Evaluating targeted plasticity therapy for new indications

Abstract

Targeted plasticity therapy has recently emerged as a potential intervention to reverse maladaptive plasticity. Vagus nerve stimulation (VNS) triggers release of plasticity enhancing neuromodulators, and promotes event-specific plasticity when coupled with an event. Through event specific plasticity, VNS therapy can improve recovery after neurological injury. Studies have consistently shown that VNS paired with various rehabilitative therapies improves recovery in a range of injury models. We sought to extend these findings to two additional, fundamentally distinct models. Here, we first characterize sensory and motor function in a new peripheral nerve injury model that captures aspects of pain. Meyers and colleagues demonstrated that injury to the median and ulnar nerve cause motor dysfunction and sensory loss. While injury to the median and ulnar nerve is one example of peripheral nerve injury, there are several different types of nerve injury that result in different outcomes. The phenotype of nerve injury is largely dependent on what nerve is injured, and the extent of injury. While both the median ulnar nerve injury and radial nerve injury result in motor dysfunction, the different variations of nerve injury produce opposite effects on somatosensory function. Instead of sensory loss, radial nerve injury causes mechanical hypersensitivity, and can serve as a model of pain. We then investigate the effects of VNS after radial nerve injury. VNS did not improve motor or sensory function after radial nerve injury, suggesting that some aspects of nerve injury may not benefit from VNS. In another study, we characterize auditory and motor function in a genetically induced neurodevelopmental disorder. The neurodevelopmental disorder, Rett Syndrome, is caused by a genetic mutation to the gene Mecp2, and results in a regression of already acquired skills. Our results demonstrate that Mecp2 rats display deficits in skilled motor learning and auditory discrimination, which is consistent with the clinical manifestation in individuals with Rett Syndrome. Impaired performance corresponds to dysregulation neural function in auditory and motor networks in Mecp2 models. We next investigated whether VNS tone pairing could improve neural processing of sounds in the auditory cortex. Our findings provide initial evidence that VNS sound pairing can restore auditory processing, and lay the groundwork for future studies examining the functional consequences of VNS tone pairing. Overall, these studies identify conditions that may limit the effects of VNS, and establishes a framework for future clinical applications.