A new method of treating conditions from depression to autoimmune diseases involves “retuning” the main nerve of the body. Cate Montana reports
The vagus nerve is the longest cranial nerve in the human body. It exits the brain stem and extends branches to both sides of the body starting at the ears, serving all major organs and systems before ending at the colon.
With more than 100,000 nerve connections, it controls the autonomic nervous system and key body functions such as respiration, blood pressure, heart rate, hormone secretion, digestion, metabolism, swallowing, coughing, speech, urine excretion and sweating. With such a vast and intricate network covering the entire trunk of the human body, it’s not surprising that the nerve’s Latin name means “wandering.”
The vagus nerve is most active when the body is in a resting state. A bilateral mixed nerve, the vagus complex contains both efferent motor and afferent sensory nerve fibers, traveling to and from the central nervous system.
Because of its extensive reach and capacity for conducting two-way information signaling, today the vagus nerve is often referred to as “the internet of the body.” And yet, as massive as it is and as critical as it is to mind-body function, the vagus nerve has only recently begun to be understood and tapped directly in ways that can facilitate health.
In particular, researchers are beginning to explore targeted electrical stimulation of the vagus nerve and other parts of the body, a field known as bioelectronic medicine (see below).
In the late nineteenth century, a theory developed that epileptic seizures were caused by the dysregulation of blood flow from the brain. To test this, a neurologist in New York named Dr James Corning created a carotid artery “electrocompressor” that both compressed and electrically stimulated the carotid artery sheath.
It was somewhat effective for stopping and preventing acute seizures. However, experimental results were difficult to interpret because both the carotid artery and the vagus nerve were involved, and the research was eventually abandoned.
In the 1930s, studies showed that vagus nerve stimulation (VNS) could stop cortical hyperexcitability—abnormal neuronal firing within the brain’s cortex—thus confirming VNS as a potential antiepileptic intervention.
In the 1980s, research into seizures artificially induced in dogs resulted in the development of an effective implantable VNS regulator called the neurocybernetic prosthesis device. The settings originally chosen to treat epilepsy were rather arbitrary: 1–5 milliamps administered every five minutes all day and all night long at 30 hertz. Human trials began, and in 1997 the US Food and Drug Administration (FDA) approved the marketing of VNS devices to treat epilepsy in humans.
The settings for this treatment have not varied over the years. Studies show that after 14 weeks, epilepsy patients experience an approximately 31 percent seizure reduction. Long-term treatment (16–18 months) results in a seizure reduction of about 52 percent.1
Interestingly, so many patients in the epilepsy trials experienced relief from depressive symptoms that researchers began looking into vagus nerve stimulation for patients with chronic depression that didn’t respond to medication. VNS was found “safe and effective” for treating participants with marked treatment-deficient depression.2
Because depression studies were based on the epilepsy experience, the same electronic settings were employed, and FDA approval was subsequently granted to market VNS devices for depression in 2005. It wasn’t until an accident occurred in the research lab of neurosurgeon and physician-scientist Dr Kevin Tracey that VNS made a stunning forward leap into the realm of autoimmune disease.
During the late 1990s, Tracey’s research team at his newly founded Feinstein Institutes for Medical Research in New York (feinstein.northwell.edu) was investigating the effects of an anti-inflammatory molecule labeled “1493,” developed to treat stroke. The team was injecting 1493 into the brains of dogs to mitigate cytokine storms and inflammation deliberately triggered by the injection of bacterial lipopolysaccharide (AKA endotoxin) into the brain.
Cytokines are small proteins vital to cell signaling, and a cytokine storm is a hyperinflammatory state that occurs when immune cells overreact to a threat and rapidly release a large number of cytokines.
However, at one point, instead of injecting endotoxin into the brain, one researcher followed a different but common protocol and injected endotoxin into the peritoneum (the abdominal wall) by mistake. When the drug 1493 was administered to the brain and Tracey’s team measured the cytokine response in the organs of the body, there was no cytokine response.
