Transcutaneous Vagus Nerve Stimulation (tVNS) in Chronic Progressive Multiple Sclerosis

 

A Neuromodulatory Therapeutic Approach Based on Current Neuroimmunological Evidence

The treatment of chronic progressive multiple sclerosis (MS) remains a major therapeutic challenge despite significant advances in modern immunotherapy. While inflammatory relapses in relapsing-remitting MS can now often be controlled effectively, no truly effective disease-modifying therapies are currently available for progressive MS.

Over the past decade, our understanding of the underlying disease mechanisms has changed substantially. Progressive MS is no longer regarded solely as a disease of demyelination. Instead, chronic low-grade neuroinflammation within the brain and spinal cord is now considered one of the principal drivers of disease progression.

This persistent inflammatory process is characterized by activated microglia, reactive astrocytes, oxidative stress, mitochondrial dysfunction, and progressive axonal and neuronal loss. These pathological processes are mediated in part by pro-inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. Numerous recent review articles identify these mechanisms as key contributors to chronic progressive MS.

 

 

Chronic Inflammation Is Not Limited to the Brain

Neuropathological investigations together with modern MRI and PET studies demonstrate that chronic inflammation in progressive MS is by no means confined to the brain. The spinal cord also exhibits persistent activation of microglia and astrocytes, diffuse axonal injury, and progressive atrophy.

In many studies, the degree of spinal cord atrophy correlates more closely with gait impairment and physical disability than cerebral atrophy in patients with chronic progressive MS.

Progressive MS should therefore increasingly be regarded as a disorder characterized by chronic neuroinflammation affecting the entire central nervous system.

 

The Vagus Nerve as a Regulator of the Immune System

The vagus nerve is the body’s principal parasympathetic nerve. Besides regulating heart rate, respiration, and gastrointestinal function, it also plays an essential role in controlling inflammatory processes.

One of the best characterized neuroimmune regulatory pathways is the cholinergic anti-inflammatory reflex. Activation of efferent vagal fibers leads to the release of acetylcholine, which binds to alpha7 nicotinic acetylcholine receptors on macrophages and other immune cells.

This interaction inhibits major inflammatory signaling pathways including NF-kappaB and JAK/STAT, thereby reducing the production of pro-inflammatory cytokines.

Initially described in experimental studies, this mechanism has subsequently been confirmed in numerous animal models and clinical studies involving various autoimmune diseases.

 

Effects of Vagus Nerve Stimulation on Cytokines and Microglia Throughout the Body

The anti-inflammatory effects of vagus nerve stimulation are not limited to peripheral immune cells.

Experimental studies demonstrate that vagal activation also influences microglia, the resident immune cells of the central nervous system. Microglia shift from a predominantly pro-inflammatory M1 phenotype toward a more regenerative M2 phenotype. Simultaneously, inflammatory signaling pathways such as NF-kappaB are suppressed, resulting in reduced production of TNF-alpha, IL-1beta, and IL-6.

Additional beneficial effects have been reported on:

• blood-brain barrier integrity
• cerebral blood flow
• neuroplasticity
• oxidative stress
• mitochondrial function

Most of these findings originate from experimental studies and animal models. Human evidence remains considerably more limited.

Clinical Evidence for Transcutaneous Vagus Nerve Stimulation

Transcutaneous vagus nerve stimulation (tVNS) activates vagal afferent fibers through specific regions of the external ear. Unlike implanted vagus nerve stimulators, tVNS is entirely non-invasive.

Clinical studies are now available for several inflammatory autoimmune disorders. A recent systematic review demonstrated that vagus nerve stimulation is associated with reductions in inflammatory biomarkers across multiple diseases. The most consistent finding was a decrease in IL-6, while several studies also reported reductions in TNF-alpha and C-reactive protein (CRP).

The authors concluded that the anti-inflammatory effects of vagus nerve stimulation are biologically plausible and clinically promising, although larger randomized controlled trials remain necessary.

 

What Does This Mean for Progressive Multiple Sclerosis?

The currently established mechanisms of vagus nerve stimulation overlap remarkably well with the pathophysiological processes believed to drive chronic progressive MS.

These include:

• chronic microglial activation
• neuroinflammation
• excessive cytokine production
• autonomic dysregulation
• oxidative cellular injury
• reduced neuronal plasticity

From a pathophysiological perspective, there is therefore a strong scientific rationale for investigating vagus nerve stimulation as an adjunctive treatment for progressive MS.

