Preliminary results earn research team NIH funding to study therapy's potential, paired with physical therapy, in patients with the neurodegenerative disease
Intrigued by the recent success of vagus nerve stimulation (VNS) in stroke rehabilitation, neuroscientist Cristin Welle, PhD, wondered: If electrical bursts sparked brain cell regeneration in stroke patients, could it promote myelin regrowth in (MS) patients?
And if it did, could it also help the nearly 1 million MS patients in the country recover motor and cognitive abilities stolen by their disease - just as it was doing for patients with stroke? So, the CU Anschutz professor of neurosurgery took her questions to the lab.
What Welle and her team found - first in animal models and then in a small pilot study in humans - was so promising, they recently received a phased National Institutes of Health grant to continue both arms of their work.
Can VNS promote myelin regeneration?
Modeling its research after the emerging VNS stroke therapy - which UCHealth University of Colorado Hospital became the first in the state to offer this past year - Welle's team paired vagus nerve stimulation with physical rehabilitation in animal models.
Just as their stroke colleagues were doing in the clinic, the researchers delivered the electrical stimulation at the exact moment a skilled motor task was performed correctly. Then they looked at the animal model brain scans. "We were very surprised," Welle said.
The researchers saw a notable increase in new oligodendrocytes - cells in the brain and spinal cord that produce myelin, the coating damaged by MS that protects nerve cell fibers.
"No one has really established a link between neuromodulation (such as VNS) and improved myelin before," said Welle, also a professor of physiology and biophysics in the CU Anschutz School of Medicine.
What is multiple sclerosis (MS)? A neurodegenerative autoimmune disease that affects women at three times the rate of men generally in the prime of life (ages 20-50). Colorado consistently ranks among states with the highest rates of the disease.
Just as promising, the brain images also suggested the regenerated myelin in the animal models was returning to the locations where it was initially lost.
"We call that myelin pattern recovery, and pattern recovery predicts improvements in motor function," Welle said. "So we are super excited about that."
The team then replicated the findings in a small human pilot study, winning the grant to continue its basic science work in the lab while, after meeting feasibility requirements, translating it into a clinical trial. The researchers hope to begin recruitment for the trial by mid-2027.
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Research partners Kimberly Gagnon (seated), Simone Capuani (center) and Cristin Welle discuss data in Welle's lab at CU Anschutz.
What role does myelin play in MS symptoms?
With stroke, a sudden lack of blood starves brain cells of oxygen and glucose, resulting in disabilities if not treated quickly.
Studies have shown more "clinically meaningful" improvement in disabilities from stroke when VNS is combined with physical therapy versus doing physical therapy alone. The results suggest improved neuroplasticity - the brain's ability to adapt by forming or reorganizing connections and pathways.
MS has a different route to disability. The autoimmune disease causes the body to attack its own myelin sheath, a coating that protects the axons of neurons in the brain, spinal cord and optic nerve.
Damage to myelin disrupts the ability of axons - nerve fibers that carry signals - to communicate effectively. People with MS can suddenly lose the ability to walk, see or use their hands, among a range of other symptoms.
"So we wanted to know: Can VNS encourage myelin plasticity in the same way that it might encourage neuroplasticity in stroke?" Welle said.
What else is VNS used to treat? The U.S. Food and Drug Administration (FDA) has approved various vagus nerve stimulation (VNS) devices for medical conditions including:
- cluster headaches
- depression
- epilepsy
- migraines
- rheumatoid arthritis
- stroke rehabilitation
What will the clinical trial involve?
The clinical trial will focus on people with relapsing-remitting MS with hand dexterity issues, which affect 75% of MS patients and can dramatically disrupt quality of life. It will have one marked difference from current stroke VNS programs:
Rather than implanting a pulse generator device in participants' chests, the researchers will apply stimulation via a more noninvasive route - the ear.
"There's a small branch of the vagus nerve in the ear, which is a crazy little biological anomaly, but it's there," Welle said.
The vagus nerve, the longest cranial nerve, runs from the brain through the neck to most of the body's organs. It's known largely for its parasympathetic effect - or the "rest and digest" part of our autonomic nervous system, Welle said. "And you can stimulate it just by using electrodes on the surface of the ear."
The standalone VNS device resembles a headset, but it wraps around the neck rather than over the head. A wire connects to a small earbud-like device that's positioned in the ear.
As with VNS stroke therapy, the clinical trial will involve multiple sessions with volunteers practicing difficult hand dexterity skills. The system senses correct movements and automatically delivers stimulation via a wireless controller whenever a movement is performed correctly.
The long-term vision is to create an at-home system using the ear-stimulation technology, Welle said.
Did you know? CU Anschutz is home to the Rocky Mountain MS Center, one of the largest MS centers in the world. The center serves as a research hub and regional provider to 4,500 patients a year, offering resources that make research such as Cristin Welle's VNS project possible.
What else will the studies include?
Also as part of the grant, the team is developing advanced magnetic resonance (MR) sequencing, led by Jeffrey Bennett, MD, PhD, a CU Anschutz professor of neurology who is overseeing the clinical aspects of the project.
"Dr. Bennett is working with neuroradiology to implement some really cutting-edge MR sequences that will let us track myelin state in the brain with a lot of specificity."
Researchers will continue their lab work, looking for the mechanisms behind the myelin recovery and exploring the role immune system-related microglial cells might play. "We have some early evidence suggesting that VNS might modulate the state of these little microglia cells so that they're more pro-regenerative and less inflammatory."
Why study neuromodulation therapies?
VNS and other neuromodulation therapies provide another treatment option beyond medications, Welle said. Using seizures as an example, Welle said many patients cannot find a medication that controls their seizures, or their drugs stop working.
What is neuromodulation? A therapy targeting nerve activity using electrical, magnetic or other stimulation.
"So, in many cases for different types of neurologic injury, there's not a great pharmaceutical solution." And that is partly because the brain is so complex and drugs are not generally targeted to a specific area, she said.
"But with neuromodulation, you can target your treatment to the parts of the brain that really need that extra support. So it creates this very precise therapy that is meant to drive plasticity in the context of regaining motor function," Welle said.
"From a big-picture perspective, what's exciting to me about vagus nerve stimulation is that it's kind of harnessing the body's own ability to repair. Rather than creating an artificial condition, it's just helping the body to use its own repair processes."
Key points:
- CU Anschutz researchers are investigating whether vagus nerve stimulation paired with rehabilitation can promote myelin repair in multiple sclerosis.
- Early animal research showed increased myelinating cells and signs that myelin returned to areas where it had been lost.
- The team, which replicated the animal model findings in a small human pilot study, received NIH funding to continue the research.
- A planned clinical trial will study people with relapsing-remitting MS who have hand-dexterity difficulties and will use noninvasive stimulation through the ear.
