Peer-Reviewed Research
Evidence Database
A curated collection of peer-reviewed research on vagus nerve stimulation. Search by condition, study type, or keyword to explore the evidence.
Transcutaneous auricular vagus nerve stimulation in insomnia: a systematic review and meta-analysis
De Oliveira et al. · Neuromodulation · 2025
Pooling data from six studies, taVNS significantly improved PSQI scores (MD = -3.60) and Insomnia Severity Index scores (MD = -5.24), with improvements across multiple sleep dimensions and minimal adverse effects.
Bilateral transcutaneous auricular vagus nerve stimulation for the treatment of insomnia in breast cancer
Do et al. · Scientific Reports · 2025
Nightly bilateral taVNS over two weeks significantly reduced insomnia severity, improved sleep quality, decreased cancer-related fatigue and depression, and increased HRV in breast cancer patients.
Vagus nerve stimulation in autoimmune conditions: a systematic review
Lombo et al. · ACR Open Rheumatology · 2025
Across 12 clinical trials of VNS in autoimmune conditions, more than half found reductions in pro-inflammatory cytokines, with IL-6 most consistently reduced (6 of 7 studies).
Transcutaneous auricular vagus nerve stimulation for post-stroke depression: a double-blind, randomized, placebo-controlled trial
Liu et al. · Journal of Affective Disorders · 2024
taVNS combined with conventional treatment significantly improved depression scores in post-stroke depression patients compared to sham, expanding potential applications beyond primary MDD.
Transcutaneous auricular vagus nerve stimulation modulating the brain topological architecture of functional network in major depressive disorder: an fMRI study
Guo et al. · Brain Sciences · 2024
Four weeks of taVNS increased global efficiency and decreased characteristic path length in functional brain networks of MDD patients, with changes in network topology correlating with depression score improvements.
Transcutaneous auricular vagus nerve stimulation for chronic insomnia disorder: a randomized clinical trial
Zhang et al. · JAMA Network Open · 2024
Active taVNS achieved a mean PSQI reduction of 8.2 points versus 3.9 for sham (Cohen's d = 1.2) in chronic insomnia, with benefits sustained over 20 weeks and no serious adverse effects.
No consistent evidence for the anti-inflammatory effect of vagus nerve stimulation in humans: a systematic review and meta-analysis
Schiweck et al. · Brain, Behavior, and Immunity · 2024
Meta-analysis of 26 studies found no consistent evidence for anti-inflammatory effects of VNS in humans, highlighting the gap between compelling preclinical data and more equivocal clinical results.
Transcutaneous vagus nerve stimulation has no anti-inflammatory effect in diabetes
Okdahl et al. · Scientific Reports · 2024
Transcutaneous cervical VNS did not reduce plasma concentrations of inflammatory cytokines (IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma) in patients with diabetes over 56 days of treatment.
The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: a systematic review and meta-analysis of randomized controlled trials
Tan et al. · Journal of Affective Disorders · 2023
Pooled analysis of RCTs found that taVNS significantly reduced depression scores compared to sham stimulation, with moderate effect sizes and fewer side effects than antidepressants.
Transcutaneous auricular vagus nerve stimulation (ta-VNS) for treatment of drug-resistant epilepsy: a randomized, double-blind clinical trial
Yang et al. · Neurotherapeutics · 2023
At 20 weeks, the responder rate and relative seizure frequency reduction were significantly higher in the active taVNS group compared to controls, supporting non-invasive VNS for drug-resistant epilepsy.
Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis
Kim et al. · Scientific Reports · 2022
Across 177 studies and 6,322 subjects, taVNS was generally well-tolerated with mild and transient side effects. Serious adverse events were rare and not clearly attributable to stimulation.
Transcutaneous vagus nerve stimulation could improve the effective rate on the quality of sleep in the treatment of primary insomnia: a randomized control trial
Wu et al. · Brain Sciences · 2022
One month of taVNS improved the effective rate of treatment for primary insomnia compared to sham, adding to evidence that taVNS produces clinically meaningful improvements in sleep quality.
Manipulation of the inflammatory reflex as a therapeutic strategy
Kelly et al. · Cell Reports Medicine · 2022
Comprehensive review of how the inflammatory reflex operates through vagal and splenic nerve signalling to modulate macrophage cytokine production via alpha7 nicotinic receptors.
Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial
Dawson et al. · The Lancet · 2021
VNS paired with rehabilitation significantly improved upper limb motor function compared to rehabilitation with sham stimulation in chronic stroke patients at 90 days.
Direct and Transcutaneous Vagus Nerve Stimulation for Treatment of Tinnitus: A Scoping Review
Yakunina & Nam · Frontiers in Neuroscience · 2021
Both direct and transcutaneous VNS show potential for tinnitus treatment, with evidence suggesting that VNS combined with sound therapy may reduce tinnitus severity.
Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress
Bremner et al. · Journal of Affective Disorders Reports · 2021
Transcutaneous cervical VNS reduced PTSD symptom severity by 17% and attenuated interleukin-6 inflammatory responses to stress in patients with PTSD.
