Subgenual Cingulate Functional Connectivity Predicts Neuromodulation Response in Depression: A Systematic Review

Resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) may predict the response to neuromodulation in major depressive disorder (MDD). We conducted a systematic review of studies examining pretreatment sgACC rsFC and subsequent neuromodulation outcomes in adults (ages 18-70 years) with MDD. Ovid MEDLINE, Embase, and APA PsycInfo were searched from inception to May 2, 2025 (PROSPERO: CRD420251038212). The primary outcome was the association between pretreatment sgACC rsFC and changes in depressive symptoms. Study quality was assessed using National Institutes of Health tools and established neuroimaging quality checklists. Reported sgACC coordinates were classified descriptively by analytic role; no inferential coordinate-based meta-analysis was performed. Twenty-two studies (N = 1366 participants) met the inclusion criteria. Greater baseline sgACC-right dorsolateral prefrontal cortex rsFC was associated with reduced symptom improvement in some studies, whereas stronger sgACC-medial orbitofrontal cortex rsFC was associated with greater improvement. Associations were reported most often in repetitive transcranial magnetic stimulation (rTMS) studies, particularly with individualized targeting, but several studies were null. Reported sgACC coordinates were predominantly investigator-defined seed or region-of-interest locations and were not treated as response-associated peaks. The methodological quality of magnetic resonance imaging was adequate (mean = 16.1/20, range 13-18). Pretreatment sgACC-prefrontal rsFC may help predict the neuromodulation response in MDD, particularly in rTMS studies using individualized targeting. However, the findings were heterogeneous, and the available coordinate evidence did not support inferential spatial convergence analysis. Larger prospective studies are needed to establish reproducibility and clinical utility.