Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke

Abstract

Neural plasticity is widely believed to support functional recovery following brain damage. Vagus nerve stimulation paired with different forelimb movements causes long-lasting map plasticity in rat primary motor cortex that is specific to the paired movement. We tested the hypothesis that repeatedly pairing vagus nerve stimulation with upper forelimb movements would improve recovery of motor function in a rat model of stroke. Rats were separated into 3 groups: vagus nerve stimulation during rehabilitation (rehab), vagus nerve stimulation after rehab, and rehab alone. Animals underwent 4 training stages: shaping (motor skill learning), prelesion training, postlesion training, and therapeutic training. Rats were given a unilateral ischemic lesion within motor cortex and implanted with a left vagus nerve cuff. Animals were allowed 1 week of recovery before postlesion baseline training. During the therapeutic training stage, rats received vagus nerve stimulation paired with each successful trial. All 17 trained rats demonstrated significant contralateral forelimb impairment when performing a bradykinesia assessment task. Forelimb function was recovered completely to prelesion levels when vagus nerve stimulation was delivered during rehab training. Alternatively, intensive rehab training alone (without stimulation) failed to restore function to prelesion levels. Delivering the same amount of stimulation after rehab training did not yield improvements compared with rehab alone. These results demonstrate that vagus nerve stimulation repeatedly paired with successful forelimb movements can improve recovery after motor cortex ischemia and may be a viable option for stroke rehabilitation.

Keywords: cortical ischemia; motor cortex; plasticity; recovery; rehabilitation; stroke.

Figure 1

A)Experimental timeline illustrating shape training, pre-lesion training, surgery, recovery, post-lesion training, and VNS+rehabilitative training. Negative value indicates training days prior to infarct, and positive values are post-infarct days. Clustered thick gray bars indicate that VNS+rehabilitative training occurred 5 days a week (weekdays only) for 25 days. B) A rehabilitative training day was composed of two 30 minute sessions per day with a two hour break between sessions. C) Shown is a representative 30 minute training session. The black bars on top specify hit trials in which VNS was delivered during rehabilitative training. The gray bars on bottom indicate miss trials were the rat failed to achieve the task requirements, no pellet or VNS delivered. D) Sketches demonstrating the movements necessary for the bradykinesia assessment task. A rat was required to press the spring-loaded lever in the downward direction twice within 0.5 s. E) Two examples of lever press data collected from a series of trials performed by a rat that received VNS during rehabilitation. The black dashed lines indicate the hit time window of 0.5 s. In the depicted hit trial, two presses occurred within the hit time window. Below the hit trial example, the repeated black bars demonstrate the VNS pulse train: 0.5 s 30 Hz pulse train at 0.8 mA 100 μs pulse width. The black arrowhead marks when the food pellet arrived in relation to stimulation. On the right, a miss trial occurred when a rat failed to press the lever twice within the dashed lines. No VNS or pellet was delivered.

Figure 2

Lever press performance on the bradykinesia assessment task. Rats were trained to press a lever located outside the cage twice within 500 msec to receive a food reward. Prior to the lesion (PRE) both groups were equally proficient at the task. Ischemic lesion of the motor cortex reduced performance equally in both groups (POST). During all 5 weeks of therapy the VNS during rehab group (black) performed significantly better compared to the rehab group (gray). Data are means ± S.E.M. (* p <0.05).

Figure 3

Schematic representations of the smallest, representative, and largest lesion following intracortical ET-1 infarct. Grey region represents the location of motor cortex, and the black line trace represents the area of infarct. Coordinates are relative to bregma.

Figure 4

Inter-press interval on the bradykinesia assessment task. Using the bradykinesia assessment task, forelimb movement speed is measured by the latency between the first and second lever press. Prior to lesion (PRE), both groups rapidly press the lever. After lesion (POST), the latency between lever presses is increased similarly in both groups, suggestive of a slowing of forelimb speed. During weeks 2, 3, and 5 the VNS during rehab group (black) performed significantly better compared to the rehab group (gray). Data are means ± S.E.M. (* p <0.05).

Figure 5

A) Individual rat performance on the bradykinesia assessment task. Symbols indicate when an animal regained 50% of pre-lesion forelimb function. X indicates that an animal that did not regain 50% of forelimb function at any point during therapy. All rats that received VNS during rehab regained 50% of forelimb function by week 2 (squares). One animal in both the rehab alone (circles) and VNS after rehab group (triangles) did not regain 50% of forelimb function. B) Number of days for each group to regain 50% of forelimb function based on lever press success rate performance. The VNS during rehab group demonstrated 50% recovery of pre-lesion performance within the first week of therapy, while rats that received rehab alone reached 50% recovery during the third week of therapy on average. Data are means ± S.E.M. (* p <0.05).