Restoration of Somatosensory Function by Pairing Vagus Nerve Stimulation with Tactile Rehabilitation

Abstract

Objective: Sensory 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.

Methods: A 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/).

Results: VNS 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.

Interpretation: Given 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.

Conflict of interest statement

Potential Conflicts of Interest: MPK has a financial interest in MicroTransponder, Inc., which is developing VNS for stroke. RLR is an owner of Teliatry, which is developing a VNS device. All other authors declare no conflicts of interest.

© 2019 American Neurological Association.

Figures

Fig. 1.. Experimental Design and Tactile Rehabilitation Paradigm

(A) Timeline of experimental design illustrating when each assessment is performed. (B) Schematic and representative images from proximal and distal cross-sections of the median nerve approximately 30 weeks after nerve transection and tubular repair. Reinnervation takes place, but the procedure results in chronic deficits in nerve architecture distal to the injury site. (C) Schematic of the tactile rehabilitation apparatus. Rats were placed in individual cages with a wire mesh floor. A variety of tactile stimuli were applied to the ventral surface of the right (injured) forepaw. A button press coincident with the delivery of the tactile stimuli initiated a 500 ms train of VNS in the appropriate group. (D) Detailed view of the devices utilized during tactile rehabilitation. The stimuli were selected to encompass a wide range of somatosensory features.

Fig. 2.. VNS paired with tactile rehabilitation restores somatosensory thresholds

Nerve damage results in chronic impairments in somatosensation in the forepaw, as indicated by a lasting increase in mechanical withdrawal thresholds. VNS paired with tactile rehabilitation (VNS+Rehab) drives robust, significant improvements in somatosensory thresholds compared to equivalent tactile rehabilitation without VNS (Rehab). The yellow shaded region denotes when tactile therapy with or without VNS was delivered. VNS-dependent restoration of somatosensory thresholds is stable, lasting many weeks after the cessation of stimulation. Unpaired t-tests across groups at each time point; *** denotes p

Fig. 3.. VNS-dependent recovery generalizes to an untrained sensorimotor forelimb task.

Nerve damage and resultant sensory loss produces an overreliance on the use of the uninjured forelimb during exploration, demonstrated by a reduction in preference for the injured paw. Rats that received VNS paired with tactile rehabilitation (VNS+Rehab) exhibited a restoration of paw preference compared to equivalent tactile rehabilitation without VNS (Rehab) after the completion of therapy, indicating greater volitional use of the injured forelimb. Improved forelimb use was observed for many weeks after the cessation of therapy. The yellow shaded region denotes when tactile therapy with or without VNS was delivered. Unpaired t-tests across groups at each time point; * denotes p

Fig. 4.. VNS paired with tactile rehabilitation does not restore motor function

(A) Grip strength is substantially reduced following nerve damage. VNS paired with tactile rehabilitation did not yield significant benefits in recovery of grip strength compared to equivalent tactile rehabilitation without VNS, suggesting that VNS therapy explicitly does not restore motor function. The yellow shaded region denotes when tactile therapy with or without VNS was delivered. (B) Representative examples illustrating grip strength at multiple time points during therapy. Unpaired t-tests across groups at each time point; n.s. denotes not significant. Error bars indicate mean ± SEM.

Fig. 5.. Skilled forelimb use during locomotion is improved by VNS paired with tactile rehabilitation

(A) Forelimb toe spread in the injured right forepaw was reduced compared to the intact left forepaw after nerve damage, consistent with sensorimotor dysfunction. VNS paired with tactile rehabilitation (n = 8) significantly increased toe spread compared to equivalent tactile rehabilitation without VNS (n = 8) on Week 30. (B) Representative examples of footprints collected from the injured right forepaw after the completion of tactile rehabilitation with or without VNS. Green lines illustrate the toe spread measurement, and dotted lines are shown for alignment. (C) Additionally, rats that received VNS paired with tactile rehabilitation (n = 9) demonstrate significantly fewer misses or slips during the ladder walking assessment compared to rats that received tactile rehabilitation without VNS (n = 8). Together, these findings indicate that the benefits of VNS paired with tactile rehabilitation generalize to measures of forelimb use during locomotion. Unpaired t-tests across groups at each time point; *** denotes p

Fig. 6.. VNS does not influence peripheral nerve regeneration or health

(A, B) Example images of fibers in the median nerve distal to the site of injury in rats that received Rehab or VNS+Rehab. (C) The number of fibers in the distal segment of the median nerve is comparable between groups. (D) Additionally, g-ratio, a metric of remyelination, is not different between groups. These findings indicate that differences in peripheral nerve regeneration cannot account for VNS-dependent improvements in sensory function. Unpaired t-tests across groups at completion of study. Circles depict data from individual subjects. Error bars indicate mean ± SEM.