Enhancing Plasticity Using Vagus Nerve Stimulation Improves Recovery Following Neurological Injury
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Damage to the central and peripheral nervous system cause physical disability, and impairment following injury is often permanent. Stroke is the leading cause of physical disability in the United States, affecting 800,000 people per year and that number is on the rise. Similarly, 20 million Americans suffer from peripheral nerve injury related disability making it alongside of stroke as one of the leading causes of disabilities in the United States. These lesions frequently affect movement control of the upper extremities, and loss of hand function is devastating for patients. There is currently an unmet clinical need for therapeutic interventions to restore function in patients suffering from these injuries. Previous work has demonstrated that vagus nerve stimulation (VNS) paired with rehabilitative training is effective in treating motor dysfunction following stroke, traumatic brain injury, and most recently spinal cord injury. In healthy subjects, VNS paired with motor training enhances plasticity in the paired motor networks. It is believed that VNS paired with rehabilitative training works through a similar plasticity-enhancing mechanism to reorganize damaged motor networks. This dissertation work demonstrates VNS paired with rehabilitative training enhances plasticity and recovery following stroke and peripheral nerve injury. In a stroke injury model we first describe the development of a novel method of assessing forelimb supination, a movement that is severely diminished following stroke. Next, we demonstrate that pairing VNS with supination training doubles the beneficial effects of rehabilitative training without VNS. We further demonstrate that the VNS-dependent benefits on the supination task transfer to an untrained task emphasizing volitional forelimb strength, and the benefits of VNS last for two months following the cessation of VNS. Transneuronal tracing from musculature of the rehabilitated forelimb demonstrates enhanced synaptic connectivity in the VNS-treated subjects. The second half of this dissertation focuses on peripheral nerve injuries affecting the upper extremities. We first describe a novel forelimb peripheral nerve injury model and demonstrate the effectiveness of the isometric pull task to quantitatively measure chronic motor deficits following injury. We next show that VNS paired with rehabilitative training following PNI improves forelimb motor and sensory function. Physiological and anatomical assessments indicate enhanced plasticity in motor networks specific to the rehabilitated movement that likely subserve improved recovery. Lastly, we demonstrate that cortical plasticity is critical for recovery following PNI by disrupting cortical cholinergic innervation thus blocking cortical plasticity. Subjects receiving NB lesions and VNS demonstrate markedly less recovery than VNS subjects and do not demonstrate motor map plasticity. The results of this dissertation first extend the findings of recent studies that demonstrate the effectiveness of VNS paired with rehabilitative training to treat motor dysfunction following stroke. We demonstrate the substantial clinical utility of VNS therapy and reveal an anatomical substrate of recovery following stroke. Furthermore, we show initial evidence for the effectiveness of plasticity-enhancing therapies to improve motor and sensory dysfunction following peripheral nerve injuries.