PLMI Blog

As a central component of the parasympathetic nervous system, the vagus nerve helps regulate homeostasis across the body and mind. When engaged to improve vagal tone, it can induce far-reaching health effects.

Vagus nerve stimulation (VNS) has evolved from a specialized therapy into a multifaceted neuromodulatory approach that engages multiple pathways to improve health. A growing body of research demonstrates its capacity to modulate autonomic nervous system function, neuroimmune signaling, systemic inflammation, and metabolism, as well as promote neuroplasticity.

How Vagus Nerve Stimulation (VNS) Works

VNS involves delivering controlled electrical impulses to the vagus nerve, either through surgically implanted devices (invasive VNS) or external stimulation at the ear or neck (noninvasive VNS, nVNS) (1). Originally developed for treatment-resistant epilepsy, VNS has since gained approval or clearance for major depression, obesity, post-stroke motor rehabilitation, and headache disorders. Exploratory research continues into its potential use in neuropsychiatric, inflammatory, cardiovascular, and systemic conditions that share overlapping mechanisms of autonomic dysregulation and impaired vagal tone.

Noninvasive VNS (nVNS) approaches allow clinicians to influence autonomic, metabolic, and immune pathways without surgery, expanding access and reducing risks. These innovations position the vagus nerve as a valuable therapeutic target in neurological, psychiatric, and systemic health (1-2).

A Conductor of Mind–Body Health

The therapeutic versatility of VNS stems from its capacity to influence shared pathological mechanisms across diverse disorders: autonomic imbalance, maladaptive stress responses, and neuroimmune dysfunction. These overlapping pathways make VNS a uniquely integrative intervention, well-aligned with integrative and systems-level approaches utilized in functional medicine.

Emerging evidence suggests potential applications across neuropsychiatric disorders (3–5), inflammatory and immune-mediated conditions (6–7), chronic pain syndromes (8), cardiovascular disease (9), and other disorders linked to autonomic dysfunction (10). The vagus nerve’s extensive innervation of thoracic and abdominal organs allows VNS to exert systemic as well as central effects, highlighting its capacity to bridge brain and body health (1–2).

Once limited to surgically implanted devices, VNS is increasingly delivered through noninvasive and closed-loop systems that tailor stimulation in real time (11–14). These innovations support individualized treatment protocols and broaden clinical applicability.

From Discovery to Modern Therapy: A Brief History of VNS

The therapeutic potential of vagus nerve stimulation was recognized in the late 1800s, when neurologist James Leonard Corning experimented with vagal stimulation to treat epilepsy (15). Though his device was abandoned, subsequent animal studies clarified neural effects: Bailey and Bremer demonstrated cortical synchronization in felines (16), Dell and Olson mapped stimulation-sensitive regions (17), and MacLean showed modulation of the cingulate cortex in primates (18).

In 1992, Zabara provided a breakthrough by showing that repetitive vagal stimulation reliably inhibited seizures in canine models (19), setting the stage for the first human clinical trials and eventual FDA approval of VNS for treatment-resistant epilepsy in the 1990s.

Mechanisms of Action: How VNS Exerts Neuromodulatory Effects

Vagus nerve stimulation (VNS) produces therapeutic effects through multiple, interconnected pathways. The vagus nerve (cranial nerve X) originates in the medulla and extends through the neck to innervate all major thoracic and abdominal organs (20). Approximately 80% of vagal fibers are afferent, relaying sensory information from the body to the brain, while the remaining efferent fibers modulate organ function. This predominance of afferent signaling is crucial: by engaging a primarily sensory nerve that simultaneously projects to visceral targets, VNS integrates peripheral signals with central regulation, enabling coordinated modulation of neural circuits, autonomic tone, immune signaling, and systemic physiology.

Forms of Noninvasive Stimulation

Transcutaneous cervical VNS (tcVNS): Targets the cervical branch of the vagus nerve through the neck.

Transcutaneous auricular VNS (taVNS): Stimulates the auricular branch via cutaneous electrodes on the ear.

Both approaches appear to reproduce key effects of implanted VNS (iVNS), though comparative trials are still limited. Current evidence suggests overlapping mechanisms—including vagal afferent activation, autonomic restoration, and central nervous system engagement—supporting their therapeutic validity (11–14).

