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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Kleitman, Naomi
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City College of New York
Other Domestic Higher Education
New York
United States
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Williams, Preston T J A; Jiang, Yu-Qiu; Martin, John H (2017) Motor system plasticity after unilateral injury in the developing brain. Dev Med Child Neurol 59:1224-1229
Song, Weiguo; Martin, John H (2017) Spinal cord direct current stimulation differentially modulates neuronal activity in the dorsal and ventral spinal cord. J Neurophysiol 117:1143-1155
Zareen, N; Shinozaki, M; Ryan, D et al. (2017) Motor cortex and spinal cord neuromodulation promote corticospinal tract axonal outgrowth and motor recovery after cervical contusion spinal cord injury. Exp Neurol 297:179-189
Song, Weiguo; Amer, Alzahraa; Ryan, Daniel et al. (2016) Combined motor cortex and spinal cord neuromodulation promotes corticospinal system functional and structural plasticity and motor function after injury. Exp Neurol 277:46-57
Martin, John H (2016) Harnessing neural activity to promote repair of the damaged corticospinal system after spinal cord injury. Neural Regen Res 11:1389-1391
Jiang, Yu-Qiu; Zaaimi, Boubker; Martin, John H (2016) Competition with Primary Sensory Afferents Drives Remodeling of Corticospinal Axons in Mature Spinal Motor Circuits. J Neurosci 36:193-203
Song, Weiguo; Truong, Dennis Q; Bikson, Marom et al. (2015) Transspinal direct current stimulation immediately modifies motor cortex sensorimotor maps. J Neurophysiol 113:2801-11
Lemmon, Vance P; Ferguson, Adam R; Popovich, Phillip G et al. (2014) Minimum information about a spinal cord injury experiment: a proposed reporting standard for spinal cord injury experiments. J Neurotrauma 31:1354-61
Carmel, Jason B; Kimura, Hiroki; Martin, John H (2014) Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control. J Neurosci 34:462-6
Carmel, Jason B; Martin, John H (2014) Motor cortex electrical stimulation augments sprouting of the corticospinal tract and promotes recovery of motor function. Front Integr Neurosci 8:51

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