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）：多达20％的儿童在他们的一生中患有抽动，大约3％的儿童患有慢性疾病（例如Tourette综合征（TS）），使TIC疾病成为具有实质性公共卫生利益的主题。尽管研究稳步增加，但对TS的治疗却没有治疗的一半以上，并且TS的原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了TIC的严重程度的观察，一个长期的假设是，TICS可能涉及纹状体中瞬时（体）多巴胺释放的异常，而基线（滋补）多巴胺释放可能是正常的。在过去的15年中，几项实验试图通过测量苯丙胺中的TS中的纹状体多巴胺释放来解决这一假设。但是，人们可能会争辩说，这仅评估了在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有或没有外源性左旋多巴的认知任务来测量纹状体多巴胺释放来直接测试TS中质量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宠物扫描仪与受体成像同时获取RCBF。申请人在该方法的大多数方面都有初步数据，可以单独考虑，但没有用于合并方法。该申请建议在一小部分TS和匹配的控制对象上测试完整协议，以证明对计划的R01应用程序的可行性和估计差异。计划中的R01资助的后续研究将包括足以测试精神病合并症，过去治疗和人口统计学变量的影响的样本量。 公共卫生相关性：大约有20％的儿童患有抽动性，不必要的运动或噪音，在他们的生活中，大约3％的儿童患有慢性抽动疾病，例如Tourette综合征（TS），其中生活质量大大降低了。不幸的是，大脑如何产生抽动仍然不清楚。专家们假设，当大脑在大脑发送与学习或运动有关的快速爆发信号时，脑部信使多巴胺虽然通常在TS中释放，但通常不会释放。该项目将使用新的，尖端的脑扫描仪和新的实验设计直接测试TS中这种短暂多巴胺释放是否正常。本申请将支持首先研究有和没有TS的一小组人，以表明该项目是可行的，并阐明在计划的结论性后续研究中需要对多少人进行测试。预计这种新方法将证明或放弃有关图雷特综合征的泰克斯原因的关键当前理论之一。