ObjectiveSensory dysfunction is a common consequence of many forms of neurological injury, including stroke and nerve damage. Rehabilitative paradigms that incorporate sensory retraining can provide modest benefits, but the majority of patients are left with lasting sensory loss. We have developed a novel strategy that uses closed‐loop vagus nerve stimulation (VNS) paired with tactile rehabilitation to enhance synaptic plasticity and facilitate recovery of sensory function.MethodsA clinical case report provides initial evidence that a similar implementation of closed‐loop VNS paired with a tactile rehabilitation regimen could improve recovery of somatosensory function. Here, we sought to build on these promising initial clinical data and rigorously evaluate the ability of VNS paired with tactile rehabilitation to improve recovery in an animal model of chronic sensory loss. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection (https://osf.io/xsnj5/).ResultsVNS paired with tactile rehabilitation resulted in a significant and nearly complete recovery of mechanosensory withdrawal thresholds. Equivalent tactile rehabilitation without VNS failed to improve sensory function. This VNS‐dependent restoration of sensory thresholds was maintained for several months after the cessation of stimulation, illustrating long‐term benefits. Moreover, VNS paired with tactile rehabilitation resulted in significant generalized improvements in other measures of sensorimotor forepaw function.InterpretationGiven the safety and tolerability of VNS therapy, these findings suggest that incorporating VNS paired with sensory retraining into rehabilitative regimens may represent a fundamentally new method to increase recovery of sensory function after neurological injury. ANN NEUROL 2020;87:194–205

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Closed-loop vagus nerve stimulation (VNS) paired with rehabilitative training has emerged as a strategy to enhance recovery after neurological injury. Previous studies demonstrate that brief bursts of closed-loop VNS paired with rehabilitative training substantially improve recovery of forelimb motor function in models of unilateral and bilateral contusive spinal cord injury (SCI) at spinal level C5/6. While these findings provide initial evidence of the utility of VNS for SCI, the injury model used in these studies spares the majority of alpha motor neurons originating in C7-T1 that innervate distal forelimb muscles. Because the clinical manifestation of SCI in many patients involves damage at these levels, it is important to define whether damage to the distal forelimb motor neuron pools limits VNS-dependent recovery. In this study, we assessed recovery of forelimb function in rats that received a bilateral incomplete contusive SCI at C7/8 and underwent extensive rehabilitative training with or without paired VNS. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection ( https://osf.io/ysvgf/ ). VNS paired with rehabilitative training significantly improved recovery of volitional forelimb strength compared to equivalent rehabilitative training without VNS. Additionally, VNS-dependent enhancement of recovery generalized to 2 similar, but untrained, forelimb tasks. These findings indicate that damage to alpha motor neurons does not prevent VNS-dependent enhancement of recovery and provides additional evidence to support the evaluation of closed-loop VNS paired with rehabilitation in patients with incomplete cervical SCI.