GABAergic Sensorimotor Dysfunction in Tourette Syndrome

 描述(申请人提供)：多发性抽动症(TS)是一种常见的儿童期起病的神经系统疾病，其特征是称为抽搐的非自愿和强制执行的模式运动，通常先于感觉上的“先兆冲动”。严重病例的发病率很高，尽管使用了抗精神病药物，甚至深部脑刺激。TS的神经生物学可能涉及不典型的运动和感觉发育；然而，到目前为止，大多数研究都集中在运动系统回路功能障碍的病理生理学和治疗意义上。现在有了创新的方法来探索儿童感觉功能和运动控制之间的关系，这些研究对于开发更好的治疗严重TS的方法至关重要。在之前由NIH资助的研究中，Mostofsky博士和Gilbert博士采用了仔细的临床表型、经颅磁刺激(TMS)和磁共振波谱(MRS)来评估儿童神经行为障碍的病理生理学。这项研究建立在先前工作的基础上，以及量化TS感觉运动适应的新数据。这一建议的总体假设是，感觉运动皮质的GABA能功能障碍导致感觉适应异常和抑制运动功能受损，这是TS出现前兆冲动和抽搐症状的基础。本研究的主要目的是量化TS儿童的感觉适应、抑制运动生理学、冲动和抽动严重程度之间的关系，并将这些指标与感觉运动皮质和辅助运动区的GABA水平进行比较。这项多PI研究的研究人员带来了互补的科学和临床专业知识的独特组合，利用创新方法建立了科学合作，并提供了坚实的初步数据来支持这项关于TS病理生理学的新研究。为此，我们提出了以下目标：目标1：评估和比较抽动秽语综合征(TS)和典型发育期儿童(TDC)的触觉敏感度和适应性，并确定触觉适应性受损是否与先兆冲动严重程度和抽动严重程度相关。目的：应用经颅多普勒超声(TMS)检测和比较TS和TDC儿童双侧运动皮质(M1)的抑制程度，并确定M1抑制程度是否与抽动严重程度相关。目的：检测和比较TS和TDC患儿双侧感觉运动皮质(S1/M1)和辅助运动区(SMA)的GABA水平，探讨S1/M1 GABA与TS的触觉适应、M1抑制、先兆冲动和抽动严重程度之间的关系。这项对儿童抽搐出现期间的触觉、运动和GABA能功能障碍的创新性研究将为确定减轻症状和防止TS不良后果的治疗提供至关重要的信息。

 DESCRIPTION (provided by applicant): Tourette Syndrome (TS) is a common, childhood-onset neurological disorder characterized by involuntary and compulsively-performed patterned movements called "tics," often preceded by sensory "premonitory urges." Severe cases suffer substantial morbidity, despite the use of antipsychotics and even deep brain stimulation. The neurobiology of TS likely involves both atypical motor and sensory development; however, the majority of investigations to date have focused on the pathophysiology and treatment implications of dysfunction in motor system circuits only. Innovative methods are now available to probe the relationship between sensory function and motor control in children, investigations critical for developing better treatments for severe TS. In prior NIH funded research, Drs. Mostofsky and Gilbert, have employed careful clinical phenotyping, transcranial magnetic stimulation (TMS), and magnetic resonance spectroscopy (MRS) in evaluating pathophysiology of neurobehavioral disorders in children. This study builds on prior work as well as new data quantifying sensorimotor adaptation in TS. The over-arching hypothesis of this proposal is that GABAergic dysfunction in sensorimotor cortex results in a combination of abnormal sensory adaptation and impaired inhibitory motor function that underlie the emergence of symptoms of premonitory urges and tics in TS. The primary aim of this study is to quantify the relationship between sensory adaptation, inhibitory motor physiology, and urge and tic severity in children with TS and to compare these metrics with GABA levels in sensorimotor cortex and supplementary motor area. The investigators in this multi-PI study bring a unique combination of complementary scientific and clinical expertise, established scientific collaborations using innovative methods, and solid preliminary data to support this novel study of the pathophysiology of TS. To this end we propose the following aims: Aim 1: To evaluate and compare tactile sensitivity and adaptation in children with Tourette Syndrome (TS) and typically developing children (TDC) and determine whether impaired tactile adaptation is associated with premonitory urge severity and tic severity. Aim 2: To measure and compare inhibition in bilateral motor cortex (M1) using TMS in children with TS and TDC and determine whether reduced M1 inhibition is associated with tic severity. Aim 3: To measure and compare GABA levels in bilateral sensorimotor cortex (S1/M1) and supplementary motor area (SMA) in children with TS and TDC and determine whether S1/M1 GABA correlates with tactile adaptation, M1 inhibition, and premonitory urge and tic severity in TS. This innovative investigation of tactile, motor, and GABAergic dysfunction during emergence of tics in childhood will provide information vital for identifying treatments that reduce symptoms and prevent adverse outcomes in TS.