Prefrontal–bed nucleus of the stria terminalis physiological and neuropsychological biomarkers predict therapeutic outcomes in depression

Linbin Wang, Yingying Zhang, Yuhan Wang, Qiong Ding, Luling Dai, Kejia Hu, Kuanghao Ye, Xin Lv, Xiaoxiao Zhang, Alekhya Mandali, Luis Manssuer, Saurabh Sonkusare, Yijie Zhao, Peng Huang, Xian Qiu, Yixin Pan, Yijie Lai, Dianyou Li, Wei Liu, Shikun Zhan, Bomin Sun () and Valerie Voon ()
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Linbin Wang: Shanghai Jiao Tong University School of Medicine
Yingying Zhang: Fudan University
Yuhan Wang: Shanghai Jiao Tong University School of Medicine
Qiong Ding: University of Cambridge
Luling Dai: Shanghai Jiao Tong University School of Medicine
Kejia Hu: Shanghai Jiao Tong University School of Medicine
Kuanghao Ye: Shanghai Jiao Tong University School of Medicine
Xin Lv: Shanghai Jiao Tong University School of Medicine
Xiaoxiao Zhang: Shanghai Jiao Tong University School of Medicine
Alekhya Mandali: University of Cambridge
Luis Manssuer: University of Cambridge
Saurabh Sonkusare: University of Cambridge
Yijie Zhao: Fudan University
Peng Huang: Shanghai Jiao Tong University School of Medicine
Xian Qiu: Shanghai Jiao Tong University School of Medicine
Yixin Pan: Shanghai Jiao Tong University School of Medicine
Yijie Lai: Shanghai Jiao Tong University School of Medicine
Dianyou Li: Shanghai Jiao Tong University School of Medicine
Wei Liu: Shanghai Jiao Tong University School of Medicine
Shikun Zhan: Shanghai Jiao Tong University School of Medicine
Bomin Sun: Shanghai Jiao Tong University School of Medicine
Valerie Voon: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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 to assess treatment efficacy and predictors of response. BNST-NAc DBS had a 50% depression response rate and 35% remission rate in the open-label phase. We identified an objective intracranial physiological biomarker using acute and chronic intracranial recordings, machine learning, and an integrated framework combining electrophysiology, neuroimaging, and behavior: lower BNST theta and 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 across eyes -open and -closed states and machine learning. We identified a physiology-guided connectivity network involving 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 refractory depression and has potential broader clinical implications. ClinicalTrials.gov registration: NCT04530942.

Date: 2025
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DOI: 10.1038/s41467-025-65179-z

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