The vagus nerve is a key communication line between the brain and organs like the heart and lungs—and stimulating it can ease conditions including epilepsy and arthritis. But this electrical therapy often hits the wrong neural fibers, causing side effects like coughing or voice changes.
A new study finds that researchers can steer stimulation toward specific fibers and away from others by overlapping high-frequency currents inside the nerve. Tested in pigs, the technique boosted signals to the lungs while sparing the throat, reducing unwanted effects without sacrificing therapeutic impact.
If the results hold up in humans, the approach could make vagus nerve therapies safer and more precise, says Stavros Zanos, a cardiologist and bioengineer at the Feinstein Institutes for Medical Research in Manhasset, N.Y. “It’s the basis for what we think is an improved way of stimulating the nerve,” he says.
A prototype for human testing is now under development. Zanos and his colleagues reported their findings in May in Nature Communications.
Vagus nerve stimulation (VNS) is already FDA-approved for epilepsy, depression, and stroke rehabilitation, and is under investigation for a range of other conditions. In recent weeks, researchers have reported encouraging findings for VNS in easing chronic cluster headaches and supporting rehabilitation in people with spinal cord injuries—and ongoing studies are probing its potential in conditions including inflammatory illnesses and heart conditions as well.
The therapy works by sending mild electrical pulses through a device implanted in the neck, nudging the body’s internal circuits toward a more balanced state. But the vagus nerve is a complex bundle of many different fibers—around 100,000 in total—each heading to different organs.
Current devices can’t easily tell one fiber from another, often lighting up off-target pathways and triggering side effects. The most common side effects are linked to unwanted activation of nerve fibers that control the voice box and throat.
That is why researchers are now searching for more selective ways to stimulate the correct fibers, delivering benefits without the drawbacks.
Turning Selectivity Into Strategy
A range of more discriminating strategies have been explored, including tweaking the shape and timing of electrical pulses and using multi-contact electrodes to maneuver currents in specific directions. Some approaches aim to block the large fibers responsible for side effects, while others try to selectively activate smaller fibers linked to specific organ functions.
But results have been mixed. Many techniques show partial success in animals, but few offer both the precision and reliability needed for clinical translation. Zanos is hopeful that his team’s new approach—which harnesses a technique called intermittent interferential current stimulation—will fare better.
Instead of stimulating the whole nerve at once, the technique sends slightly offset high-frequency signals to different electrodes embedded in a cuff implanted around the vagus nerve in the neck. These signals then interact to produce localized interference, effectively steering activation toward chosen nerve fibers and away from others.
“It’s a cool concept,” says Kip Ludwig, a biomedical engineer at the University of Wisconsin-Madison who was not involved in the study. “They’re using the spot interference to make it a bit harder to activate the stuff you don’t want—which is kind of paradigm” since researchers had long assumed that, at the point of maximal interference, nerve activation would be enhanced, not suppressed.
Reducing Side Effects
The researchers conducted experiments with pigs, which confirmed that targeted nerve activation is possible. By delivering two high-frequency, sinusoidal signals through different pairs of electrodes—one set at 20 kilohertz and the other at 22 kHz—they created a subtle interference pattern inside the vagal nerve bundle.
Like a slow ripple in the ocean riding atop fast-moving swells, the combined signals produced a gentle 2-kHz wave that reshaped the nerve’s internal electric field. By adjusting the signal strength and electrode placement, the team could then navigate the stimulation zone as desired.
As a proof of concept, the researchers selectively turned on fibers linked to the lungs, prompting the pigs to slow their breathing. And they did so without the stimulation spilling over into nearby fibers that control the throat and voice box, as shown by minimal muscle activity in those areas.
In principle, targeting lung-related fibers in this way could help treat conditions like asthma or chronic anxiety in which controlled breathing plays a therapeutic role. But according to Zanos, the real promise of the technique lies in its flexibility, with the potential to improve VNS-based treatments across a wide range of conditions—anywhere specific fiber groups can be precisely targeted.
“The same principle can be used for any organ,” he says, “as long as the fibers that project to that organ are also somewhat distinct.”
The approach is still a ways off from human use. As co-author and computer scientist Vojkan Mihajlović points out, his health technology group at Imec—which developed the stimulation technique and created the integrated circuit to enable its precise delivery—still needs to fine-tune a range of parameters, from electrode placement to the exact frequencies and amplitudes of the stimulation currents. “There are knobs we can further turn to optimize the stimulation,” he says.
But with a few more tweaks, vagus therapies might finally hit just the right nerve—selectively.
