The timing and amount of vagus nerve stimulation during rehabilitative training affect poststroke recovery of forelimb strength

Abstract

Loss of upper arm strength after stroke is a leading cause of disability. Strategies that can enhance the benefits of rehabilitative training could improve motor function after stroke. Recent studies in a rat model of ischemic stroke have demonstrated that vagus nerve stimulation (VNS) paired with rehabilitative training substantially improves recovery of forelimb strength compared with extensive rehabilitative training without VNS. Here we report that the timing and amount of stimulation affect the degree of forelimb strength recovery. Similar amounts of Delayed VNS delivered 2 h after daily rehabilitative training sessions resulted in significantly less improvement compared with that on delivery of VNS that is paired with identical rehabilitative training. Significantly less recovery also occurred when several-fold more VNS was delivered during rehabilitative training. Both delayed and additional VNS confer moderately improved recovery compared with extensive rehabilitative training without VNS, but fail to enhance recovery to the same degree as VNS that is timed to occur with successful movements. These findings confirm that VNS paired with rehabilitative training holds promise for restoring forelimb strength poststroke and indicate that both the timing and the amount of VNS should be optimized to maximize therapeutic benefits.

Fig. 1

Timeline of experiment and VNS delivery. (i) Timeline of daily experimental procedures. (ii) Representative data collected for 30 sec using the isometric force task. (iii) VNS delivery matched to the data in (ii). Rats in the Rehab group do not receive VNS. The Paired VNS group received VNS with successful trials during behavioral testing sessions. The Delayed VNS group received similar amounts of VNS in a dummy cage 2 hr after the last daily training session. The Extra VNS group received 6-fold more stimulations during the behavioral testing sessions compared to Paired VNS. The gray VNS markers denote the extra stimulations which were not paired with successful trials.

Fig. 2

The timing and amount of VNS affect the recovery of multiple parameters of forelimb function after stroke. (A) Maximal pull force per trial over the course of the experiment. Paired VNS demonstrates the greatest recovery of maximal pull force during the therapy phase (Weeks 1 – 6). (B) Hit rate over the course of the experiment. Paired VNS results in the greatest recovery of hit rate. Error bars represent SEM. * indicates a significant difference (unpaired t-test, P < 0.05) for each group compared to Rehab on weeks 1 – 6. The color of the * marker indicates the group for the comparison.