Therefore, we propose a model focusing on taVNS that can act on three pathways that may treat MDD: (1) regulation of the brain–gut axis through activation of the HPA axis; (2) inhibition of TNF-α release by macrophages through the CAP; (3) direct and indirect modulation of the activity of, and connectivity between, the DMN, SN, and reward circuits. Here, TNF is linked to major depressive disorder.