A limited range of vagus nerve stimulation intensities produce motor cortex reorganization when delivered during training

Abstract

Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to improve recovery after neurological injury, an effect ascribed to VNS-dependent enhancement of synaptic plasticity. Previous studies demonstrate that pairing VNS with forelimb training increases forelimb movement representations in motor cortex. However, it is not known whether VNS-dependent enhancement of plasticity is restricted to forelimb training or whether VNS paired with other movements could induce plasticity of other motor representations. We tested the hypothesis that VNS paired with orofacial movements associated with chewing during an unskilled task would drive a specific increase in jaw representation in motor cortex compared to equivalent behavioral experience without VNS. Rats performed a behavioral task in which VNS at a specified intensity between 0 and 1.2 mA was paired with chewing 200 times per day for five days. Intracortical microstimulation (ICMS) was then used to document movement representations in motor cortex. VNS paired with chewing at 0.8 mA significantly increased motor cortex jaw representation compared to equivalent behavioral training without stimulation (Bonferroni-corrected unpaired t-test, p < 0.01). Higher and lower intensities failed to alter cortical plasticity. No changes in other movement representations or total motor cortex area were observed between groups. These results demonstrate that 0.8 mA VNS paired with training drives robust plasticity specific to the paired movement, is not restricted to forelimb representations, and occurs with training on an unskilled task. This suggests that moderate intensity VNS may be a useful adjuvant to enhance plasticity and support benefits of rehabilitative therapies targeting functions beyond upper limb movement.

Keywords: Cortical reorganization; Intracortical microstimulation; Motor cortex; Orofacial activity; Vagus nerve stimulation.

Figure 1.. Behavioral task and experimental design.

(A) Illustration of a rat performing the task. A stimulating cable stimulating cable plugged into a headmount-connector, the subcutaneous stimulation leads and nerve cuff, and the vagus nerve are shown. A feeder dispenses food pellets into a nosepoke and an infrared beam monitors movement into and out of the nosepoke. B) Representative image depicting task performance, superior masseter EMG activity, and the relative timing of pellet dispensal and VNS. C) Experimental timeline.

Figure 2.. VNS paired with chewing and associated orofacial movements enhances jaw-specific plasticity in motor cortex.

(A) 0.8 mA VNS paired with chewing and associated orofacial movements significantly increases jaw movement representation area in motor cortex compared to equivalent behavioral experience without VNS and VNS at 0.4, 0.6, 1.0, and 1.2 mA. (B) No change in total motor cortex area was observed between groups. Bars represent mean ± SEM. “*” indicates p < 0.01.