Pathophysiology and neurobiology of insomnia

Chronic insomnia, as defined by the DSM-5 and ICSD-3, is characterized by difficulties falling asleep, maintaining sleep, or waking up too early, occurring at least three times a week for more than three months, with daytime consequences. Long considered a secondary symptom, it is now recognized as a distinct condition resulting from a persistent disruption of sleep-wake regulation. Genetic and epigenetic studies show substantial heritability, suggesting a strong biological influence. More than 500 loci have been identified, linking insomnia to both metabolic and psychiatric traits. Gene-environment interactions, particularly through DNA methylation, may explain how stress can durably alter sleep system reactivity and promote chronicity. Brain imaging research highlights hyperactivation of key regions such as the anterior cingulate cortex, thalamus, insula, and precuneus, which are involved in arousal, vigilance, and emotional regulation. Electroencephalography confirms increased cortical activity, particularly in the beta and alpha bands, reflecting a persistent state of wakefulness during sleep. Explanatory models describe a set of mechanisms in which conditioning, stress reactivity, and co-activation of sleep and wake networks maintain the disorder. Insomnia thus appears as a hybrid state between wakefulness and sleep. These advances underline the complexity of insomnia and the need for integrated therapeutic approaches combining cognitive, behavioral, and physiological interventions to restore normal sleep regulation.