Assessing aberrant motor learning in Parkinson's patients

描述（由申请人提供）：本项目将研究异常运动学习对帕金森病（PD）相关运动缺陷的贡献，以及纠正异常学习在治疗疗效中的作用。虽然人类研究已经证明PD中存在运动学习障碍，但学习障碍的程度和性质及其与疾病进展和治疗的关系一直存在争议。该项目提出了一个假设，即多巴胺去神经诱导异常的皮质纹状体可塑性，如在动物模型中观察到的那样，导致背外侧纹状体异常，不适当的抑制性学习，阻碍而不是优化运动表现。因此，在多巴胺减少的情况下，异常的运动学习将逐渐取代使有效运动成为可能的已建立的学习（编码为突触强度），而学习和突触权重使运动失效。相比之下，多巴胺替代疗法纠正了这种异常的学习，重新启用了与背外侧纹状体相关的优化功能，并促进了运动。本项目中的人体研究将采用在家中使用两个基于iPad的新任务测试受试者的策略，以便在不同时间进行扩展测试，并在受试者每日药物治疗方案中每日药代动力学波动的不同阶段测试受试者（即，峰值与谷值药物）。目的是明确区分这些波动对运动学习和表现的影响，并评估运动学习成分的贡献，独立于药物的直接表现影响。从这些研究中获得的知识将有助于更好地理解（a）学习机制在PD核心症状和进展中的作用和（B）学习对当前治疗疗效的贡献。确立异常学习在PD的病理生理学和治疗中的作用将为开发靶向异常学习基础的信号通路的新型药物开辟新的途径。最后，由于康复治疗最终是基于实践，它们基本上是基于学习。了解如何优化基于实践的学习可能会提供洞察力，以加强康复治疗的策略。

DESCRIPTION (provided by applicant): This project will investigate the contribution of aberrant motor learning to the motor deficits associated with Parkinson's disease (PD) and the role that correcting aberrant learning plays in treatment efficacy. Though human studies have demonstrated motor learning impairments in PD, the extent and nature of learning impairments and their relationship to disease progression and treatment have been controversial. This project proposes the hypothesis that dopamine denervation induces abnormal corticostriatal plasticity, as has been observed in animal models, that results in aberrant, inappropriate inhibitory learning in the dorsolateral striatum that impedes rather than optimizes motor performance. As a consequence, under decreased dopamine, aberrant motor learning will gradually replace the established learning (encoded as synaptic strengths) that enables effective movement with learning and synaptic weights that disable movement. In contrast, dopamine replacement therapy corrects this aberrant learning and re-enables the optimization function associated with the dorsolateral striatum and facilitates movement. The human studies in this project will utilize a strategy of testing subjects at home using two novel iPad based task in order to conduct extended testing across time and to test subjects during different phases in the daily pharmacokinetic fluctuations in their daily medication regimen (i.e., peak vs. trough medication). The intent is to clearly distinguish the effects of these fluctuations on motor learning and performance and to assess the contribution of the motor learning component, independent of the direct performance effects of medication. Knowledge gained from these studies will contribute to greater understanding of (a) the role of learning mechanisms in the core symptoms and progression of PD and (b) the contribution of learning to the therapeutic efficacy of current treatments. Establishing a role for aberrant learning in the pathophysiology and treatment of PD will open new avenues for the development novel pharmaceuticals targeting signaling pathways that underlie aberrant learning. Finally, as rehabilitative therapies are ultimately based on practice, they are fundamentally based on learning. Understanding how practice-based learning may be optimized could potentially provide insight to enhance strategies for rehabilitation treatments.