Redefining insomnia: from neural dysregulation to personalized therapeutics

Insomnia disorder (ID) affects nearly one in three individuals across the lifespan and confers elevated risk for cognitive decline, psychiatric illness, cardiometabolic disease, and neurodegeneration. Despite its recognition as a distinct clinical entity, ID remains underdiagnosed and undertreated. Current diagnostic frameworks fail to capture its neurobiological complexity, and available models inadequately reflect its chronic, heterogeneous, and hyperarousal-driven nature.

We advance the view that ID is fundamentally a disorder of arousal regulation. Converging evidence implicates persistent hyperactivity in salience and executive networks, heightened cortical excitability, and disrupted emotional processing. Genetic susceptibility-most notably polymorphisms in MEIS1, CLOCK, and PER2-interacts with environmental exposures such as prenatal stress and early-life adversity. These gene-environment interactions recalibrate stress-regulatory systems through epigenetic mechanisms, shaping enduring vulnerability. Existing treatments, including CBT-I, pharmacotherapy, neuromodulation, and digital therapeutics, remain limited in their mechanistic precision and generalizability.

The field requires a decisive shift from symptom-based classification toward precision neuroscience. Integrating circuit-level dysfunction, stress responsivity, and genetic architecture with advanced EEG, neuroimaging, and machine learning will enable biologically grounded subtyping. Such an approach is essential to deliver personalized interventions, identify novel therapeutic targets, and ultimately redefine care in insomnia disorder.