Multifactorial Mechanisms

• Autonomic & neuroimmune modulation. VNS recalibrates autonomic balance by enhancing parasympathetic tone and reducing sympathetic dominance, while simultaneously influencing the neuroendocrine–immune axis (6, 21). Through this pathway, VNS dampens systemic inflammation and modifies immune signaling—a mechanism relevant for conditions such as depression, metabolic syndrome, chronic pain, and inflammatory disorders.
• Anticonvulsant pathways. VNS activates noradrenergic signaling via the locus coeruleus. Preclinical lesion studies show that disrupting this nucleus prevents the expression of the anticonvulsant effect, demonstrating its necessity in seizure suppression (22).

• Monoamine modulation. Animal and translational studies show that VNS enhances serotonin and norepinephrine release, increases their concentration in cerebrospinal fluid, and increases the firing rates of serotonergic and noradrenergic neurons (23, 24). These changes are thought to underlie the antidepressant and mood-stabilizing effects observed clinically.

• Neuroplasticity & repair. Evidence from animal models shows that VNS upregulates brain-derived neurotrophic factor (BDNF) and promotes dendritic spine growth in the hippocampus (25). In human studies, pairing VNS with rehabilitative therapy enhances neuroplasticity and accelerates functional recovery following stroke (26). These findings support its role in network-level repair and resilience in neurological and psychiatric conditions.

These mechanisms act synergistically, producing far-reaching therapeutic effects that influence multiple physiological systems.

Immune, Autonomic, & Systemic Effects

VNS extends its influence beyond the central nervous system, coordinating immune, autonomic, and systemic functions.

• Neuroimmune regulation. By engaging the cholinergic anti-inflammatory pathway, VNS downregulates pro-inflammatory cytokines: TNF-α and IL-6. This mechanism has been implicated in improvements seen in PTSD, inflammatory bowel disease, rheumatoid arthritis, and other immune-mediated conditions.
• Autonomic & cardiovascular effects. VNS enhances parasympathetic activity, improves heart rate variability and baroreflex sensitivity, thereby balancing blood pressure and mitigating sympathetic overdrive (27, 28). These effects are particularly relevant in disorders characterized by dysautonomia or cardiovascular risk.
• Gut–brain axis effects. VNS modulates GI motility, secretory function, and immune signaling through vagal efferents. By influencing enteric and systemic inflammation, it provides a direct mechanistic link between gut physiology and systemic disease processes.

VNS CLINICAL IMPLICATIONS

The multisystemic mechanisms of VNS drive therapeutic effects across diverse conditions.

Epilepsy

Epilepsy affects nearly 50 million people worldwide, with 20–40% of patients not responding to medications. VNS, first validated for seizure control, can reduce seizure frequency by half in 25–45% of patients, with progressive and sustained benefits over time. Seizure suppression involves multiple mechanisms: stabilization of cortical hyperexcitability via locus coeruleus–noradrenergic pathways, modulation of autonomic tone, and attenuation of neuroinflammation (22). Advances such as closed-loop iVNS and noninvasive VNS are expanding accessibility and improving quality-of-life outcomes.

Major Depression & Treatment-Resistant Depression (TRD)

Roughly 30% of individuals with major depression meet criteria for treatment-resistant depression (TRD), representing a significant unmet therapeutic need. Implanted VNS produces gradual yet durable improvements, with long-term response rates of 40–46% and remission rates up to 29% (29–30). VNS modulates neural circuits by triggering the release of neurotransmitters (acetylcholine and norepinephrine) enhancing monoamine signaling, promoting neuroplasticity, strengthening forward-directed neural signaling, restoring autonomic balance, and downregulating inflammatory pathways (27-28, 31).

Noninvasive modalities, such as taVNS and tcVNS, are also showing promising reductions in depressive symptoms, suggested to be mediated by rebalancing limbic–cortical networks and vagal afferent–driven neuroimmune modulation.

