TESTING THE PHASIC DOPAMINE RELEASE HYPOTHESIS IN TOURETTE SYNDROME: PILOT

描述(由申请人提供)：高达20%的儿童在一生中的某个时候会出现抽搐，约3%的儿童患有抽动症(TS)等慢性抽动障碍，这使得抽动障碍成为公共卫生关注的主题。尽管研究稳步增加，但治疗TS的患者中没有超过一半的人有效，而且TS的病因和病理生理学还知之甚少。根据多巴胺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搐可能涉及纹状体一过性(时相)多巴胺释放的异常，而基线(强直)多巴胺的释放可能是正常的。过去15年的几个实验试图通过测量TS对苯丙胺的反应释放纹状体多巴胺来解决这一假说。然而，人们可能会争辩说，这只评估了非生理条件下最大可能的多巴胺释放。本提案代表了一项计划的第一步，该计划通过测量纹状体多巴胺释放来直接测试TS的相性多巴胺释放，以响应有和没有外源性左旋多巴的认知任务。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。申请者有关于这一方法的大多数方面的初步数据，单独考虑，但没有关于综合方法的数据。该应用程序建议在一小群TS和匹配的对照对象上测试完整的协议，以证明可行性并估计计划中的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大的样本大小，以测试精神疾病共病、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%的儿童在一生中的某个时候会出现抽搐--突然的、不必要的动作或噪音--，大约3%的儿童患有抽动障碍，如抽动症(TS)，生活质量大幅下降。不幸的是，大脑是如何产生抽搐的还不清楚。专家们假设，大脑信使多巴胺，虽然在大多数时候在TS中正常释放，但当大脑发出与学习或运动有关的快速脉冲信号时，并不正常释放。该项目将使用一种新的尖端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。本申请将支持首先对患有和不患有TS的一小群人进行研究，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对多少人进行测试。这一新方法有望证明或推翻目前关于抽动症抽动原因的关键理论之一。

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.