Search Results (202)

Background: Insomnia is prevalent and difficult to treat safely over the long term. Given the role of the microbiota–gut–brain axis in melatonin and hypothalamic–pituitary–adrenal (HPA) regulation, and preclinical evidence for Limosilactobacillus fermentum PS150, we evaluated whether a heat-treated formulation (HT-PS150) could improve sleep and modulate endocrine/circadian markers in adults with poor sleep. Methods: In a randomized, double-blind, placebo-controlled trial, 84 adults aged 20–60 years with PSQI ≥ 5 and ISI < 22 were assigned to receive either placebo or HT-PS150 for eight weeks. Outcomes included patient-reported sleep (PSQI, ISI), anxiety/depression (GAD-7, PHQ-9), quality of life (QLESQ-SF), gastrointestinal symptoms (VAS-GI), wrist actigraphy (Fitbit Inspire 3), and sleep-relevant biomarkers measured from urine, saliva, and/or blood samples (melatonin, cortisol, orexin, serotonin, GABA, and/or norepinephrine). Repeated measures were analyzed using generalized estimating equations. An exploratory proportional regulation analysis classified individual biomarker changes as up- or down-regulated and compared proportions between study arms. Per-protocol analyses required ≥80% compliance. Results: Improvements in the primary outcomes, PSQI and ISI, were observed over time in both groups, while no significant group × time interactions were detected. In exploratory proportional analyses, a higher proportion of participants in the HT-PS150 group exhibited up-regulated nocturnal melatonin secretion and improved daytime plasma orexin levels, as well as a tendency toward greater reductions in nocturnal salivary cortisol compared with placebo. In subgroup analyses with higher baseline insomnia severity (ISI ≥ 8), HT-PS150 was associated with greater improvements in PSQI (notably sleep duration and efficiency) and reduction in anxiety (GAD-7) upon post hoc testing. Conclusions: Although group mean scores on sleep symptom scales did not differ significantly in the full cohort, HT-PS150 appeared to modulate sleep–wake regulation by enhancing nocturnal melatonin secretion, attenuating HPA-axis activity, and stabilizing wakefulness. Clinical benefits were most evident among participants with greater baseline symptom burden, suggesting potential utility in more symptomatic populations. Full article

Female cancers, including breast and gynecological malignancies, are among the most prevalent oncological conditions worldwide. Advances in screening, diagnosis, and treatment have markedly improved survival, resulting in a growing population of female cancer survivors. Consequently, long-term health and quality of life have become essential aspects of comprehensive cancer care. Among survivorship issues, sleep disturbances—particularly insomnia—are highly prevalent and associated with adverse outcomes including mood and cognitive impairment, fatigue, immune and cardiometabolic dysregulation, and reduced adherence to therapy. Insomnia, defined as difficulty initiating or maintaining sleep or experiencing poor sleep quality with daytime impairment, affects 6–10% of the general population and is more common in women. In cancer survivors, poor sleep quality appears to be three times more frequent, reaching 62% in breast cancer survivors, although these data may be underestimated, especially for other cancer types, due to the small sample size and heterogeneity of the studies. The pathogenesis of insomnia in female cancer patients is multifactorial, involving cancer-related inflammation, hypothalamic–pituitary–adrenal axis dysregulation, neuroimmune alterations, treatment effects, psychological distress, and behavioral factors. Hormonal disruption plays a central role, as oncological treatments are often the cause of iatrogenic menopause, leading to vasomotor symptoms, mood and cognitive disturbances, sexual dysfunction, and genitourinary complaints, all contributing to sleep disruption. Importantly, estrogens and progesterone independently regulate sleep–wake pathways via central mechanisms, influencing sleep quality even in the absence of vasomotor symptoms. Management requires a multidisciplinary approach integrating oncology, gynecology, and sleep medicine. Cognitive Behavioral Therapy for Insomnia (CBT-I) is first-line, while pharmacologic options include benzodiazepines, Z-drugs, SSRIs/SNRIs, melatonin, or new medication like DORAs. Menopausal hormone therapy (MHT) should be considered for premature menopause management in selected women without contraindications, improving both vasomotor symptoms and sleep quality. Emerging neurokinin receptor (NK-R) antagonists show promise, and ongoing trials suggest significant potential even in breast cancer survivors. Full article

