Heterogeneous brain alterations in treatment-resistant depression converge on common control networks

Treatment-resistant depression (TRD) imposes a substantial clinical and societal burden. However, it remains unclear whether neuroimaging abnormalities associated with TRD converge onto specific large-scale brain networks. We systematically reviewed neuroimaging articles comparing patients with TRD to both healthy controls (HCs) and patients with non-treatment-resistant depression (non-TRD), encompassing functional and structural imaging modalities. Using a validated coordinate network mapping (CNM) approach and a normative human brain connectome, we derived TRD-associated networks. Overlap analyses with canonical large-scale networks were performed to delineate the functional architecture of these networks. In addition, spatial correlations between TRD-associated probability maps and whole-brain neurotransmitters density maps to explore potential neurochemical substrates. In the TRD-HC contrast, TRD-associated functional and structural networks were distributed across frontal, cingulate, insular, striatal, and thalamic regions, showing their greatest overlap with the frontoparietal (FPN) and cingulo-opercular network (CON). In the TRD-non-TRD contrast, TRD-associated functional and structural networks were more selectively localized, with predominant overlap confined to the CON. Spatial correlation analyses further anchored these network-level abnormalities to glutamatergic, dopaminergic, and monoaminergic neurotransmitter systems. These findings indicate that the general neurobiological burden of TRD is anchored within large-scale control networks involving the FPN and CON, whereas treatment resistance is characterized by more focal alterations within the CON. This network-based dissociation provides insight into the neural organization of TRD and highlights potential circuit-level targets for therapeutic intervention.