The vagus nerve, also known as the “wandering nerve,” winds a path all around your torso, intersecting with everything from the heart to the lungs to the digestive tract. That makes it a natural target for a wide range of therapeutic interventions: In the late ’90s, the Food and Drug Administration cleared the first surgically implantable devices to stimulate the vagus nerve, and today they’re used to treat medication-resistant cases of depression and epilepsy.
After weaving its way through your body, the vagus nerve ultimately ends up in your cranium, passing up through your neck and branching off to whisper past the outer edge of your ear. Which is where some companies are hoping they can make an impact without implants.
There are clear signs the FDA is watching their progress. In July, the agency issued an emergency use authorization to electroCore; the company’s handheld device, which was already cleared to treat cluster headaches and migraines by stimulating the vagus nerve on the neck, can now be used to tackle asthma-related breathing difficulties in Covid-19 patients for the duration of the pandemic. In January, the FDA cleared a stim device to treat opioid withdrawal from Spark Biomedical, which is working on a similar approach to help infants undergoing withdrawal.
The agency has recently marked that developmental device and a number of others with breakthrough status, a designation that could speed them through the review process. Most recently, it issued a breakthrough device designation to Nēsos, a California-based company developing a small, earbud-shaped device that could play a role in treating rheumatoid arthritis, a painful chronic inflammatory condition that destroys joints’ ability to move smoothly.
While the device looks like something you might use for listening to music, the primary output isn’t audio waves; it’s an electrical impulse that stimulates vagus nerve endings on the outer ear. “The area where you have more vagus nerve endings is actually not in the ear canal, it’s right on top of it,” said Konstantinos Alataris, CEO and co-founder of Nēsos.
The outer ear is one of the newer places clinicians are exploring as an access point to the vagus nerve. Implantable stimulation came first, followed by the noninvasive neck-based approach used by electroCore. “The big new thing is this idea of getting at the vagus through the transcutaneous or transauricular route,” said Mark George, a brain stimulation researcher at the Medical University of South Carolina and editor-in-chief of the journal Brain Stimulation.
Nēsos received its breakthrough designation after presenting data from a proof-of-concept study published in March in The Lancet Rheumatology. In an uncontrolled study of 30 patients who were not blinded to their treatment, the researchers saw statistically significant improvement in a standard marker of rheumatoid arthritis severity. “I think the trial looked good; really very significant,” said Imanuel Lerman, a pain management physician and researcher at UC San Diego. “It was nice, it was multicenter; the more centers, the more clout.”
The biological approach to treating rheumatoid arthritis makes sense, said Kevin Tracey, president and CEO of the Feinstein Institutes for Medical Research; he and colleagues discovered it. The idea underlies an implantable vagus nerve device developed by a company he founded called SetPoint, which also received a breakthrough designation last year. By activating parts of the brainstem, vagus nerve stimulation can send messages to the spleen, causing it to release anti-inflammatory signals. Theoretically, that could help any number of inflammation-driven disorders, from rheumatoid arthritis to sepsis to depression.
When a device stimulates the sensory nerves in the outer ear, some of the same parts of the brainstem light up. “So that’s a good thing, we think,” said Tracey. “What happens after that, who the heck knows? The pieces of the puzzle fit together, but you can’t go and prove clinical causality.”
There’s also a question of whether the outer ear is the best place to access the vagus nerve for therapeutic stimulation. Reaching the nerve through the neck, where it travels close to the carotid artery, could offer more bandwidth.
“If you actually were to go into the vagus nerve in the neck, pull it out, and then slice it open, it’s like a big fiber optic cable,” said George. “There are a gazillion different cables in there, each of which is within a sheath, and each of those fibers is doing one thing.” The vagus nerve in the ear is necessarily much smaller. “So that’s one of the questions: Can you send enough signal into the brain to have the clinical behavioral effects that you want?” said George. “But by and large I haven’t seen any deal breaker that would say that the ear is substantially different and insufficient.”
Nēsos is continuing to test the effects of its device. The company is currently running a randomized controlled trial for the rheumatoid arthritis indication, and has completed proof-of-concept work for preventing migraines. Next in the pipeline are major depressive disorders, including postpartum depression.
It’s not clear how, exactly, such stimulation of the vagus nerve might be optimized for certain illnesses. “We’re doing a lot more work right now with academic groups in order to understand if we play with different parameters, how we can increase or decrease or kind of modulate what we see happening in the central nervous system,” said Alataris. Different frequencies, durations of treatment, and pulse lengths could change their impact, along with the behaviors paired with the stimulation.
“The resistance to this idea is we don’t know everything about how it works,” said Tracey, “and I don’t think that’s the right question.” Just like with some pharmaceuticals, understanding the biological mechanism of action isn’t always necessary for success; the intervention just needs to be proven to work in rigorous clinical trials.
To Tracey, the promise of these bioelectronic devices is in distributed and low-cost care for chronic conditions. “I look at the monthly or weekly costs of biologics, and I look at the cost of surgery plus a device, and the potential for savings is enormous,” he said. Without the cost of surgery, noninvasive devices could offer an even better deal.
Despite Tracey’s math — and publications from device developers to make their case — many payers are still reticent to reimburse for FDA-cleared noninvasive therapies like electroCore’s. “The use of electric medicine has been new, and required a deeper evaluation than just another drug,” Peter Staats, electroCore’s chief medical officer wrote in an email. “Insurers have had to figure out how to pay for a medical device in what was essentially a pharmaceutical model with monthly prescriptions.”
The lack of buy-in isn’t surprising to George, who saw a similar roadblock as a developer of a different form of noninvasive brain stimulation: transcranial magnetic stimulation for the treatment of persistent depression. “We had FDA approval in 2008, and not one but two large, multicenter randomized controlled trials showing clinically significant efficacy,” he said. “And it took almost a decade to get payers on board fully.”
While clinical studies on the devices exist, they’re often small, unblinded, and not randomized. Funding for sufficiently powered studies can be hard to come by. And with so many indications and devices in development for vagus nerve therapies, it’s reasonable to be skeptical.
“I think there are just so many different ways to stimulate the brain and spine, and I think doctors and the general public and insurance companies struggle to separate wheat from chaff,” said George.
But breakthrough designation for Nēsos’ device and others could accelerate that adoption timeline. In the final stretch of the Trump administration, the Centers for Medicare and Medicaid Services proposed a new rule that would provide up to four years of national Medicare coverage for all devices that were awarded breakthrough status and went on to win clearance. The final decision on the Medicare Coverage of Innovative Technology pathway, initially slated to go into effect on March 15, has been delayed until May 15 due to the Biden administration’s regulatory freeze.
Providers have argued against the rule, arguing that it doesn’t require enough careful vetting of safety and efficacy before automatically providing coverage for new devices. But if it manages to eke through, it would offer these noninvasive devices a clear path to reimbursement.