However, it must be emphasized that large randomized clinical trials demonstrating a disease-modifying effect of tVNS in chronic progressive multiple sclerosis are currently lacking. Consequently, based on current evidence, tVNS cannot yet be regarded as an established disease-modifying therapy for progressive MS.

Why Are Large Clinical Trials in PPMS and SPMS Still Missing?

The absence of large randomized clinical trials should not automatically be interpreted as evidence that the treatment is ineffective.

Modern multicenter registration trials involving several hundred patients frequently require investments ranging from tens to hundreds of millions of dollars. Such studies are almost exclusively financed by pharmaceutical companies whose business models depend on patented drugs that generate continuous revenue.

In contrast, non-invasive medical devices such as tVNS systems are typically purchased only once and therefore generate comparatively limited long-term revenue. As a result, manufacturers often lack the financial incentives or resources necessary to fund very large registration trials. These economic realities may partly explain why high-level clinical evidence develops much more slowly than it does for patented pharmaceuticals.

Nevertheless, convincing clinical proof of efficacy remains an essential prerequisite for broad scientific and medical acceptance.

 

 

Why We Recommend Transcutaneous Vagus Nerve Stimulation in Our Clinical Practice

Transcutaneous vagus nerve stimulation (tVNS) has become a regular component of our neuromodulation treatment program for patients suffering from chronic progressive neurological disorders, including multiple sclerosis.

Our recommendation is not based on proven disease-modifying effects in progressive MS. Rather, it is based on the combination of a compelling pathophysiological rationale, the excellent safety profile of the method, and our own clinical experience within multimodal neuromodulation programs.

Our therapeutic concept assumes that the clinical course of chronic neurodegenerative diseases is largely determined by the balance between two opposing biological processes occurring simultaneously:

• ongoing neuroinflammation, characterized by persistent microglial activation and progressive neuronal injury
• regeneration and neuronal plasticity within the central nervous system

Neuromodulatory techniques such as transcranial direct current stimulation (tDCS), transcranial pulse stimulation (TPS/FUS) and EMTT are, in our opinion, capable of providing regenerative impulses. Many patients demonstrate measurable functional improvements or at least stabilization of neurological function during these treatments.

Whether these improvements translate into sustained clinical benefit most likely depends on whether regenerative capacity can outweigh the simultaneously progressing inflammatory and neurodegenerative processes.

If inflammatory activity predominates, treatment may merely slow clinical deterioration or temporarily stabilize neurological function. When both processes remain approximately balanced, consistent home-based neuromodulation may help maintain the functional gains achieved during intensive treatment.

For this reason, we consider it reasonable to combine regenerative neuromodulation with therapeutic approaches that may simultaneously reduce chronic neuroinflammation. This is where we see the potential role of transcutaneous vagus nerve stimulation. The well-documented activation of the cholinergic anti-inflammatory reflex, together with experimentally demonstrated modulation of central inflammatory pathways, may help shift the biological balance toward regeneration.

At present, however, this concept should be regarded as a pathophysiologically based working hypothesis. Clinical proof that tVNS actually slows disease progression or permanently improves the course of chronic progressive multiple sclerosis is still lacking and should be addressed in future prospective clinical trials.

Nevertheless, when combined with tDCS, TPS, and other neuromodulatory techniques, we repeatedly observe clinical courses that appear consistent with this model. Similar observations have also been reported by several international research groups.

Particularly well known are the clinical cases presented on social media by Sir Petros Kattou, demonstrating functional neuromodulation in patients with severe neurological disabilities. In several cases, remarkable functional improvements were observed. One such patient, who had been wheelchair-bound because of multiple sclerosis for four years before regaining independent ambulation, has been presented in detail on our website. This case is representative of approximately fifty comparable cases published by Petros.

 

chronic progressive MS – 4y wheelchair – walks again

 

progressive schwere Multiple Sklerose – Rollstuhl seit 1 Jahr – Besserung durch Neuromodulation

 

Naturally, an individual case cannot replace scientific proof obtained from randomized clinical trials. Nevertheless, it illustrates the potential that neuromodulatory therapies may possess and underscores why we believe systematic scientific investigation of these treatment combinations is urgently warranted.

 

Summary

The central role of chronic neuroinflammation, persistent microglial activation, and pro-inflammatory cytokines in chronic progressive multiple sclerosis is now well established scientifically.

Likewise, the neuroimmunological mechanisms of vagus nerve stimulation and its ability to modulate central inflammatory pathways through the cholinergic anti-inflammatory reflex have been extensively investigated.

Whether these biological effects ultimately translate into slower disease progression in progressive multiple sclerosis remains to be determined by larger prospective clinical trials. Nevertheless, the underlying pathophysiological rationale appears scientifically convincing.

