Clustering depression subgroups based on dorsolateral prefrontal-subgenual anterior cingulate cortex peak functional connectivity reveals different symptom profiles and TMS treatment outcomes

Abstract Background Aberrant functional connectivity (FC) between the left dorsolateral prefrontal cortex (DLPFC) and subgenual anterior cingulate cortex (sgACC) is a replicated neural correlate of major depressive disorder (MDD). Emerging evidence suggests that individualized DLPFC-sgACC peak connectivity profiles may optimize transcranial magnetic stimulation (TMS) targeting and therapeutic outcomes. We hypothesized that the heterogeneity of DLPFC-sgACC peak FC locations could serve as a neurological basis for classifying distinct MDD subgroups. Methods We recruited 120 patients with MDD and used resting-state functional magnetic resonance imaging (MRI) to identify the peak of DLPFC-sgACC FC. Using the personalized peaks’ spatial distribution, we clustered patients with MDD into subgroups and compared between-subgroup depressive and anxiety profiles. The classification performance of different clinical profiles between the subgroups was evaluated. The TMS therapeutic outcomes were retrospectively compared between these two subgroups in a small subsample of 37 patients who completed TMS treatment. Results The personalized DLPFC-sgACC peaks of patients with MDD were spread widely within the left DLPFC, clustering into the anterior (73.3%) and posterior (26.7%) subgroups. Peaks in the anterior subgroup were closer to the group-averaged peak, whereas peaks in the posterior subgroup were localized in the posterior DLPFC. The two subgroups showed comparable depressive symptom severity; however, the posterior subgroup showed more severe anxiety symptoms. The clustering of MDD subgroups demonstrated robust consistency across two datasets and different radii parameters. The logistic regression classifier based on the clinical profiles with between-subgroup differences showed good discrimination (AUC = 0.83). The anterior subgroup exhibited greater improvements in the anxiety and depressive symptoms than the posterior subgroup after receiving anterior DLPFC-targeted TMS treatment in the subsample. Conclusions Our findings suggest two distinct MDD subgroups characterized by differential spatial distribution of personalized DLPFC-sgACC peak FC. These subgroups demonstrate clinical differences in both anxiety symptom severity and TMS therapeutic outcomes, warranting validation through large-sample prospective studies in the future.