Cortical Stimulation to Enhance Experience-Dependent Plasticity After Stroke

描述（由申请人提供）：中风后的适应性大脑可塑性严重依赖于行为经验。包括康复训练在内的经验操纵正在成为脑损伤后驱动功能适当的脑重组的核心策略。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电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。还有很大的改进余地。该建议侧重于促进中风后“再学习”的新方向，即将康复训练与对中风影响半球的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，这种方法改善并增强了针对受损上肢的一段时间运动康复的功能益处。然而，我们实际上并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，以提高我们的理解，神经 运动皮层刺激（CS）与运动训练相结合产生的行为改善的基础。中心假设是CS通过促进运动皮层和连接区域中的学习诱导的神经可塑性来改善行为结果。这将在感觉运动皮层单侧缺血性梗死的大鼠中进行研究，并进行熟练伸展的康复训练以改善前肢功能。有三个具体目标。目的1：验证训练后运动皮层的可塑性易化是否介导了CS的功能效应。目的2是检验与单独运动训练相比，CS+运动训练导致运动皮层内持续突触结构可塑性的假设。目的3是测试的假设，CS+运动训练，促进可塑性和减少长期恶化的运动皮层传出区相比，单独的运动训练。这些假设将进行测试与敏感的行为措施，定量光学和电子显微镜的组合，以分析神经元活动和突触结构的变化，以及皮质内微刺激（ICMS）映射，以揭示功能的完整性和组织的运动皮层。目前的目标是获得CS诱导的可塑性的特点，这是有用的指导更详细的未来研究和其临床应用的数据。更普遍的目标是获得对CS机制的充分理解， 提高使用它和相关疗法的能力，以改善中风后的功能。公共卫生相关性：物理治疗和康复可用于改善中风后的功能，但即使付出极大的努力，这种治疗的疗效也有限。最近发现皮层刺激（CS）可以增强大鼠和猴子的运动康复训练效果。通过获得CS有益作用的神经机制的知识，我们希望更好地了解如何使用这种和相关的治疗方法来优化卒中后的功能结局。

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.