 

our Star Device: tVNS® – Transauricular Vagus Nerve Stimulation (taVNS)

 

 

 

References

Pathophysiology of Progressive Multiple Sclerosis

1. Yong HYF, Yong VW.
   Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis. Nature Reviews Neurology. 2022.

Comment: Reviews the current understanding of the pathophysiological mechanisms underlying progressive MS and proposes future disease-modifying therapeutic strategies.

2. Klotz L, Antel J, Kuhlmann T, et al.
   Inflammation in multiple sclerosis: consequences for remyelination and disease progression. Nature Reviews Neurology. 2023.

Comment: Excellent review discussing chronic neuroinflammation, impaired remyelination, and axonal degeneration as key drivers of disease progression.

3. Bittner S, Pape K, Klotz L, et al.
   Implications of immunometabolism for smouldering MS pathology and therapy. Nature Reviews Neurology. 2023.

Comment: Describes the concept of “smouldering inflammation” in progressive MS and discusses novel therapeutic targets involving immunometabolism and microglia.

4. Magliozzi R, et al.
   Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis. Nature Reviews Neurology. 2023.

Comment: Demonstrates the central role of meningeal inflammation in cortical demyelination, brain atrophy, and clinical progression.

 

Microglia, Neuroinflammation and Immunometabolism

5. Distéfano-Gagné F, Bitarafan S, Lacroix S, et al.
   Roles and regulation of microglia activity in multiple sclerosis: insights from animal models. Nature Reviews Neuroscience. 2023.

Comment: Comprehensive review of the role of microglia in MS pathogenesis, chronic neuroinflammation, neurodegeneration, and potential therapeutic targets.

6. Guo Y, Yang X, Cheng Y.
   Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation. Frontiers in Immunology. 2026.

Comment: Describes the molecular mechanisms through which cholinergic signaling and the vagus nerve regulate microglia, immunometabolism, and central inflammatory processes.

Vagus Nerve, the Cholinergic Anti-inflammatory Reflex, and Mechanisms of Action

7. Bonaz B, et al.
   Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. Journal of Physiology. 2016.

Comment: Landmark review introducing the cholinergic anti-inflammatory reflex and discussing its potential clinical significance.

8. Bu X, et al.
   A Review of Vagus Nerve Stimulation for Disease: Comprehensive Theory and Evidence for Mechanisms of Action. Comprehensive Physiology. 2026.

Comment: Comprehensive review summarizing the known mechanisms of action of both invasive and transcutaneous vagus nerve stimulation across neurological and systemic diseases.

Clinical Evidence for Vagus Nerve Stimulation

9. Garcia R, et al.
   Vagus Nerve Stimulation in Autoimmune Conditions: A Systematic Review. ACR Open Rheumatology. 2025.

Comment: Systematic review evaluating clinical studies of vagus nerve stimulation in autoimmune diseases, focusing on inflammatory biomarkers and clinical efficacy.

10. A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis.
    Neuromodulation. 2024.

Comment: Meta-analysis demonstrating consistent reductions in inflammatory signaling pathways and pro-inflammatory cytokines following vagus nerve stimulation across different diseases.

11. Vagus nerve stimulation in autoimmune diseases: Mechanisms, therapeutic potential, and clinical applications.
    Autoimmunity Reviews. 2026.

Comment: Recent review summarizing the immunomodulatory effects of vagus nerve stimulation and its potential therapeutic role in autoimmune diseases.

 

Interpretation of the Evidence

The first two sections summarize the currently well-established scientific understanding of the pathophysiology of chronic progressive multiple sclerosis and the pivotal role of neuroinflammation.

The following sections review the biological mechanisms underlying vagus nerve stimulation together with the currently available clinical evidence.

Taken together, these findings provide a strong pathophysiological rationale for investigating transcutaneous vagus nerve stimulation as an adjunctive therapy for chronic progressive multiple sclerosis. However, convincing proof of disease-modifying efficacy from large randomized clinical trials is still lacking.

 

The Device We Recommend Is Supported by MDR Studies Covering 17 Indications

For commercial reasons, the manufacturer has decided to officially market only four indications, despite previously obtaining MDR documentation for seventeen indications. I have discussed this topic in detail in a separate article:

https://ganzemedizin.at/tvns-unser-star-der-hirnstamm-stimulation/

 

In Contrast to the Widely Advertised Vagus Stimulator N..m

The supporting studies for our recommended device represent genuine clinical investigations. In fact, a substantial proportion of the vagus nerve stimulation studies indexed in PubMed were performed using exactly this device.