Fronto-Cingulate Gamma Synchrony Predicts Deep Brain Stimulation Response in Treatment-Resistant Depression: Preliminary Evidence

Background: Gamma-band activity has been linked to cognitive-affective processing in depression. However, its role in deep brain stimulation (DBS) response in treatment-resistant depression (TRD) remains unclear. This exploratory study investigated whether ventral capsule/ventral striatum DBS (VCVS-DBS) modulates gamma activity during cognitive-affective processing and whether DBS-related gamma changes are associated with improvement in depressive symptoms. Methods: Seven participants with TRD completed an affective Multi-Source Interference Task during DBS ON and OFF. Source-localized electroencephalography estimated local gamma power, synchrony, and effective connectivity in fronto-cingulate regions. DBS- and task-related effects were identified with cluster-based permutation testing, and follow-up analyses used Bayesian modelling. Results: During cognitive control under affective context, VCVS-DBS was associated with increased mid-gamma (41–55 Hz) power in left dorsal anterior cingulate cortex (L-dACC) and right ventrolateral prefrontal cortex (R-VLPFC) after affective stimuli. In the time window where power increases overlapped (0.76–0.86 s), DBS was also associated with increased mid-gamma synchrony between these regions. The DBS-related increase in synchrony—not local power—was associated with clinical improvement (Bayesian Spearman ρ = 0.52). Granger causality further indicated that effective connectivity shifted toward greater L-dACC influence over R-VLPFC during DBS. Exploratory cross-validation suggested that DBS-related synchrony change and baseline effective connectivity together accounted for individual differences in clinical improvement. Limitations: The primary limitation was the necessarily small sample size, which was partially addressed using Bayesian analyses leveraging extensive within-participant data. Conclusions: These preliminary findings suggest that VCVS-DBS may engage a fronto-cingulate gamma network involved in cognitive-affective control in TRD. They further suggest that clinical response may depend on both baseline dACC–VLPFC network organization and DBS-related modulation of gamma synchrony, highlighting potential relevance to cognitive-affective regulation across psychiatric disorders. Given the small sample size, these findings should be considered hypothesis-generating and require confirmation in larger cohorts.