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Waking the Vagus: Wandering nerve could lead to range of therapies

Vagus nerve illustration1

Scientists have invested a lot of time into researching the effects of vagus. It is believed that vagus can help fight epilepsy and depression.

Electrical stimulation of the vagus through a surgically implanted device has already been approved by the U.S. Food and Drug Administration as a therapy for patients who don’t get relief from existing treatments.

Now, researchers are taking a closer look at the nerve to see if stimulating its fibers can improve treatments for rheumatoid arthritis, heart failure, diabetes and even intractable hiccups. In one recent study, vagus stimulation made damaged hearts beat more regularly and pump blood more efficiently. Researchers are now testing new tools to replace implants with external zappers that stimulate the nerve through the skin.

Anchored in the brain stem, the vagus travels through the neck and into the chest, splitting into the left vagus and the right vagus. Each of these roads is composed of tens of thousands of nerve fibers that branch into the heart, lungs, stomach, pancreas and nearly every other organ in the abdomen. This broad meandering earned the nerve its name — vagus means “wandering” in Latin — and enables its diverse influence.

The nerve plays a role in a vast range of the body’s functions. It controls heart rate and blood pressure as well as digestion, inflammation and immunity. It’s even responsible for sweating and the gag reflex. “The vagus is a huge communicator between the brain and the rest of the body,” says cardiologist Brian Olshansky of the University of Iowa in Iowa City. “There really isn’t any other nerve like that.”

The FDA approved the first surgically implanted vagus nerve stimulator for epilepsy in 1997. Data from 15 years of vagus nerve stimulation in 59 patients at one hospital suggest that the implant is a safe, effective approach for combating epilepsy in some people, researchers in Spain reported in Clinical Neurology and Neurosurgery in October. Twenty of the patients experienced at least 50 percent fewer seizures; two of those had a 90 percent drop in seizures. The most common side effects were hoarseness, neck pain and coughing. In other research, those effects often subsided when stimulation was stopped.

Early on, researchers studying the effects of vagus stimulation on epilepsy noticed that patients experienced a benefit unrelated to seizure reduction: Their moods improved. Subsequent studies in adults without epilepsy found similar effects. In 2005, the FDA approved vagus nerve stimulation to treat drug-resistant depression.

In 2011, rheumatologist Paul-Peter Tak, of the University of Amsterdam, and his colleagues implanted vagus nerve stimulators into four men and four women who had rheumatoid arthritis, an autoimmune inflammatory condition that causes swollen, tender joints. After 42 days of vagus stimulation — one to four minutes per day — six of the eight arthritis patients experienced at least a 20 percent improvement in their pain and swelling. Two of the six had complete remission, the researchers reported at an American College of Rheumatology conference in 2012.

If these results hold up in future studies, Tak hopes to see the procedure tested in a range of other chronic inflammatory illnesses, including inflammatory bowel disorders such as Crohn’s disease. Studies in animals have shown promise in this area: In 2011, researchers reported in Autonomic Neuroscience: Basic and Clinical that vagus stimulation prevented weight loss in rats with inflamed colons.

Treating inflammatory conditions with vagus stimulation is fundamentally different from treating epilepsy or depression, Tak says. More research with patients will be necessary to develop the technique. “We are entering a completely unknown area, because it’s such a new approach,” he says. There could be financial hurdles as well, he says. But GlaxoSmithKline, which Tak joined after initiating the arthritis study, has purchased shares of SetPoint Medical, a company in Valencia, Calif., that produces implantable vagus nerve stimulators, Tak says.

As he and others put stimulation to the test for inflammation, some scientists are attempting to see if manipulating the nerve can help heal the heart.

Results from studies on the effects of vagus stimulation on heart failure have been inconsistent. In 2011, researchers reported in the European Heart Journal that repeated vagus nerve stimulation improved quality of life and the heart’s blood-pumping efficiency in heart failure patients. A vagus stimulation trial of heart failure patients in India published in the Journal of Cardiac Failure in 2014 echoed these results. After six months of therapy, the patients’ left ventricles pumped an average of 4.5 percent more blood per beat.

Last August, however, researchers reported that a six-month clinical trial of vagus stimulation failed to improve heart function in heart failure patients in Europe. This study had the most participants — 87 — but used the lowest average level of electrical stimulation. “All the results thus far are preliminary. The studies that have been finished to date are relatively small,” Lauer says. “But there certainly are promising findings that [suggest] we may be barking up the right tree.”

Vagus manipulation isn’t limited to heart failure research. It’s also being tried in atrial fibrillation, in which the heart flutters erratically. “When it flutters, it doesn’t really push blood very efficiently,” says clinical electrophysiologist Benjamin Scherlag of the University of Oklahoma in Oklahoma City. Atrial fibrillation is common in people over age 60, Scherlag says, and can ultimately lead to blood clots and strokes. Treatments include drugs that alter heart rhythm or thin the blood, but they don’t work for all patients and some have nasty side effects, Scherlag says.

In the lab, scientists can use high-intensity vagus stimulation to alter heart rhythm and induce atrial fibrillation in animals. But milder stimulation that alters heart rate only slightly, if at all, can actually quell atrial fibrillation, animal studies and one human study show.

Vagus stimulation for atrial fibrillation is still in its infancy, and clinical applications haven’t been adequately tested, says Indiana’s Zipes. “Nevertheless, the concept bears looking into.”

Even for depression and epilepsy, Tak says, researchers still need to figure out the best ways of stimulating the vagus — exactly where to place a device, and how much of a shock to deliver.

The intensity of electrical current, duration of stimulation and each patient’s health status could all affect the results of a vagus stimulation trial, Ackland says. And it’s possible that a widespread effect, such as suppressing inflammation caused by the immune system, could even be harmful to some patients.


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