John H. Martin - US grants

DESCRIPTION (provided by applicant): The overall goal of our experiments is to use activity to promote corticospinal system function after partial injury to the corticospinal tract (CST), such as occurs after most spinal cord injuries or stroke. Repair of CST connections through reactive sprouting and recovery of function occurs spontaneously after injury, but both are limited. However, our studies show that augmenting the activity of the spared CST can be used to promote repair and motor recovery. This is based on our findings that selective electrical stimulation of the CST in the mature rat, as in development, increases CST axon outgrowth and promotes formation of spinal connections. Importantly, our newly published and preliminary findings show that stimulation of CST axons spared after injury augments reactive sprouting. strengthens CST connections, and can improve motor skills. We use a reproducible partial injury model in the adult rat, a unilateral pyramidal tract (PT) lesion, which destroys the CST from one cortex. The rat CST, like in humans, is largely crossed, but there is a significant contingent of axons that terminate ipsilaterally. After unilateral PT damage, the spinal cord contralateral to the lesion losses its dense contralateral CST projection;only the sparse ipsilateral axons remain. Our studies focus on these ipsilateral CST axons as a model of spared axons after partial spinal cord injury and stroke. In the proposed experiments we will selectively activate the undamaged CS system by electrical stimulation of spared CST axons in the PT, to augment spontaneous recovery after PT lesion. In Aim 1 we will determine whether specific interactions between spared ipsilateral CST terminations on the impaired side of the spinal cord and mechanosensory afferents limit CST outgrowth, and if augmenting CST activity mitigates this. In Aim 2 we will determine if augmenting sprouting after PT lesion leads to a more "contralateral" pattern of connections between spared ipsilateral CST axons and identified spinal neuron classes on the impaired side, a pattern that may ensure stronger motoneuron activation. We will also determine if activity augments outgrowth into brain stem motor centers that comprise relays for indirect cortical paths to the spinal cord. In Aim 3 we will determine if augmenting CST activity after PT lesion promotes recovery of skilled limb movements and the extent to which this recovery is mediated by the damaged or undamaged side. Elucidating systems-level mechanisms of spontaneous CS system repair, and the capacity for selective CS stimulation to augment repair, will help to devise new strategies for promoting recovery of motor skills after injury. Our research has the strong potential to be translated to patients with brain or spinal cord injury. Selective stimulation of the Mi outflow can be achieved non-invasively in humans using transcranial magnetic stimulation (TMS). Our stimulation approach would likely apply to various levels of severity and different times after injury. PUBLIC HEALTH RELEVANCE: The overall goal of our experiments is to promote motor function after spinal cord injury or stroke. We focus on the corticospinal tract, the principal motor control pathway in humans. Using a rat model, we increase neural activity of the corticospinal tract after injury, by electrical stimulation, to restore lost connections to spinal cord motor control centers. We will determine the importance of plasticity in the cerebral cortex, brain stem, and spinal cord in recovery of skilled motor function.