Redefining insomnia: from neural dysregulation to personalized therapeutics

Insomnia disorder (ID) is a prevalent and disabling neurological condition, affecting about one in three individuals over the lifespan. It is linked to elevated risks of cognitive decline, psychiatric illness, cardiometabolic conditions, and neurodegenerative disease. Despite being recognized as a distinct clinical entity, ID remains underdiagnosed and undertreated. Traditional diagnostic tools lack sensitivity to the neurobiological complexity of this condition, and current preclinical and clinical models fail to capture its chronic, heterogeneous, and hyperarousal-driven nature adequately. This review integrates interdisciplinary evidence framing insomnia as a disorder of arousal regulation. Key features include persistent hyperactivity in salience and executive control networks, heightened cortical excitability and disrupted emotional processing. This article also presents an examination of how genetic predispositions - particularly polymorphisms in circadian and emotion-related genes such as MEIS1, CLOCK, and PER2-interact with environmental stressors like early-life adversity and prenatal stress. These interactions shape vulnerability through epigenetic modification of stress-regulatory systems. Current treatments, including CBT-I, pharmacotherapy, and emerging neuromodulatory and digital therapeutics, are evaluated with attention to their limitations and potential. Future research should adopt a precision neuroscience approach, moving from symptom-based classifications to biologically informed models. Integrating neurocircuit dysfunction, stress responsivity, and genetic architecture - alongside advanced tools like EEG, neuroimaging, and machine learning - will enable personalized care and novel therapeutic targets.