Study: VNS Shows Promise for Improving Peripheral Nerve Recovery

When a nerve in an arm or leg is damaged, the brain adapts rapidly to the suddenly missing signal from that part of the body. This reaction complicates later efforts at rehabilitation.

In an effort to restore function after peripheral nerve injury, researchers at The University of Texas at Dallas have demonstrated in an animal model that sparking change in the central nervous system during physical rehabilitation enhances recovery.

Postdoctoral researcher Eric Meyers PhD’17 (left) uses a surgical microscope while discussing findings with Dr. Seth Hays, assistant professor of bioengineering at UT Dallas. Both were part of a team that found that vagus nerve stimulation during physical rehabilitation may help restore brain function after a peripheral nerve injury. 

Postdoctoral researcher Eric Meyers PhD’17 is the lead author of a study published Dec. 19 in Nature Communications describing this finding. He was part of an interdisciplinary team from the Texas Biomedical Device Center (TxBDC) — representing the School of Behavioral and Brain Sciences and the Erik Jonsson School of Engineering and Computer Science — that used vagus nerve stimulation (VNS) to reverse brain dysfunction caused by damage to a nerve outside the brain and spinal cord, which comprise the central nervous system.

“We’ve long known that if you damage a peripheral nerve, the brain changes,” Meyers said. “We set out to show that these changes that the brain makes after peripheral damage contribute to dysfunction and that reversing those brain changes could then improve recovery.”

Dr. Seth Hays, assistant professor of bioengineering and senior author of the study, explained that cells in an injured peripheral nerve will generally grow back and reconnect — unlike those in the spinal cord — but residual issues remain.

“Because the brain has reorganized, it can’t deal with the information from the restored nerve,” said Hays, who is also a Fellow, Eugene McDermott Professor.

When a nerve is cut, the neurons in the brain that previously received and sent sensory and motor information for that region of the body are repurposed very quickly, Hays said.

“Over the course of hours, or even just minutes, the surrounding neurons annex the space in the brain that’s no longer receiving a signal,” he said.

“We’ve long known that if you damage a peripheral nerve, the brain changes. We set out to show that these changes that the brain makes after peripheral damage contribute to dysfunction and that reversing those brain changes could then improve recovery.”

Eric Meyers PhD’17, postdoctoral researcher at UT Dallas

The resulting difficulties don’t come from neural connections changing along the path to the brain, but rather, as Meyers puts it, “when these neurons regenerate, the signals don’t know where to go.”

To treat this dysfunction, researchers focused on the vagus nerve, which connects the brain with the parasympathetic nervous system, which oversees unconscious functions such as circulation and digestion. With VNS, the nerve is stimulated electrically via a device implanted in the neck. Work pioneered by researchers at UT Dallas has documented that stimulating the nerve during rehabilitation can fine-tune brain function, and recent research has shown it to be effective in stroke recovery.

In the current study, researchers tracked the course of restored nerve signals by injecting a fluorescent virus into the muscles controlled by the injured nerve.

“Since the signal only goes to brain neurons to which it is synaptically connected, we can document the precise path of these signals,” Meyers said.

This tracking method showed that the reconnection of an injured nerve tends to result in misdirected signals. Some impulses reach unintended destinations, while others are duplicated.

“VNS, however, refines the restoration of connectivity, not only increasing connections from the reconnected nerve, but also reducing the number of misdirected connections,” Meyers said.

To prove that the recovery was tied solely to the central nervous system, the researchers tried VNS on rodents depleted of the neurotransmitter acetylcholine, which modulates connectivity between neurons.

“If you deplete a neuromodulator like acetylcholine from the cortex of the brain, you can’t drive changes there,” Meyers said. “So the recovery-inducing changes are tied to plasticity in the cortex.”

Hays and Meyers said their results suggest that augmenting physical or occupational therapy with simultaneous VNS would promote the correct function of the injured nerve. Further, there is no magic window during which therapy must occur as long as the peripheral nerve has already reconnected.

“We are already in the process of translating VNS therapy forward in humans for stroke and spinal cord injury, and some stroke patients who’ve benefited from the therapy suffered their stroke at least 10 years ago,” Hays said. “They can still benefit.”

For nerve injury patients, the tools to deliver the therapy in humans are in development and will require regulatory approval. Hays expects to be able to test the method in such patients in two to three years.

At that point, VNS could prove an important method of intervention for approximately 20 million Americans who have peripheral neuropathy.

“Treating the brain is a fundamentally new way to approach peripheral nerve damage and restore function,” Hays said.

Meyers added: “Central nervous system therapy is largely an unexplored area in the context of addressing nerve damage. Hopefully, this opens up a door to a lot of new therapeutics. This is 30 years in the making.”

Additional authors of the paper on the UT Dallas faculty include Dr. Michael Kilgard, the Margaret Fonde Jonsson Professor of Neuroscience; Dr. Robert Rennaker, the Texas Instruments Distinguished Chair in Bioengineering; and Dr. Mario Romero-Ortega, associate professor of bioengineering. Authors formerly affiliated with UT Dallas include Geetanjali Bendale PhD’19, postdoctoral researcher Dr. Patrick Ganzer, Elaine Lai BS’19, research assistant Bleyda Solorzano BS’14, research assistant Nimit Kasliwal and research technician Abigail Berry.

This work was supported by grants R01NS085167 and R01NS094384 from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, and by the U.S. Department of Defense’s Advanced Research Projects Agency’s Biological Technologies Office.