1/2-Anomalous Motor Physiology in ADHD

描述(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普遍存在于许多遗传性和获得性神经和精神疾病中。尽管精神刺激剂对儿童时期的核心ADHD症状有短期疗效，但成年后的结果包括学习成绩不佳、精神疾病、药物滥用和犯罪活动的高比率。改善长期ADHD治疗结果的一个关键障碍是缺乏量化标记物，这些标记物与症状相关，并揭示神经生物学机制，从而指向更准确的预后和更有效的未来治疗。在最初的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(在发育时机和解剖上的接近)来解决这一障碍，以探索ADHD抑制机制的生理学。我们开发、改进和比较了各种技术，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。在运动皮质进行经颅磁刺激(TMS)，我们发现ADHD儿童的短间隔皮质抑制(SICI)减少，这种抑制是由GABA能中间神经元介导的，受多巴胺能/奖赏输入的调节。重要的是，这种SICI降低与ADHD行为症状严重程度以及运动障碍的衡量标准相关。我们还产生了新的初步发现，将磁共振波谱(MRS)测量的运动皮质GABA与ADHD和SICI联系起来。本申请的主要目的是1)利用创新的f(功能)SICI范式，通过从基线(静息)皮质功能(RSICI)扩展到信息行为(反应抑制)和动机(奖赏延迟厌恶)领域，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DAR和GABA基础。目的1定量检测反应抑制过程中的fSICI作为ADHD的生物标志物。目的2量化即时和延迟奖赏呈现过程中的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)确定运动皮质GABA水平在ADHD与TD之间是否存在差异，以及2)在AIMS 1和2中是否与rSICI和fSICI相关。实现这些目标将为SICI作为一种实用的、具有生物学意义的量化指标的使用奠定基础，该量化指标可用于ADHD治疗、遗传学和严重长期预后的危险因素的研究。

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.