Intra- and Inter-Network connectivity of the default mode network differentiates Treatment-Resistant depression from Treatment-Sensitive depression

Understanding why some patients with depression remain resistant to antidepressant medication could be elucidated by investigating their associated neural features. Although research has consistently demonstrated abnormalities in the anterior cingulate cortex (ACC) – a region that is part of the default mode network (DMN) − in treatment-resistant depression (TRD), a considerable research gap exists in discerning how these neural networks distinguish TRD from treatment-sensitive depression (TSD). We aimed to evaluate the resting-state functional connectivity (rsFC) of the ACC with other regions of the DMN to better understand the role of this structure in the pathophysiology of TRD. 35 TRD patients, 35 TSD patients, and 38 healthy controls (HC) underwent a resting-state functional MRI protocol. Seed-based functional connectivity analyses were performed, comparing the three groups for the connectivity between two subregions of the ACC (the subgenual ACC (sgACC) and the rostral ACC (rACC)) and the DMN (p < 0.05 FWE corrected). Furthermore, inter-network connectivity of the DMN with other neural networks was explored by independent component (ICA) analyses (p < 0.01, FDR corrected). The results demonstrated hyperconnectivity between the rACC and the posterior cingulate cortex in TRD relative to TSD and HC (F(2,105) = 5.335, p < 0.05). ICA found DMN connectivity to regions of the visual network (TRD<TSD) and a parietal region of the DMN (TRD>TSD), differentiating the two clinical groups. These results provide confirmatory evidence of DMN hyperconnectivity and preliminary evidence for its interactions with other neural networks as key neural mechanisms underlying treatment non-responsiveness.