Assessing aberrant motor learning in Parkinson's patients

项目描述（由申请人提供）：本项目将探讨运动学习异常对帕金森病（PD）相关运动缺陷的影响，以及纠正异常学习对治疗效果的作用。虽然人类研究已经证实PD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。该项目提出了一种假设，即多巴胺去神经支配导致皮质纹状体可塑性异常，正如在动物模型中观察到的那样，这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既定的学习（编码为突触强度），使运动有效，而学习和突触权重使运动无效。相比之下，多巴胺替代疗法纠正了这种异常的学习，并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。本项目的人体研究将采用一种策略，即在家中使用两个基于iPad的新任务对受试者进行测试，以便进行跨时间的扩展测试，并在受试者每日服药方案中每日药代动力学波动的不同阶段（即服药高峰与服药低谷）对受试者进行测试。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的核心症状和进展中的作用，以及(b)学习对当前治疗效果的贡献。建立异常学习在PD的病理生理和治疗中的作用，将为开发针对异常学习背后的信号通路的新型药物开辟新的途径。最后，由于康复疗法最终是基于实践的，它们从根本上是基于学习的。了解如何优化基于实践的学习可能会为增强康复治疗策略提供潜在的见解。

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.