TESTING THE PHASIC DOPAMINE RELEASE HYPOTHESIS IN TOURETTE SYNDROME: PILOT

描述（由申请人提供）：高达20%的儿童在其一生中的某个时候患有抽动，约3%的儿童患有慢性抽动障碍，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。尽管研究稳步增加，但没有一种治疗方法对超过一半的患者有效，而且对TS的病因和病理生理学知之甚少。基于对多巴胺D2受体拮抗剂显著降低抽动严重程度的观察，一个长期存在的假设是，抽动可能涉及纹状体中短暂（相）多巴胺释放异常，而基线（强直）多巴胺释放可能正常。在过去的15年里，几个实验试图通过测量对安非他明反应的TS纹状体多巴胺释放来解决这一假设。然而，有人可能会说，这只是评估了在非生理条件下最大可能的多巴胺释放。目前的建议是通过测量纹状体多巴胺在有或没有外源性左旋多巴的认知任务下的释放来直接测试TS中阶段性多巴胺释放计划的第一步。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获取rCBF。申请人对这种方法的大多数方面都有初步的数据，单独考虑，但没有对联合方法。这个应用程序建议在一小群TS和匹配的控制对象上测试完整的协议，以证明可行性并估计计划的R01应用程序的方差。计划中的r01资助的后续研究将包括足够的样本量来测试精神合并症、既往治疗和人口统计学变量的影响。

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.