The circadian phase difference between morning and evening types is a fundamental aspect of chronotype. However, results of categorizations into chronotypes based on reported sleep times show low concordance with those based on measurements of the hormonal or physiological or molecular rhythm–markers of the circadian phase. This might be partially explained by the profound individual differences in the phase angle between the sleep–wake cycle and these rhythms that depends on chronotype, age, sex, and other factors. Here, we examined the possibility of using self-reported sleep times in the condition of 5-days-on/2-days-off school/work schedule to estimate circadian phase differences between various chronotypes. In an in silico study, we determined that, for such an estimation, similarities of the compared chronotypes in weekend sleep duration and weekend–weekday gap and in risetime are required. In the following empirical and simulation studies of sleep times reported by 4940 survey participants, we provided examples of the estimation of circadian differences between chronotypes, and the model-based simulations of sleep times in morning and evening types exemplified a way to confirm such estimations. The results of in silico, empirical, and simulation studies underscore the possibility of using bedtimes and risetimes for direct estimation of the circadian phase differences between individuals in real-life situations, such as a 5-days-on/2-days-off school/work schedule. Additionally, the results of these studies on different chronotypes provided further mathematical modeling and empirical evidence for our failure to sleep more on weekends to recover/compensate/pay back/ catch up on lost sleep. Full article

Sleep disorders represent a growing global health concern with significant socio-economic impacts. GABA, a natural bioactive compound abundant in various fermented foods, especially probiotic-fermented foods, has garnered increasing attention for its potential to improve sleep quality. This review systematically elucidates the multi-pathway mechanisms by which GABA regulates sleep, focusing on (1) indirect modulation of central sleep–wake circuits via the gut–brain axis through vagal nerve, neuroendocrine, and immune pathways; (2) potential entry into the brain by leveraging the dynamic permeability of the blood–brain barrier (BBB) and transporter-mediated active transport; and (3) metabolic conversion into active substances like γ-hydroxybutyrate (GHB), which synergistically optimizes sleep architecture via multiple receptor systems and energy metabolism. Furthermore, we summarize the sleep-promoting effects of GABA-enriched foods observed in animal and clinical studies and discuss emerging applications, including high-GABA-yielding probiotics and personalized nutrition strategies for sleep intervention. This review provides a theoretical basis and innovative directions for the development of GABA-based functional foods and sleep health management. Full article

Animal models have been pivotal in uncovering the orexin (hypocretin) system as the fulcrum of sleep–wake regulation and in shaping therapeutic discovery for narcolepsy. Early canine and murine models established that orexin loss underlies narcolepsy type 1, while conditional and receptor-specific manipulations refined mechanistic insight. However, current paradigms capture only fragments of the human phenotype, often exaggerating cataplexy and under-representing narcolepsy type 2. Here, we follow the evolution of narcolepsy modelling from classical knockout and receptor-deficient systems to immune-driven and cell-replacement models, identifying critical translational gaps and proposing strategies to bridge them. We highlight how immune-competent mouse lines, astrocyte-to-neuron reprogramming, and patient-derived hypothalamic organoids bridge pathogenic insight with therapeutic innovation. Integrating these advances with small-molecule OX2R agonists, gene therapy, and multi-omics-based patient stratification defines a roadmap for moving beyond symptomatic control. This review seeks to unify immune, cellular, and computational perspectives to guide the next generation of animal models toward the prevention, repair, and long-term cure of narcolepsy. Full article

