Non-rapid eye movement (NREM) parasomnias are sleep disorders characterized by abnormal, involuntary behaviours during partial arousals from slow-wave sleep. NREM parasomnias are common in childhood and usually remit, but a subset persist into or first emerge in adulthood, where they may cause significant morbidity. Evidence to guide treatment is limited, and no formal treatment guidelines exist. This review summarises evidence for behavioural, psychological, and pharmacological interventions. Ovid (Embase), the Cochrane Library, and PubMed were searched for English-language reports on the treatment of NREM parasomnias (confusional arousals, sleepwalking, sleep terrors, sexsomnia, sleep-related eating disorder) from January 2003 to 25 February 2026. The review followed PRISMA and was prospectively registered with PROSPERO (CRD420261327423). Risk of bias was assessed with RoB 2, ROBINS-I, and Joanna Briggs Institute tools, as appropriate; certainty of evidence was rated using GRADE. Heterogeneity precluded meta-analysis; findings were synthesized narratively. Fourteen studies were included, mostly retrospective and uncontrolled. Pharmacotherapy, particularly benzodiazepines, was the most studied modality; cognitive behavioural therapy was the leading non-drug intervention. Interventions also included melatonin, antidepressants, Z-drugs, topiramate for sleep-related eating disorder, serotonergic precursors in children, and hypnosis. Most interventions suggested benefit, but small samples, reliance on subjective outcomes, and the absence of comparators limited interpretation. Certainty was very low for most outcomes. High-quality trials with standardized and ideally objective measurements are needed to guide clinical practice.

Post-traumatic stress disorder (PTSD) is characterized by symptoms including hypervigilance, intrusive memories, and sleep disturbance. Insomnia and nightmares are among the most common and clinically important sleep-related symptoms in PTSD, yet effective and well-tolerated pharmacotherapies remain limited. Suvorexant, a dual orexin receptor antagonist (DORA) approved for insomnia, represents a mechanistically distinct approach to traditional hypnotics. The orexin/hypocretin system is composed of two wake-promoting neuropeptides, orexin A and orexin B, which signal through orexin 1 (OX1R) and orexin 2 receptors (OX2R) to regulate arousal and sleep-wake transitions. The adaptive stress response, which is canonically disrupted in PTSD, is also moderated by the orexin system. Here, we used an acute inescapable footshock paradigm to disrupt sleep in adult male Sprague Dawley rats and evaluated whether orexin receptor antagonism restores sleep after stress. Systemic administration of a dual orexin receptor antagonist (suvorexant), an OX1R-preferring antagonist (SB334867), and an OX2R-selective antagonist (EMPA), partially restored REM sleep and attenuated increases in NREM sleep following footshock stress exposure. We also examined the relative contribution of OX1R and OX2R to these effects at the doses used. Although all antagonists increased time spent in REM after footshock stress, attenuation of the stress-induced increases in NREM and reductions in sleep-onset latency were most evident following dual receptor blockade. These findings demonstrate that orexin receptor antagonism can mitigate acute stress-induced alterations in sleep state allocation and sleep latency, and support further investigation of DORAs for stress-related sleep disturbance.

Osteoarthritis (OA) is one of the leading causes of pain-related disability. Sleep health and sex-associated differences contribute to OA pain, yet their roles remain poorly defined. Sleep disruption can bidirectionally exacerbate OA pain and independently increase risk of OA, with females showing greater vulnerability. Moreover, chronic pain and poor sleep alter central neurophysiology, including hippocampal synaptic plasticity, yet how these factors relate to OA pain remains unclear. We investigated sex-specific hippocampal glutamatergic function in a monoiodoacetate knee pain mouse model along with mechanical sensitivity and sleep architecture. Both sexes developed mechanical hypersensitivity following injury, but females exhibited poorer sleep outcomes. Injured males demonstrated increased AMPAR-mediated excitatory activity, whereas injured females showed reduced NMDAR activity. Mechanical hypersensitivity correlated with reduced NMDAR/GluN2B function in females, while sex-specific altered AMPAR and NMDAR activity associated with REM sleep. These findings reveal divergent, sex-specific alterations in hippocampal glutamatergic signaling associated with chronic OA pain and sleep disruption. Together, these results suggest that sleep and pain-related synaptic changes reflect interacting processes that differ by sex, highlighting hippocampal excitatory signaling, sleep health, and sex-specific neurophysiology as key contributors to variability in the OA pain experience and potential targets for chronic pain management.

