Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery

Abstract

Background and purpose: Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks.

Methods: Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks.

Results: VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery.

Conclusions: This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.

Keywords: forelimb; rats; rehabilitation; supination; vagus nerve.

Conflict of interest statement

Conflicts of Interest / Disclosures

MPK is a consultant for and shareholder in MicroTransponder, Inc., which is developing VNS for stroke and tinnitus.

© 2018 American Heart Association, Inc.

Figures

Figure 1.

Experimental design and methods. (A) Timeline of experiment. (B) Daily rehabilitative training paradigm on the supination task. Subjects in the VNS+Rehab group received VNS immediately upon crossing the turn angle success threshold. An illustration of an animal performing the supination task is shown below. (C) Daily rehabilitative training on the isometric pull task. No VNS was delivered at any point during isometric pull training. Illustration of an animal performing the isometric pull task is shown below.

Figure 2.

VNS paired with rehabilitative training improves forelimb function after stroke. (A) VNS improves recovery of supination turn angle during task-oriented rehabilitative training (Post-Wk6). The beneficial effects of VNS delivered on the supination task transfer to the isometric pull task although no VNS is delivered during this time (Wk7-Wk10). Furthermore, when subjects are retested on the supination task, the benefits of VNS were maintained 7 weeks following the cessation of stimulation (Wk11 & 12). (B) Similar effects were observed for success rate. (C) All subjects (9 of 9) in the VNS+Rehab group achieved at least 50% recovery of function, compared to only 3 of 10 Rehab subjects. No differences in trials performed through Week 6 were observed across groups. (D) No significant difference in cortical or subcortical lesion volume was observed. Asterisks denote: *p<0.05, **p<0.01, ***p<0.001 between the VNS+Rehab and Rehab groups. Filled circles denote significant difference compared to Post timepoint.

Figure 3.

VNS paired with rehabilitative training increases synaptic connectivity in motor networks. (A) Representative cortical lesion location and PRV labeled cells from a Rehab subject and (B) a VNS subject. Inset illustrates a PRV-positive cell. (C) VNS paired with rehabilitative training increases cortical PRV labeling in both the left and right sensorimotor cortices.

Figure 4.

VNS delivered on supination training results in equivalent recovery on the isometric pull task compared to previous studies in which VNS was delivered during pull training. (A) Experimental timelines of previous VNS stroke studies and the current study. (B) Pull forces of the VNS+Rehab and Rehab groups. Previous studies demonstrate recovery on the isometric pull task in which VNS was delivered. The current study extends these findings by showing equivalent recovery on the isometric pull task despite that VNS was delivered only during supination training.