Abnormal insular-cingulate hierarchical integration in belief-updating in major depressive disorder

MDD patients displayed hyperactive top-down intrinsic connectivity from the cingulate to lower regions, coupled with weakened bottom-up integration and decreased self-inhibition in ACC/MCC and bilateral anterior insula. Clinical correlation analysis also echoed a positive association between both depression and anxiety severity and top-down cingulate-insular regulation, and a negative association between anxiety severity, lack of pleasure and bottom-up signaling in DCM.

Posterior insula of MDD exhibited blunted PE encoding and reduced self-inhibition during viewing of non-extreme unfair offers. Notably, the glutamate receptor mGluR5 spatially aligned with this insula-cingulate network. By mapping systems-level computational deficits in cognitive rigidity onto a molecular target, these findings provide a mechanistic and translational framework for developing targeted pharmacological and neuromodulatory therapies to restore belief plasticity in MDD.