Sleep disturbance is a common feature of depressive disorders and may be influenced by antidepressant-associated alterations in sleep architecture. Mirtazapine is a noradrenergic and specific serotonergic antidepressant with a distinctive pharmacologic profile involving histamine H1 receptor antagonism, alpha-2 adrenergic antagonism, and serotonergic receptor modulation, which may contribute to its effects on sleep regulation. This focused narrative review examines the neurobiological mechanisms through which mirtazapine may influence sleep architecture and summarizes available human polysomnographic (PSG) evidence, with particular emphasis on N3 sleep and slow-wave sleep-related measures. Current evidence suggests that mirtazapine can produce measurable changes in objective sleep architecture; however, findings specifically regarding N3 sleep and slow-wave sleep remain preliminary and mixed. Available studies are limited by small sample sizes, heterogeneous populations, variable treatment durations, differences in comparator conditions, and methodological variability. Although selected studies have reported increases in slow-wave sleep measures or N3 sleep, available evidence does not establish a consistent dose-response relationship or demonstrate that sedative effects directly translate into enhancement of slow-wave sleep. Mechanistic evidence supports several biologically plausible pathways through which mirtazapine may influence sleep regulation, including histaminergic, adrenergic, and serotonergic effects; however, human PSG studies evaluate the integrated effects of the complete medication and cannot establish receptor-specific mechanisms responsible for observed sleep changes. Future studies using standardized PSG protocols, quantitative electroencephalography (EEG) analysis, larger samples, longer treatment durations, and direct dose comparisons are needed to clarify whether mirtazapine-associated alterations in sleep architecture contribute meaningfully to clinical outcomes.

Genomic measurements of DNA methylation, gene expression or protein levels are becoming more prevalent and are increasingly used to study health outcomes. However, most proposed association testing methods consider only marginal effects of each feature on a single outcome variable and are not set up to handle highly correlated, continuous data. Here, we introduce MAJA, a method to learn shared and outcome-specific effects for multiple traits in multi-omics data. MAJA determines the unique contribution of individual loci, genes, or molecular pathways to variation in one or more traits, conditional on all other measured "omics" data genome-wide. Simulations show MAJA accurately finds shared and distinct associations between omics-data and multiple traits and estimates omics-specific (co)variances, allowing for sparsity and correlations within the data. Applying MAJA to 12 outcome traits in Generation Scotland methylation data (n = 18 264), we find novel shared epigenetic probes among cholesterol metabolism, osteoarthritis, blood pressure and asthma. In contrast to marginal testing, we find only 10 CpG probes with significant effects above the genome-wide background. This highlights the need for joint association testing in highly correlated methylation data from whole blood and for studies of increased sample size in order to refine epigenomic associations in observational data.

Sleep architecture is characterized by dynamic transitions between non-rapid eye movement (NREM) and rapid eye movement (REM) stages, each defined by distinct oscillatory signatures. Although quantitative EEG has been widely used to study primary insomnia (PI), reported findings remain inconsistent, partly due to limited consideration of cortical regional differences, sleep-stage specificity, and sex-related variability. This study integrates spectral power analysis with explainable machine learning to provide a comprehensive characterization of neural dynamics in PI. EEG recordings from 100 adults (50 healthy sleepers and 50 PI patients) were analyzed across frontal (F3, F4), central (C3, C4), and occipital (O1, O2) regions. Stage-specific classifiers were developed for NREM and REM using LASSO, random forest, CatBoost and XGBoost models, and Shapley Additive Explanations (SHAP) were employed to quantify the contribution of each spectral and regional feature to model predictions. Models trained on NREM features demonstrated superior discrimination compared with those trained on REM features, suggesting that slow-wave neural activity captures insomnia-related alterations more reliably than REM dynamics. SHAP analysis identified reduced delta power and elevated beta activity most prominently in central regions as the dominant predictors of PI during NREM sleep. In contrast, REM-based models pointed to prefrontal beta1 and occipital alpha as secondary discriminative features. Sex-stratified analyses further revealed systematically higher spectral power in females and distinct SHAP feature-importance patterns between sexes. Collectively, this work establishes an interpretable, stage-specific framework for identifying EEG biomarkers of insomnia and demonstrates the value of explainable artificial intelligence in advancing the neurophysiological understanding of sleep disturbance.

The coexistence of multiple primary sleep disorders in a single patient is uncommon and poses significant diagnostic and therapeutic challenges. We report a 45-year-old woman with severe mixed sleep apnea (OSA/CSA), NREM parasomnia (night terrors), sleep-related eating disorder (SRED), nightmare disorder (with RBD like behavior but no REM atonia on PSG), and central hypersomnolence phenotype minimally affected with PAP optimization and delayed sleep-wake phase disorder. Symptoms began more than two decades earlier and included violent dream-enactment behaviors, hypnopompic hallucinations, sleep inertia, and chronic excessive daytime sleepiness (EDS). Treatment required multi-modal therapy. Positive airway pressure therapy successfully treated sleep disordered breathing while pitolisant and solriamfetol produced the most durable improvement in daytime sleepiness. Together melatonin plus clonazepam reduced parasomnia frequency and severity. Several other agents (including prazosin, sodium oxybate, paroxetine, and modafinil) were tried and discontinued for limited benefit or adverse effects. Notably, GLP-1 receptor agonist (GLP-1 RA) therapy for obesity was followed by a substantial weight loss and coincided with resolution of SRED. Because this occurred alongside improved sleep stability, PAP adherence, behavioral adaptation, and medication changes, causality cannot be inferred. The observation may justify further study of metabolic and incretin-related pathways in sleep-related eating behaviors. Overall, this case highlights the complexity of overlapping sleep-wake disorders, the need for individualized pharmacologic sequencing, and a potential emerging role for GLP-1 agonists in SRED.

