GABAergic Sensorimotor Dysfunction in Tourette Syndrome

抽动秽语综合征中的 GABA 能感觉运动障碍

• 批准号: 9262305
• 负责人: DONALD L GILBERT
• 金额: $ 57.11万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262305
• 关键词: 12 year old; Address; Adult; Adverse event; Age; Animals; Antipsychotic Agents; Area; Behavior Therapy; Bilateral; Child; Childhood; Clinical; Collaborations; Corpus striatum structure; Coupled; Data; Deep Brain Stimulation; Development; Devices; Disinhibition; Dopamine Receptor; Frequencies; Functional disorder; Funding; Gilles de la Tourette syndrome; Goals; Impairment; Injury; Interneurons; Investigation; Laboratories; Magnetic Resonance Spectroscopy; Measures; Mediating; Medical; Methods; Morbidity - disease rate; Motor; Motor Cortex; Motor output; Movement; Neurobiology; Patients; Pattern; Pharmacology; Physiology; Population; Quality of life; Recruitment Activity; Reporting; Research; Research Personnel; Research Project Grants; Sampling; Scientist; Sensory; Severities; Site; Social Discrimination; Solid; Symptoms; System; Tactile; Teenagers; Time; Transcranial magnetic stimulation; United States National Institutes of Health; Work; adverse outcome; base; clinical phenotype; cost; design; effective therapy; experience; functional disability; gamma-Aminobutyric Acid; innovation; insight; motor control; motor impairment; nervous system disorder; neurobehavioral disorder; novel; prevent; public health relevance; reduce symptoms; sensorimotor system; sensory discrimination; social; somatosensory; tic-related

 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.

 描述（由申请人提供）：抽动秽语综合症（TS）是一种常见的儿童期发病的神经系统疾病，其特征是不自主和强迫性的模式性运动（称为“抽动”），通常先有感觉“预兆冲动”，严重的病例会出现严重的发病率。尽管使用了抗精神病药物甚至深部脑刺激，但 TS 的神经生物学可能涉及非典型运动和感觉发育，但迄今为止的大多数研究都集中在这方面。 Mostofsky 博士表示，现在可以使用创新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。和吉尔伯特，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的工作基础上。以及量化 TS 感觉运动适应的新数据 该提议的首要假设是感觉运动皮层的 GABA 功能障碍导致感觉适应异常和抑制性运动功能受损，这是出现预兆冲动和抽动症状的基础。本研究的主要目的是量化 TS 儿童的感觉适应、抑制性运动生理学以及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层和中枢神经系统中的 GABA 水平进行比较。这项多 PI 研究的研究人员将互补的科学和临床专业知识独特地结合起来，利用创新方法建立了科学合作，并提供了可靠的初步数据来支持这项关于 TS 病理生理学的新颖研究。目标如下： 目标 1：评估和比较抽动秽语综合征 (TS) 儿童和正常发育儿童 (TDC) 的触觉敏感性和适应能力，并确定触觉适应受损是否与先兆冲动严重程度和抽动严重程度相关。目标 2：使用 TMS 测量和比较 TS 和 TDC 儿童双侧运动皮层 (M1) 的抑制，并确定 M1 抑制的减少是否与抽动严重程度相关。目标 3：测量和比较双侧感觉运动皮层 (S1) 的 GABA 水平。 /M1) 和辅助运动区 (SMA) 的 TS 和 TDC 儿童，并确定 S1/M1 GABA 是否与触觉适应、M1 抑制、先兆冲动和抽动严重程度相关。 TS。这项针对儿童抽动出现期间的触觉、运动和 GABA 功能障碍的创新研究将为确定减轻 TS 症状和预防不良后果的治疗方法提供重要信息。