Non-invasive vagus nerve stimulation for the treatment of neurological and psychiatric disorders

Non-invasive vagus nerve stimulation (nVNS), including transcutaneous cervical (tcVNS) and auricular (taVNS) modalities, has emerged as a promising neuromodulatory therapy for a range of neurological and psychiatric disorders. This narrative review synthesizes evidence from over 80 studies, including randomized controlled trials (RCTs), meta-analyses, and observational research, to evaluate the efficacy and mechanisms of nVNS in epilepsy, depression, stroke rehabilitation, headache disorders, Parkinson's disease (PD), and Alzheimer's disease (AD). The review highlights the safety, accessibility, and potential of nVNS as a therapeutic alternative, while addressing challenges such as protocol variability and the need for standardized methodologies.

Introduction
Vagus nerve stimulation (VNS) has evolved from its origins in the late 19th century to become a cornerstone of neuromodulation therapy. Initially developed for drug-resistant epilepsy, its applications have expanded to include treatment-resistant depression, stroke rehabilitation, and exploratory uses in neurodegenerative diseases. Traditional invasive VNS, while effective, is limited by surgical risks. Non-invasive VNS (nVNS), including tcVNS and taVNS, offers a safer, patient-friendly alternative with FDA approvals for cluster headaches and migraines. This review explores the mechanisms, clinical applications, and future directions of nVNS, emphasizing its potential to transform treatment paradigms.

Mechanisms of Non-invasive Vagus Nerve Stimulation
nVNS modulates neural, chemical, and immune pathways through vagal afferent fiber stimulation. Key mechanisms include:

• Neural Modulation: Signals from the vagus nerve reach the nucleus tractus solitarius, influencing the limbic system, cortex, and autonomic centers, enhancing neurotransmitter release (e.g., noradrenaline, serotonin).

• Anti-inflammatory Effects: nVNS suppresses microglial activation and pro-inflammatory cytokines, mitigating neuroinflammation.

• Neuroplasticity: Upregulation of brain-derived neurotrophic factor (BDNF) supports synaptic integrity and recovery.

These multifaceted actions underpin nVNS's therapeutic potential across diverse conditions.

Clinical Applications of nVNS

Epilepsy
nVNS, particularly taVNS, has shown efficacy in reducing seizure frequency and improving quality of life in drug-resistant epilepsy. RCTs report responder rates up to 50%, with minimal adverse effects. However, heterogeneity in stimulation parameters and sham controls necessitates further standardization.

Depression
taVNS demonstrates antidepressant effects comparable to pharmacotherapy, with improvements in mood and symptom severity. Challenges include variability in outcome measures and the need for large-scale trials to confirm long-term benefits.

Post-Stroke Rehabilitation
nVNS enhances motor recovery when paired with rehabilitation, with studies reporting clinically meaningful gains in upper limb function. Innovations like closed-loop systems show promise for synchronizing stimulation with motor intent.

Headache Disorders
tcVNS is FDA-approved for acute and preventive treatment of migraines and cluster headaches. RCTs support its efficacy in pain relief and attack frequency reduction, though taVNS requires further investigation.

Parkinson's Disease
Preliminary evidence suggests nVNS may improve motor and non-motor symptoms in PD, but results are inconsistent. Future research should optimize stimulation protocols to clarify its therapeutic role.

Alzheimer's Disease
taVNS shows potential in improving cognitive function and reducing neuroinflammatory markers in mild cognitive impairment. Preclinical studies highlight its role in modulating amyloid-beta pathways and enhancing memory.

Limitations and Future Directions
Current limitations include methodological heterogeneity, small sample sizes, and a lack of long-term safety data. Future research should prioritize:

• Standardized protocols for stimulation parameters.

• Large-scale, multicenter RCTs with robust clinical endpoints.

• Biomarker development to personalize treatment.

• Mechanistic studies to elucidate nVNS's effects on neural circuits and inflammation.

Conclusion
nVNS represents a transformative, non-pharmacological approach for neurological and psychiatric disorders. Its safety, accessibility, and broad therapeutic potential make it a promising tool for treatment-resistant populations. However, overcoming existing challenges through rigorous research and innovation will be critical for its integration into clinical practice.

Full text:

https://www.xiahepublishing.com/2472-0712/ERHM-2025-00015

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.

Follow us on X: @xiahepublishing

Follow us on LinkedIn: Xia & He Publishing Inc.