Vagus nerve

Zapping the Vagus Nerve Could Relieve Some Long COVID Symptoms

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Ongoing research shows electrical vagus nerve stimulators could relieve some long COVID symptoms. But are the expensive devices worth the price?

Vagus nerves, illustration
Credit: Sebastian Kaulitzki/Science Photo Library

Can a condition as gnarly and disparate as long COVID be treated without drugs? Social media is buzzing over an experimental therapy that taps the vagus nerve, which acts as the body’s “information superhighway” by carrying crucial signals between the brain and various internal organs. A mild electrical zap to this long cranial nerve triggers a rush of autonomic responses associated with relaxation—and may confer health benefits well beyond this.

Researchers are increasingly recognizing that long COVID is as much a neurological disorder as a cardiovascular and respiratory one. Treatment studies have highlighted the condition’s neurological aspects, including some that are potentially related to the vagus nerve. Early small-scale trials of vagal stimulation have seen reductions in hallmark long COVID symptoms such as chronic fatigue, headaches and irregular blood pressure. Another study demonstrated that the devices used to send electrical stimulation through the skin are safe and easy to use at home—offering convenience, accessibility and less risk of contagion. Scientists are still studying which long COVID symptoms this technique can reliably address, which patients will benefit and how long the effects last. In any case, the vagus nerve’s influence throughout the body appears to be key for treating some of the all-encompassing manifestations of long COVID.

“Your body is an electrical and chemical organ,” says Peter Staats, co-chair of the Vagus Nerve Society and co-founder of the neuromodulation company electroCore. “Modern medicine has been really focused on the chemical side of things. And it’s time to be focusing a little bit more on the electrical side.”

Vagus nerve stimulation is already used to treat some other thorny neurological conditions. Implantable stimulators were first approved for epilepsy in 1997 and for depression in 2005. But despite the procedure’s promise for treating long COVID, researchers say it won’t be enough on its own. Long COVID is an unresolved enigma that’s tricky to understand, let alone diagnose or treat. Symptoms vary wildly between individuals, and no single approach can address the viral aftermath throughout the body. Experts say combination therapy appears best for lifting people out of this chronic condition. But vagus nerve stimulation could be a niche tool in the long COVID treatment arsenal. It has potential to address neurological symptoms in a way that limited pharmacological solutions so far have not.

“Whenever we have a single treatment option, we’re generally pretty wary of saying this is going to be the cure-all,” says Stephanie Grach, an internist at the Mayo Clinic. But “at this point, almost any sort of management or treatment option that could feasibly help a number of people is a game changer.”

Stress Buster

The vagus nerve—a bundle of fibers that run from the brain stem and fan out around the body—is the impresario of our involuntary background processes and organ functions. It’s also part of the parasympathetic nervous system, which is in charge of calming the body after a stressful event. During this recovery phase, the heart rate slows to normal, the immune system lets down its guard, and the digestive system starts up again. The vagus nerve acts as an “off” switch to the sympathetic system’s fight-or-flight mode. This nerve is also activated during activities such as yoga, meditation and slow breathing, all of which commonly leave practitioners feeling calm and restful.

Electrical stimulation harnesses the vagus nerve’s healing power on command more easily. Some people may be able to reengage their own dysfunctional vagus nerve through mindfulness exercises, but most need an external aid. That includes many who live with long COVID, given that they often have severe tissue damage and depleted energy levels. “To tell somebody who has struggled with long COVID for three years and has seen 500 doctors to go do some mindfulness—that’s not going to go over well,” says Mayo Clinic internist Ravindra Ganesh, who is currently leading a clinical trial of vagus nerve stimulation for long COVID using electroCore devices.

During the early days of the pandemic, researchers quickly noticed that several symptoms of acute COVID infection were similar to those of the vagus nerve going haywire. People hospitalized with COVID often suffered from the so-called cytokine storm, in which the infection triggered an excessive, runaway immune response that eventually turned inward to wreck the host’s own tissues.

After the initial infection waned, a large percentage those experiencing long COVID still reported symptoms typically seen with vagal dysfunction. And this past June researchers found smoking-gun evidence: postmortems of deceased people who had COVID revealed viral RNA and inflammation cells in the vagal tissues, indicating the virus had infiltrated and damaged this key nerve.

To many researchers, jump-starting a decommissioned vagus nerve seemed like an obvious solution for treating long COVID. “It’s a really fundamental nerve,” says Michael VanElzakker, a neuroscientist at Massachusetts General Hospital. Targeting it as a treatment approach “really ought to be considered and deserves more research.”

