2/2-Anomalous Motor Physiology in ADHD

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是最常见的儿童行为诊断。此外，它的注意力不集中和冲动的症状普遍发生在许多遗传和获得性神经和精神疾病中。尽管精神兴奋剂在儿童时期对治疗核心ADHD症状具有短期疗效，但成年后的结果包括学业不良、精神疾病、药物滥用和犯罪活动的高发生率。改善ADHD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志物，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。在最初的资助期内资助的研究中，我们通过利用运动控制与认知和情绪控制之间的关系（在发育时间和解剖接近度方面）来解决这一障碍，以追求ADHD抑制机制的生理学。我们开发、改进和比较了一些技术，以方便准确地评估8-12岁ADHD儿童的运动功能和生理发育。利用经颅磁刺激（TMS）在运动皮层，我们发现，短间隔皮层抑制（SICI），这是由GABA能中间神经元介导和多巴胺能/奖励输入调制，在ADHD儿童减少。重要的是，这种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。我们还产生了新的初步发现，运动皮层GABA，测量磁共振波谱（MRS），ADHD和SICI。本申请的广泛目的是1）通过使用创新的f（功能性）SICI范例从基线（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，2）使用药理学挑战和磁共振波谱（MRS）技术阐明SICI的DA能和GABA能基础。目的1定量反应抑制期fSICI作为ADHD的生物标志物。目的2定量即刻和延迟奖赏呈现中的fSICI作为ADHD的生物标志物。目的3定量研究DA对rSICI和fSICI的影响。目的4确定运动皮层GABA水平是否1）ADHD与TD不同，以及2）与目的1和2中的rSICI和fSICI相关。实现这些目标将为将来使用SICI作为一种实用的和生物学上有意义的定量测量奠定基础，该测量可应用于ADHD治疗，遗传学和严重长期结果的风险因素的调查。

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.