Altered Connectivity of Locus Coeruleus in Insomnia Disorder During Wakefulness and NREM Sleep

ABSTRACT Insomnia disorder (ID) frequently coexists with substantial psychiatric comorbidity, particularly anxiety and depression. The neurobiological mechanisms underlying the association between ID and emotional dysregulation remain incompletely understood. The locus coeruleus (LC), a pontine nucleus within the ascending reticular activating system, plays a crucial role in sleep–wake regulation and emotional processing. Here, we acquired simultaneous electroencephalography and functional magnetic resonance imaging (EEG‐fMRI) data from 37 patients with ID and 30 healthy controls (HCs) during their nocturnal sleep. Group‐by‐stage interactions in LC‐based functional connectivity (FC) were assessed using a linear mixed‐effects model. Associations were evaluated between FC patterns and the Pittsburgh sleep quality index (PSQI), the self‐rating depression scale (SDS) and the self‐rating anxiety scale (SAS). Significant group‐by‐stage interactions were observed in multiple brain regions, including the cingulate cortex, right insular cortex, left temporal cortex and left insular cortex. Post hoc analyses revealed that patients with ID exhibited significantly enhanced FC between the LC and cingulate cortex during N2 sleep compared to HCs ( p = 0.023). In the pooled sample, N2‐specific LC–cingulate cortex connectivity strength demonstrated significant positive correlations with both SDS scores ( r = 0.337, p = 0.018) and PSQI scores ( r = 0.401, p = 0.003). In conclusion, the observed alterations in LC–cingulate cortex FC during N2 sleep suggest a distinct neural circuit that may underlie the dysregulation of emotional processing in ID. These findings may provide insights into neurobiological mechanisms in ID.