“Something in the brain was turning off inflammation in the body,” says Tracey, now president and chief executive officer of the Laboratory of Biomedical Science at the Feinstein Institutes. “And that was a shocking moment, because there was no way to explain a mechanism for that response. So, we started to study possible ways that the brain could control the immune system.”
At first Tracey tried looking at the pituitary gland, but it turned out that had nothing to do with it. Then he came across an obscure paper about how cutting the vagus nerve can interrupt bodily responses and illness by Linda Watkins, a distinguished professor in the Department of Psychology and Neuroscience at the University of Colorado.
“Apparently, we had discovered the efferent motor arm, which would carry signals from the brain down the vagus nerve to regulate the immune system and turn off the inflammation in the body,” says Tracey. “With that in mind, we abandoned injections altogether and just put an electrode on the vagus nerve, turned it on, and measured cytokine responses. And it worked.
“After we published our results in Nature, that placed the vagus nerve and neuroimmunology front and center for immunology and neuroscience. Because what does nerve fiber do in the context of an immune response? By simply focusing on that question, you can make new maps that lead to therapies for many, many conditions.”
Inflammation is a symptom of many infectious diseases as well as autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, Guillain-Barré syndrome and psoriasis. Tracey’s discovery of what is now called the “inflammatory reflex”—a neurological circuit that regulates the immune response to invasion and injury by using the vagus nerve to direct cytokine production3—has put the vagus nerve front and center on the medical research map as a means of blocking the inflammatory process.
One of the first applications Tracey and his team investigated was the impact of vagus nerve stimulation on rheumatoid arthritis (RA). Separately, he and Dr Paul-Peter Tak at the Academic Medical Centre of the University of Amsterdam conducted research into vagus nerve stimulation to treat RA, preventing inflammation and damage to the joints in rodent models.
Their tests and those in other labs showed that stimulation of the parasympathetic vagus nerve caused regression of RA as well as a reversal in bone erosion. The exact physiological process by which this occurs is decidedly complex.
But eventually it was discovered that VNS produces norepinephrine (the organic chemical noradrenaline), which in turn stimulates an enzyme to produce the anti-inflammatory mediator acetylcholine. Acetylcholine then binds to a key receptor in the anti-inflammatory path between the immune system and nervous system, reducing cytokine production.
In rats, surgically cutting the vagus nerve has been found to increase signaling in the immune system, inducing inflammation. However, electrical stimulation of the vagus nerve in the neck decreases it.4
Inhibition of proteins that control gene expression, cytokine production and cell survival has been found to affect anti-inflammatory signaling in various inflammatory conditions. Activation of a signaling path involved in immunity, cell division, cell death and tumor formation also influences this signaling. Inhibition of the inflammasome, a set of multiprotein complexes in the immune system responsible for inflammatory responses and cell death, has this effect as well.5
In July 2025, the FDA approved the SetPoint System for rheumatoid arthritis, a VNS implant device developed by Tracey (see below). It offers RA sufferers the opportunity to reduce lifelong dependence on pills, injections and infusions carrying the risk of infections, liver damage, bone marrow suppression and gastrointestinal intolerance—all common side effects of traditional RA treatment.6
The clinical benefits of vagus nerve stimulation tend to increase with time. Some patients have significant improvements within the first few weeks, and many notice even better results six months or more after the therapy begins.
For most conditions, prescribed medications are continued as the VNS device is turned on and the physician adjusts the strength of the electrical impulses. As symptoms improve, patients may be able to reduce medications or eliminate them altogether. But this should be done only under the supervision of a physician.
Despite this success, Tracey is among the first to admit that vagus nerve stimulation as a therapy still has a long way to go to reach its full potential.
Research is currently being conducted to treat strokes with VNS and enhance rehabilitation therapy in patients who’ve had a stroke. Clinical trials treating multiple sclerosis using vagus nerve stimulation are underway, as is research for Crohn’s disease, ulcerative colitis and inflammatory bowel disease.
