Mechanistic insights into combined prefrontal tDCS and vagal nerve stimulation for stress regulation

Stress disrupts prefrontal cortex (PFC) functioning through converging top-down and bottom-up mechanisms, posing a challenge for interventions aimed at restoring adaptive regulation under stress. In this context, this conceptual review explores the mechanistic rationale for combining transcranial direct current stimulation (tDCS) and transauricular vagus nerve stimulation (taVNS) as a dual-modality approach to stress regulation. We first outline the neurobiological substrates of the stress response, focusing on prefrontal dysregulation mediated by the locus coeruleus, norepinephrine (LC-NE) system. We then review the current evidence for tDCS and taVNS as individual tools for modulating stress-related behavioral, physiological, and subjective outcomes. Finally, we develop a mechanistic rationale at multiple levels (cellular, systems, and network) for their combined application, grounded in the state-dependency and priming effects of tDCS. While tDCS modulates top-down cortical excitability via targeted prefrontal stimulation, taVNS activates bottom-up vagal afferents, dampening autonomic hyperarousal and reducing LC-NE activity, as inferred from indirect physiological measures. We propose that taVNS-mediated reduction in autonomic hyperarousal may contribute to a more favorable neural context for tDCS-induced neuroplasticity, with the two techniques engaging complementary regulatory loops that may be difficult to engage simultaneously with either technique alone. Combined tDCS and taVNS represents a theoretically motivated framework with potential for clinical translation, pending systematic empirical validation. Key challenges for the combination include optimizing stimulation timing, sequencing, dosage, and addressing inter-individual variability. Future work should systematically examine synergistic and antagonistic interaction effects and explore clinical translation in populations characterized by prefrontal hypoactivity and autonomic dysregulation.