The Long COVID Connection

Researchers think vagus nerve stimulation weakens long COVID symptoms by turning up the body’s parasympathetic pathways. One sign of heightened sympathetic activity is when an immune system keeps firing up, even after the initial infection has passed. The vagus nerve quiets this overactive defense by reducing the production of cytokines, signaling chemicals that promote inflammation. In 2000 researchers discovered the vagus nerve’s anti-inflammatory role when they found that stimulating it reduced lethal septic shock in rats exposed to bacterial toxins. Many scientists think reactivating the vagus nerve could also potentially reset immunity in people with acute COVID or chronic symptoms.

Rousing the portion of the vagus nerve entering the brain stem might also engage neighboring cortical areas that are involved in memory and attention, according to Elisabetta Burchi, head of translational research at the neuromodulation start-up Parasym. Such stimulation sets off a release of neurotransmitter chemicals, which may help reduce long COVID’s neurocognitive effects. The evidence is still inconclusive, though. One preprint study that’s awaiting peer review found that vagal stimulation had only a minimal impact on “brain fog,” a frequently reported symptom of long COVID.

So far pilot studies have demonstrated that vagus nerve stimulation works best for reducing long COVID’s debilitating fatigue. Researchers have been encouraged that some participants in these studies reported improvements—but they have noted that some did not. “There is no trial of any drug or anything I’ve ever done in all my years that makes a patient so well that he or she no longer fulfills criteria for chronic fatigue syndrome,” says Benjamin Natelson, a neurologist at Mount Sinai, who has run several clinical studies on vagus nerve stimulation for various health conditions, some of which used devicesfrom electroCore and Parasym. (Natelson says he did not receive funding for the studies from these companies.)

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Because the vagus nerve consists of so many fibers, researchers can’t control which individual fiber gets triggered to target any particular organ; multiple parasympathetic pathways get turned on at once during stimulation. This may sound worrying, but researchers agree there aren’t many negative side effects from excessive parasympathetic action. If such a device is used properly, the worst potential complications will probably be mild skin irritation from the electrical zaps or diarrhea from an overstimulated digestive system.

Vagal therapy still has scientific gaps to address, so doctors are hesitant to prescribe it broadly for long COVID before a confirmatory trial is complete. Scientists are still working out treatment details, including the best delivery method. For example, electroCore’s strategy is a series of mild shocks with a handheld device that a user can touch to either side of the neck for a few minutes every day. Staats, the firm’s co-founder, says this is where the vagus bundle is thickest, making it the most effective stimulation site. Other researchers, including those at Parasym, say taming long COVID’s symptoms requires a longer stimulation time. These scientists note that the tip of a vagal branch ends in the folds of the ear. Wearing a hands-free, earbudlike clip there could be a relatively convenient way to deliver an hour of electrical stimulation daily.

But electrically stimulating the neck or ear might not activate the entire vagal column, argues Gemma Lladós, an infectious disease physician at the Germans Trias i Pujol University Hospital in Spain. She suggests a more invasive approach: a device implanted under the skin directly over the vagal bundle to deliver close-up and continuous stimulation, similar to implants for epilepsy and depression. Lladós’s team is finalizing plans for a 2024 clinical study on treating long COVID with a vagus nerve implant.

Sticker Shock

There’s also one glaring caveat to vagus nerve stimulation: the price. The electroCore device, for example, is offered on a pay-per-use basis that can cost a person more than $7,000 per year without any discounts. Parasym’s stimulator has a one-time price tag of €699 (approximately $770) and is only sold in Europe (though Natelson says some of the people he treats in the U.S have managed to purchase the device by using European addresses). U.S. regulators have approved electroCore’s device and some other companies’ versions as well—but exclusively for non-COVID-related problems such as migraines. People with long COVID can buy these products only if their physicians prescribe them off-label, and insurance companies are unlikely to cover the cost without specific approval for long COVID.

Researchers caution against trying to build one’s own device or purchasing untested versions on the Internet. Vagus nerve stimulation involves running an electrical current close to your heart or brain. “Let’s not mess with that,” Ganesh says. Approved medical devices are calibrated to be safe, but an unapproved device with incorrect settings could slow or stop the heart. In extreme cases, vagal tampering can lead to sudden death.

As with any long COVID therapy, the key is pacing to ration one’s energy levels according to the body’s limits, Grach says. At the Mayo Clinic, she often sees patients who are so excited to embark on a new treatment that they push their body too far and eventually crash. “If you continue to push past the reserve that your body has,” Grach says, “you’re not going to end up feeling the benefit of the interventions regardless.”

Vagus Nerve: What It Is and How to Make It Better

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Getting this critical nerve into better ‘shape’ can have far reaching effects on how you feel

Your body relies on tight communication between senses, organs, muscles, brain, and more—and one of the most critical communication lines is the vagus nerve.(Axel_Kock/Shutterstock)

Your body relies on tight communication between senses, organs, muscles, brain, and more—and one of the most critical communication lines is the vagus nerve.

