Suanzaoren decoction and estazolam improve insomnia symptoms by altering insular subregional functional connectivity in chronic insomnia disorder.

Chronic insomnia disorder (CID) is characterized by dysregulation of the insula, a key hub integrating emotional, cognitive, and autonomic processes. This study investigated insular subregional functional connectivity (FC) abnormalities in CID, longitudinal FC modulation following treatment with Suanzaoren Decoction (SZRD) or estazolam, and the associated molecular signatures. We recruited 82 patients with CID and 80 healthy controls. Patients underwent clinical assessments and resting-state functional magnetic resonance imaging at baseline and after six weeks of treatment. Twelve insular subregions were defined as seeds for whole-brain FC analyses. Longitudinal treatment effects were examined using mixed-effects models. Spatial correlations between FC alterations and gene expression maps from the Allen Human Brain Atlas were analyzed. At baseline, CID patients exhibited increased FC between the hypergranular insula and the opercular part of the left inferior frontal gyrus (IFG). Following treatment, both the SZRD and estazolam groups showed enhanced FC between the left hypergranular insula and the bilateral anterior cingulate cortex, and between the right dorsal agranular insula and the right mid/posterior cingulate cortex. Estazolam treatment was further associated with decreased FC between the left dorsal agranular insula and the left cerebellar lobule VI, and increased FC with the bilateral precuneus. Gene enrichment analysis indicated that the identified genes were significantly involved in fatty acid transport, neuronal ensheathment, and early endosome localization. CID is characterized by aberrant insular-IFG connectivity. Both SZRD and estazolam effectively modulate the insular subregional FC, and functional alterations are linked to specific transcriptomic profiles.