2/2-Anomalous Motor Physiology in ADHD

2/2-ADHD 中的异常运动生理学

• 批准号: 8467055
• 负责人: DONALD L GILBERT
• 金额: $ 25.58万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467055
• 关键词: 12 year old; Academic achievement; Address; Adult; Age; Agonist; Anatomy; Attention; Attention deficit hyperactivity disorder; Base of the Brain; Behavior; Behavior Control; Behavior Therapy; Behavioral; Behavioral Symptoms; Biological; Biological Markers; Brain; Chemicals; Child; Childhood; Cognitive; Combined Modality Therapy; Data; Development; Diagnosis; Dimensions; Disinhibition; Dopamine; Emotional; Evaluation; Failure; Funding; Future; Genetic; Goals; Grant; Impairment; Impulsivity; Individual; Interneurons; Intervention; Investigation; Learning; Levodopa; Link; Magnetic Resonance Spectroscopy; Measures; Mediating; Medical; Mental disorders; Methods; Motor; Motor Cortex; Neurobiology; Outcome; Outcomes Research; Output; Physiology; Pyramidal Cells; Research; Rest; Rewards; Risk Factors; Severities; Signal Transduction; Subgroup; Substance abuse problem; Symptoms; Synaptic Transmission; System; Techniques; Time; Transcranial magnetic stimulation; Treatment outcome; Underachievement; Variant; adverse outcome; base; cohort; community based treatment; cost; criminal behavior; discounting; effective therapy; expectation; experience; follow-up; gamma-Aminobutyric Acid; genetic risk factor; improved; inattention; innovation; motor control; motor impairment; nervous system disorder; neurobehavioral; neurobiological mechanism; novel; outcome forecast; peer; prevent; psychostimulant; relating to nervous system; response; social

DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is the most common childhood behavioral diagnosis. In addition, its symptoms of inattention and impulsivity occur pervasively in many genetic and acquired neurological and psychiatric diseases. Despite the short-term efficacy of psychostimulants to treat core ADHD symptoms in childhood, adult outcomes include high rates of academic underachievement, mental illness, substance abuse, and criminal activity. A critical obstacle to improving long term ADHD treatment outcomes is the lack of quantitative markers which correlate with symptoms and reveal neurobiological mechanisms in ways that could point toward more accurate prognosis and more effective future treatments. In research funded during the initial grant period we addressed this barrier by taking advantage of the relationship (in developmental timing and anatomic proximity) between motor control and both cognitive and emotional control to pursue the physiology of inhibitory mechanisms in ADHD. We developed, refined, and compared techniques to easily and precisely evaluate developing motor function and physiology in 8-12 year old children with ADHD. Using Transcranial Magnetic Stimulation (TMS) in motor cortex, we found that Short Interval Cortical Inhibition (SICI), which is mediated by GABAergic interneurons and modulated by dopaminergic/reward input, is reduced in children with ADHD. Importantly, this SICI reduction correlates with ADHD behavioral symptom severity as well as measures of motor impairment. We also generated novel preliminary findings linking motor cortex GABA, measured with magnetic resonance spectroscopy (MRS), to ADHD and SICI. The broad aim of this application is to 1) develop this ADHD SICI biomarker from resting M1 by extending from baseline (resting) cortical function (rSICI) to informative behavioral (response inhibition) and motivational (reward delay aversion) domains using innovative f(functional)SICI paradigms, 2) clarify the DAergic and GABAergic basis for SICI using pharmacologic challenge and magnetic resonance spectroscopy (MRS) techniques. AIM 1 To quantify fSICI during response inhibition as a biomarker of ADHD. AIM 2 To quantify fSICI during immediate and delayed reward presentation as a biomarker of ADHD. AIM 3 To quantify effects of DA on rSICI and fSICI. AIM 4 To determine whether motor cortex GABA levels 1) differ in ADHD vs. TD and 2) correlate with rSICI and fSICI in Aims 1 and 2. Achieving these aims will lay groundwork for future use of SICI as a pragmatic and biologically meaningful quantitative measure that can be applied to investigations of ADHD treatment, genetics, and risk factors for serious long term outcomes.

描述（由申请人提供）：注意力缺陷多动障碍（ADHD）是最常见的儿童行为诊断。此外，注意力不集中和冲动的症状普遍存在于许多遗传性和后天性神经和精神疾病中。尽管精神兴奋剂对治疗儿童多动症的核心症状具有短期疗效，但成年后的结果包括学业成绩不佳、精神疾病、药物滥用和犯罪活动的比例很高。改善多动症长期治疗结果的一个关键障碍是缺乏与症状相关的定量标记物，并以可能指向更准确的预后和更有效的未来治疗的方式揭示神经生物学机制。在最初资助期间资助的研究中，我们通过利用运动控制与认知和情绪控制之间的关系（发育时间和解剖学接近性）来研究多动症抑制机制的生理学，从而解决了这一障碍。我们开发、完善和比较了一些技术，可以轻松、准确地评估 8-12 岁 ADHD 儿童的运动功能和生理机能发育情况。在运动皮层使用经颅磁刺激 (TMS)，我们发现 ADHD 儿童中由 GABA 能中间神经元介导并受多巴胺能/奖励输入调节的短间隔皮质抑制 (SICI) 减少。重要的是，SICI 的减少与 ADHD 行为症状的严重程度以及运动障碍的测量相关。我们还得出了新的初步发现，通过磁共振波谱 (MRS) 测量，将运动皮层 GABA 与 ADHD 和 SICI 联系起来。该应用的主要目标是 1) 通过使用创新的 f(功能) 从基线（静息）皮质功能 (rSICI) 扩展到信息行为（反应抑制）和动机（奖励延迟厌恶）领域，从静息 M1 开发这种 ADHD SICI 生物标志物)SICI 范例，2) 使用药理学挑战和磁共振波谱 (MRS) 技术阐明 SICI 的 DAergic 和 GABAergic 基础。目标 1 量化反应抑制期间的 fSICI，作为 ADHD 的生物标志物。目标 2 量化即时和延迟奖励期间的 fSICI 作为 ADHD 的生物标志物。目标 3 量化 DA 对 rSICI 和 fSICI 的影响。目标 4 确定运动皮层 GABA 水平 1) 在 ADHD 与 TD 中是否存在差异，2) 与目标 1 和 2 中的 rSICI 和 fSICI 相关。实现这些目标将为将来使用 SICI 作为实用且具有生物学意义的定量测量奠定基础可应用于多动症治疗、遗传学和严重长期后果的危险因素的研究。