**9. Conclusions**

Major depressive disorder is a debilitating psychiatric condition, which is a ffected by treatment resistance. Although safety concerns were raised on the risks of ablative treatment, it paved the way for deep brain stimulation as an adjustable therapy against depression. This review summarized the e fficacies of deep brain stimulation in the subcallosal cingulate, one of the most extensively studied targets of stimulation, and in the ventromedial prefrontal cortex, which is the rodent homolog. Research on DBS initially focused on symptomatic relief. As the decades have progressed, studies have started to branch out and utilize modern technology to improve targeting of brain regions and to investigate a broader list of symptoms in patients. This has allowed us to better understand the impact of DBS on underreported parameters, such as heart rate, skin conductance, and brain waveforms. Additionally, preclinical research has expanded our understanding of the molecular factors modulated by stimulation. Besides the local e ffects, DBS has been shown to modulate distal structures, which can involve numerous projections to and from the stimulated targets, and can contribute to the antidepressant e ffects. This review also described some of the neuroplasticity-dependent and -independent changes brought about by DBS. Progress in di fferent areas of research has helped lay the groundwork for the next wave of DBS research investigating more targeted and more e ffective applications of DBS for treating MDD. Last but not least, with further customization, more precise approaches, and more stringent regulation, it is anticipated that deep brain stimulation has grea<sup>t</sup> promise to treat severe, refractory depressive disorders in the near future.

**Author Contributions:** Methodology, Investigation, Formal Analysis, Data Curation, Visualization, & Writing-Original Draft Preparation, Review & Editing: S.K., F.Y.N. and L.W.L.; Conceptualization, Supervision, Project Administration, Resources, & Funding Acquisition: L.W.L.; Validation: S.K., L.A., W.L.L. & L.W.L.;

Manuscript Intellectual Inputs: W.L.L., L.A., N.A.K., M.-L.F., Y.-S.C. and Y.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This scientific work was funded by grants from the Hong Kong Research Grants Council (27104616; 17119420) and the University of Hong Kong Seed Funding for Basic Research awarded to L.W.L.

**Conflicts of Interest:** The authors declare no conflict of interest.
