2/2 - Anomalous Motor System Physiology in ADHD: Biomarker Validation and Modeling Domains of Function

项目总结 注意缺陷多动障碍(ADHD)是最常见的儿童行为诊断，是一种 异质性障碍与成人成绩差有关，包括学习成绩不佳的高比率， 精神疾病、药物滥用和犯罪活动。改善长期ADHD的关键障碍 结果是目前缺乏可用于提高精确度的定量神经生理学标记物 治疗(行为和药理学)。在两个资助期内资助的研究中，我们解决了这个问题 障碍：利用观察到的ADHD相关运动控制障碍与CORE的关联 寻求与ADHD相关的运动生理生物标记物的认知和情绪控制障碍 诊断和症状严重程度。利用不同城市的两个研究团队的专业知识，我们开发了， 改进并有效实施评估学龄儿童运动生理学的创新方法 患有多动症。在第一次资助期间，我们启动了经颅磁刺激(TMS)研究 运动皮质，发现ADHD儿童的短间隔皮质抑制(SICI)减少， 这种降低的SICI与ADHD症状严重程度的父母评级相关，在整个 两个地点。在第二次资助期间，我们开发了(与TMS兼容的)儿童友好游戏作为范例 用于在需要认知和情绪控制的条件下评估运动皮质生理学。我们发现 ADHD儿童在动作选择和抑制(以及休息)过程中的SICI减少。此外，我们 发现TMS诱发的运动诱发电位(MEP)波幅从休息到任务增加 参与度(我们将其表示为“任务相关的向上调制”--TRUM)在 多动症。有趣的是，虽然trum和sici都与ADHD的严重程度密切相关，但它们表现出的局限性。 相互关联。这些发表的发现，加上对TMS的有希望的初步分析- 行为关联，提出了一种模型，在该模型中，这两个有希望的、不同的生理生物标志物反映了 ADHD患者功能障碍的不同领域，SICI反映了与维持注意力相关的机制 和过滤干扰，而trum反映了调节反应控制的能力，特别是在 认知和情感上的苛刻条件。追求SICI和TRUM作为生理学的验证 生物标志物，我们现在建议：目标1建立ADHD儿童SICI和TRUM的重测信度 并且通常开发(TD)控件。目的2量化刺激治疗引起的SICI和SICI的变化。 TRUM在ADHD儿童中的应用，作为这些生物标记物在治疗重点研究中的有效性的验证。目标3 SICI和TRUM与ADHD相关RDoC认知结构的差异关联研究 控制力和情绪积极/消极价值。实现这些目标将为将来使用 SICI和TRUM作为一种实用的、具有生物意义的量化指标，可以应用于 研究ADHD的精确治疗、遗传学和严重长期结局的危险因素。

PROJECT SUMMARY Attention Deficit Hyperactivity Disorder (ADHD), the most common childhood behavioral diagnosis, is a heterogeneous disorder linked to poor adult outcomes including high rates of academic underachievement, mental illness, substance abuse, and criminal activity. A critical obstacle to improving long-term ADHD outcomes is the current lack of quantitative neurophysiologic markers that could be used to improve precision treatment (behavioral and pharmacologic). In research funded during two grant periods, we addressed this barrier: Leveraging observed associations of ADHD-associated impairments in motor control with core impairments in cognitive and emotional control to pursue motor physiologic biomarkers linked to ADHD diagnosis and symptom severity. Engaging expertise of two research teams in different cities, we developed, refined, and effectively implemented innovative methods for evaluating motor physiology in school-age children with ADHD. During the first grant period we initiated Transcranial Magnetic Stimulation (TMS) investigations of motor cortex, discovering that Short Interval Cortical Inhibition (SICI) is reduced in children with ADHD and that this reduced SICI correlates with parent-ratings of ADHD symptom severity, with consistent findings across the two sites. During the second grant period, we developed (TMS-compatible) child-friendly games as paradigms for evaluation of motor cortex physiology under conditions requiring cognitive and emotional control. We found that SICI is reduced in children with ADHD during action selection and inhibition (as well as rest). Further, we discovered that TMS-evoked increases in motor evoked potential (MEP) amplitude from rest to task engagement (which we have denoted as “Task Related Up Modulation” - TRUM) are significantly diminished in ADHD. Interestingly, while both TRUM and SICI robustly correlate with ADHD severity, they show limited correlation with each other. These published findings, in conjunction promising preliminary analyses of TMS- behavioral associations, suggest a model in which these two promising, distinct physiologic biomarkers reflect differential domains of dysfunction in ADHD, with SICI reflecting mechanisms linked to maintaining attention and filtering distractions, while TRUM reflects the capacity to modulate response control particularly under cognitively and emotionally demanding conditions. To pursue validation of SICI and TRUM as physiologic biomarkers, we now propose: AIM 1 To establish test-retest reliability of SICI and TRUM in children with ADHD and typically developing (TD) controls. AIM 2 To quantify stimulant treatment-induced changes in SICI and TRUM in children with ADHD as a validation of utility of these biomarkers for treatment focused studies. AIM 3 To explore the differential association of SICI and TRUM with ADHD-relevant RDoC constructs of Cognitive Control and Emotional Positive/Negative Valence. Achieving these aims will lay groundwork for future use of SICI and TRUM as a pragmatic and biologically meaningful quantitative measure that can be applied to investigations of precision ADHD treatment, genetics, and risk factors for serious long-term outcomes.