Assessing aberrant motor learning in Parkinson's patients

评估帕金森病患者的异常运动学习

• 批准号: 8848150
• 负责人: JEFF A. BEELER
• 金额: $ 23.26万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848150
• 关键词: Adopted; Affect; Alzheimer' s Disease; Animal Model; Clinical; Clinical Research; Complement; Corpus striatum structure; Data; Denervation; Development; Disease Progression; Distress; Dopamine; Drug Kinetics; Dyskinetic syndrome; Effectiveness; Functional disorder; Future; Goals; Health; Home environment; Hospitals; Human; Impairment; Knowledge; Learning; Levodopa; Mediating; Methods; Modeling; Motor; Motor Skills; Movement; Nature; Parkinson Disease; Participant; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pilot Projects; Play; Population; Process; Publishing; Reaction Time; Regimen; Rehabilitation therapy; Replacement Therapy; Role; Sensory; Serial Learning; Signal Pathway; Speed; Symptoms; Synapses; Task Performances; Testing; Therapeutic; Time; Treatment Efficacy; Validation; Variant; Weight; base; cost; design; drug development; improved; innovation; insight; motor control; motor deficit; motor learning; motor skill learning; novel; novel strategies; novel therapeutics; rehabilitation strategy; research study; response; sequence learning

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.

描述（由申请人提供）：该项目将调查异常运动学习对帕金森病 (PD) 相关运动缺陷的影响，以及纠正异常学习在治疗效果中所起的作用。尽管人类研究已经证明帕金森病存在运动学习障碍，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。该项目提出了这样的假设：正如在动物模型中观察到的那样，多巴胺去神经支配会导致皮质纹状体可塑性异常，从而导致背外侧纹状体出现异常、不适当的抑制学习，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既定的学习（编码为突触强度），该学习可以通过学习和禁止运动的突触权重实现有效的运动。相反，多巴胺替代疗法可以纠正这种异常学习并重新启用与背外侧纹状体相关的优化功能并促进运动。该项目中的人体研究将采用一种策略，即使用两个基于 iPad 的新颖任务在家中测试受试者，以便跨时间进行扩展测试，并测试受试者在日常用药方案中的每日药代动力学波动的不同阶段（即用药峰值与谷值）。目的是清楚地区分这些波动对运动学习和表现的影响，并评估运动学习成分的贡献，独立于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理解（a）学习机制在帕金森病的核心症状和进展中的作用，以及（b）学习对当前治疗的疗效的贡献。确定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背后的信号通路的新型药物开辟新的途径。最后，由于康复治疗最终基于实践，因此它们从根本上基于学习。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见解。

项目成果

Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses.

慢性尼古丁改变由含有 NR2B 的沉默突触介导的纹状体苍白球通路中的皮质纹状体可塑性。

• DOI: 10.1038/npp.2017.87
• 发表时间: 2017
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Xia,Jianxun;Meyers,AllisonM;Beeler,JeffA
• 通讯作者: Beeler,JeffA