“This is a bottle of pills,” says J.P. Errico, showing me something that’s obviously not a bottle of pills.
Errico, who is cofounder and CEO of ElectroCore Medical, is holding the GammaCore, a noninvasive vagus nerve stimulator. If ElectroCore’s R&D work holds up, this device is about to turn decades of evidence about the importance of a single nerve into a new kind of medicine: an electrical therapy as benign as a morning swim and as straightforward as popping a pill with your coffee.

Look at an anatomy chart and the importance of the vagus nerve jumps out at you. Vagus means “wandering” in Latin, and true to its name, the nerve meanders around the chest and abdomen, connecting most of the key organs—heart and lungs included—to the brain stem. It’s like a back door built into the human physiology, allowing you to hack the body’s systems.

Vagus nerve stimulation, or VNS, got its start in the 1990s, when Cyberonics, of Houston, developed an implanted stimulator to treat particularly tough cases of epilepsy. That application was just the beginning. Researchers soon found that stimulation had the potential to treat a variety of ailments, including painful neurological conditions such as migraine headaches and fibromyalgia, inflammatory problems such as Crohn’s disease and asthma, and psychiatric ailments such as depression and obsessive- compulsive disorder.

Scientific enthusiasm notwithstanding, the clinical history of VNS has been mixed. Trials with patients suffering from treatment-resistant depression produced good results—but not quite good enough to convince U.S. government-run insurance programs to pay for its use. This past August, a stimulator produced by Boston Scientific performed poorly in a major trial with heart-failure patients. Cyberonics and its competitors are still figuring out what signals are best to send along the vagus nerve to tap into the brain’s systems and fix what ails us.

Progress has been excruciatingly slow. Treatments typically require implanting a pocket-watch-size pulse generator in a patient’s chest, which is wired to a pair of electrodes encircling the vagus nerve in the neck. These trials involve patients for whom all other options have either failed or been ruled out and who are willing to undergo an invasive “treatment of last resort.”

But what if VNS could be the first thing your doctor prescribed? What if, as ElectroCore promises, it really was as easy as taking a pill? That’s what the New Jersey–based startup is aiming for. ElectroCore has developed the first vagus nerve stimulator that isn’t implanted: It’s a handheld device you simply press against your neck. If that’s all it takes to hack into the brain and treat some of the most troubling conditions around, medicine might look very different a decade from now.

The idea that this single nerve can have such a profound effect on so many different organs and ailments might seem far-fetched. To understand the underlying logic of this treatment, consider the anatomy of the vagus nerve and where it connects to the brain.

The nerve terminates in the brain stem at a structure called the nucleus tractus solitarius. “The NTS is a junction in the brain,” explains Milton Morris, who until recently was senior vice president of R&D at Cyberonics. From there, the vagus nerve’s signals travel to other important brain structures with bewildering Latin names, such as the locus coeruleus and the dorsal raphe nuclei. Most of these structures produce neuro transmitters—the chemicals brain cells use to communicate—that have an inhibitory effect, decreasing a neuron’s excitability.

That anatomical perspective clarifies how VNS produces its therapeutic benefits. An epileptic seizure, for example, is the result of waves of excitation sweeping through the brain. Deploying the brain’s natural dampers should—and apparently does—cause these waves to peter out. Many of the ailments now being investigated by vagus nerve researchers likely involve similar overexcitation, or oversensitivity. “Epilepsy might be just one end of a spectrum,” Errico says.

Some connections along this spectrum have been known for a long time: About 2,400 years ago, Hippocrates noted an association between epilepsy and depression, two ailments now treated with VNS. Researchers have stumbled upon other links more recently: Errico and scientists at Columbia University discovered that asthmatics they successfully treated with stimulation reported fewer headaches.

ElectroCore found further hints of relationships between maladies by delving into patient complaints collected by the United Kingdom’s National Health Service. Sorting through the data helped the company identify its first clinical targets—migraines and cluster headaches—but also suggested future research directions. The data showed that care for patients with headaches is surprisingly expensive, as they consult doctors up to three times as often as average and take up to four times as much medication. But all this extra health care isn’t necessarily to address their headaches; these patients tend to have other chronic conditions such as fibromyalgia, anxiety, and asthma that may be treatable through VNS. The data suggest that these conditions may have a common root, at least in some patients.

