Review of the Dual-Axis Regulatory Framework Unifying Vagus Nerve Stimulation Mechanisms Across Central and Peripheral Disorders

Vagus nerve stimulation (VNS) is a versatile neuromodulatory modality with demonstrated efficacy across diverse central and peripheral disorders, yet a unifying mechanistic framework reconciling its central neuromodulatory and peripheral somatic actions remains elusive. This review proposes a dual‑axis regulatory paradigm centered on the nucleus of the solitary tract (NTS) as the core signal integration hub, synthesizing preclinical and clinical evidence to systematically unify VNS mechanisms across brain‑derived and systemic diseases. The ascending afferent‑dominant brain regulatory axis mediates therapeutic effects in drug‑resistant epilepsy, treatment‑resistant depression, and ischemic stroke via a conserved NTS‑mediated neurotransmitter‑cytokine cascade: it drives norepinephrine and serotonin release to rebalance neural excitatory‑inhibitory homeostasis, suppresses NF‑κB‑dependent neuroinflammation, and activates BDNF/TrkB signaling to promote neuroplasticity and neuronal survival. The descending efferent‑mediated visceral regulatory axis targets rheumatoid arthritis, functional dyspepsia, and atrial fibrillation (under low‑intensity stimulation paradigms) through a neural‑immune‑target organ synergistic axis, with core actions including cholinergic anti‑inflammatory pathway activation, sympathovagal balance restoration, and stabilization of tissue electrophysiological and structural homeostasis, exhibiting disease‑specific functional dominance. This dual‑axis framework resolves the mechanistic heterogeneity of VNS across central and peripheral pathologies, delineates hierarchical therapeutic circuits, and provides a mechanistic foundation for clinical indication expansion and precision neuromodulation strategies.