Bioelectronic medicine is also being used in oncology studies.7 The effects of vagus nerve stimulation on metabolism and obesity continue to be researched as well.8
The number of conditions vagus nerve stimulation could positively impact include Alzheimer’s, diabetes, metabolic syndrome, hypertension, cardiovascular disease, stroke, cancer, Parkinson’s disease and neurodegeneration, just to name a few. Additionally, because inflammation enhances the sensitivity of neurons that transmit pain signals to the brain (nociceptors), one area of active research is the use of VNS to reduce chronic pain. As well, VNS is known to be able to modulate pain pathways in the brain stem and spinal cord.
But before focusing on the discovery of future treatment applications, existing patients would be well served if researchers would investigate the specifics of VNS for established conditions like epilepsy and depression.
“Epilepsy patients with VNS devices receive electronic stimulation every five minutes for 30 seconds at a higher amperage than the SetPoint devices used for RA, which treatment is only once a day for 60 seconds,” he says. “And epilepsy treatment effectiveness is about 50 percent. VNS as a therapy for severe treatment-resistant depression also seems to be effective about half the time. And that’s because we don’t know exactly how all this works yet.”
Bottom line, the effective parameters of VNS treatment are basically still unknown territory (see box, page xx). As Tracey points out, the vagus nerve has some 80,000 fibers on each side, and the number of fibers needed to control the cytokine response in the spleen through the vagus nerve is likely a few thousand.
“How it works or how it can be used to direct the therapy toward conditions like Crohn’s disease, inflammatory bowel disease or the parts of the brain affected by Parkinson’s or multiple sclerosis is very, very exciting and promising,” says Tracey. “But we’ve still got so much to figure out.”
Bioelectronic medicine is similar to the way in which the pharmaceutical industry approaches specific conditions and diseases.
Big Pharma researchers identify a molecular mechanism of action and then screen molecular biochemicals that hit the selected target. In bioelectronic medicine, researchers pick a condition or a disease, find nerves or neural signals that affect that disease, then create a device that influences the nerve controlling the target.
Bioelectric medicine is more device-oriented, using a variety of tools to interact with and regulate the body’s electrical systems. Implanted pacemakers and deep brain stimulators are decades-old examples of technology used to correct electrical imbalances in the heart and brain.
Transcranial magnetic stimulation is a noninvasive bioelectric medicine technique in which a changing magnetic field is used to induce an electric current in targeted areas of the brain, affecting conditions such as depression and obsessive-compulsive disorder.
Wearable devices that monitor bioelectric signals in real time, such as smart watches and fitness trackers, are also part of bioelectric medicine. They provide valuable data that can help individuals make informed decisions about their health and lifestyle choices.
VNS device implantation is about a one-hour outpatient procedure conducted in same-day surgery centers.
There are two types of devices. One consists of a pulse generator containing a battery and stimulation system, which is implanted under the skin in the chest, connecting to a lead with electrodes in the neck. This requires two incisions, each about an inch and a half long.
The device must be replaced when its battery runs out of power. The battery has a lifespan of 7–10 years for epilepsy treatment and would most likely last longer in rheumatoid arthritis (RA) patients due to the vastly reduced frequency of use.
The other device type is simply a large supplement-capsule-sized implant in the neck, requiring one incision. Its battery charges wirelessly using an electronic necklace. One example of this type is Dr Kevin Tracey’s SetPoint device.
In the case of RA, the SetPoint system is the only VNS device that has received FDA approval. The rheumatologist activates it from their office via a computer program a week or two after implantation. According to Tracey, most patients have the device turned on for one minute a day, starting at a low dose of stimulation with an output current of 0.25 milliamps (mA).
The dosage is increased slowly in steps of 0.25 mA to a maximum output current of 3.5 mA. Other stimulation conditions that can be selected are pulse width (130–1,000 mcs), frequency (10–30 Hz), and duration of stimulation (7–60 s).