Background/Objective: Sleep is a vital determinant of human health, where both its quantity and quality directly impact physical and mental well-being. Thermoregulation plays a pivotal role in sleep quality, as the body’s ability to regulate temperature varies across different sleep stages. This study examines the effects of a novel real-time temperature adjustment (RTA) mattress, which dynamically modulates temperature to align with sleep stage transitions, compared to constant temperature control (CTC). Through polysomnographic (PSG) assessments, this study evaluates how adaptive thermal regulation influences sleep architecture, aiming to identify its potential for optimizing restorative sleep. Methods: A prospective longitudinal cohort study involving 25 participants (13 males and 12 females; mean age: 39.7 years) evaluated sleep quality across three conditions: natural sleep (Control), CTC (33 °C constant mattress temperature), and RTA (temperature dynamically adjusted: 30 °C during REM sleep; 33 °C during non-REM sleep). Each participant completed three polysomnography (PSG) sessions. Sleep metrics, including total sleep time (TST), sleep efficiency, wake after sleep onset (WASO), and sleep stage percentages, were assessed. Repeated-measures ANOVA and post hoc analyses were performed. Results: RTA significantly improved sleep quality metrics compared to Control and CTC. TST increased from 356.2 min (Control) to 383.2 min (RTA, p = 0.030), with sleep efficiency rising from 82.8% to 87.3% (p = 0.030). WASO decreased from 58.2 min (Control) and 64.6 min (CTC) to 49.0 min (RTA, p = 0.067). REM latency was notably reduced under RTA (110.4 min) compared to Control (141.8 min, p = 0.002). The REM sleep percentage increased under RTA (20.8%, p = 0.006), with significant subgroup-specific enhancements in males (p = 0.010). Females showed significant increases in deep sleep percentage under RTA (12.3%, p = 0.011). Conclusions: Adaptive thermal regulation enhances sleep quality by aligning mattress temperature with physiological needs during different sleep stages. These findings highlight the potential of RTA as a non-invasive intervention to optimize restorative sleep and promote overall well-being. Further research could explore long-term health benefits and broader applications. Full article

Animal studies show that sleep regulation depends on subcortical networks, but whether the connectivity between subcortical areas contributes to human sleep variability remains unclear. We investigated whether the effective connectivity between the LC and hypothalamic subparts during wakefulness relates to sleep electrophysiology. Thirty-three younger (~22 y, 27 women) and 18 late middle-aged (~61 y, 14 women) healthy individuals underwent 7-Tesla functional MRI during wakefulness to assess LC–hypothalamus effective connectivity. Additionally, sleep EEG was recorded at night in the lab to examine the relationships between effective connectivity measures and REM sleep theta energy as well as sigma power prior to REM. Connectivity analyses revealed strong mutual positive influences between the LC and both the anterior–superior and posterior hypothalamus, consistent with animal studies. Aging was negatively associated with the connectivity from the anterior–superior hypothalamus (including the preoptic area) to the LC. In late middle-aged adults, but not younger adults, stronger effective connectivity from the anterior–superior hypothalamus to the LC was associated with lower REM theta energy. This association extended to other low-frequency bands during REM and NREM sleep. These findings highlight the age-dependent modulation of LC–hypothalamus interactions and their potential roles in sleep regulation, providing new insights into neural mechanisms underlying age-related sleep changes. Full article

Introduction: Tumor- and/or treatment-associated hypothalamic damage results in reduced quality of life and increased morbidity due to sleep disorders in survivors of craniopharyngioma. Methods: The narrative review is based on a search of Web of Science, MEDLINE/PubMed, and Embase databases for the identification of publications. The search terms craniopharyngioma, sleep disorders, fatigue, and daytime sleepiness were used. Selected English language papers published 1970–2025 were included. Results: Circadian rhythms (wakefulness and sleep) are controlled by hypothalamic suprachiasmatic nuclei and regulated by melatonin. A dysregulation of circadian rhythms due to altered melatonin secretion can be observed in craniopharyngioma with hypothalamic involvement. Furthermore, sleep quality is regulated by lateral hypothalamic areas, the ventrolateral preoptic nucleus, and monoaminergic nuclei which function as the arousal system. Flexible changes between sleep and wakefulness can be achieved through interaction of arousal and sleep-promoting systems named “flip–flop” switch. Insomnia can be the result of damage to the ventrolateral preoptic nucleus. Excessive daytime sleepiness and disrupted sleep patterns can be observed due to dysregulation of lateral hypothalamic areas. Obesity, chronic fatigue, headache, and excessive daytime sleepiness can be the result of poor sleep quality. “Primary” hypothalamic sleep dysfunction, including narcolepsy, dysregulated sleep–wake cycles, and hypersomnia, can be observed due to hypothalamic dysfunction. “Secondary” sleep disturbances including obstructive sleep apnea, insufficient substitution medication for arginine vasopressin deficiency (nocturia), or psychosocial factors are sequelae in patients with craniopharyngioma and hypothalamic lesions. Conclusions: Further research on novel treatment approaches for sleep disorders due to hypothalamic syndrome are warranted to improve the outcome after craniopharyngioma. Full article

