Motor Learning in Parkinson's Disease

说明(申请人提供)：原建议书的具体目的 其中包括： 1.研究帕金森病(Parkinson‘s disease，PD)对大鼠学习记忆的影响 运动学习任务的时空特征，与正常对照 人口老龄化。 2.检验帕金森病患者运动学习障碍是由 特定皮质和皮质下网络的功能改变，其 在年龄匹配的对照组中，表情与任务表现相关。 3.评估新疗法(如苍白球)对运动学习的影响 消融和苍白球刺激。 过去两年半，我们在以下方面取得了广泛进展 如进度报告和 出版记录。在这个竞争的延续应用程序中，我们计划 完成最初的研究和教育目标，并扩展我们的工作。 具体地说，我们将追求以下目标： 1.研究DBS和左旋多巴对小鼠运动学习的影响 警察。我们已经证明，运动学习的某些方面在最早的时候是有缺陷的 帕金森病的不同阶段与异常的脑组织有关。初步 数据表明，这些异常不能被左旋多巴纠正，但GPI DBS可以改善序列学习，增加大脑区域的活动 通常参与这一过程。在这里，我们问STN DBS(推动GPI和 调节简单和复杂运动行为的其他结构)可以改进 通过调节参与序列的大脑回路在帕金森病中的表现 学习，类似于GPI DBS。运动任务期间的宠物录音将被 在一组患有STN DBS的PD患者、一组患有GPI DBS的患者和一组 左旋多巴输液组在开启和关闭状态下进行治疗。大脑网络 表情和表现将在不同组和不同条件下进行比较。 2.研究帕金森病患者运动和认知功能障碍的发展过程。我们 发现处于I期和11期的PD患者需要更长的时间和需要 招募更多的大脑区域来学习运动序列。在这里，我们问的是性能如何 以及大脑网络激活的变化与疾病进展的关系。在这 纵向研究，我们还将评估马达获得的变化 序列学习以外的技能，例如适应新的参照系 或者是新奇的惯性构型。我们将使用我们最近开发的任务 并在一群年轻的正常受试者中进行了测试。我们将询问以下问题 问：哪些是不同类型的正常大脑网络？ 学习吗？他们是独立的，还是有共同的基础？他们的 帕金森病患者早期的表达变化？大脑网络表达 帕金森病是否会随着疾病进展而改变？这些研究包括心理物理和成像 研究将在帕金森病患者组和年龄匹配的对照组中进行 我们已经在上一次授权期内进行了测试。 3.高动力基底节运动学习与执行的研究 精神错乱。氟脱氧葡萄糖(FDG)和正电子发射计算机断层扫描的研究表明 临床未显性携带者的异常代谢网络 特发性扭转肌张力障碍(ITD)Dyt I基因。在初步研究中，我们有 发现在这些相同的基因携带者中，运动序列学习可能受到损害。 我们计划在非显性DYTI携带者中完成心理物理研究 并评价GPiDBS对DYTI患者Rcbf的影响。 具体地说，我们将问以下问题：未显现的DYTI是否会 携带者表现出运动学习和网络激活的异常 他们休息时的代谢异常？会不会出现非显性DYT I携带者和 肌张力障碍患者在运动学习和网络激活方面有差异吗？通过 比较苍白球刺激前和刺激期间的rcbf，我们将确定 改变苍白球功能影响激活模式的表达 在ITD中辅助性运动学习。 总体而言，这些研究将为全面了解 基底节和相关环路在运动学习和执行中的作用 至于基底节的新治疗策略的发展 精神错乱。

DESCRIPTION (provided by applicant): The specific aims of the original proposal were: 1. To determine the effect of Parkinson's disease (PD) on the learning of spatial and temporal features of motor learning tasks, compared to a normally aging population. 2. To test the hypothesis that the deficits in motor learning in PD result from the altered function of specific cortical and subcortical networks whose expression correlates with task performance in age-matched controls. 3. To assess the effect on motor learning of new therapies, such as pallidal ablation and pallidal stimulation. Over the past two and a half year, we have made extensive progress in accomplishing these aims, as described in Progress Report and in the publication track record. In this competing continuation application, we plan to complete the initial research and educational aims and to extend our work. Specifically, we will pursue the following aims: 1. To study the effects of DBS and levodopa administration on motor learning in PD. We have shown that aspects of motor learning are defective in the earliest stages of PD and are associated with abnormal brain organization. Preliminary data indicate that these abnormalities are not rectified by levodopa, but, GPi DBS can improve sequence learning and increase activity in brain regions normally involved in this process. Here we ask if STN DBS (which drives GPi and other structures mediating simple and complex motor behavior) can improve performance in PD by modulating the brain circuits involved in sequence learning, similarly to GPi DBS. PET recordings during motor tasks will be conducted in a group of PD patients with STN DBS, a group with GPi DBS, and a group treated with levodopa infusion in on and off conditions. Brain network expression and performance will be compared across groups and conditions. 2. To characterize the progression of motor and cognitive dysfunction in PD. We found that PD patients in stage I and 11 require longer time and need to recruit more brain areas to learn a motor sequence. Here we ask how performance and brain network activation change in relation to disease progression. In this longitudinal study, we will also evaluate changes in acquisition of motor skills other than sequence learning, such as adaptation to new reference frames or novel inertial configuration. We will use tasks we have recently developed and tested in a population of young normal subjects. We will ask the following questions: Which are the normal brain networks involved in the different types of learning? Are they independent or share some common bases? Does their expression change in PD patients in early stages? Does brain network expression in PD change with disease progression? These studies psychophysical and imaging studies will be conducted in the group of PD patients and age-matched controls we have tested in the previous grant period. 3. To study motor learning and execution in hyperkinetic basal ganglia disorders. Studies with "F-fluoro-deoxyglucose (FDG) and PET have demonstrated an abnormal metabolic network in clinically non-manifesting carriers of Idiopathic Torsion Dystonia (ITD) DYT I gene. In preliminary studies, we have found that motor sequence learning may be impaired in these same gene carriers. We plan to complete the psychophysical studies in non-manifesting DYTI carriers and to assess the effect of GPiDBS on rcbf in affected DYTI patients. Specifically, we will ask the following questions: Will non-manifesting DYTI carriers show motor learning and network activation abnormalities that parallel their resting metabolic abnormalities? Will non-manifesting DYT I carriers and dystonic patients show differences in motor learning and network activation? By comparing rcbf before and during pallidal stimulation, we will determine how altering pallidal function affects the expression of activation patterns subserving motor learning in ITD. Overall, these studies will provide the bases for a comprehensive understanding of basal ganglia and related cicuitry in motor learning and execution, as well as for the development of new therapeutical strategies for basal ganglia disorders.