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

Overcoming treatment resistance in major depressive disorder (MDD) requires addressing the core cognitive drivers of the disease, particularly the rigid negative beliefs that resist updating. However, the exact macro-network and molecular mechanisms underlying this cognitive rigidity remain poorly defined, hindering the development of targeted interventions. Here, we investigated whether impaired belief updating in MDD stems from an imbalance between top-down processing of prior beliefs and bottom-up integration of prediction errors (PEs) in the insular-cingulate network. Using task-based fMRI during an ultimatum game combined with computational modeling and dynamic causal modeling, we evaluated 69 unmedicated patients with MDD and 62 healthy controls. MDD patients exhibited impaired belief adjustment, indicated by reduced learning rates. Dynamic causal modeling of the insula-cingulate-sensory network revealed a systematic disruption in hierarchical processing. 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.