*Review* **A Decade of Progress in Deep Brain Stimulation of the Subcallosal Cingulate for the Treatment of Depression**

**Sharafuddin Khairuddin 1,**†**, Fung Yin Ngo 1,**†**, Wei Ling Lim 1,2, Luca Aquili 3, Naveed Ahmed Khan 4, Man-Lung Fung 1, Ying-Shing Chan 1, Yasin Temel 5 and Lee Wei Lim 1,2,\***


Received: 14 August 2020; Accepted: 28 September 2020; Published: 12 October 2020

**Abstract:** Major depression contributes significantly to the global disability burden. Since the first clinical study of deep brain stimulation (DBS), over 446 patients with depression have now undergone this neuromodulation therapy, and 29 animal studies have investigated the e fficacy of subgenual cingulate DBS for depression. In this review, we aim to provide a comprehensive overview of the progress of DBS of the subcallosal cingulate in humans and the medial prefrontal cortex, its rodent homolog. For preclinical animal studies, we discuss the various antidepressant-like behaviors induced by medial prefrontal cortex DBS and examine the possible mechanisms including neuroplasticity-dependent/independent cellular and molecular changes. Interestingly, the response rate of subcallosal cingulate Deep brain stimulation marks a milestone in the treatment of depression. DBS achieved response and remission rates of 64–76% and 37–63%, respectively, from clinical studies monitoring patients from 6–24 months. Although some studies showed its stimulation e fficacy was limited, it still holds grea<sup>t</sup> promise as a therapy for patients with treatment-resistant depression. Overall, further research is still needed, including more credible clinical research, preclinical mechanistic studies, precise selection of patients, and customized electrical stimulation paradigms.

**Keywords:** deep brain stimulation; treatment-resistant depression; major depressive disorder; subcallosal cingulate; medial prefrontal cortex
