Dopaminergic Effects on Cortical Function in Tourette's

描述（由申请人提供）：慢性抽动障碍，包括抽动秽语综合征（TS）影响至少2%的所有学龄儿童，并经常持续到成年。症状通常会影响教育、就业或社会关系，在某些个体中，症状会导致明显的残疾。抗精神病药物和其他药物可减轻抽搐的严重程度，但所有的TS治疗都是经验性的，因为抽搐的病理生理学还不完全清楚。然而，最近的一项功能成像研究显示，大脑功能存在药物敏感性异常。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。这种药物非常适合神经影像学研究，因为它在TS中耐受性良好，并且（当与卡比多巴一起给药时）基本上仅将多巴胺递送到大脑。本文提出的研究旨在阐明认知任务的组成部分和联合收割机的临床变量，产生异常反应的WM任务和左旋多巴。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日期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以及匹配的空间和言语工作记忆任务。对受试者的仔细表征将允许测试成像结果如何受到临床变量的影响，例如合并症（例如，ADHD、OCD）、严重程度或既往药物暴露。此外，将在不同的扫描日使用相同的认知任务给予混合（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，以帮助确定左旋多巴效应的药理学机制。这项研究的意义包括它的潜力，以确定未来的发展或遗传研究TS的内表型。

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.