# A Review of Vagus Nerve Stimulation for Disease: Comprehensive Theory and Evidence for Mechanisms of Action

## TL;DR

This paper reviews how vagus nerve stimulation affects various body systems and offers insights into its mechanisms and future improvements.

## Contribution

The paper provides a unified synthesis of VNS mechanisms across multiple organ systems, addressing a critical gap in the field.

## Key findings

- VNS modulates functions through neuromodulator release, synaptic plasticity, and autonomic regulation.
- The review identifies limitations like biological heterogeneity and proposes innovations such as AI-guided personalization.
- It serves as a foundational resource for advancing bioelectronic medicine and precision neuromodulation.

## Abstract

Vagus nerve stimulation (VNS) is an established neuromodulatory therapy approved for epilepsy, depression, obesity, stroke rehabilitation, rheumatoid arthritis, migraine, and cluster headaches. Its therapeutic potential has expanded dramatically, with growing evidence supporting its efficacy across a wide spectrum of neurological, psychiatric, cardiovascular, immunological, metabolic, and gastrointestinal disorders. Despite this progress, the field has lacked a comprehensive synthesis that unifies mechanistic insights with translational applications across organ systems. This review addresses that gap by systematically integrating current knowledge in the multifactorial mechanisms through which VNS modulates central and peripheral functions, including neuromodulator release, synaptic plasticity, autonomic regulation, neuroimmune control, and endocrine integration. In addition, this review identifies key limitations of VNS, including biological heterogeneity, technical constraints, and methodological variability, and proposes future innovations such as selective fiber targeting, closed‐loop systems, and artificial intelligence‐guided personalization. By providing a rigorous, system‐level overview of VNS mechanisms and their translational relevance, this article serves as a foundational resource for advancing the science and clinical deployment and helping illustrate future directions for precision neuromodulation and bioelectronic medicine.

Vagus nerve stimulation (VNS) effects span central and peripheral organ systems through diverse mechanistic pathways. This comprehensive review provides a unified synthesis of these mechanisms across neurological, cardiovascular, immunological, metabolic, and gastrointestinal domains, filling a critical gap and serving as a foundational resource for bioelectronic medicine.