Subcallosal cingulate functional connectivity in depression: a systematic review of brain stimulation–induced changes and pretreatment connectivity predictors

Major depressive episode (MDE) is a common mental disorder that severely impacts patients' lives and carries a high suicide risk. About 30% of patients are resistant to oral antidepressants, necessitating alternative approaches such as neurostimulation. The subcallosal cingulate (SCC), characterized by hyperactivity and altered functional connectivity (FC) in MDE, has emerged as a key target for interventions like deep brain stimulation (DBS) and transcranial focused ultrasound stimulation (TUS). Other techniques, including repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), may influence SCC activity indirectly via network-level effects. We searched multiple databases for studies investigating changes in SCC connectivity following various neurostimulation techniques in depression. We included 28 studies using resting-state functional MRI to investigate SCC FC changes following neurostimulation for depression with different modalities: ECT, DBS, rTMS, tDCS, TUS. Results showed high variability across studies. rTMS targeting the DLPFC modulated SCC FC with the OFC, precuneus, and default mode network (DMN), while other targets affected connectivity with the hippocampus and supramarginal gyrus. Stronger baseline anticorrelation between SCC and DLPFC predicted better rTMS response. ECT studies reported heterogeneous effects, involving the temporal pole and vmPFC. TUS targeting SCC increased FC with the DLPFC, whereas TUS to the DLPFC enhanced FC between SCC subregions and mPFC or cerebellum. Findings remain heterogeneous, likely due to methodological inconsistencies, including variability in SCC ROI definitions and stimulation protocols. Standardizing analysis methods is essential to improve reproducibility and clarify the SCC's role in treatment response.