Increased insular functional connectivity during repetitive negative thinking in major depression and healthy volunteers.

Background: Repetitive negative thinking (RNT) in major depressive disorder (MDD) involves a persistent focus on negative self-related experiences. Resting-state fMRI shows that the functional connectivity (FC) between the anterior insula and the superior temporal sulcus is associated with RNT intensity. This study examines how insular FC patterns differ between resting state and RNT induction in MDD and healthy control (HC) participants.

Methods: Forty-one individuals with MDD and 28 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 the bilateral anterior, middle, and posterior insular regions and the cerebellum (z = 4.31-6.15). During RNT induction, both MDD and HC participants demonstrated increased FC between bilateral anterior/middle insula and prefrontal cortices, parietal lobes, posterior cingulate cortex (PCC), and medial temporal gyrus, encompassing the STS (z = 4.47-8.31). In exploratory correlation analyses, higher trait RNT was associated with increased FC between the right dorsal anterior/middle insula and the PCC, middle temporal gyrus, and orbital frontal gyrus in MDD participants (z = 4.31-6.15). Greater state RNT was linked to increased FC in similar insular regions, as well as the bilateral angular gyrus and right middle temporal gyrus (z = 4.47-8.31).

Conclusions: Hyperconnectivity in insula subregions during active rumination, especially involving the default mode network 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.