Abstract
BACKGROUND: Repetitive negative thinking (RNT) in major depressive disorder (MDD) involves persistent focus on negative self-related experiences. Resting-state fMRI shows that the functional connectivity (FC) between the insula and the superior temporal sulcus is critical to RNT intensity. This study examines how insular FC patterns differ between resting-state and RNT-induction in MDD and healthy participants (HC). METHODS: Forty-one individuals with MDD and twenty-eight HCs (total n=69) underwent resting-state and RNT-induction fMRI scans. Seed-to-whole brain analysis using insular subregions as seeds was performed. RESULTS: No diagnosis-by-run interaction effects were observed across insular subregions. MDD participants showed greater FC between bilateral anterior, middle, and posterior insular regions and the cerebellum (z = 4.31 to 6.15). During RNT-induction, both MDD and HC participants demonstrated increased FC between bilateral anterior and middle insula and key brain regions, including prefrontal cortices, parietal lobes, posterior cingulate cortex, and medial temporal gyrus, encompassing the STS (z = 4.47 to 8.31). Higher trait-RNT was associated with increased FC between the right dorsal anterior and middle insula and regions in the DMN and salience network in MDD participants (z = 4.31 to 6.15). Greater state-RNT scores were linked to increased FC in similar insular regions, the bilateral angular gyrus and right middle temporal gyrus (z = 4.47 to 8.31). CONCLUSIONS: Hyperconnectivity in insula subregions during active rumination, especially involving the DMN and salience network, supports theories of heightened self-focused and negative emotional processing in depression. These findings emphasize the neural basis of RNT when actively elicited in MDD.