Bed Nucleus of the Stria Terminalis-Nucleus Accumbens Deep Brain Stimulation for Depression: A Randomized Controlled Trial and an Intracranial Physiological Biomarker Predictor

Therapeutic options for refractory depression are urgently needed. We conducted a deep brain stimulation (DBS) randomized controlled trial of the bed nucleus of the stria terminalis (BNST), an extended amygdala structure, and nucleus accumbens (NAc) in 26 refractory depression patients. BNST-NAc DBS had a 50% depression response rate and 35% remission rate in the open-label phase. Stimulation improved depression, anxiety, quality-of-life and disability more than sham in the blinded controlled trial (-9.8, p < 0.001, 95% CI 6.1–13.5). Lower BNST theta, prefrontal-BNST coherence with top-down connectivity predicted better depression outcomes and quality-of-life after chronic stimulation at 3, 6 and 12 months, confirmed using separate data sets and machine learning. We identified a physiology-guided connectivity network involved dorsal anterior cingulate and lateral inferior frontal cortex tracts. These biomarkers, linked to negative emotional bias and anxiety, highlight the efficacy of BNST-NAc DBS for MDD and has potential broader clinical implications.