Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury

Abstract

Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly 2 million people every year. The effects of TBI, including weakness and loss of coordination, can be debilitating and last years after the initial injury. Recovery of motor function is often incomplete. We have developed a method using electrical stimulation of the vagus nerve paired with forelimb use by which we have demonstrated enhanced recovery from ischemic and hemorrhagic stroke. Here we have tested the hypothesis that vagus nerve stimulation (VNS) paired with physical rehabilitation could enhance functional recovery after TBI. We trained rats to pull on a handle to receive a food reward. Following training, they received a controlled-cortical impact (CCI) in the forelimb area of motor cortex opposite the trained forelimb, and were then randomized into two treatment groups. One group of animals received VNS paired with rehabilitative therapy, whereas another group received rehabilitative therapy without VNS. Following CCI, volitional forelimb strength and task success rate in all animals were significantly reduced. VNS paired with rehabilitative therapy over a period of 5 weeks significantly increased recovery of both forelimb strength and success rate on the isometric pull task compared with rehabilitative training without VNS. No significant improvement was observed in the Rehab group. Our findings indicate that VNS paired with rehabilitative therapy enhances functional motor recovery after TBI.

Keywords: motor recovery; neuromodulation; traumatic brain injury; vagal nerve stimulation; vagus nerve stimulation.

FIG. 1.

Rats were trained on the isometric pull task. Following CCI, animals were divided into two groups (VNS+Rehab and Rehab), and received 5 weeks of rehabilitative therapy with or without VNS, followed by one week of further testing. (A) The experimental time line. (B) This plot demonstrates a typical 30-min behavior session. (C) An example individual trial is shown here. This trial shows two individual pull attempts by the animal, and a hit was achieved on the second pull attempt. (D) Rats were trained to reach out of a small window in a booth to pull on an aluminum handle. CCI, controlled-cortical impact; VNS, vagus nerve stimulation.

FIG. 2.

VNS paired with rehabilitative training enhances recovery of performance on the isometric pull task. (A) Two example trials are shown to illustrate measures of behavioral performance. Maximal force generated during a trial was one primary measure of performance. (B) The overall success rate of all animals was impaired following CCI. During the therapy period, VNS+Rehab animals demonstrated a significant recovery of success rate, whereas Rehab animals did not. (C) Maximal force of all animals was also impaired following CCI. VNS+Rehab animals demonstrated a significant recovery of force, whereas Rehab animals showed no recovery. Data are plotted as mean±SEM. An * indicates a significant difference between VNS+Rehab and Rehab groups at each time point (p<0.05 with unpaired t tests). Filled circles at each time point indicate a significant difference from the POST time point (Bonferroni-corrected paired t tests p<0.0083). Open circles indicate no significant difference from POST. CCI, controlled-cortical impact; SEM, standard error of the mean; VNS, vagus nerve stimulation.

FIG. 3.

The distribution of maximal force generated was significantly altered following CCI and at the end of therapy. Both groups were highly trained on the task before CCI, achieving hit rates above the 85% criterion (left panels). Following CCI, both groups demonstrated a significant impairment in maximal pull force (middle panels). A significantly greater proportion of trials had maximal force below the 120g hit threshold. VNS+Rehab animals demonstrate a significant recovery of maximal pull force (right panels). The proportion of trials exceeding the 120g threshold was significantly greater in the VNS+Rehab group than the Rehab group. The dashed line in each panel indicates 120g, or the force criterion required for a successful trial. The numbers reported on each dashed line indicate the percentage of trials at each time point in the experiment in which the maximal force exceeded 120g. Each value is reported as the mean±SEM. CCI, controlled-cortical impact; SEM, standard error of the mean; VNS, vagus nerve stimulation.

FIG. 4.

A moderate effect of VNS was also observed in the number of attempts to pull 120g and the maximal pull speed of animals. (A) An example pull trial is shown that demonstrates how the number of pull attempts to reach 120g was calculated. (B) To calculate maximal pull speed, we derived the change in force from the original force signal of each trial. (C) Both groups of animals were impaired on the number of attempts to reach 120g following CCI, but a moderate effect of VNS was observed during therapy. (D) Both groups demonstrated a decrease in peak pull speed after CCI. During therapy, there was a significant effect of VNS comparing across the two groups. Data are plotted as mean±SEM. An * indicates a significant difference between VNS+Rehab and Rehab groups at each time point (p<0.05 with unpaired t tests). Filled circles at each time point indicate a significant difference from the POST time point (Bonferroni-corrected paired t tests p<0.0083). Open circles indicate no significant difference from POST. CCI, controlled-cortical impact; SEM, standard error of the mean; VNS, vagus nerve stimulation.

FIG. 5.

Therapy intensity and lesion size cannot account for the enhanced recovery observed in the VNS+Rehab group. (A) Total trials performed during therapy by animals in both groups were not significantly different. (B) The calculated lesion size was not significantly different between groups. (C) Lesion reconstruction of one representative animal. Tissue damage often extended beyond the cortical layers into the corpus callosum and external capsule. Ventricle enlargement was also observed in the lesioned hemisphere, and the ventricular space often merged with the lesion cavity.