Insomnia is a common and complex disorder, rooted in the dysregulation of circadian rhythms, impaired neurotransmitter function, and disturbances in sleep–wake homeostasis. While conventional hypnotics such as benzodiazepines and Z-drugs are effective in the short term, their use is limited by a high potential for dependence, cognitive side effects, and withdrawal symptoms. In contrast, melatonergic receptor agonists—melatonin, ramelteon, tasimelteon, and agomelatine—represent a pharmacologically targeted alternative that modulates MT1 and MT2 receptors, which are pivotal to the regulation of circadian timing and sleep initiation. Clinical evidence supports the efficacy of these agents in reducing sleep onset latency, extending total sleep duration, and re-aligning disrupted circadian rhythms, particularly among older individuals and patients with non-24 h sleep–wake disorders. Notably, agomelatine offers additional antidepressant properties through selective antagonism of the 5-HT_2C receptor in micromolar concentrations. In contrast, its agonistic activity at melatonergic receptors is observed in the low sub-nanomolar range, which illustrates the complexity of this drug’s interactions with the human body. All compounds reviewed demonstrate a generally favorable safety and tolerability profile. Accumulating evidence highlights that selected medicinal plants, such as chamomilla, lemon balm, black cumin, valeriana, passionflower and lavender, may exert relevant hypnotic or anxiolytic effects, thus complementing melatonergic strategies in the management of insomnia. This structured narrative review presents a comprehensive analysis of the molecular pharmacology, receptor affinity, signaling pathways, and clinical outcomes associated with melatonergic agents. It also examines their functional interplay with serotonergic, GABAergic, dopaminergic, and orexinergic systems involved in arousal and sleep regulation. Through comparative synthesis of pharmacokinetics and neurochemical mechanisms, this work aims to inform the development of evidence-based strategies for the treatment of insomnia and circadian rhythm sleep–wake disorders. Full article

Background/Objectives: Sleep is essential for children’s well-being, yet insufficient sleep duration and quality are common among preschoolers. The brain–gut microbiota axis, a bidirectional communication network connecting the brain, the gastrointestinal tract, and the microorganisms living there, known as the gut microbiota, influences sleep regulation, but its role in children remains largely unexplored. Here, we examined the association between gut microbiota and sleep in preschoolers from Étude Longitudinale Française depuis l’Enfance (ELFE) birth cohort study. Methods: This study included 597 children (51.2% boys) with available stool samples and sleep data at 3.5 years. The gut microbiota data was analyzed using bacterial 16S rRNA sequencing. Data on day and night sleep durations and frequencies of sleep onset difficulties and night waking were collected through telephone questionnaires and grouped into ‘optimal’ and ‘suboptimal’ clusters using Latent Class Analysis. Statistical analyses involved multivariate logistic regressions or multivariate permutation analysis of variance, controlling for confounders. Results: In total, 25% of the included children were in the suboptimal sleep cluster. No significant associations were found between gut microbiota diversity and composition and sleep clusters at age 3.5 years. Similarly, no differences were found in the abundance of specific microbiota genera between the two sleep clusters. Conclusions: While emerging evidence suggests correlations between gut microbiota and sleep in preschool children, our results do not confirm such correlations. The data used in this study were obtained from a homogeneous, high socioeconomic population, which must be considered when interpreting the findings. Further research is needed to validate the results of this study. Full article

Background/Objectives: Wolfram syndrome is a rare neurodegenerative disorder primarily known for its multisystemic manifestations. Although classically associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, emerging evidence suggests a consistent pattern of executive dysfunction in many affected individuals. Methods: Based on findings from a scoping review and results obtained through the Dysexecutive Questionnaire in a Spanish patient cohort, we propose that WFS1 gene mutations—via chronic endoplasmic reticulum stress—disrupt serotonergic and cholinergic neurotransmission, leading to impairments in planning, inhibition, and emotional regulation. Results: Importantly, recent studies have highlighted the interplay between WFS1-related molecular dysfunction and circadian regulation. Given the role of the endoplasmic reticulum and mitochondrial signaling in circadian homeostasis, and the frequent sleep disturbances observed in patients with Wolfram syndrome, we hypothesize that circadian dysregulation may contribute to the neurobehavioral phenotype. Conclusions: This essay explores neuropsychological foundations of executive dysfunction in WS, and frames the current evidence as hypothesis-generating rather than causal; executive difficulties may be a salient clinical feature and merit consideration in routine care. Furthermore, the potential involvement of circadian mechanisms opens new avenues for future research and therapeutic approaches. Because circadian disruption is linked to psychiatric symptoms and fatigue, emphasizing diurnal patterns, sleep–wake timing, and chronotype may guide circadian-informed assessment. Full article

