Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats

Abstract

Background and objective: Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke. Here, we evaluated the ability of VNS paired with rehabilitative training to improve recovery of forelimb strength when initiated many weeks after a cortical and subcortical ischemic lesion in subjects with stable, chronic motor deficits.

Methods: Rats were trained to perform an automated, quantitative measure of voluntary forelimb strength. Once proficient, rats received injections of endothelin-1 to cause a unilateral cortical and subcortical ischemic lesion. Then, 6 weeks after the lesion, rats underwent rehabilitative training paired with VNS (Paired VNS; n = 10), rehabilitative training with equivalent VNS delivered 2 hours after daily rehabilitative training (Delayed VNS; n = 10), or rehabilitative training without VNS (Rehab, n = 9).

Results: VNS paired with rehabilitative training significantly improved recovery of forelimb function compared with control groups. The Paired VNS group displayed an 86% recovery of strength, the Rehab group exhibited 47% recovery, and the Delayed VNS group exhibited 42% recovery. Improvement in forelimb function was sustained in the Paired VNS group after the cessation of stimulation, potentially indicating lasting benefits. No differences in intensity of rehabilitative training, lesion size, or MAP-2 expression were observed between groups.

Conclusion: VNS paired with rehabilitative training confers significantly greater recovery of forelimb function after chronic ischemic stroke in rats.

Keywords: ischemic stroke; recovery; rehabilitation; vagal stimulation; vagus nerve.

Fig. 1. Experimental Timeline

Illustration of the experimental timeline. Example data from the isometric force task is pictured. VNS treatment began in the appropriate groups on week 7 and continued through week 11. VNS was delivered coincident with successful trials in the Paired VNS group. The Delayed VNS group received a matched number of stimulations delivered 2 hours after daily rehabilitative training.

Fig. 2. VNS paired with rehabilitative training improves forelimb function after chronic stroke

(A) Paired VNS improves recovery of hit rate performance on the isometric pull task compared to Rehab alone and Unpaired VNS. (B) Paired VNS similarly improves forelimb strength compared to control groups. (C) All subjects that receive Paired VNS demonstrate >50% recovery of hit rate at the end of therapy. Only a subset of subjects in the control groups demonstrate >50% recovery. * denotes p < 0.05 between Rehab and Paired VNS at each time point. Error bars indicate mean ± SEM.

Fig. 3. VNS does not affect lesion size

(A) Example of typical lesion size. (B) No differences were observed in lesion size between groups.