The long-range goals of this project are to examine the neural mechanisms contributing to functional motor recovery following stroke. These studies will use behavioral training, neurophysiological, neuroanatomical, angioarchitectural, cellular and molecular techniques to examine functional and structural plasticity in motor cortex after an ischemic infarct, and the effects of rehabilitative training on the extent of plasticity and functional motor recovery. To determine whether training modulates the functional organization of motor regions remote from the site of injury, the ventral premotor cortex (PMv) will be used as a model to examine functional topography before, and a few months after an infarct in primary motor cortex. Animals undergoing post-infarct rehabilitative training will be compared with spontaneously recovering animals. Other studies will explore the necessity of the reorganized tissue in supporting the recovered motor abilities. To determine whether alterations in intracortical connectivity occur after an ischemic infarct, neuroanatomical tract-tracing techniques will be used to examine the connectional patterns of the reorganized PMv with other cortical regions. To shed light on molecular mechanisms underlying functional plasticity in PMv, microarray technology will be employed to examine regulation of neurotransmitter systems and the expression of neurotrophins in early and late phases after ischemic injury. To determine the extent of vascular changes in remote areas, markers for angiogenesis will be examined and angioarchitecural techniques will be used to quantify alterations in vascular anatomy in PMv. Finally, the role of the intact (contralesional) primary motor cortex in recovery will be examined. These studies have strong clinical relevance for understanding motor recovery in the acute as well as chronic stages after stroke, and the role of physical rehabilitation in recovery. The correlation of neural and vascular events with motor recovery after stroke may eventually lead to innovative approaches to rehabilitative therapy. It is hoped that eventually, therapeutic techniques for improving recovery of function after stroke will be based on the rules underlying plastic mechanisms in the central nervous system.
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