Insomnia disorder (ID) is a common sleep–wake disorder characterized by persistent difficulty initiating or maintaining sleep, early-morning awakening, or non-restorative sleep, accompanied by daytime functional impairment. ID has traditionally been explained by the hyperarousal model, which emphasizes cognitive, emotional, cortical, neuroendocrine, and autonomic overactivation. However, this model alone does not fully account for the chronic persistence, relapse tendency, and multisystem associations of ID. Emerging evidence suggests that circadian rhythm disruption, impaired melatonin signaling, hypothalamic–pituitary–adrenal (HPA) axis activation, autonomic imbalance, and low-grade inflammation may also contribute to the development and maintenance of ID. Available evidence indicates that sleep disturbance is more consistently associated with selected inflammatory markers, particularly C-reactive protein (CRP) and interleukin-6 (IL-6), whereas findings for tumor necrosis factor-alpha (TNF-α) remain less consistent. The circadian system regulates sleep, endocrine function, metabolism, and immune-inflammatory activity through the suprachiasmatic nucleus, melatonin and cortisol rhythms, peripheral clock genes, and rhythmic immune-cell responses. Disruption of this temporal network may alter melatonin secretion, inflammatory rhythmicity, and stress-related neuroendocrine responses, thereby contributing to the persistence of insomnia symptoms. Compared with previous reviews that have separately discussed hyperarousal, circadian rhythm disruption, melatonin signaling, or sleep-related inflammation, this review integrates these processes into a circadian–immune perspective for understanding ID. We summarize alterations in sleep–wake rhythms, melatonin signaling, HPA-axis activity, autonomic regulation, and immune-inflammatory responses in ID, and discuss potential intervention strategies, including light management, melatonin and melatonin receptor agonists, cognitive behavioral therapy for insomnia (CBT-I), physical activity, time-restricted eating, and stress management. This review aims to provide a mechanistic basis for understanding the chronicity and heterogeneity of ID and for developing individualized intervention strategies.
Yini Huang, Xiuying Wang, Xiang-Jiao Chen et al.· Frontiers in Neuroscience· 0 citations
Insomnia disorder is one of the most common sleep disorders and is traditionally conceptualized in terms of hyperarousal, altered sleep homeostasis, and cognitive-behavioral perpetuating factors. The two-process model of sleep regulation indicates that sleep initiation and maintenance depend not only on homeostatic sleep pressure but also on circadian phase, amplitude, and stability. Evidence suggests that some patients presenting with insomnia complaints have misalignment between endogenous circadian phase and the intended sleep window, whereas others show reduced rest-activity amplitude, increased sleep-timing variability, or abnormal light exposure patterns. This narrative review integrates clinical, measurement, mechanistic, and intervention evidence on circadian dimensions in insomnia disorder and proposes a candidate circadian phenotyping framework for future validation. The framework combines sleep diaries, actigraphy, light exposure assessment, dim-light melatonin onset (DLMO), and core body temperature rhythms to distinguish circadian rhythm sleep-wake disorder (CRSWD)-dominant insomnia complaints, insomnia disorder with circadian modifiers, and comorbid insomnia disorder and CRSWD. Cognitive behavioral therapy for insomnia (CBT-I) remains first-line treatment. Fixed wake time, morning light, evening light restriction, timed low-dose melatonin, scheduled activity, and multicomponent approaches are positioned as candidate adjunctive modules to be tested in phenotype-stratified trials. These phenotypes are not diagnostic categories, clinical decision algorithms, or treatment guidelines. The review instead translates circadian evidence in insomnia into testable propositions, including provisional phenotype definitions, recommended measurement strategies, falsifiable predictions, and future trial designs. Operational thresholds, reproducibility, predictive validity, incremental treatment benefit, optimal parameters, safety, implementation feasibility, and cost-effectiveness require prospective phenotype-stratified randomized trials and long-term follow-up.
Shasha Zhang, Yan Liu, Jinzhi Tan et al.· Frontiers in Psychiatry· 0 citations