Vagus nerve stimulation does not improve recovery of forelimb motor or somatosensory function in a model of neuropathic pain

Abstract

Nerve injury affecting the upper limb is a leading cause of lifelong disability. Damage to the nerves in the arm often causes weakness and somatosensory dysfunction ranging from numbness to pain. Previous studies show that combining brief bursts of electrical vagus nerve stimulation (VNS) with motor or tactile rehabilitation can restore forelimb function after median and ulnar nerve injury, which causes hyposensitivity of the ventral forelimb. Here, we sought to determine whether this approach would be similarly effective in a model of radial nerve injury that produces allodynia in the ventral forelimb. To test this, rats underwent complete transection of the radial nerve proximal to the elbow followed by tubular repair. In the first experiment, beginning ten weeks after injury, rats received six weeks of tactile rehabilitation, consisting of mechanical stimulation of either the dorsal or ventral region of the forepaw in the injured limb, with or without concurrent VNS. In a second experiment, a separate cohort of rats underwent six weeks of forelimb motor rehabilitative training with or without paired VNS. Contrary to findings in previous models of hyposensitivity, VNS therapy fails to improve recovery of either somatosensory or motor function in the forelimb after radial nerve injury. These findings describe initial evidence that pain may limit the efficacy of VNS therapy and thus highlight a characteristic that should be considered in future studies that seek to develop this intervention.

Figure 1

VNS paired with tactile rehabilitation fails to improve forelimb withdrawal thresholds. Radial nerve injury produces lasting allodynia in the forelimb, as demonstrated by sustained reductions in forelimb withdrawal thresholds. VNS paired with tactile therapy, consisting of mechanical stimulation of either the dorsal (Dorsal Tactile + VNS, n = 8) or ventral (Ventral Tactile + VNS, n = 7) surface of the forepaw, fails to improve withdrawal thresholds compared to tactile therapy without VNS (Ventral Tactile, n = 6) or no therapy (Untreated, n = 8). Data presented as mean ± SEM. *** denotes p < 0.001 at the indicated timepoints; n.s. denotes not significant group effect.

Figure 2

VNS paired with motor rehabilitation fails to improve recovery of skilled forelimb function. (a) Radial nerve injury results in chronic forelimb weakness, indicated by a sustained reduction in success rate on a skilled forelimb motor task. VNS paired with rehabilitative training (Motor Rehab + VNS, n = 8) fails to improve recovery of motor function compared to equivalent rehabilitative training without VNS (Motor Rehab, n = 8). (b) Additionally, VNS paired with motor training also fails to improve recovery of forelimb withdrawal thresholds. Data presented as mean ± SEM. *** denotes p < 0.001 at the indicated timepoints; n.s. denotes not significant group effect.

Figure 3

Comparison of VNS-dependent recovery in hypersensitive and hyposensitive models of nerve injury. (a) In previous studies, damage to the median and ulnar nerves causes somatosensory hyposensitivity and weakness in the forelimb. Pairing VNS with tactile rehabilitation significantly improves elevated sensory thresholds, restoring them to normal levels. Data from. Additionally, VNS paired with motor rehabilitation significantly improves forelimb weakness compared to equivalent training without VNS. Data from. (b) In the present study, injury to the radial nerve in the forelimb causes allodynia and weakness. Pairing VNS with tactile rehabilitation fails to restores somatosensory function. Moreover, VNS paired with motor rehabilitation fails to improve recovery forelimb strength compared to equivalent training without stimulation. The absence of VNS-dependent benefits in either somatosensory and motor recovery after radial nerve injury likely arise due to the chronic pain induced by the injury.