Dopaminergic Modulation Of Cognitive Aspects Of Skill Acquisition In PD

描述（由申请方提供）：帕金森病（PD）的特征为运动迟缓、僵硬和静息性震颤的主要症状，认为反映了黑质纹状体束中多巴胺能（DA）神经元的损失。这些运动症状可伴有认知障碍，尽管与PD相关的认知缺陷存在异质性。虽然DA耗竭与PD运动障碍的严重程度相关，但先前研究DA药物对认知任务的影响并不一致，基底神经节在认知中的作用也存在争议。很少有研究对处于药物治疗和药物治疗状态的患者进行评价，并且在已进行的研究中存在不一致的结果。因此，PD认知功能障碍的神经解剖学和神经化学相关性尚不确定。这项研究背后的具体假设是，只有一些PD障碍行为是由DA介导的，并且DA治疗根据任务要求具有不同的效果。我们的假设基于以下观察：首先，并非所有的行为缺陷PD可以解释的基础上，纯运动障碍，和/或DA耗竭。第二，多巴胺能治疗的差异影响性能取决于任务的要求，并在受影响的电路多巴胺耗尽的程度有关。基于这些观察，该提议的实验重点是确定在PD中在哪些条件下（即，任务要求）DA调节机制影响绩效。具体的目的是提供一个评估多巴胺能调制的认知方面的运动控制在PD。具体目的如下：（1）确定DA在PD的增量技能获得、反馈控制过程和运动幅度中的作用。(2)探讨PD患者内隐记忆障碍的特点及DA对内隐记忆的调节作用。(3)确定DA在调节PD肢体序列时空特征中的作用。我们建议，DA调节规划方面的增量技能收购时，依赖于内部线索，但不是PD赤字的运动幅度或肢体序列收购。相反，DA会对肢体序列的空间特征产生不利影响。我们预测，PD的内隐记忆缺陷可以分为亚型，其中只有一些是由DA介导的。我们基于这些假设的解离在我们的试点数据，存在于各种任务的需求。提出的目标将有助于阐明DA调节机制控制运动和认知症状的PD，作为一个必要的先决条件，发展的治疗方案，能够治疗所有方面的PD紊乱的行为。公共卫生相关性：帕金森病（PD）是一种进行性疾病，通常会影响运动系统，但它也与非运动症状复杂，大大有助于发病率和制度化，超过四倍的护理成本。最近的证据表明，非运动症状，如认知功能障碍可能是临床前阶段的PD的标志物，虽然认知症状在PD中没有得到很好的认识，在临床实践中，它是不确定的，目前的治疗与多巴胺受体激动剂如何影响认知。拟议的研究将描述PD中的认知症状，并评价多巴胺能药物治疗，作为开发能够治疗PD症状全部症状的治疗方案的必要前提。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is characterized by cardinal symptoms of bradykinesia, rigidity, and resting tremor considered reflective of dopaminergic (DA) neuronal loss in the nigrostriatal tract. These motor symptoms can be accompanied by impairments in cognition, although there is heterogeneity in the cognitive deficits associated with PD. While DA depletion has been correlated with the severity of motor impairment in PD, prior studies investigating the effects of DA medication on cognitive tasks have been inconsistent and the role of the basal ganglia in cognition is controversial. Few studies have evaluated patients in both on and off medication states, and there are inconsistent results in the studies which have been conducted. Thus, the neuroanatomical and neurochemical correlates of cognitive dysfunction in PD are uncertain. The specific hypothesis behind the research is that only some PD disordered behaviors are mediated by DA, and that DA treatment has differential effects depending on task demands. We base that hypothesis on the following observations: First, not all behavioral deficits of PD can be accounted for on the basis of pure motor impairment, and/ or DA depletion. Second, dopaminergic treatment differentially impacts performance depending on task demands, and is related to the extent of dopamine-depletion in the affected circuits. Based on these observations, the experimental focus of this proposal is on determining in PD under which conditions (i.e., task demands) DA regulatory mechanisms influence performance. The specific aims are designed to provide an assessment of the dopaminergic modulation of the cognitive aspects of motor control in PD. The specific aims are the following: (1) To determine the role of DA in regulating incremental skill acquisition, feedback control processes, and movement amplitude in PD. (2) To characterize implicit memory deficits in PD and investigate DA modulation. (3) To determine the role of DA in regulating spatiotemporal features of limb sequences in PD. We propose that DA regulates planning aspects of incremental skill acquisition when reliant on internal cues, but not PD deficits in movement amplitude or limb sequence acquisition. Conversely, DA will have a detrimental effect on spatial features of limb sequences. We predict that implicit memory deficits in PD can be divided into subtypes only some of which are mediated by DA. We base these hypotheses on dissociations in our pilot data that exist across various task demands. The proposed aims will help elucidate DA regulatory mechanisms controlling motor and cognitive symptoms of PD, as a necessary prerequisite to development of therapeutic protocols capable of treating all aspects of PD disordered behavior. PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is a progressive disease that usually affects the motor system, but it is also associated with a non-motor symptom complex that contributes significantly to morbidity and institutionalization, more than quadrupling the cost of care. Recent evidence suggests that non-motor symptoms such as cognitive dysfunction may be markers of a preclinical stage of PD, although cognitive symptoms in PD are not well recognized in clinical practice and it is uncertain how current treatments with dopamine agonists affect cognition. The proposed study will characterize cognitive symptoms in PD and evaluate treatment with dopaminergic medication as a necessary prerequisite to the development of therapeutic protocols capable of treating the full constellation of PD symptoms.