Lateralization of the sgACC‐Based Neural Network in Treatment‐Resistant Depression

Background While the left subgenual anterior cingulate cortex (sgACC) is a validated target for treating major depressive disorder (MDD) (e.g., with rTMS), the therapeutic relevance of the right sgACC is unknown. Given emerging evidence that treatment‐resistant depression (TRD) and non‐TRD (nTRD) may involve distinct neural circuits, a more precise, circuit‐based understanding is needed. This study, therefore, sought to determine the degree of sgACC functional lateralization and to elucidate TRD‐specific neural mechanisms, thereby informing the development of targeted neuromodulation therapies. Methods Resting‐state fMRI (rs‐fMRI) data were acquired for 20 patients with TRD, 53 patients with nTRD, and 51 healthy controls (HCs). Analysis was performed to compare the static functional connectivity (sFC), dynamic functional connectivity (dFC), and effective connectivity via Granger causality analysis (GCA) of left and right sgACC between the three groups, followed by clinical correlation analyses. Results Group analysis revealed significant sFC and dFC between left sgACC and temporal pole (TP), fusiform gyrus (FG), parahippocampal gyrus (PHG), and orbitofrontal cortex (OFC), and between right sgACC and cerebellum posterior lobule (CPL) and right dorsolateral prefrontal cortex (DLPFC.R). Furthermore, GCA showed increased effective connectivity between bilateral sgACC and left caudate (CAU.L), left thalamus (THA.L), right postcentral gyrus (PoCG.R), and DLPFC.L. Compared to the nTRD group the TRD group showed decreased sFC and dFC between sgACC and DLPFC and cerebellum, along with decreased effective connectivity between sgACC and CAU and DLPFC, indicating disrupted fronto‐limbic and cerebellar circuits in TRD. Conclusion The distinct sgACC‐centered connectivity profiles of TRD and nTRD delineate a neurobiological continuum across MDD subtypes, pinpointing the sgACC, DLPFC, CAU, and cerebellum as key circuit targets for individualized neuromodulation in TRD.