Obesity & Metabolic Disorders

Implanted cervical VNS has demonstrated modest yet meaningful metabolic benefits, including 14–33% excess weight loss (32–38). These effects appear to stem from afferent signaling to the hypothalamic centers that govern satiety and energy balance. VNS also enhances parasympathetic (and vagal) tone, as well as gut–brain communication, supporting systemic metabolism. Noninvasive approaches extend these benefits by improving postprandial glucose regulation and blood pressure, even without significant weight loss (39), suggesting a broad utility for metabolic syndrome and related disorders.

Post-Stroke Motor Rehabilitation

Pairing iVNS with rehabilitative therapy produces functional benefits in chronic stroke patients that are two to three times greater than rehabilitation alone (40). Closed-loop approaches, such as movement-activated auricular VNS (MAAVNS), synchronize stimulation with motor activity, further enhancing outcomes (41). Mechanistic drivers include facilitated neuroplasticity, enhanced cholinergic and noradrenergic signaling, improved autonomic regulation, and BDNF-mediated cortical reorganization, all of which converge to support motor recovery and resilience.

Headaches

Noninvasive VNS (both tcVNS and taVNS) reduces the frequency, severity, and duration of migraines and cluster headaches (42–48). Proposed mechanisms include modulation of trigeminovascular pathways, recalibration of central pain networks, restoration of autonomic balance, and inhibition of inflammatory signaling (49). These effects highlight VNS’s capacity to address both neural and systemic drivers of chronic pain.

Pain Disorders

VNS has demonstrated efficacy in fibromyalgia, IBS, pancreatitis, systemic lupus erythematosus (SLE), and other chronic pain syndromes (50–60). Noninvasive stimulation has been shown to reduce pain intensity, dampen temporal summation, and alleviate fatigue while also lowering proinflammatory mediators, including IL-6 and substance P (51–57). Mechanisms include modulation of central nociceptive circuits, rebalancing of autonomic function, and broad suppression of systemic inflammation.

Inflammatory Disorders

VNS exerts promising immunomodulatory effects in Crohn’s disease, rheumatoid arthritis, SLE, sepsis, and post-viral syndromes such as long COVID (61–66). Clinically, this is reflected in reductions in CRP, calprotectin, IL-6, and substance P. These effects are mediated by the cholinergic anti-inflammatory pathway, which links autonomic rebalance with systemic immune regulation.

Cardiovascular Disorders

Through its impact on autonomic tone, VNS has shown therapeutic benefit in heart failure, arrhythmias, hypertension, and angina (67–72). Mechanisms include parasympathetic enhancement, suppression of sympathetic overactivity, and improved baroreflex sensitivity. Importantly, these effects extend beyond cardiovascular health to influence mood, stress resilience, and overall autonomic function (27–28, 70).

GI Disorders

VNS exerts therapeutic effects across the gut–brain axis. Benefits have been documented in gastroparesis, IBS, obesity-related gastrointestinal dysfunction, and functional bowel disorders (53, 73-76). Clinical outcomes include enhanced gastric motility, improved bowel regularity, and reduced abdominal pain. These effects likely arise from parasympathetic modulation of gut motor activity, vagally mediated neuroimmune signaling, and systemic anti-inflammatory effects —mechanisms that also intersect with mood, metabolism, and pain pathways.

A Unifying Mechanistic Theme

Vagus nerve stimulation (VNS) supports the body’s innate ability to maintain balance by enhancing autonomic regulation, modulating neuroimmune signaling, and reducing systemic inflammation. Its effects ripple across multiple systems, offering benefits for both physical and mental health.

Unlocking the Power of VNS

Originally developed for medication-resistant epilepsy, VNS is now recognized as a versatile tool for systemic neuromodulation. By influencing neural circuits, autonomic function, and immune pathways, it shows promise across neurological, psychiatric, metabolic, inflammatory, and GI  disorders—making it a valuable modality in integrative and functional medicine.

Join us on October 21, from 5-7 pm PST, for Unlocking the Power of Vagus Nerve Stimulation: Real Cases, Real Results, a webinar exploring practical strategies for integrating VNS into clinical practice with leading experts Jeffrey Bland, PhD; Navaz Habib, DC; and Peter Staats, MD, MBA, ABIPP, FIPP.

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