TESTING THE PHASIC DOPAMINE RELEASE HYPOTHESIS IN TOURETTE SYNDROME: PILOT

描述（由申请人提供）：高达20%的所有儿童在其生命中的某个时候有抽搐，约3%的所有儿童有慢性抽动障碍，如图雷特综合征（TS），使抽动障碍成为重大公共卫生利益的主题。尽管不断增加的研究，没有治疗TS工程超过一半的治疗，和TS的原因和病理生理学知之甚少。基于多巴胺D2受体拮抗剂显著降低抽搐严重程度的观察，一个长期存在的假设是抽搐可能涉及纹状体中瞬时（阶段性）多巴胺释放的异常，而基线（强直性）多巴胺释放可能是正常的。在过去的15年中，一些实验试图解决这一假设，通过测量纹状体释放多巴胺在TS安非他明的反应。然而，有人可能会说，这只评估了在非生理条件下最大可能的多巴胺释放。本提案代表了计划中的第一步，直接测试阶段性多巴胺释放TS测量纹状体多巴胺释放的认知任务，有和没有外源性左旋多巴。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。申请人有关于这种方法的大多数方面的初步数据，单独考虑，但没有关于组合方法的数据。本申请建议在一小组TS和匹配对照受试者中测试完整方案，以证明可行性并估计计划的R01应用的方差。计划的R01资助的随访研究将包括足够的样本量来测试精神病合并症，既往治疗和人口统计学变量的影响。 公共卫生相关性：大约20%的儿童在他们生命中的某个时候有抽搐-突然的，不必要的运动或噪音，大约3%的儿童患有慢性抽动障碍，如图雷特综合征（TS），生活质量大大降低。不幸的是，大脑如何产生抽搐仍然不清楚。专家们假设，大脑信使多巴胺虽然在TS中的大部分时间都正常释放，但当大脑发出与学习或运动有关的快速突发信号时，它就不会正常释放。该项目将使用一种新的、尖端的大脑扫描仪和一种新的实验设计来直接测试这种短暂的多巴胺释放在TS中是否正常。本申请将支持首先研究一小群患有和不患有TS的人，以表明该项目是可行的，并澄清在计划的结论性后续研究中需要测试多少人。这种新的方法有望证明或奠定目前的关键理论之一，抽动秽语综合征的抽搐原因。

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.