Today these problems are served by a multibillion-dollar pharmaceuticals market. But those drugs don’t always work, and they can have troubling side effects. So instead of trying to squash these electronic upstarts, some big pharma companies are getting in on the game.

British drug giant GlaxoSmithKline has been the most public with its support, even coining the term “electroceuticals” to describe the emerging therapies. “Our goal, basically, is to speak the electrical language of the nerves to achieve a higher treatment effect,” said Kristoffer Famm, head of bioelectronics research at GSK, in a recent interview. In 2013, GSK created a US $50 million venture capital arm, Action Potential Venture Capital, to fund electroceutical startups. It’s first pick was the vagus nerve implant company SetPoint Medical.

SetPoint was cofounded by Kevin Tracey, a neurosurgeon and immunologist. Motivated by the mysterious death of an infant burn patient under his care, Tracey went on to prove the existence of the “inflammatory reflex”—a pathway through which the brain can quell inflammation by sending signals through the vagus nerve to the spleen. SetPoint Medical is dedicated to manipulating that reflex to treat rheumatoid arthritis and Crohn’s disease, among other inflammatory afflictions. Though its therapy requires an implanted stimulator, the small device fits entirely in the patient’s neck, greatly reducing the extent of surgery. The company has always aimed to make the device as much like a drug therapy as possible, explains SetPoint chief technical officer Mike Faltys. “We didn’t get pharmaceutical funding until recently,” he says, “but we had the pharmaceutical idea from the start.”
Think about pills for a moment: You take them either on a schedule or in response to a symptom. They’re portable, and their number can be limited by prescription.

ElectroCore’s device shares all these attributes, says Errico. A typical regimen is two or three 2-minute doses twice a day, but if you sense a migraine coming on, you can use the stimulator to head off a full-blown attack. ElectroCore’s device is smaller than an iPhone 6, so it’s easy to tote around. (The company’s engineers recently built a stimulator into the case of a Samsung smartphone just to show it could be done.) And it can be programmed by your doctor to deliver a set number of doses.

Making the world’s first noninvasive nerve stimulator was quite an engineering challenge. Consider the signaling problem: The vagus nerve is made up of many individual nerve fibers of several different types, some transmitting signals up into the brain and some signaling down to the organs. Some do helpful things such as calming over excitation in the brain or signaling the spleen to reduce inflammation, but others do things that could be dangerous such as slowing your heart rate. The signal must be able to activate the “good” fibers while leaving the “bad” ones unchanged.

Adding to the difficulty is that to reach the nerve, the stimulator has to transmit its signal through several centimeters of flesh without causing excessive muscle contractions. The signal must also pass through a layer of skin that’s both electrically resistive and chock-full of pain receptors.

ElectroCore’s researchers knew that directing the signal through the good fibers instead of the bad ones is just a matter of hitting a sweet spot of signal strength. Their real innovation was sending that signal painlessly through the skin, explains vice president of research Bruce J. Simon. The key, he says, is to understand that the skin acts the way a capacitor in a filter circuit does: It blocks direct current and low frequencies, but a high enough frequency signal will pass through it. But brain responses to VNS are frequency dependent. ElectroCore’s brain- hacking code needs 25 one- millisecond pulses per second—but this low a frequency would trigger pain receptors while passing through the skin. So the stimulator forms each of the 25 pulses from a burst of 5,000 hertz. The high- frequency signals slip painlessly past the skin, losing only about half their strength along the way. The nerve fibers themselves do the rest of the job, modifying the signal that reaches them so that only the train of 25 pulses remains to propagate up into the brain.

The handheld stimulator can produce pulses at a range of voltages; because people’s necks and nerves vary anatomically, the voltage is adjustable for each patient—though it always remains below the level that would trigger the bad nerves. ElectroCore’s researchers found that the optimum voltage is about equal to the level that causes a person’s lower lip to twitch.

