Session: SPINAL PLASTICITY AFTER CNS INJURY: MECHANISMS AND MOLECULAR CORRELATES

Motor Cortex and Produces Corticospinal Structural and Functional Plasticity to Promote Motor System Repair after and Spinal Cord Injury John H Martin, PhD Department of Molecular, Cellular, and Biomedical Science, City University of New York School of Medicine at CCNY, New York; Neuroscience Program City University of New York Graduate Center, New York

Strategies for spinal circuit repair and motor recovery after cervical spinal cord and brain injury • Fewer descending projectionsàweaker connections • Partially denervated spinal cordàaberrant synaptic interactions and transneuronal spinal loss • Common elements: corticospinal tract (CST) dependence and loss of connections produces a loss of activity

Strategies for neuromodulation • WeaknessàMotor cortex (MCX) neuromodtiona to promote CST sprouting and synaptogenesis • Changes in activity-dependent synaptic competitionàrebalance spinal connections with cortical and spinal neuromodulation • Spinal interneuron lossàprotect neuronal changes with spinal neuromodulation

1 Stimulation drives CST outgrowth in development and maturity

• Aim: increase CST gray matter axon length per descending axon • MCX stimulation upregulates mTOR and Jak/Stat for axonal outgrowth and formation, respectively

Competition between:

• Ipsilateral and contralateral CST in the spinal gray matter • CST axons and proprioceptive axons • Bi-directional

2 CST lesion or MCX inactivation leads to a large significant loss of cholinergic premotor

• 42% reduction • Rescue with Minocycline or spinal stimulation

MCX alone and in combination with spinal DC stimulation promotes full recovery after CST lesion in the caudal brain stem in rats

• Recovery of skilled walking • This associates with significant sprouting of CST axons on the affected (ipsilateral) side

3 MCX in combination with spinal DC stimulation promotes full partial recovery after C4 bilateral contusion in rats

• Theta burst stimulation of motor cortex • Increased CST axon sprouting caudal to the lesion • Improvement in skilled walking and manipulation

Spinal DC stimulation can be targeted

• Finite element method modeling can be used in conjunction with high-resolution imaging to construct a model of current flow in the rat (as well as other species and humans) • We target to the cervical enlargement Key conclusions: • Activity & lesion: Role for spinal neuromodulation • MCX stim à durable change in spared CST circuits à skilled motor recovery • Non-invasive/minimally-invasive implementation MCX stimulation [rTMS; tDCS]; tsDCS is non-invasive • tsDCS à spatially tunable • Stimulation-based approaches do not depend on performance or concurrent rehabilitation.

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