Orexin is a neuropeptide produced in the hypothalamus that plays a key role in regulating slee—wake cycles, energy metabolism, feeding behavior, and physical activity. It exists in two forms, orexin-A and orexin-B, which bind to G protein-coupled receptors OX₁R and OX₂R with differing affinities. Orexin signaling is widespread in the brain and extends to peripheral tissues, including adipose tissue. Its involvement in hypothalamic and extrahypothalamic circuits suggests a broad role in homeostatic regulation. Dysfunctions in the orexinergic system are implicated in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis, particularly through mechanisms involving sleep disturbances and neuroinflammation. This study examines how orexin influences neural circuits related to arousal, motivation, and motor control. It also explores how physical activity stimulates orexin release, enhancing neuroplasticity and cognitive resilience. In addition, orexin’s role in reward-related feeding, genetic susceptibility to obesity, and brown adipose tissue thermogenesis is discussed. Overall, the orexinergic system represents a vital neurochemical link between physical activity, metabolism, and cognitive health. Although many of its mechanisms remain to be clarified, its central role in integrating energy balance and behavioral responses makes it a promising target for future therapeutic strategies. Full article

The circadian rhythm controls the sleep/wake cycle and a wide variety of metabolic and physiological functions. Clock genes regulate it in response to both external and endogenous stimuli, and their expression may change because of aging, leading to an increased risk of health problems. Despite the well-described benefits of physical exercise as a circadian synchronizer, there is a lack of literature regarding the role of chronic exercise intensity in clock gene expression during aging. This article aims to analyze the differential expression of genes that regulate the biological clock under the effects of variable-intensity aerobic swimming training in aging mice, determining whether these exercise regimens interfere with the genomic regulation of the circadian rhythm. For this purpose, the mice were exposed to low- and high-intensity exercise and had their heart and gastrocnemius tissues molecularly analyzed by cDNA synthesis and qPCR to determine the expression levels of the selected genes: Clock, Arntl, Per1, Per2, Cry1, Cry2, and Nr1d1. The results showed that low-intensity exercise, performed at workloads below the anaerobic threshold, significantly changed their expression in the gastrocnemius muscle (p < 0.05), while high-intensity exercise had no statistically significant effects (p > 0.05), with the heart being immune to exercise influence except when it comes to the Per1 gene, for which expression was increased (p = 0.031) by low-intensity exercise. Additionally, both body weight and lactate thresholds had no change during the experiment (p > 0.05), while the maximum supported workload was maintained for high-intensity exercise (p > 0.05) and increased for low-intensity exercise (p < 0.01), with the control group experiencing a decay instead (p < 0.05). Thus, the present study highlights the importance of chronic exercise in modulating clock genes and opens exciting possibilities for circadian medicine, such as improvements in exercise capacity, heart condition, and lipid metabolism for subjects of low-intensity regimens. Full article

The orexin (hypocretin) system plays a central role in regulating the sleep–wake cycle through two neuropeptides, orexin-A and orexin-B, which act on OX1R and OX2R receptors. Emerging evidence links heightened orexin signaling with the pathophysiology of chronic insomnia. This review outlines the neurobiology of the orexinergic system, compares the pharmacological profile of dual orexin receptor antagonists (DORAs) to traditional GABAergic hypnotics, and evaluates the clinical efficacy and safety of Suvorexant, Lemborexant, and Daridorexant. DORAs function by selectively dampening orexin-driven arousal, thereby facilitating sleep onset and maintenance without disrupting natural sleep architecture. Clinical trials have shown that these agents significantly reduce sleep latency and enhance sleep continuity, with a favorable side effect profile. Overall, DORAs represent a distinct and clinically advantageous option for insomnia treatment, with growing interest in their potential utility across mood, anxiety, and neurodegenerative disorders. Full article

Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST). Methods: We analyzed the proteome in cortical–hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs). Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated. Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression. Full article