The network localization and underlying biological basis of heterogeneous structural and functional brain abnormalities in insomnia disorder

Insomnia disorder (ID) has become a prevalent sleep disorder worldwide, yet its underlying neural mechanisms remain unclear due to heterogeneous neuroimaging findings and uncertain network localization. We identified brain structural and functional abnormality locations associated with ID from 63 published neuroimaging studies, including 3391 patients and 3433 healthy controls. Using coordinate network mapping combined with a normative connectome database, we mapped these abnormalities to large-scale brain networks of ID across imaging modalities and further decoded them by integrating microscale chemo-architectural, cellular, and cognitive maps. The structural network widely involved the ventral attention (VAN), sensorimotor (SMN), dorsal attention (DAN) and default mode network (DMN); the task-induced network showed a similar but less extensive pattern, predominantly implicating the VAN, DMN, SMN and subcortical network (SCN); in contrast, the resting-state network was largely confined to the left middle frontal gyrus and the bilateral mid-cingulate cortex. Molecular mapping revealed both shared and distinct neurotransmitter signatures across the three networks, involving cholinergic, histaminergic, glutamatergic, noradrenergic, and opioid systems. Cellular decoding showed relatively selective associations of the structural and task-based networks with glial cells and excitatory neurons, whereas the resting-state network exhibited broader associations with glial cells and multiple excitatory and inhibitory neuronal subtypes. Cognitive decoding linked structural and task-based networks to sensorimotor processing and the resting-state network to memory-related functions. Our findings reconcile heterogeneous neuroimaging results and reveal neurobiological substrates of ID from a network perspective, providing a promising biomarker and paving the way for circuit-based precision therapies of ID.