Neural mechanisms responsible for vagus nerve stimulation-dependent enhancement of somatosensory recovery

Abstract

Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized, moderate intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention.

Figure 1

Moderate VNS improves recovery of somatosensory thresholds. (A) Nerve injury worsens withdrawal thresholds in all groups, indicative of chronic hyposensation. Moderate VNS paired with tactile rehabilitation (n = 15) enhances recovery compared to no stimulation with equivalent tactile rehabilitation after therapy (n = 15). Low (n = 15) and high (n = 15) intensity VNS fail to produce equivalent improvements in recovery. (B) Only moderate intensity VNS produces significant improvements in recovery. (C) Moderate intensity VNS results in the greatest proportion of animals exhibiting full recovery of withdrawal thresholds after therapy. *Indicates p < 0.05.

Figure 2

VNS-dependent recovery does not generalize to other measures of forelimb function. None of the tested VNS paradigms improved recovery of (A) volitional forelimb use during exploratory behavior or (B) weight bearing during locomotion. n.s. denotes no significant difference. n = 15 for each group.

Figure 3

VNS increases Arc mRNA transcript levels. (A) VNS paired with tactile rehabilitation (n = 8) significantly increases the levels of Arc mRNA in cortex compared to equivalent tactile rehabilitation without VNS (n = 7). (B) Arc mRNA levels are weakly, but significantly, correlated with the degree of forelimb somatosensory recovery. *Indicates p < 0.05. Data are presented as mean ± SEM in panel A, and panel B shows datapoints from individual subjects.

Figure 4

Blocking plasticity prevents VNS-dependent enhancement of somatosensory recovery. VNS paired with tactile rehabilitation significantly improves recovery of forelimb somatosensation in control rats (ACh+; VNS, n = 4). Depletion of forebrain acetylcholine, which blocks cortical plasticity, significantly impairs VNS-dependent recovery (ACh−; VNS, n = 6). **Indicates p < 0.001 across groups. Data are presented as mean ± SEM.