Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats

Abstract

Advanced age is associated with a higher incidence of stroke and worse functional outcomes. Vagus nerve stimulation (VNS) paired with rehabilitative training has emerged as a potential method to improve recovery after brain injury but to date has only been evaluated in young rats. Here, we evaluated whether VNS paired with rehabilitative training would improve recovery of forelimb function after ischemic lesion of the motor cortex in rats 18 months of age. Rats were trained to perform the isometric pull task, an automated, quantitative measure of volitional forelimb strength. Once proficient, rats received an ischemic lesion of the motor cortex and underwent rehabilitative training paired with VNS for 6 weeks. VNS paired with rehabilitative training significantly enhances recovery of forelimb function after lesion. Rehabilitative training without VNS results in a 34% ± 19% recovery, whereas VNS paired with rehabilitative training yields a 98% ± 8% recovery of prelesion of forelimb function. VNS does not significantly reduce lesion size. These findings demonstrate that VNS paired with rehabilitative training enhances motor recovery in aged subjects in a model of stroke and may suggest that VNS therapy may effectively translate to elderly stroke patients.

Keywords: Aging; Elderly; Ischemic stroke; Motor function; Recovery; Rehabilitation; Vagus nerve stimulation.

Conflict of interest statement

statement Navid Khodaparast is a consultant for, and Michael P. Kilgard is a consultant for and has a financial interest in MicroTransponder, Inc, a company which is developing VNS-based therapies. Robert L. Rennaker owns Vulintus, Inc. Other authors declare no conflicts of interest.

Copyright © 2016 Elsevier Inc. All rights reserved.

Figures

Fig. 1

Experimental design. (A) Illustration of the experimental timeline. (B) Example isometric force task data from a behavioral session. The VNS+Rehab group received a brief burst of VNS paired with trials that exceeded the 100-g hit threshold. (C) A rat performing the isometric force task. Abbreviation: VNS, vagus nerve stimulation.

Fig. 2

VNS paired with rehabilitative training improves forelimb function after stroke in aged rats. (A) VNS+Rehab improves recovery of hit rate performance on the isometric pull task compared to Rehab without VNS. (B) VNS+Rehab similarly enhances recovery of forelimb strength compared to the Rehab group. (C) All subjects that receive VNS+Rehab demonstrate a >50% recovery of hit rate at the end of therapy, while only a subset of subjects in the control groups demonstrate >50% recovery. (D) Peak force of individual subjects before lesion and on week 6 of therapy. Thin symbols represent individual subjects, and thick symbols represent the group mean. Note that subjects in the VNS+Rehab group tend to cluster near the unity line, consistent with a restoration of forelimb strength after therapy. *Denotes p < 0.05 between Rehab and paired VNS at each time point. Filled markers in (A) and (B) indicate p < 0.05 compared to postlesion performance (POST) for each group. Error bars indicate mean ± SEM. Abbreviations: SEM, standard error of mean; VNS, vagus nerve stimulation.

Fig. 3

Distribution of pull forces. Probability distribution histograms of pull forces before lesion (PRE, left column), after lesion (POST, middle column), and on the sixth week of therapy (week 6, right column) for the Rehab (A) and VNS+Rehab groups (B). The numbers in the dashed box indicates the percent of trials that exceeded the 100-g hit threshold. Note the similarity of the distributions of pull forces at PRE and week 6 in the VNS+Rehab group consistent with a restoration of forelimb strength. Abbreviation: VNS, vagus nerve stimulation.

Fig. 4

VNS does not affect lesion size. Lesion reconstructions from representative subjects from the Rehab group (A) and the VNS+Rehab group (B). Red represents lesion area, and gray lines outline corpus callosum and cortex. Scale bar is 1 mm. (C) No significant difference in lesion volume was observed between groups. Abbreviations: n.s., not significant; VNS, vagus nerve stimulation. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)