Dopaminergic Effects on Cortical Function in Tourette's

多巴胺能对妥瑞氏症皮质功能的影响

• 批准号: 7036100
• 负责人: KEVIN J BLACK
• 金额: $ 37.03万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036100
• 关键词: Tourette' s syndrome; antiparkinson drugs; brain imaging /visualization /scanning; brain mapping; clinical research; cognition; dopamine; dopamine agonists; dopamine receptor; frontal lobe /cortex; functional magnetic resonance imaging; human subject; levodopa; neuropharmacology; parietal lobe /cortex; pergolide; psychological tests; short term memory; thalamus

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.

描述（由申请人提供）：包括图雷特综合症（TS）在内的慢性疾病至少影响所有学童的2％，并且经常持续到成年。症状通常会干扰教育，就业或社会关系，在某些人中，症状会产生明显的残疾。神经疗法和其他药物降低了抽动的严重程度，但所有TS治疗都是经验性的，因为尚不完全了解TICS的病理生理学。但是，最近的一项功能成像研究表明，脑功能的药物敏感异常。涉及工作记忆（WM）的认知任务导致了多个大脑区域的过度激活，但是在给药多巴胺前体左旋多巴后，过度激活归一化。该药物非常适合神经影像学研究，因为它在TS中的耐受性良好，并且（与碳纤维一起给予）基本上仅向大脑提供多巴胺。本文提出的研究旨在阐明结合对WM任务和Levodopa产生异常反应的认知任务成分和临床变量。患有TS或慢性疾病的成年人以及匹配的对照组将在左旋多巴或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内存负载的参数缩放以及匹配的空间和口头工作记忆任务。仔细表征受试者将允许对成像发现如何受到临床变量（例如合并症（例如ADHD，OCD），严重程度或过去的药物暴露）的测试。此外，将在单独的扫描日内给出具有相同认知任务的混合（pergolide）和D2样选择性（pramipexole）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机制。这项研究的意义包括其定义TS未来发育或遗传研究的内表型的潜力。