“My number is 28 [volts],” says company chief operating officer Frank Amato, as he demonstrates the device. You get the sense that everyone at ElectroCore knows his or her number. I tried it as well, though on my arm and with the goal of causing my hand to contract. My number was 12.

ElectroCore isn’t alone in seeking a noninvasive way to access the vagus nerve. Germany-based Cerbomed has developed a stimulator that hangs on a part of the ear where a minor branch of the vagus nerve lies close to the skin. Competitors are skeptical that stimulating this small branch will cause sufficient changes in the brain, but Cerbomed cites studies showing that its stimulator produces a pattern of neural activation similar to that produced by more typical forms of VNS. The company is now conducting a clinical trial for the treatment of epilepsy and has experimented with treatments for migraine, schizophrenia, and tinnitus as well.

You might think ElectroCore’s noninvasive vagus nerve stimulator would have makers of more conventional systems worried. It doesn’t. For those companies, it’s all a matter of compliance and control.

Compliance is the ability or willingness of a patient to follow through with a therapy. As former Cyberonics staffer Morris points out, some of the company’s patients may be too sick to reliably use a self-administered system. Some epileptic patients, for example, can feel their seizures coming on and activate their implants, but others don’t experience such foreshadowing. Implanted stimulators can deliver their therapies automatically. What’s more, it can take months or even a few years for epileptic patients to get the full benefits of vagus nerve stimulation, he says. “If he’s not getting relief, a patient might quit before it gets there.”

Companies making invasive vagus nerve stimulators also like the guarantee that they can control the delivery of a precisely tuned signal to the vagus nerve alone. Cyberonics is also working on a heart-failure therapy, in which the doctor carefully ramps up the electrical signal over many weeks. Morris thinks this progression would be too difficult to control without an implant.

The Dallas-based company MicroTransponder is developing an implanted device to treat tinnitus and stroke. The company’s chief scientific officer, Navzer Engineer, says external stimulators couldn’t match the timing precision and signal integrity of his system. “We know it works and we know the parameters,” he says. “I’m not sure we’d know these parameters if we used a noninvasive system.”
ElectroCore’s Errico acknowledges that compliance may be a problem for some patients, but he’s convinced that his company’s device has exact enough control to treat a broad range of ailments.
Perhaps the biggest advantage of the noninvasive approach is the economics. Implants must operate inside the body for years without being damaged or causing problems themselves, and that doesn’t come cheap: The U.S. government insurance program Medicaid pays about $20,000 for the Cyberonics epilepsy device and its implantation. At that price, it’s not surprising that implants are often a last resort. By contrast, ElectroCore’s noninvasive system costs the equivalent of $200 to $400 in Europe, depending on how many doses are programmed into the device.

At that price, Medical University of South Carolina brain-stimulation scientist Mark S. George imagines a scenario that would be a win for both invasive and noninvasive technology. Like any therapy, VNS doesn’t work for everybody. Even in its most established use, epilepsy, VNS helps only about 40 percent of those who get the implant. George suggests that patients might start with noninvasive stimulation, and if they respond to it, they could go ahead with the implantation procedure knowing ahead of time that they’ll benefit. This would cut costs overall, because fewer patients would needlessly get implants.

In any case, ElectroCore still has a lot to prove: While its device has met Europe’s regulatory standards as a treatment for migraines and other headaches, U.S. market approval requires more rigorous clinical trials, which are now being reviewed by the Food and Drug Administration. And the company’s scientists are still investigating potential applications in gastroenterology, psychiatry, and pulmonology.

If clinical trials eventually prove this system’s worth for other chronic ailments, its low price tag would make it competitive with standard drug treatments. And unlike pharmaceutical treatments, the nerve stimulator seems to have no major side effects. Hence the buzz about electroceuticals. Anyone who will ever suffer from one of those ailments or cares about someone who does—in other words, just about everyone—may soon benefit from this new electronic age of medicine.
This article originally appeared in print as “Follow the Wandering Nerve.”