GABAergic Sensorimotor Dysfunction in Tourette Syndrome

 描述（由申请人提供）：图雷特综合征（TS）是一种常见的儿童期发作的神经系统疾病，其特征是不自主和强迫性的模式化运动，称为“抽搐”，通常在感觉“先兆冲动”之前。“尽管使用了抗精神病药物，甚至深部脑刺激，严重的病例仍有很大的发病率。TS的神经生物学可能涉及非典型运动和感觉发育;然而，迄今为止的大多数研究仅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至关重要。 在之前NIH资助的研究中，Mostofsky和吉尔伯特博士采用了仔细的临床表型分析、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。这项研究建立在以前的工作，以及新的数据量化感觉运动适应TS。该建议的过度假设是感觉运动皮层中的GABA能功能障碍导致异常感觉适应和抑制运动功能受损的组合，这是TS中出现先兆冲动和抽搐症状的基础。本研究的主要目的是量化感觉适应，抑制性运动生理学，并敦促和抽搐的严重程度与TS儿童之间的关系，并比较这些指标与感觉运动皮层和辅助运动区的GABA水平。 这项多PI研究中的研究者带来了互补的科学和临床专业知识的独特组合，使用创新方法建立了科学合作，并提供了坚实的初步数据，以支持TS病理生理学的这项新研究。为此，我们提出了以下目标：目标1：评估和比较儿童抽动秽语综合征（TS）和典型发育儿童（TDC）的触觉敏感性和适应性，并确定受损的触觉适应是否与先兆冲动的严重程度和抽搐的严重程度。目标二：使用经颅磁刺激（TMS）测量和比较患有抽动症和上止点抽动症儿童的双侧运动皮层（M1）抑制，并确定M1抑制降低是否与抽动严重程度相关。目标3：测量并比较TS和TDC儿童双侧感觉运动皮层（S1/M1）和辅助运动区（SMA）的GABA水平，并确定S1/M1 GABA是否与TS的触觉适应、M1抑制、先兆冲动和抽搐严重程度相关。 这种创新的调查触觉，运动和GABA能功能障碍出现抽搐在儿童时期将提供重要的信息，确定治疗，减少症状和预防不良后果的TS。

 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.