Will Non-Invasive Vagus Nerve Stimulation Help Improve Upper Limb Function Following Stroke?

Lay Summary

Will non-invasive vagus nerve stimulation help improve upper limb function following stroke?

A randomized controlled trial of post-acute stroke patients is planned to provide preliminary evidence that non-invasive vagus nerve stimulation, combined with arm motor training, improves motor function of patients’ affected arm and hand. Investigators first will demonstrate that it is feasible to enroll at least two patients per month who fit tight requirements so that the results can be interpreted (Phase I). Pending demonstration of enrollment feasibility, Phase II may be recommended to conduct the study in a total of 30 patients.

Why do investigators think that stimulating the vagus nerve might help improve arm motor function? Some branches of the vagus nerve send signals from the body to the brain. Prior research indicates that stimulating the vagus nerve might improve motor recovery after stroke, both by increasing plasticity in motor regions of the brain and by suppressing lingering brain inflammation that follows the acute stroke phase.

Therapies, including non-invasive brain stimulation and certain drugs, have been tested as potential therapies to improve motor recovery following a stroke. Effects of these therapies, though, have been short-lasting, and have produced side effects and unpredictable responsiveness. Surgically implanted (invasive) vagus nerve stimulators with electrodes that are coiled around the left vagus nerve in the neck are used to treat epilepsy and depression, but these stimulators have two drawbacks. They pose surgical risks, and they frequently produce cardiac and respiratory side effects because they inadvertently stimulate branches of the vagus nerve going to the body.

A newly developed non-invasive transcutaneous vagal nerve stimulation (tVNS) approach may elude problems such as these. Called RAVANS, this vagus nerve stimulating approach was developed by one of the investigators. It stimulates the outer ear to activate only the branch of the vagus nerve that sends signals to the brain, not those going to the body. Moreover, RAVANS synchronizes the stimulating pulses with the patient’s respiratory cycle, which may send strongly signals to the brain than the traditional tVNS approach.

The investigators hypothesize that RAVANS, when used in conjunction with arm motor training, during 10 sessions over 2 weeks will improve motor recovery. Additionally, they hypothesize that outcomes seen following the first few sessions of the combined RAVANS and motor training will predict long-term outcomes, and help to determine whether a particular patient is likely to derive benefit from the combined therapy.

In Phase I, the investigators in combination with a team of physicians, will test the feasibility of enrolling two to three patients a month who fit within the essential stringent criteria (Phase I). If Phase I shows this is feasible, Phase II funding may be recommended. In the potential Phase II study, investigators then would test RAVANS versus sham stimulation as an adjunct to arm motor training in a total of 30 patients. If this small controlled trial shows promise, the pilot study would lead to a larger controlled trial of RAVANS.

Significance: Ultimately, RAVANS used in conjunction with arm motor training could improve recovery of arm motor function for about 50-75 percent of patients following a stroke.

Abstract

Efficacy of a Novel Transcutaneous Vagus Nerve Stimulation Therapy on Motor Recovery after Stroke

Stroke causes loss of motor function of the arm in the great majority of patients. While most patients experience some recovery during the first 3 months after stroke as a result of spontaneous biological processes and standard rehabilitation, most are left with deficits in arm function that limit their daily activities. New therapies that improve functional recovery are urgently needed. Recent studies in animals and patients with stroke have shown that arm recovery can be improved by pairing stimulation of the vagus nerve in the neck using an implanted device along with physical rehabilitation. Stimulating this nerve causes release of chemicals in the brain that, when coupled with physical rehabilitation, is thought to amplify beneficial plastic changes in motor areas of the brain. However, there are several risks of the surgically implanted vagus nerve stimulation (VNS) device. Fortunately, a non-invasive VNS device can be used to stimulate a sensory branch of the vagus nerve that connects to the skin of the outer ear, and thereby avoid these risks. The proposed study will test, for the first time, the effect of non-invasive transcutaneous VNS on arm recovery in stroke patients. We recently developed an optimized approach for non-invasive transcutaneous VNS that synchronizes the stimulation with the respiratory cycle, and showed that it increased activity in a brain region important for clinical efficacy more so than the traditional transcutaneous VNS approach. We call this optimized approach Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS). The first aim of the proposed study will be to assess effects of 10 RAVANS sessions, delivered daily over 2 weeks concurrent with arm rehabilitation, on arm function in persons who recently had a stroke. We will look at changes in arm motor function from just before the therapy to just after the 10 RAVANS session and again at 3 months after stroke onset. Towards determining a quick test for how much a patient may benefit from RAVANS therapy in the future, the second aim of the proposed study will be to determine if the change in arm function in response to the initial RAVANS sessions helps predict how much improvement in arm function the person will make after 10 RAVANS sessions. The findings our study could provide groundbreaking preliminary evidence that a non-invasive, adjunctive therapy increases motor recovery of the arm in stroke patients, which ultimately could lead to improved quality of life for stroke survivors.

We recently developed an optimized approach for non-invasive transcutaneous VNS that synchronizes the stimulation with the respiratory cycle, and showed that it increased activity in a brain region important for clinical efficacy more so than the traditional transcutaneous VNS approach. We call this optimized approach Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS). The first aim of the proposed study will be to assess effects of 10 RAVANS sessions, delivered daily over 2 weeks concurrent with arm rehabilitation, on arm function in persons who recently had a stroke. We will look at changes in arm motor function from just before the therapy to just after the 10 RAVANS session and again at 3 months after stroke onset. Towards determining a quick test for how much a patient may benefit from RAVANS therapy in the future, the second aim of the proposed study will be to determine if the change in arm function in response to the initial RAVANS sessions helps predict how much improvement in arm function the person will make after 10 RAVANS sessions. The findings our study could provide groundbreaking preliminary evidence that a non-invasive, adjunctive therapy increases motor recovery of the arm in stroke patients, which ultimately could lead to improved quality of life for stroke survivors.