Six times a day, Katrin pauses whatever she's doing, removes a small magnet from her pocket and touches it to a raised patch of skin just below her collar bone. For 60 seconds, she feels a soft vibration in her throat. Her voice quavers if she talks. Then, the sensation subsides.
The magnet switches on an implanted device that emits a series of electrical pulses — each about a milliamp, similar to the current drawn by a typical hearing aid. These pulses stimulate her vagus nerve, a tract of fibres that runs down the neck from the brainstem to several major organs, including the heart and gut.
The technique, called vagus-nerve stimulation, has been used since the 1990s to treat epilepsy, and since the early 2000s to treat depression. But Katrin, a 70-year-old fitness instructor in Amsterdam, who asked that her name be changed for this story, uses it to control rheumatoid arthritis, an autoimmune disorder that results in the destruction of cartilage around joints and other tissues. A clinical trial in which she enrolled five years ago is the first of its kind in humans, and it represents the culmination of two decades of research looking into the connection between the nervous and immune systems.
For Kevin Tracey, a neurosurgeon at the Feinstein Institute for Medical Research in Manhasset, New York, the vagus nerve is a major component of that connection, and he says that electrical stimulation could represent a better way to treat autoimmune diseases, such as lupus, Crohn's disease and more.
Several pharmaceutical companies are investing in 'electroceuticals' — devices that can modulate nerves — to treat cardiovascular and metabolic diseases. But Tracey's goal of controlling inflammation with such a device would represent a major leap forward, if it succeeds.
He is a pioneer who "got a lot of people onboard and doing research in this area", says Dianne Lorton, a neuroscientist at Kent State University in Ohio, who has spent 30 years studying nerves that infiltrate immune organs such as the lymph nodes and spleen. But she and other observers caution that the neural circuits underlying anti-inflammatory effects are not yet well understood.
Tracey acknowledges this criticism, but still sees huge potential in electrical stimulation. "In our lifetime, we will see devices replacing some drugs," he says. Delivering shocks to the vagus or other peripheral nerves could provide treatment for a host of diseases, he argues, from diabetes to high blood pressure and bleeding. "This is the beginning of a field."
A patient approach
People given vagus-nerve stimulation for seizures or depression experience some side effects — pain and tightening in the larynx, or straining in their voice, for example; Katrin feels a minor version of this when she stimulates her vagus. Shocking this nerve can also lower the heart rate or increase stomach acid, among other effects.
In this respect, Tracey has cause for optimism. The human vagus nerve contains around 100,000 individual nerve fibres, which branch out to reach various organs. But the amount of electricity needed to trigger neural activity can vary from fibre to fibre by as much as 50-fold.
Yaakov Levine, a former graduate student of Tracey's, has worked out that the nerve fibres involved in reducing inflammation have a low activation threshold. They can be turned on with as little as 250-millionths of an amp — one-eighth the amount often used to suppress seizures. And although people treated for seizures require up to several hours of stimulation per day, animal experiments have suggested that a single, brief shock could control inflammation for a long time.
By 2011, Tracey was ready to try his technique in humans, thanks to his animal studies, Levine's optimization of electrical stimulation, and funding from SetPoint. That first trial was overseen by Paul-Peter Tak, a rheumatologist at the University of Amsterdam. Over the course of several years, 18 people with rheumatoid arthritis have been implanted with stimulators, including Katrin.
She and 11 other participants saw their symptoms improve over a period of 6 weeks. Lab tests showed that their blood levels of inflammatory molecules decreased. These improvements vanished when the devices were shut off for 14 days — and then returned when stimulation was resumed.
Katrin, who has continued to use the stimulator ever since, still takes weekly injections of the anti-rheumatic drug methotrexate, as well as a daily dose of an anti-inflammatory pill called diclofenac — but she was able to stop taking high-dose, immune-suppressive steroids, and her joints improved enough for her to return to work.
Bruno Bonaz, a gastroenterologist at the University Hospital in Grenoble, France, implanted stimulators into seven people with Crohn's disease. Over a period of six months, five of them reported experiencing fewer symptoms, and endoscopies of their guts showed reduced tissue damage. SetPoint is also midway through a clinical trial of its own, using vagus-nerve stimulation to treat Crohn's disease.
Tracey and Bonaz aren't the only people looking to harness neural circuits to treat inflammation. Raul Coimbra, a trauma surgeon at the University of California, San Diego, is studying it as a way to treat septic shock, which affects hundreds of thousands of people each year. Many people who die from the condition are pushed past the point of no return by a singular event: the rapid deterioration of the gut lining, which releases bacteria into the body — triggering inflammation that damages organs, including the lungs and kidneys.
The small clinical trials run so far have revealed that some people don't respond to vagal stimulation. It may be that testing could determine who will benefit from the treatment before people receive implants.
Despite the uncertainties, however, the field of electroceuticals is starting to gain momentum. Last October, the US National Institutes of Health announced a programme called Stimulating Peripheral Activity to Relieve Conditions (SPARC), which will provide US$238 million in funding until 2021 to support research updating the maps of neural circuitry in the thoracic and abdominal cavities.
The UK pharmaceutical company GlaxoSmithKline is also showing interest. It has invested in SetPoint, and it announced last year the formation of a joint venture with Google — called Galvani Bioelectronics — that will develop therapies for a range of conditions, including inflammatory diseases. Tak, who ran the rheumatoid-arthritis trial for Setpoint, joined GlaxoSmithKline in 2016.
Whether vagus-nerve stimulation lives up to expectations remains to be seen. The number of people who have been treated so far is minuscule — just 25 individuals in 2 completed trials. And treatments often look promising in early trials such as these, but then flop in larger ones.
But people with autoimmune disorders are starting to take notice. Treatments for rheumatoid arthritis and Crohn's disease carry some risks, and they don't help everyone. Katrin was one of more than 1,000 people who inquired about the trial for vagal stimulation. "I had nothing else," she says. "I wanted it."
Source and images: Nature