Obstructive sleep apnea (OSA) is a common disorder whose clinical expression and daytime sleepiness may evolve over time, particularly in the presence of coexisting sleep disorders. We report a nine-year longitudinal case of a 29-year-old man presenting initially with severe excessive daytime sleepiness (EDS) (Epworth Sleepiness Scale (ESS) score: 19/24) and mild OSA (apnea-hypopnea index (AHI): 10 events/h), who represented nine years later with disabling sleepiness, weight gain (body mass index: 30.2 kg/m[2]), and typical cataplexy. No documented sleep medicine follow-up or OSA treatment was available during the intervening nine-year period. Repeat polysomnography demonstrated moderate, rapid eye movement (REM)-predominant OSA (AHI: 20.4 events/h; REM-AHI: 52.9 events/h; non-REM (NREM)-AHI: 9.4 events/h; REM-AHI/NREM-AHI ratio: 5.6), with increased sleep fragmentation. The Multiple Sleep Latency Test (MSLT), performed after diagnostic polysomnography and before continuous positive airway pressure (CPAP) optimization, showed severe objective sleepiness (mean sleep latency: 3.7 minutes) with sleep-onset REM periods in all five nap opportunities. In the setting of typical cataplexy, these findings strongly supported a diagnosis of narcolepsy type 1; however, untreated OSA and sleep fragmentation at the time of testing were acknowledged as potential confounders in the interpretation of the MSLT. Management included fixed-pressure CPAP at 8 cm H2O, sertraline for cataplexy, and modafinil for EDS. At 30-day follow-up, CPAP downloads showed use on 60% of nights, with a residual AHI of 3.1 events/h and mean leak of 35 L/min, indicating effective control of respiratory events when therapy was used, but suboptimal adherence and mask leak likely limiting clinical benefit. This case highlights three key clinical messages: EDS disproportionate to OSA severity should prompt evaluation for a coexisting central disorder of hypersomnolence; REM-predominant OSA can coexist with narcolepsy type 1 without implying a causal relationship between the two disorders; and their relative contributions to sleepiness may change over time. When MSLT is required in a patient with OSA, effective treatment of OSA and adequate documentation of prior sleep are important for reliable interpretation. Management should address both OSA and narcolepsy and include periodic reassessment as the clinical phenotype evolves.

Clinical confusion around restless legs syndrome (RLS), periodic limb movements during sleep (PLMS), and periodic limb movement disorder (PLMD) usually begins with a familiar sequence: the patient sleeps badly, the sleep study shows leg movements, and the report starts to sound like the diagnosis. The labels need more separation than that. RLS is diagnosed clinically from the history: an urge to move, often with uncomfortable sensations, brought out by rest, eased by movement, and worse in the evening or at night. PLMS are scored motor events. PLMD is reserved for the smaller group in whom those events plausibly account for sleep disturbance or daytime impairment after RLS, sleep-disordered breathing, narcolepsy, REM sleep behavior disorder, drug effects, and other neurological or medical causes have been considered. Biology is not a tidy dopamine story. Iron handling in the brain remains one of the more reproducible findings, although ferritin and transferrin saturation are only rough clinical proxies for central iron. Dopaminergic, adenosinergic, glutamatergic, spinal, autonomic, and genetic findings each explain part of the syndrome. Large genetic datasets, quantitative imaging, home movement recording, automated PLMS scoring, and autonomic measures have widened the field. Their immediate value is uneven: some help with mechanisms, some with measurement, and only a few currently change treatment decisions. Management still begins at the bedside. A typical RLS history, an incidental PLMS index, and possible PLMD lead to different choices. Iron indices should be checked early, medication and respiratory triggers need to be addressed, and dopamine agonist escalation should be avoided when augmentation is suspected. Current treatment is more cautious than older dopamine-centered practice: iron repletion when indicated, alpha-2-delta ligands for many chronic persistent cases, specialist use of opioids for severe refractory disease, and a selective role for device-based therapy. The chapter follows that clinical order rather than treating leg movement as a single target.

This chapter provides an exhaustive review of the neural substrates associated with insomnia and hyperarousal, considering the chronic disturbance of sleep from the complex perspective of a reciprocal biopsychosocial model. It focuses on several critical abnormalities observed on the structure and function of neuroanatomy, especially the hypersensitive reaction of the amygdala and insular cortex along with reduced reactivity of the prefrontal cortex that results in the development of emotional dysregulation and a continuous feeling of danger. At the circuitry level, it is possible to observe a substantial disturbance of the DMN and ECN connectivity. From a neurochemical point of view, this chapter describes the impact of the imbalances of GABA, serotonergic and noradrenergic systems in specific nuclei, such as the locus coeruleus and the tuberomammillary nucleus, together with HPA-axis overactivation and elevated cortisol levels that cause systemic cortical hyperarousal. As far as electrophysiological markers are concerned, there is a specific increase of beta wave activity in the waking resting-state as well as a decrease of restorative SWS and REM sleep stability. Lastly, this chapter gives some information about clinical relevance, especially about CBT-I, new neuromodulation strategies and brain-region specific pharmacotherapeutic options.