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

Figures

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  Figure 1. Schematic representation of the heart-brain autonomic circuitry and major neuromodulation intervention sites. The central panel depicts selected cortical and subcortical components of the central autonomic network and bidirectional cardiac-neural communication through sympathetic, vagal afferent, and vagal efferent pathways. The surrounding panels summarize the principal targets and HBA-relevant effects of TMS, TES, VNS, ECT, and DBS. TMS and TES are presented as predominantly top-down cortical approaches, VNS as a bottom-up autonomic approach, and ECT and DBS as network-level approaches. VNS has the most direct mechanistic link to HBA engagement, whereas evidence for HBA-specific effects of TMS, TES, ECT, and DBS is more indirect or heterogeneous. Created with BioRender.com.

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  Figure 2. Neural, biochemical, and mechanical pathways implicated in heart-brain axis dysfunction in depression. The schematic summarizes central, interface, and peripheral alterations across neural, biochemical, and mechanical domains. In the neural pathway, blue arrows denote predominantly descending brain-to-heart signaling, whereas the red arrow denotes ascending heart-to-brain feedback. Horizontal arrows in the biochemical pathway indicate proposed directions of signaling or interaction. Upward and downward arrows adjacent to text indicate relative increases and decreases, respectively, compared with non-depressed controls or the relevant reference condition. Human studies provide predominantly observational evidence for autonomic and HRV abnormalities, HPA-axis and inflammatory alterations, interoceptive abnormalities, and regional perfusion changes. Baroreflex findings are heterogeneous across clinical samples, and the causal sequences linking the depicted domains remain unestablished. Cardiac mitochondrial and Ca2+-handling mechanisms, and particularly mechanosensitive neural transduction, are supported mainly by indirect or preclinical evidence; the mechanosensitive pathway should…