The vagus nerve is the longest cranial nerve in the body, traveling from the brain stem down through the spinal cord to the abdominal area. Along the way, it reaches out and affects many organs.

Also known as cranial nerve X and the pneumogastric nerve, the vagus nerve is the primary component of the parasympathetic nervous system, which is part of the autonomic nervous system. The autonomic nervous system also includes the sympathetic nervous system. 

While the sympathetic nervous system triggers the fight-or-flight response, the parasympathetic nervous system sets off a calming response after the danger has passed. Feelings of safety trigger the front (ventral) part of the vagus nerve while danger activates the back (dorsal). When a vagus nerve is healthy, it leads an individual to respond in an appropriate or mindful way.

What the Vagus Nerve Does

The vagus nerve is named after the Latin word for “wandering,” which is appropriate because it affects so many organs and functions in the body. It performs two types of functions:

  • Sensory: involved in sensations on the skin, in muscles, and in organs
  • Motor: includes activities such as swallowing, digestion, breathing, coughing, vomiting, and heart rate variability

This versatile nerve is also involved in the fight/flight response and how the body responds in a healthy way to stress. A healthy vagal tone, that is, the activity of the vagus nerve, would indicate generally healthy emotional regulation and physical health as well.

How to Stimulate Your Vagus Nerve

All of these important functions indicate that you should strive to maintain a healthy vagus nerve (good vagal tone). You can do this by stimulating your vagus nerve, which then results in feelings of calm and relaxation, a decrease in heart rate, and slowed breathing. Here are some ways to stimulate your vagus nerve at home. 

Exercise: Physical activity has many health benefits, and better vagal tone is one of them. In research involving individuals with heart problems, exercise therapy improved heart rate variability by increasing vagal tone and reducing the activity of the sympathetic nervous system.

Meditation: A 2020 study found that practicing mindfulness meditation can improve heart rate variability as well as sleep quality. In another study, individuals who participated in a six-week loving-kindness-meditation program showed an improvement in vagal tone while those who were on a waiting list for the program didn’t.

Singing or humming: When you sing or hum, it’s been shown you are activating your parasympathetic nervous system, slowing breathing, and increasing heart rate variability. Chanting also results in the same benefits.

Yoga: This activity activates the parasympathetic nervous system and can help with blood flow, digestion, and heart rate.

Deep slow breathing: Research shows that practicing deep, slow breathing can improve vagal tone and reduce anxiety.

Relaxing (chillin’ out): Activities that are relaxing and calming help improve vagal tone, whether it’s Tai Chi, socializing with friends, kicking back with a book, or some of the stress-reducing recommendations already noted here.

Gargling: The benefit from gargling is similar to that achieved by singing or humming. 

According to clinical psychologist Dr. Glenn Doyle, “The vagus nerve is deeply plugged into our heart, our guts, and our voice. … When we speak, shout, sing, the vagus nerve is lit up like a Christmas tree—which is one of the reasons why those activities can be so cathartic and emotional for so many of us.”

Bottom Line

A healthy vagus nerve is essential for optimal function of many organ systems and overall good health. Take care of yours by engaging in stimulating activities as much as possible!

Vagus Nerve Stimulation for Children With Epilepsy.

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The Vagus Nerve Stimulator

The first vagus nerve stimulator (VNS) was implanted in 1988.[1]Since then, more than 70,000 have been implanted for epilepsy worldwide.[2]

The VNS consists of a generator, typically implanted in the chest, and an electrode surgically fastened to the left vagus nerve. In addition, an external handheld magnet may be used if the patient senses an aura or to stop a seizure already in progress.

US Food and Drug Administration Approval

In 1997, VNS received US Food and Drug Administration (FDA) approval for the adjunctive treatment of refractory seizures in patients older than 12 years.[3] In 2005, the VNS was approved for the treatment of chronic or recurrent depression in patients older than 18 years.

VNS may also have a beneficial effect on mood in patients with epilepsy in addition to its antiepileptic effect.[1] The mechanism of action of VNS is uncertain, but may be related to metabolic activation of brain stem, limbic, or thalamic structures.[4]

To date, the VNS is the only FDA-approved medical device for the treatment of epilepsy. However, other approaches, such as deep-brain stimulation of the anterior nucleus of the thalamus, responsive neurostimulation, trigeminal nerve stimulation, and transcranial magnetic stimulation, are in development.

