Deep brain stimulation and neuroimmune mechanisms in major depressive disorder

Major depressive disorder (MDD) is increasingly associated with neuroinflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and disrupted neuroimmune interactions mediated by cytokine signaling aberrations, glial dysfunction, inflammasome activation, and impaired neuroplasticity. Within this pathophysiological context, deep brain stimulation (DBS) has emerged as a promising neuromodulatory intervention for treatment-resistant depression (TRD), though its underlying biological mechanisms remain poorly elucidated. This review systematically examines the role of neuroinflammation in MDD, with a specific focus on HPA axis-immune crosstalk, cytokine- and inflammasome-dependent signaling pathways, and the regulatory contributions of neuroglial cells to inflammatory cascades and neuroplastic remodeling. We further evaluate the multifaceted biological effects of DBS in depression beyond conventional neural circuit modulation, encompassing its potential modulatory impacts on glial function, neuroplasticity, stress endocrine homeostasis, and neuroimmune signaling. Current preclinical and clinical evidence supports a biologically plausible, clinically testable role of DBS in regulating neuroinflammatory processes in MDD; however, direct clinical evidence validating its anti-inflammatory efficacy remains limited and methodologically heterogeneous. Notably, implantation-induced tissue responses, stimulation-dependent biological alterations, and long-term clinical outcomes represent distinct biological and clinical processes that require differentiated interpretation. By synthesizing empirical findings from preclinical depression models, clinical DBS studies, and convergent neuromodulation research, this review proposes that neuroimmune modulation constitutes a plausible candidate mechanism and potential biomarker framework for DBS efficacy in MDD, rather than a fully established therapeutic pathway. Future longitudinal studies incorporating disease-relevant experimental models, standardized neuroimmune biomarkers, and rigorous clinical trial designs are warranted to clarify whether DBS-associated neuroimmune alterations mediate therapeutic responses, reflect secondary treatment improvements, or arise as nonspecific biological correlates of clinical remission.