Effects of transcutaneous auricular vagus nerve stimulation on brain functional connectivity of medial prefrontal cortex in patients with primary insomnia
Zhang et al. · Anatomical Record · 2021
taVNS altered functional connectivity of the medial prefrontal cortex in patients with primary insomnia, providing a neuroimaging correlate for the sleep-improving effects of vagal stimulation.
Effect of Transcutaneous Vagus Nerve Stimulation at Auricular Concha for Insomnia: A Randomized Clinical Trial
Jiao et al. · Evidence-Based Complementary and Alternative Medicine · 2020
Four weeks of taVNS significantly improved Pittsburgh Sleep Quality Index scores and sleep efficiency in patients with chronic insomnia compared to sham stimulation.
The Impact of Auricular Vagus Nerve Stimulation on Pain and Life Quality in Patients with Fibromyalgia Syndrome
Kutlu et al. · BioMed Research International · 2020
Auricular VNS was evaluated alongside exercise therapy in fibromyalgia patients, with improvements observed in select quality-of-life subparameters over 4 weeks of treatment.
Transcutaneous vagus nerve stimulation reduces spontaneous but not induced negative thought intrusions in high worriers
Burger et al. · Biological Psychology · 2019
taVNS reduced spontaneous negative thought intrusions in high worriers compared to sham stimulation, suggesting vagal afferent pathways may modulate anxiety-related rumination.
Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa)
Hong et al. · International Journal of Colorectal Disease · 2019
Transcutaneous auricular VNS modulated gastrointestinal muscle activity as measured by electromyography, supporting its therapeutic potential for gastrointestinal motility disorders.
Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation
Bretherton et al. · Aging · 2019
Two weeks of daily taVNS improved autonomic balance, baroreflex sensitivity, and some aspects of quality of life, mood, and sleep in adults aged 55 and over.
Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives
Kong et al. · Frontiers in Psychiatry · 2018
Transcutaneous auricular VNS shows promise as a non-invasive treatment for depression, with evidence of antidepressant effects through modulation of brain networks including the default mode network.
Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study
Tassorelli et al. · Neurology · 2018
Non-invasive cervical VNS was safe and well-tolerated for acute migraine treatment, though the primary endpoint of pain-free status at 2 hours did not reach significance versus sham.
The vagus nerve at the interface of the microbiota-gut-brain axis
Bonaz et al. · Frontiers in Neuroscience · 2018
Review establishing the vagus nerve as a key communication pathway between gut microbes and the brain, with vagal afferents sensing microbial metabolites and the cholinergic anti-inflammatory pathway modulating intestinal inflammation.
Non-invasive Vagal Nerve Stimulation Effects on Hyperarousal and Autonomic State in Patients with Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury: Preliminary Evidence
Lamb et al. · Frontiers in Medicine · 2017
Non-invasive vagal nerve stimulation reduced PTSD symptom severity and showed promising effects on autonomic regulation in veterans with combat-related PTSD.
A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality
Aaronson et al. · American Journal of Psychiatry · 2017
Over 5 years, VNS plus treatment as usual produced significantly higher cumulative response rates (67.6% vs 40.9%) and remission rates (43.3% vs 25.7%) compared to treatment as usual alone in treatment-resistant depression.
Optimization of transcutaneous vagus nerve stimulation using functional MRI
Yakunina et al. · Neuromodulation · 2017
fMRI comparison of four ear stimulation locations found that the cymba conchae activated the vagal pathway most effectively, providing evidence for optimal taVNS electrode placement.
Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study
Rong et al. · Journal of Affective Disorders · 2016
Four weeks of taVNS significantly reduced Hamilton Depression Rating Scale scores compared to sham, with a response rate of 37.5% versus 12.5% in controls.
Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis
Koopman et al. · Proceedings of the National Academy of Sciences · 2016
Implanted VNS significantly inhibited TNF production and improved clinical signs in rheumatoid arthritis patients, providing direct evidence of the inflammatory reflex in humans.
Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder
Fang et al. · Biological Psychiatry · 2016
taVNS modulated functional connectivity in the default mode network and showed antidepressant effects, suggesting a central mechanism for its therapeutic action in depression.
Chronic vagus nerve stimulation in Crohn's disease: a 6-month follow-up pilot study
Bonaz et al. · Neurogastroenterology and Motility · 2016
Chronic VNS improved clinical and biological markers of Crohn's disease in 5 of 7 patients over 6 months, supporting the role of the cholinergic anti-inflammatory pathway.
Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans
Frangos et al. · Brain Stimulation · 2015
Electrical stimulation of the cymba conchae activated classical central vagal projections including the NTS, locus coeruleus, and dorsal raphe, providing fMRI evidence that vagal afferents can be accessed non-invasively via the external ear.
Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children
Orosz et al. · Epilepsia · 2014
Long-term VNS in paediatric epilepsy showed progressive improvement over 24 months, with 32% of patients achieving at least 50% seizure reduction.
Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial
Premchand et al. · Journal of Cardiac Failure · 2014
Chronic VNS was safe and improved left ventricular ejection fraction, heart rate variability, and six-minute walk distance in patients with symptomatic heart failure.
Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity
Clancy et al. · Brain Stimulation · 2014
Transcutaneous VNS reduced muscle sympathetic nerve activity and shifted autonomic balance toward parasympathetic dominance in healthy volunteers, demonstrating a direct physiological mechanism for anxiolytic effects.
Relationship between vagal tone, cortisol, TNF-alpha, epinephrine and negative affects in Crohn's disease and irritable bowel syndrome
Pellissier et al. · PLoS ONE · 2014
Vagal tone was inversely correlated with TNF-alpha in Crohn's disease and with epinephrine in IBS, supporting the relevance of vagus nerve reinforcement interventions in inflammatory bowel conditions.
Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study
Hein et al. · Journal of Neural Transmission · 2013
Active auricular transcutaneous electrical nerve stimulation produced significantly greater improvement in Beck Depression Inventory scores compared to sham stimulation over two weeks in depressed patients.
Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response
Englot et al. · Journal of Neurosurgery · 2011
VNS reduced seizure frequency by at least 50% in approximately half of patients with drug-resistant epilepsy, with greater efficacy observed in generalised versus partial seizures.
Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response
Elliott et al. · Epilepsy & Behavior · 2011
At mean 5-year follow-up, 63.8% of patients achieved at least 50% seizure reduction, demonstrating that VNS efficacy progressively improves over years of treatment in drug-resistant epilepsy.
Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation
Manta et al. · Journal of Psychiatry & Neuroscience · 2009
Sustained VNS initially increases noradrenergic neuron firing (after 1 day) and subsequently serotonergic neuron firing (after 14 days), representing a unique cascade antidepressant mechanism.
Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain
Follesa et al. · Brain Research · 2007
Acute VNS increased the expression of BDNF and fibroblast growth factor in the hippocampus and cortex, and increased norepinephrine concentration in the prefrontal cortex, suggesting neuroplastic mechanisms.
Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission
Dorr & Debonnel · Journal of Pharmacology and Experimental Therapeutics · 2006
VNS significantly increased the basal firing rates of both serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the locus coeruleus, suggesting a novel antidepressant mechanism of action.
Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis
Huston et al. · Journal of Experimental Medicine · 2006
Splenectomy abolished the anti-inflammatory effect of cervical VNS, confirming that the spleen is the principal site of immune modulation in the cholinergic anti-inflammatory pathway.
Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial
Rush et al. · Biological Psychiatry · 2005
In the pivotal 10-week acute phase trial, active VNS produced a 15.2% response rate versus 10.0% for sham in treatment-resistant depression; the primary endpoint did not reach statistical significance.
The cholinergic anti-inflammatory pathway
Pavlov & Tracey · Brain, Behavior, and Immunity · 2005
Established that the efferent vagus nerve inhibits pro-inflammatory cytokine release through acetylcholine signalling at alpha7 nicotinic receptors, defining the cholinergic anti-inflammatory pathway.
Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway
de Jonge et al. · Nature Immunology · 2005
VNS ameliorated surgery-induced inflammation and post-operative ileus by activating STAT3 in intestinal macrophages through alpha7 nicotinic receptor-mediated Jak2-STAT3 signalling.
Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation
Wang et al. · Nature · 2003
Established that the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway, identifying the critical receptor on macrophages.
Vagus-nerve stimulation for the treatment of epilepsy
Ben-Menachem · The Lancet Neurology · 2002
Comprehensive review establishing VNS as an accepted treatment for refractory epilepsy, with efficacy that improves over 18-24 months and evidence of broad-spectrum antiseizure effects.
The inflammatory reflex
Tracey · Nature · 2002
Landmark review defining the 'inflammatory reflex' — a neural circuit by which the vagus nerve modulates the immune response, with cholinergic neurons inhibiting acute inflammation in real time.
Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin
Borovikova et al. · Nature · 2000
Landmark discovery that electrical stimulation of the vagus nerve dramatically reduced TNF production and attenuated systemic inflammation in an endotoxemia model, establishing the cholinergic anti-inflammatory pathway.
Functional and chemical anatomy of the afferent vagal system
Berthoud & Neuhuber · Autonomic Neuroscience · 2000
Comprehensive anatomical review establishing that approximately 80% of vagal fibres are afferent, carrying sensory information from visceral organs to the brain, with the vagus innervating nearly the entire gastrointestinal tract.
Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial
Handforth et al. · Neurology · 1998
High-stimulation VNS produced a significantly greater reduction in seizure frequency (28%) compared to low-stimulation controls (15%) in drug-resistant epilepsy.
Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures
Ben-Menachem et al. · Epilepsia · 1994
In the first major controlled trial of VNS for epilepsy (E03), high-stimulation VNS achieved a 24.5% median reduction in seizure frequency versus 6.1% in the low-stimulation group in drug-resistant partial seizures.
Peripheral control of hypersynchronous discharge in epilepsy
Zabara · Electroencephalography and Clinical Neurophysiology · 1985
Seminal preclinical demonstration that vagus nerve stimulation could suppress experimentally induced seizure activity, providing the scientific foundation for the development of clinical VNS therapy.