Cortical Stimulation to Enhance Experience-Dependent Plasticity After Stroke

描述（由申请人提供）：脑卒中后的适应性可塑性严重依赖于行为经验。包括康复训练在内的经验操作正在成为脑损伤后驱动功能适当的大脑重组的核心策略。然而，学习引起的大脑变化可能很难实现，尤其是当被驱动重组的回路由于去神经支配和其他损伤引起的退行性变化而功能失调时。还有很大的改进空间。这一建议着眼于促进中风后“再学习”的新方向，即将康复训练与脑卒中半球剩余皮层的电刺激相结合。在局灶性皮质梗死的动物模型中，这种方法改善并延长了上肢损伤的运动康复期的功能益处。然而，我们几乎不了解这是如何以及为什么起作用的。我们提出了一系列的初步实验，以提高我们对神经系统的理解

DESCRIPTION (provided by applicant): Adaptive brain plasticity after stroke is critically dependent upon behavioral experience. Manipulations of experience, including rehabilitative training, are emerging as a core strategy for driving functionally appropriate brain reorganization after brain damage. However, learning-induced brain changes can be laborious to achieve, perhaps especially when the circuits being driven to reorganize are dysfunctional due to denervation and other injury-induced degenerative changes. There is much room for further improvement. This proposal focuses on a new direction in facilitating "re-learning" after stroke, that of combining rehabilitative training with electrical stimulation of remaining cortex of a stroke-affected hemisphere. In animal models of focal cortical infarcts, this approach improves and prolongs the functional benefits of a period of motor rehabilitative focused on the impaired upper extremity. However, we have practically no understanding of how and why this works. We propose a series of initial experiments to improve our understanding of the neural basis of the behavioral improvements resulting from combining motor cortical stimulation (CS) with motor training. The central hypothesis is that CS improves behavioral outcome by facilitating learning-induced neural plasticity in the motor cortex and connected regions. This will be investigated in rats with unilateral ischemic infarcts of the sensorimotor cortex and rehabilitative training in skilled reaching to improve forelimb function. There are three specific aims. Aim 1 is test the hypothesis that facilitation of training-induced neural plasticity in remaining motor cortex mediates the functional efficacy of CS. Aim 2 is to test the hypothesis that CS+motor training results in persistent synaptic structural plasticity within motor cortex in comparison to motor training alone. Aim 3 is to test the hypotheses that CS+motor training promotes plasticity and lessens long-term deterioration in motor cortical efferent regions compared with motor training alone. These hypotheses will be tested with a combination of sensitive behavioral measures, quantitative light and electron microscopy to assay changes in neuronal activity and synaptic structure as well as intracortical microstimulation (ICMS) mapping to reveal the functional integrity and organization of motor cortex. The immediate goal is to obtain data on the characteristics of CS-induced plasticity that are useful both for guiding more detailed future studies and for its clinical applications. The more general goal is to obtain a sufficient understanding of CS mechanisms to improve the ability to use it and related therapies to improve function after stroke. PUBLIC HEALTH RELEVANCE: Physical therapy and rehabilitation can be used to improve function after stroke but, even with extreme effort, such treatments can be limited in efficacy. Cortical stimulation (CS) has recently been found to enhance motor rehabilitative training effects in rats and monkeys. By gaining knowledge of the neural mechanisms underlying the beneficial effects of CS, we hope to better understand how to use this and related therapies to optimize functional outcome after stroke.