Feedback Learning and L-Dopa in Parkinson's Disease

描述(申请人提供)：许多以前的研究表明，帕金森氏病(PD)患者患有各种认知缺陷。虽然早期对这些缺陷的研究主要集中在对额叶损伤敏感的执行或工作记忆任务上，但最近的研究表明，帕金森病患者也损害了通过纠错反馈逐渐获得的程序性学习任务。然而，帕金森病患者的程序性学习受到L-多巴的强烈影响，多巴是一种多巴胺前体，通过增加全球多巴胺水平来缓解运动症状。来自我们实验室和其他实验室的初步数据表明，L-多巴可能导致了早期帕金森病患者的一些学习障碍，这样当患者停止使用正常药物进行测试时，患者的表现实际上会有所改善。这与其他数据显示L-多巴纠正帕金森病在“正面”任务中的表现形成了鲜明对比。目前的建议集中在了解L-多巴药物在帕金森患者联想学习过程中如何与反馈处理相互作用的具体目标。特别是，我们将检验两个与这一目标相关的具体假设：具体假设#1：帕金森患者在服用L-多巴药物时，通过反馈训练进行联想学习的能力比停药时更差。具体假设2：帕金森氏症患者，无论是服药还是停药，在接受观察训练而不是反馈训练时，都可以正常学习这些相同的联想任务；这与我们之前对健康正常受试者进行的功能成像研究一致，该研究表明，与反馈训练相比，观察训练激活了更多的内侧颞叶结构，而不是纹状体区域。目前治疗帕金森病的标准做法是使用多巴胺能前体和激动剂，通过评估运动症状的缓解来评估这些药物的疗效。然而，更好地了解帕金森病和多巴胺能药物如何影响认知，可能会使治疗在评估药物疗效时考虑认知症状。因此，拟议的工作可以为未来开发同时解决运动和认知功能的治疗计划提供一个框架。此外，我们建议的研究将导致行为标记物，这些标记物可能有助于评估个别患者的认知症状。这将使医生能够为每个患者确定最佳的剂量和药物组合，从而增强运动和认知功能。

DESCRIPTION (provided by applicant): Many previous studies have shown that patients with Parkinson's disease (PD) suffer from a variety of cognitive deficits. Although early studies of these deficits focused primarily on executive or working memory tasks sensitive to frontal lobe impairment, more recent studies have demonstrated that patients with PD are also impaired on procedural learning tasks acquired incrementally through error-correcting feedback. However, procedural learning in PD patients is strongly influenced by L-Dopa, a dopamine precursor that alleviates motor symptoms by increasing global levels of dopamine. Preliminary data from our lab and others indicate that L-dopa may contribute to some learning deficits in early-stage PD, such that patient performance actually improves when patients are tested off their normal medication. This contrasts markedly with other data showing that L-dopa remediates PD performance on "frontal" tasks. The current proposal focuses on the specific aim of understanding how L-Dopa medication interacts with feedback processing during associative learning by Parkinson's patients. In particular, we will test two specific hypotheses relevant to this aim: Specific Hypothesis #1: Parkinson's patients are more impaired at associative learning through feedback training when on L-Dopa medication than when off-medication. Specific Hypothesis #2: Parkinson's patients, both on and off medication, can learn these same associative tasks normally when trained in an observational rather than feedback format; this is consistent with our prior functional imaging studies in healthy normal subjects which indicate that observational training activates more medial temporal lobe structures, rather than striatal regions, as compared to feedback training. The standard current practice for treating PD is with dopaminergic precursors and agonists, where the efficacy of these drugs is evaluated by assessing relief of motor symptoms. However, a better understanding of how PD and dopaminergic drugs affect cognition may allow treatment to take cognitive symptoms into account when assessing drug efficacy. Thus, the proposed work can provide a framework for future development of treatment programs that address both motor and cognitive functioning. In addition, our proposed studies will lead to behavioral markers that could be useful for assessing individual patients' cognitive symptoms. This will allow doctors to identify optimal dosing and medication combinations for each individual patient that lead to enhanced motor and cognitive functioning.