1/2 - Anomalous Motor System Physiology in ADHD: Biomarker Validation and Modeling Domains of Function

1/2 - ADHD 中的异常运动系统生理学：生物标志物验证和功能建模领域

• 批准号: 10214465
• 负责人: DONALD L GILBERT
• 金额: $ 40.09万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10214465
• 关键词: 12 year old; Acute; Address; Adult; Adverse event; Attention; Attention deficit hyperactivity disorder; Base of the Brain; Behavior Disorders; Behavior Therapy; Behavioral; Biological; Biological Markers; Blinded; Categories; Child; Childhood; Cities; Clinical; Clinical Trials; Cognitive; Data; Diagnosis; Diagnostic; Disease; Dopamine; Dose; Emotional; Evaluation; Foundations; Frustration; Functional disorder; Funding; Future; Grant; Hand; Hospitalization; Impairment; Individual; Intervention; Investigation; Link; Measures; Membrane Potentials; Mental disorders; Methods; Modeling; Motor; Motor Cortex; Motor Evoked Potentials; Muscle; Negative Valence; Outcome; Parents; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacology Study; Physiological; Physiology; Placebos; Precision therapeutics; Publishing; Reaction Time; Research; Research Domain Criteria; Rest; Rewards; Risk; Ritalin; School-Age Population; Selection for Treatments; Severities; Signal Transduction; Site; Subgroup; Substance abuse problem; Surface; Symptoms; System; Testing; Transcranial magnetic stimulation; Underachievement; Validation; Work; base; behavioral pharmacology; biomarker development; biomarker performance; biomarker validation; clinical practice; clinically relevant; cognitive control; criminal behavior; design; distraction; effective intervention; follow-up; genetic risk factor; improved; improved outcome; innovation; motor control; neurochemistry; neurophysiology; novel; potential biomarker; prognostic; psychostimulant; response; treatment strategy

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.

项目概要 注意力缺陷多动障碍 (ADHD) 是最常见的儿童行为诊断，是一种 异质性障碍与不良的成年结果有关，包括学业成绩不佳的比例很高， 精神疾病、药物滥用和犯罪活动是改善长期多动症的关键障碍。 结果是目前缺乏可用于提高精度的定量神经生理学标记 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核心的关联 认知和情绪控制障碍，以追求与多动症相关的运动生理生物标志物 利用不同城市的两个研究团队的专业知识，我们开发了， 完善并有效实施评估学龄儿童运动生理学的创新方法 在第一个拨款期间，我们启动了经颅磁刺激（TMS）研究。 运动皮层，发现患有 ADHD 的儿童的短间隔皮质抑制 (SICI) 减少，并且 SICI 的减少与家长对 ADHD 症状严重程度的评分相关，并且整个研究结果一致 在第二个资助期间，我们开发了（TMS 兼容）儿童友好游戏作为范例。 我们发现，在需要认知和情绪控制的条件下评估运动皮层生理学。 患有 ADHD 的儿童在行动选择和抑制（以及休息）期间 SICI 会减少。 发现 TMS 诱发的运动诱发电位 (MEP) 振幅从休息到任务时增加 参与度（我们将其表示为“任务相关向上调制”-TRUM）在 ADHD 具有提示性，虽然 TRUM 和 SICI 与 ADHD 严重程度密切相关，但它们的表现有限。 这些已发表的研究结果与 TMS 的初步分析相结合。 行为关联，提出了一个模型，其中这两个有前途的、不同的生理生物标志物反映了 ADHD 功能障碍的不同领域，SICI 反映了与维持注意力相关的机制 并过滤干扰，而 TRUM 则反映了调节响应控制的能力，特别是在以下情况下 追求 SICI 和 TRUM 作为生理条件的验证。 生物标志物，我们现在建议： 目标 1 建立 ADHD 儿童 SICI 和 TRUM 的重测可靠性 和开发 (TD) 对照 AIM 2 量化刺激治疗引起的 SICI 和变化。 ADHD 儿童中的 TRUM 验证了这些生物标志物在 AIM 3 治疗重点研究中的效用。 探讨 SICI 和 TRUM 与 ADHD 相关 RDoC 认知结构的差异关联 控制和情绪正/负效价的实现将为未来的使用奠定基础。 SICI 和 TRUM 作为实用且具有生物学意义的定量测量，可应用于 对 ADHD 精确治疗、遗传学和严重长期结果的危险因素的研究。