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，注意力不集中和冲动的症状在许多遗传和获得性神经和精神疾病中普遍存在。尽管精神兴奋剂对治疗儿童时期的核心多动症症状有短期疗效，但成年后的结果包括学业成绩不佳、精神疾病、药物滥用和犯罪行为的高发率。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记物和揭示神经生物学机制的方法，这些方法可以指向更准确的预后和更有效的未来治疗。在最初资助期间的研究中，我们通过利用运动控制与认知和情绪控制之间的关系（在发育时间和解剖学上的接近性）来解决这一障碍，以追求ADHD抑制机制的生理学。我们开发，完善和比较技术，以方便和准确地评估8-12岁ADHD儿童的运动功能和生理发育。通过对运动皮层进行经颅磁刺激（TMS），我们发现ADHD儿童的短间隔皮质抑制（SICI）减少，该抑制由gaba能中间神经元介导，并由多巴胺能/奖励输入调节。重要的是，这种SICI减少与ADHD行为症状的严重程度以及运动损伤的测量相关。我们还产生了新的初步发现，用磁共振波谱（MRS）测量运动皮层GABA与ADHD和SICI之间存在联系。该应用程序的主要目的是：1)通过使用创新的f（功能性）SICI范式，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DAergic和GABAergic基础。目的1：量化反应抑制期间fSICI作为ADHD的生物标志物。目的2：量化即时和延迟奖励呈现期间的fSICI作为ADHD的生物标志物。目的3量化DA对rSICI和fSICI的影响。目的4：在目的1和2中，确定运动皮质GABA水平在ADHD和TD中是否存在差异，以及是否与rSICI和fSICI相关。实现这些目标将为SICI作为一种实用的、具有生物学意义的定量测量方法的未来使用奠定基础，这种定量测量方法可以应用于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.