Heart-Brain Axis Dysregulation in Depression: Mechanisms and Implications for Neuromodulation

Major depressive disorder (MDD) is increasingly recognized as a systemic disorder involving dysregulation of the heart-brain axis (HBA). Mounting evidence links impaired HBA signaling to the pathogenesis of major depressive disorder. Emerging data indicate that neuromodulation-mediated autonomic alterations correlate with depressive symptom remission. Although neuromodulatory therapies are widely deployed clinically, HBA-based biomarkers remain experimental, and no consistent physiological predictors of treatment response have been established to date. This review summarizes HBA dysfunction in depression across neural, biochemical, and mechanical pathways, integrating evidence from preclinical and clinical studies. We critically evaluate recent advances in leveraging these pathways to optimize neuromodulation strategies. Emerging evidence suggests that certain neuromodulation approaches-including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), and deep brain stimulation (DBS)-may modulate heart-brain axis function. It has been hypothesized that such modulation could represent a physiological pathway contributing to mood improvement, providing a rationale for a heart-oriented framework in neuromodulation research. However, the clinical utility of this framework and its underlying biomarkers remain to be established through rigorous long-term investigations. By bridging the conventional conceptual divide between psychiatric and cardiovascular diseases, this review offers a systems-level perspective on neuromodulation efficacy and highlights the potential of HBA-related biomarkers for assessing pathological states and guiding treatment strategies in depression and other psychosomatic conditions.