Phase 3 Trials for Epilepsy

A randomized, multicenter, clinical trial (Study E03) of 114 patients with partial seizures demonstrated a mean seizure reduction of 31% and a 50% seizure reduction in 39% of patients.[5] A second randomized trial (Study E05) of 254 patients with intractable partial seizures demonstrated an average reduction in seizure frequency of 28% in the high-stimulation group vs a 15% reduction in the low-stimulation (pseudo-placebo) group (P = .04).[4] These results are modest, but similar to those obtained with new antiepileptic drugs in phase 3 trials. Unlike antiepileptic drugs, VNS efficacy appears to improve over time.[3]

Adverse Effects of VNS

Compared with antiepileptic drugs, VNS has a completely different side effect profile. Adverse effects are related to the surgical implantation of the generator, which may result in discomfort and deep or superficial infection. The lead attached to the vagus nerve is subject to breakage. In addition, the electrical stimulation in the neck may be uncomfortable and result in cough, hoarseness, or a feeling of shortness of breath.[4] On the other hand, VNS does not cause sedation or adverse cognitive effects, which are often limiting factors with antiepileptic drug treatment.[6]

Magnet Activation of VNS

Neurostimulation by the VNS occurs at prespecified, continuous intervals (eg, 30 seconds on, 5 minutes off). In addition, the patient may trigger additional stimulation on demand by holding a magnet over the implanted device. Magnet-activated stimulation may abort, diminish, or terminate a seizure.

A retrospective analysis of seizure data collected from the E03 trial demonstrated an increased likelihood of improved seizure control (aborted and decreased) after magnet activation (P = .0479). In the E04 trial, 31% of patients were able to diminish seizures and 22% of patients terminated seizures, but 47% reported no effect with the magnet.[1] The magnet may offer psychological benefits to patients by providing some sense of control over seizures when they occur.[1]

Personal Experience

Years ago, I enrolled 5 of my patients with intractable epilepsy in the open-label E04 VNS safety trial. None of the patients became seizure-free, although as a group they experienced a modest benefit in seizure reduction. One college student did not like the stimulator and insisted that it be removed, even though he had not allowed adequate time for us to assess its therapeutic effects. The other 4 patients continued to use the VNS.

Source: Medscape.com

Early Success in New Treatment for Stroke Recovery.

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Researchers at The University of Texas at Dallas have taken a step toward developing a new treatment to aid the recovery of limb function after strokes.

In a study published online in the journalNeurobiology of Disease, researchers report the full recovery of forelimb strength in animals receiving vagus nerve stimulation.

“Stroke is a leading cause of disability worldwide,” said Dr. Navid Khodaparast, a postdoctoral researcher in the School of Behavioral and Brain Sciences and lead author of the study. “Every 40 seconds, someone in the U.S. has a stroke. Our results mark a major step in the development of a possible treatment.”

Vagus nerve stimulation (VNS) is an FDA-approved method for treating various illnesses, such as depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve, which relays information about the state of the body to the brain.

 

Khodaparast and his colleagues used vagus nerve stimulation precisely timed to coincide with rehabilitative movements in rats. Each of the animals had previously experienced a stroke that impaired their ability to pull a handle.

Stimulation of the vagus nerve causes the release of chemicals in the brain known to enhance learning and memory called neurotransmitters, specifically acetylcholine and norepinephrine. Pairing this stimulation with rehabilitative training allowed Khodaparast and colleagues to improve recovery.

 

Many rehabilitative interventions try to enhance neuroplasticity (the brain’s ability to change) in conjunction with physical rehabilitation to drive the recovery of lost functions, according to Khodaparast. Unfortunately, up to 70 percent of stroke patients still display long-term impairment in arm function after traditional rehabilitation.

 

“For years, the majority of stroke patients have received treatment with various drugs and/or physical rehabilitation,” Khodaparast said. “Medications can have widespread effects in the brain and the effects can last for long periods of time. In some cases the side effects outweigh the benefits. Through the use of VNS, we are able to use the brain’s natural way of changing its neural circuitry and provide specific and long lasting effects.”

“Through the use of VNS, we are able to use the brain’s natural way of changing its neural circuitry and provide specific and long lasting effects.”

 

Khodaparast acknowledged the study has some limitations. For example, the animals were young and lacked some of the other illnesses that accompany an aged human population, such as diabetes or hypertension. But Khodaparast and his colleagues said they are optimistic about vagus nerve stimulation as a future tool. They will continue testing in chronically impaired animals with the hopes of translating the technique for stroke patients. Working with MicroTransponder Inc., a partner company in the current study, researchers at the University of Glasgow in Scotland have begun a small-scale trial in humans.

 

“There is strong evidence that VNS can be used safely in stroke patients because of its extensive use in the treatment of other neurological conditions,” said Dr. Michael Kilgard, professor in neuroscience at UT Dallas and senior author of the study.

 

Kilgard is also conducting clinical trials using vagus nerve stimulation to treat tinnitus, the medical condition of unexplained ringing in the ears. Kilgard’s lab first demonstrated the ability of vagus nerve stimulation to enhance brain adaptability in a 2011Nature paper.