comprehensive list of these phasic activities in the human body. The first part of the review describes rapid eye movements and muscle twitches in the striated muscles of the face, pharynx, larynx, neck and torso, and the limbs. It describes their putative functions. These activities can result in brief movements such as tympanic movements (middle ear muscle activity) and facial expressions. Phasic activities such as middle ear muscle activity, swallowing, smiling and head jerks occur more frequently during REM sleep than NREM sleep; however, rhythmic masticatory muscle activity occurs less frequently during REM sleep than NREM sleep. While some phasic activities occur alongside rapid eye movements, this is not always the case. This calls into question the definition of phasic and tonic REM sleep as distinct sub-phases.
Non-rapid eye movement (NREM) sleep is not a static state but a dynamically regulated process in which cortical, autonomic, and neuromodulatory activity fluctuates across nested temporal scales. This review proposes that the cyclic alternating pattern (CAP), a scored marker of NREM sleep instability with a dominant periodicity near 25 s, and the approximately 50-s infraslow oscillation (ISO) of sigma/spindle activity may represent different expressions of a shared nonlinear regulatory architecture. Rather than interpreting CAP as a simple second harmonic of sigma-ISO, we propose that CAP phase A reflects a thresholded, state-dependent, subtype-specific event output of a putative broader thalamocortical-autonomic and neuromodulatory NREM sleep infraslow process, provisionally termed the NREM sleep infraslow cycle. CAP-favorable windows may arise twice within each 50-s cycle at transition phases, maximal-slope points, turning points, or other instability phases of a demeaned sigma-ISO component, producing an apparent 2:1 relationship. This coupling is likely modulated by ultradian position, CAP subtype, slow oscillation-spindle coupling, autonomic and noradrenergic state, small-world network reconfiguration, and aperiodic 1/f background activity. Phase-resolved multimodal studies could test this framework and reposition CAP as a mechanistic index of nonlinear NREM sleep-state regulation.
Sleep is a fundamental physiological process closely linked to autonomic homeostasis. Rather than being governed by a localized neural switch, sleep-wake regulation depends on coordination between central circuits and peripheral physiology. The gastrointestinal tract is a major interface where this integration is evident. Ascending visceral signals can influence brain circuits involved in arousal and sleep, while sleep disruption can feed back onto the gut through descending autonomic pathways, altering motility, secretion, immune function, barrier integrity, and the intestinal environment. Here, we propose Gut-Autonomic-Brain Loops (GABLs) as a framework in which gut-derived microbial, immune, and metabolic cues reach sleep-relevant circuits through region- and stimulus-dependent vagal and spinal visceral afferents, while descending sympathetic and parasympathetic outputs feed back to shape gut physiology and the intestinal microenvironment. We outline the anatomical substrates of these loops, summarize autonomic dynamics across sleep and sleep disorders, and review evidence linking gut-derived signals to brain function and behavior through autonomic and interoceptive pathways. By specifying autonomic routes linking gut physiology to sleep-related brain function, this framework may help guide mechanistic studies and phenotype-informed translational research.
Anxiety is the most prevalent mental health difficulty in adolescence, a period characterised by a shift towards an eveningness chronotype that is not aligned with societal demands (i.e., school start times). Experiencing “social jetlag” (SJL), a discrepancy in weekday-weekend sleep timing, is proposed to be associated with increased anxiety. A PRISMA-compliant systematic review and meta-analysis was conducted to investigate the relationship between SJL and anxiety in adolescents (age range: 12-18 years). Systematic searches were conducted in PsycINFO, Web of Science, Embase, PubMed, MEDLINE, and ProQuest Dissertations & Theses Global on 14th November 2024 to retrieve empirical studies analysing the relationship between SJL and anxiety in 12-18-year-olds. A multi-level random-effect meta-analysis was conducted in R to estimate the magnitude of the association between SJL and anxiety. After screening 2,138 records, 18 studies were included in the systematic review, with 12 included in the meta-analysis (235,526 participants in total) and six in a narrative review. A small association was found between increased SJL and more severe anxiety (Fisher's z = 0.0614, 95% CI [0.0268, 0.0961], p = 0.0011). These findings highlight the importance of addressing behavioural strategies targeting healthy regular sleep as a tool to improve mental health in adolescence.
During deep space exploration, astronauts are exposed to external environmental stressors, including microgravity and ionizing radiation. They also experience internal physiological disruptions, such as circadian rhythm dysregulation and sleep disturbance. Within this complex stress environment, functional alterations may occur in multiple organ systems, particularly the heart and brain. This review examines alterations in heart and brain function during spaceflight and explores their potential relationships with microgravity, circadian rhythm dysregulation, and sleep disturbance. Evidence from spaceflight observations, spaceflight experiments, and ground-based analog or mechanistic studies suggests that these changes may involve mitochondrial dysfunction, oxidative stress, metabolic disturbance, autonomic dysregulation, and inflammatory responses. However, direct causal evidence in astronauts remains limited, and many mechanistic findings still require validation under actual spaceflight conditions. By clarifying how circadian rhythm dysregulation and sleep disturbance may be linked to alterations in heart and brain function in the spaceflight environment, this review aims to inform monitoring and countermeasure strategies for forthcoming lunar and Mars missions.
