Cognitive Neurorehabilitation to Enhance Recovery After Stroke

描述(申请人提供)：这些研究的主要目标是确定认知神经康复是否改善记忆并诱导中风后残留脑区的神经可塑性。有一个完善的模型系统来研究实验性中风后康复诱导的运动恢复和可塑性。运动恢复被认为是一个重新学习的过程，在这个过程中，运动功能通过大脑备用区域的功能补偿重新获得。几个实验室已经证明，这种功能补偿是由康复驱动的残留神经回路中的突触可塑性支持的。然而，认知神经康复训练是否会改善认知表现，如改善记忆力，目前尚不清楚。集中认知神经康复似乎有可能改善认知功能的特定区域，并在与康复认知功能相关的备用脑区诱导更大的神经适应性变化。然而，基础神经生物学研究表明，运动技能获得和表现的神经基础不同于认知任务，如情景记忆。运动技能和认知功能涉及不同的神经网络，因此这些网络对学习诱导的神经可塑性的要求也可能不同。本研究旨在系统探讨认知康复疗法对缺血性损伤后认知能力的改善作用，包括改善认知能力的神经基础以及康复与药物治疗相结合的疗效。这将在中风(大脑中动脉闭塞)的大鼠模型中进行研究，使用敏感的行为测量和认知功能的操作以及海马区神经元和突触结构可塑性的分析相结合。本项目的目的是验证如下假设：1)中风后需要情景记忆的任务训练比未训练组在中风动物模型的认知能力测试中的表现更好；2)与未训练组相比，提高中风后认知能力的认知康复训练将导致海马区恢复可塑性；3)认知神经康复训练与乙酰胆碱酯酶抑制剂相结合将增强中风后认知神经康复的疗效。这些研究有望阐明脑损伤后认知恢复的机制，有可能导致更好的临床治疗方法。公共卫生相关性：目前，还没有一种成熟的啮齿动物模型来研究神经侮辱后的认知神经康复。我们建议开发一种认知神经康复训练的大鼠模型，该模型将提供关于任务特异性认知训练的有效性以及中风后潜在治疗效果的神经机制的知识。这些研究将作为测试辅助疗法以优化中风康复的基础。

DESCRIPTION (provided by applicant): The main objective of these studies is to determine if cognitive neurorehabilitation improves memory and induces neural plasticity in residual brain areas following stroke. There is a well-established model system to examine rehabilitation-induced motor recovery and plasticity following experimental strokes in rats. Motor recovery is thought to be a process of "relearning" in which motor functions are reacquired through functional compensation within spared brain regions. Several laboratories have demonstrated that such functional compensation is supported by synaptic plasticity within residual neural circuits that is driven by rehabilitation. However, it is unknown whether cognitive neurorehabilitative training will improve cognitive performance, such as improved memory. It seems possible that focused cognitive neurorehabilitation would improve specific areas of cognitive function and induce greater neural adaptive changes in spared brain regions that are relevant to the rehabilitated cognitive function. However, basic neurobiology research suggests that the neural basis of motor skills acquisition and performance is different from cognitive tasks such as episodic memory. Motor skills and cognitive functions involve different neural networks and thus the requirements of learning- induced neural plasticity in these networks are also likely different. This proposal is to systematically investigate how cognitive rehabilitative therapy after ischemic insult can improve cognitive ability, including the neural bases of the improvements and the efficacy of combining rehabilitation with pharmacological treatments. This will be investigated in a rat model of stroke (middle cerebral artery occlusion) using a combination of sensitive behavioral measures and manipulations of cognitive function and assays of neuronal and synaptic structural plasticity in the hippocampus. The aims of this project are to test the hypotheses that: 1) Post-stroke training in tasks requiring episodic memory will improve performance on tests of cognitive ability in an animal model of stroke compared to non- trained groups; 2) Cognitive rehabilitative training that improves cognitive ability following stroke will result in restorative plasticity in the hippocampus compared to non-trained groups; 3) Coupling cognitive neurorehabilitative training with an acetylcholinesterase inhibitor will enhance the efficacy of post-stroke cognitive neurorehabilitation. These investigations are expected to elucidate mechanisms involved in cognitive recovery after brain injury, with the potential of leading to better clinical treatment approaches. PUBLIC HEALTH RELEVANCE: Currently, there is not a well-developed rodent model of cognitive neurorehabilitation following neurological insult. We propose to develop a rat model of cognitive neurorehabilitative training that will provide knowledge regarding the effectiveness of task specific cognitive training and the neural mechanisms underlying its therapeutic efficacy following stroke. These investigations will serve as a foundation to test adjunctive therapies to optimize recovery from stroke.