Dopaminergic Effects on Cortical Function in Tourette's

描述（由申请人提供）：包括抽动秽语综合征（TS）在内的慢性抽动障碍影响至少2%的学龄儿童，并且通常持续到成年。症状通常会干扰教育、就业或社会关系，在某些个体中，症状会导致明显的残疾。抗精神病药和其他药物可减轻抽动的严重程度，但由于抽搐的病理生理尚不完全清楚，因此所有的TS治疗都是经验性的。然而，最近的一项功能成像研究显示了一种药物敏感的脑功能异常。一项涉及工作记忆（WM）的认知任务产生了几个大脑区域的过度激活，但在给予多巴胺前体左旋多巴后过度激活正常化。这种药物非常适合用于神经影像学研究，因为它在TS中耐受性良好，而且（当与卡比多巴一起服用时）基本上只向大脑输送多巴胺。本研究旨在阐明对WM任务和左旋多巴产生异常反应的认知任务成分和临床变量。患有TS或慢性抽动障碍的成年人，以及匹配的对照组，将在不同的日子左旋多巴或生理盐水输注后使用功能性MRI和WM任务进行研究。认知任务将包括工作记忆负荷的参数缩放和匹配的空间和语言工作记忆任务。对受试者进行仔细的特征描述，可以测试成像结果如何受到临床变量的影响，如共病（如ADHD、OCD）、严重程度或既往药物暴露。此外，混合（培高利特）和d2样选择性（普拉克索）多巴胺受体激动剂，或安慰剂，将在不同的扫描日给予相同的认知任务，以帮助确定左旋多巴效应的药理学机制。这项研究的意义在于它有可能为TS的未来发育或遗传研究确定一种内表型。

DESCRIPTION (provided by applicant): Chronic tic disorders including Tourette syndrome (TS) affect at least 2% of all school children and often persist into adulthood. Symptoms commonly interfere with education, employment, or social relationships, and in some individuals symptoms produce marked disability. Neuroleptics and other drugs reduce tic severity, but all TS treatment is empiric since the pathophysiology of tics is incompletely understood. However, a recent functional imaging study showed a medication- sensitive abnormality of brain function. A cognitive task involving working memory (WM) produced excessive activation of several brain regions, but the excessive activation normalized after administration of the dopamine precursor levodopa. This drug is well suited for neuroimaging studies as it is well tolerated in TS and (when given with carbidopa) essentially delivers dopamine to the brain only. The research proposed herein aims to clarify the cognitive task components and the clinical variables that combine to produce the abnormal responses to the WM task and levodopa. Adults with TS or chronic tic disorders, and matched controls, will be studied using functional MRI and WM tasks after levodopa or saline infusion on different days. Cognitive tasks will include parametric scaling of working memory load and matched spatial and verbal working memory tasks. Careful characterization of subjects will allow tests of how the imaging findings are affected by clinical variables such as comorbidity (e.g., ADHD, OCD), severity, or past medication exposure. Additionally, a mixed (pergolide) and D2-like-selective (pramipexole) dopamine receptor agonist, or placebo, will be given on separate scanning days with the same cognitive tasks to help determine the pharmacological mechanism of the levodopa effect. The significance of this research includes its potential to define an endophenotype for future developmental or genetic studies of TS.