Dopaminergic Modulation Of Cognitive Aspects Of Skill Acquisition In PD

描述（由申请人提供）：帕金森病（PD）以运动迟缓、僵硬和静息性震颤为主要症状，被认为是黑质纹状体束多巴胺能（DA）神经元损失的反映。这些运动症状可伴有认知障碍，尽管与PD相关的认知障碍存在异质性。虽然DA耗竭与PD患者运动障碍的严重程度相关，但之前关于DA药物对认知任务影响的研究并不一致，基底神经节在认知中的作用也存在争议。很少有研究对患者在服药和停药状态下进行评估，并且在已经进行的研究中存在不一致的结果。因此，PD患者认知功能障碍的神经解剖学和神经化学相关因素尚不确定。研究背后的具体假设是，只有部分PD障碍行为是由DA介导的，而DA治疗在不同的任务需求下具有不同的效果。我们基于以下观察得出这一假设：首先，并非所有PD的行为缺陷都可以用单纯的运动障碍和/或DA消耗来解释。第二，多巴胺能处理对表现的不同影响取决于任务需求，并且与受影响回路中多巴胺消耗的程度有关。基于这些观察结果，本提案的实验重点是确定PD在哪些条件下（即任务需求）DA调节机制影响表现。具体目的是提供一个评估多巴胺能调节运动控制的认知方面在PD。研究的具体目的如下：(1)确定DA在PD中调节技能习得增量、反馈控制过程和运动幅度的作用。(2)研究PD的内隐记忆缺陷特征及DA调制机制。(3)确定DA对PD肢体序列时空特征的调节作用。我们认为，当依赖于内部线索时，DA调节增量技能习得的计划方面，但不影响PD在运动幅度或肢体序列习得方面的缺陷。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几个亚型，其中只有一部分是由DA介导的。我们基于这些假设的解离在我们的试点数据中存在于各种任务需求。提出的目的将有助于阐明控制PD的运动和认知症状的DA调节机制，这是开发能够治疗PD障碍行为各个方面的治疗方案的必要前提。公共卫生相关性：帕金森病（PD）是一种进行性疾病，通常影响运动系统，但它也与非运动症状复合物相关，这对发病率和制度化有重要影响，使护理成本增加了四倍以上。最近的证据表明，非运动症状如认知功能障碍可能是帕金森病临床前阶段的标志，尽管帕金森病的认知症状在临床实践中尚未得到很好的认识，而且目前使用多巴胺激动剂治疗如何影响认知尚不确定。提出的研究将表征帕金森病的认知症状，并评估多巴胺能药物治疗作为开发能够治疗帕金森病全部症状的治疗方案的必要先决条件。

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.