Assessing aberrant motor learning in Parkinson's patients

描述(申请人提供)：这个项目将调查异常运动学习对与帕金森氏病(PD)相关的运动缺陷的贡献，以及纠正异常学习在治疗效果中所起的作用。尽管人类研究表明帕金森病患者存在运动学习障碍，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。这个项目提出了一个假说，即多巴胺去神经可以诱导皮质纹状体的异常可塑性，就像在动物模型中观察到的那样，这会导致背外侧纹状体异常的、不适当的抑制性学习，从而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现有的学习(编码为突触强度)，以学习和禁止运动的突触重量来实现有效的运动。相比之下，多巴胺替代疗法纠正了这种异常学习，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。该项目中的人体研究将使用两个基于iPad的新任务在家中测试受试者，以便进行跨时间的扩展测试，并在受试者日常用药方案的不同阶段(即用药高峰与服药低谷)测试受试者的每日药代动力学波动。其目的是清楚地区分这些波动对运动学习和表现的影响，并评估运动学习部分的贡献，而不是药物对表现的直接影响。从这些研究中获得的知识将有助于更好地了解(A)学习机制在帕金森病核心症状和进展中的作用，以及(B)学习对当前治疗方法的疗效的贡献。建立异常学习在帕金森病的病理生理学和治疗中的作用将为开发针对异常学习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的，它们从根本上讲是基于学习的。了解如何优化以实践为基础的学习可能会为加强康复治疗的战略提供潜在的见解。

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.