TESTING THE PHASIC DOPAMINE RELEASE HYPOTHESIS IN TOURETTE SYNDROME: PILOT

测试抽动秽语综合症中的阶段性多巴胺释放假说：试点

• 批准号: 8402513
• 负责人: KEVIN J BLACK
• 金额: $ 30.4万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402513
• 关键词: Address; Adult; Affect; Amphetamines; Appearance; Back; Brain; Brain imaging; Carbidopa; Cerebrovascular Circulation; Child; Childhood; Chronic; Cognitive; Comorbidity; Core-Binding Factor; Corpus striatum structure; Data; Disadvantaged; Dopamine; Dopamine D2 Receptor; Euphoria; Experimental Designs; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Genes; Gilles de la Tourette syndrome; Image; Intravenous infusion procedures; Learning; Levodopa; Life; Link; Magnetic Resonance Imaging; Measures; Methods; Motor; Movement; Nature; Noise; Performance; Persons; Pilot Projects; Placebos; Positron-Emission Tomography; Protocols documentation; Public Health; Quality of life; Raclopride; Radiation; Randomized Controlled Trials; Research; Rest; Role; Sample Size; Scanning; Sensory; Severities; Short-Term Memory; Signal Transduction; Spin Labels; Stereotyping; Study Subject; Technology; Testing; Thalamic structure; Tic disorder; Time; Work; base; behavior change; experience; follow-up; in vivo; indexing; interest; monoamine; novel strategies; postsynaptic; presynaptic; psychosocial; putamen; rapid technique; receptor; research study; response; sequence learning; success; theories; uptake

DESCRIPTION (provided by applicant): Up to 20% of all children have tics at some time in their life, and about 3% of all children have a chronic tic disorder such as Tourette syndrome (TS), making tic disorders a subject of substantial public health interest. Despite steadily increasing research, no treatment for TS works for more than half those treated, and the cause and pathophysiology of TS are poorly understood. Based on the observation that dopamine D2 receptor antagonists significantly reduce tic severity, one longstanding hypothesis has been that tics may involve abnormalities in transient (phasic) dopamine release in the striatum, while baseline (tonic) dopamine release may be normal. Several experiments in the past 15 years attempted to address this hypothesis by measuring striatal dopamine release in TS in response to amphetamine. One could argue, however, that this assessed only maximal possible dopamine release under nonphysiological conditions. The present proposal represents the first step in a plan to directly test phasic dopamine release in TS by measuring striatal dopamine release in response to a cognitive task with and without exogenous levodopa. The proposal will exploit the newly developed Siemens PET-MRI scanner to acquire rCBF simultaneously with the receptor imaging. The applicants have preliminary data on most aspects of this approach, considered individually, but none for the combined approach. This application proposes to test the full protocol on a small group of TS and matched control subjects, in order to demonstrate feasibility and estimate variance for a planned R01 application. The planned R01-funded follow-up study would include sample sizes adequate to test the effects of psychiatric comorbidity, past treatment, and demographic variables. PUBLIC HEALTH RELEVANCE: About 20% of all children have tics-sudden, unwanted movements or noises-at some time in their life, and about 3% of all children have a chronic tic disorder such as Tourette syndrome (TS), in which quality of life is substantially reduced. Unfortunately, how the brain generates tics is still not clear. Experts have hypothesized that the brain messenger dopamine, while released normally most of the time in TS, is not released normally when the brain sends a quick burst signal related to learning or movement. This project will use a new, cutting-edge brain scanner and a new experimental design to directly test whether such transient dopamine release is normal in TS. The present application will support first studying a small group of people with and without TS to show that the project is feasible and to clarify how many people need to be tested in the planned conclusive follow-up study. This new approach is expected to prove or lay to rest one of the key current theories about the cause of tics in Tourette syndrome.

描述（由申请人提供）：高达 20% 的儿童在一生中的某个时期患有抽动症，约 3% 的儿童患有抽动秽语综合征 (TS) 等慢性抽动障碍，这使得抽动障碍成为重大公共卫生问题。尽管研究不断增加，但 TS 的治疗方法对一半以上的治疗者无效，而且 TS 的病因和病理生理学知之甚少。基于多巴胺 D2 受体拮抗剂显着降低抽动严重程度的观察，一种长期存在的假设是抽动可能涉及纹状体短暂（阶段性）多巴胺释放异常，而基线（强直性）多巴胺释放可能正常。过去 15 年的几项实验试图通过测量 TS 中对安非他明的反应而释放的纹状体多巴胺来解决这一假设。然而，有人可能会争辩说，这仅评估了非生理条件下最大可能的多巴胺释放。本提案代表了通过测量纹状体多巴胺释放以响应有或没有外源性左旋多巴的认知任务来直接测试 TS 中阶段性多巴胺释放的计划的第一步。该提案将利用新开发的西门子 PET-MRI 扫描仪在受体成像的同时采集 rCBF。申请人拥有该方法大多数方面的初步数据（单独考虑），但没有组合方法的初步数据。该应用程序建议在一小组 TS 和匹配的对照受试者上测试完整协议，以证明计划的 R01 应用程序的可行性并估计方差。计划中的 R01 资助的后续研究将包括足够的样本量，以测试精神共病、既往治疗和人口变量的影响。 公共卫生相关性：约 20% 的儿童在一生中的某个时间会出现抽动（突然的、不想要的动作或噪音），约 3% 的儿童患有抽动秽语综合征 (TS) 等慢性抽动障碍，导致生活质量大幅下降。不幸的是，大脑如何产生抽动仍不清楚。专家推测，大脑信使多巴胺虽然在 TS 中大部分时间都能正常释放，但当大脑发送与学习或运动相关的快速突发信号时，多巴胺就不会正常释放。该项目将使用新型、尖端的脑部扫描仪和新的实验设计来直接测试 TS 中这种短暂的多巴胺释放是否正常。本申请将支持首先对一小群患有或未患有 TS 的人进行研究，以表明该项目是可行的，并明确在计划的结论性后续研究中需要对多少人进行测试。这种新方法有望证明或推翻当前有关抽动秽语综合征抽动病因的关键理论之一。