Approximately 10 percent of patients experience some coughing or brief hoarseness after stimulation, although Dr Tracey says that most people, especially those who choose to be stimulated at night, sleep right through it. “Some patients feel a little buzzing in their neck for about one minute, but that’s it.”
The VNS device can be removed if desired and can also be deactivated. It is not affected by x-rays, such as those used in airport security areas. The first device type does, however, limit magnetic resonance imaging (MRI) to areas away from the chest because when the device is in place, there is a risk of overheating the lead.1 The SetPoint model allows MRI scanning under specific conditions, such as scheduling it when the device is not actively stimulating and using only a closed MRI scanner.
The following stories are from Dr Kevin Tracey’s book The Great Nerve: The New Science of the Vagus Nerve and How to Harness Its Healing Reflexes (Avery, 2025), cited with permission from the author.
Pero Dragoje was a middle-aged father with two young children, making a living as a truck driver. But the onset of rheumatoid arthritis had crippled him to the point where he was unable to work.
His doctors had treated him for years with the steroid medication prednisone as well as with methotrexate. By the time he underwent VNS implant surgery, he was 57 and his arthritis was so advanced that he was unable to move his fingers or pick things up.
Within a week of his implant being activated, his hands and feet stopped hurting and he was able to start work again. Within several weeks he was completely pain-free and was even back to playing tennis.
After two years Pero stopped taking all medication for rheumatoid arthritis. Regarding his vagus nerve stimulator, he says, “I would be a dead man without it.”
Kelly Owens was diagnosed with Crohn’s disease and inflammatory arthritis at age 13. By her late 20s, she had been on a treadmill of pain, hospitalizations, surgeries and immune-suppressing medications and had developed severe osteoporosis from all the steroids she was on.
Nothing helped. A newlywed, she had to quit her job as a teacher because the pain was so bad she couldn’t stand. She said her husband had to carry her on his back to and from restaurants because she couldn’t walk the distance from their car.
Desperate for relief, as a last resort she searched clinicaltrials.gov, where she learned that SetPoint was performing clinical trials for RA in Europe. With the support of friends and family, Kelly and her husband moved from New Jersey to Amsterdam to be part of the VNS trial.
Within weeks of receiving the VNS device, she was walking without a cane for the first time since her teen years. Within eight weeks the RA was in clinical remission, and she was running two miles a day and working out. Within six months she was finally taken off prednisone and was living medication-free.
Nick Fournie experienced depression that could not be alleviated by four or more antidepressants. His treatment-deficient depression qualified him for a VNS clinical trial with nearly 600 participants at Washington University School of Medicine in St. Louis, Missouri. Among the 14 quality-of-life categories the researchers were evaluating were physical health, family relationships, ability to work and overall well-being.
Within a short time, Nick said his severe depression was behind him. He noticed the sensation of the device being “on” for those 30 seconds every five minutes only if he was “real calm and real still.” When he was busy, he said, he didn’t even know it was there. He was too busy riding his motorcycle and enjoying life with his wife Mary.
The way vagus nerve stimulation (VNS) works varies depending on the condition. Take depression. Some proposed mechanisms include VNS stimulation influencing the brain’s limbic structures, including the cingulate cortex and amygdala, potentially reducing their hyperactivity and alleviating depressive symptoms. It may also promote the production of brain-derived neurotrophic factor (BDNF), a protein that enhances neuroplasticity and resilience in brain regions affected by depression.
Instead of continued high-level VNS use based on the original epilepsy studies, Dr Kevin Tracey wants to see a depression trial carried out that uses the same parameters as rheumatoid arthritis trials, with treatments of one or two minutes once or twice a day. He speculates this approach to treatment-deficient depression might work much better because when a nerve is stimulated over and over again, it’s far too easy to induce tachyphylaxis, or desensitization, in the nerve itself, which would theoretically lessen much of the treatment’s effect.
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