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

2/2 - 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: 10651641
• 负责人: Stewart H Mostofsky
• 金额: $ 34.53万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651641
• 关键词: 12 year old; Acute; Address; Adult; Adverse event; Attention; Attention deficit hyperactivity disorder; Behavior; Behavior Therapy; Behavioral; Biological Markers; Blinded; Categories; Child; Childhood; Cities; Clinical; Clinical Trials; Cognitive; Data; Diagnosis; Diagnostic; Disease; Dopamine; Dose; Emotional; Evaluation; Foundations; Friends; Functional disorder; Funding; Future; Genetic; 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 Study; Physiological; Physiology; Placebo Control; Placebos; Precision therapeutics; Publishing; Reaction Time; Research; Research Domain Criteria; Rest; Rewards; Risk; Risk Factors; Ritalin; School-Age Population; Selection for Treatments; Severities; Signal Transduction; Site; Stimulant; Subgroup; Substance abuse problem; Surface; Symptoms; System; Testing; Transcranial magnetic stimulation; Underachievement; Validation; Work; biomarker development; biomarker performance; biomarker validation; brain based; clinical practice; clinically relevant; cognitive control; criminal behavior; design; distraction; effective intervention; follow-up; improved; improved outcome; innovation; motor control; neurochemistry; neurophysiology; novel; pharmacologic; 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.

项目摘要 注意力缺陷多动障碍（ADHD）是最常见的儿童行为诊断， 异质性疾病与不良的成人结果有关，包括高比例的学业成绩不佳， 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 认知和情绪控制障碍，以追求与ADHD相关的运动生理学生物标志物 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， 完善并有效实施了用于评估学龄儿童运动生理学的创新方法 注意力缺陷多动症在第一个资助期内，我们启动了经颅磁刺激（TMS）研究， 运动皮层，发现ADHD儿童的短间隔皮层抑制（SICI）减少， 这种降低的SICI与父母对ADHD症状严重程度的评价相关， 两个网站。在第二次资助期间，我们开发了（TMS兼容）儿童友好型游戏作为范例 用于在需要认知和情绪控制的条件下评估运动皮层生理学。我们发现 ADHD儿童在动作选择和抑制（以及休息）期间SICI降低。我们还 发现TMS诱发的运动诱发电位（MEP）振幅从休息到任务的增加 参与度（我们称之为“任务相关向上调制”- TRUM）显著降低， 多动症。有趣的是，虽然TRUM和SICI都与ADHD严重程度密切相关，但它们显示出有限的 相互关联。这些已发表的研究结果，结合有希望的TMS初步分析- 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反映了与保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 在认知和情感上都很苛刻继续确认SICI和TRUM作为生理 目的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变化， TRUM在ADHD儿童中作为这些生物标志物用于治疗重点研究的效用的验证。AIM 3 探索SICI和TRUM与ADHD相关认知RDoC结构的差异性关联， 控制和情绪的积极/消极效价。实现这些目标将为今后使用 SICI和TRUM作为一种实用的和生物学上有意义的定量测量，可以应用于 研究ADHD的精确治疗，遗传学和严重长期结果的风险因素。

项目成果

Motor overflow in children with attention-deficit/hyperactivity disorder is associated with decreased extent of neural activation in the motor cortex.

• DOI: 10.1016/j.pscychresns.2015.08.001
• 发表时间: 2015-09-30
• 期刊: Psychiatry research
• 影响因子: 11.3
• 作者: Gaddis A;Rosch KS;Dirlikov B;Crocetti D;MacNeil L;Barber AD;Muschelli J;Caffo B;Pekar JJ;Mostofsky SH
• 通讯作者: Mostofsky SH

Dissociation in Neural Correlates of Hyperactive/Impulsive vs. Inattentive Symptoms in Attention-Deficit/Hyperactivity Disorder.

注意力缺陷/多动症障碍中多动/冲动性症状的神经相关性分离。

• DOI: 10.3389/fnins.2022.893239
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Luo, Yu;Adamek, Jack H.;Crocetti, Deana;Mostofsky, Stewart H.;Ewen, Joshua B.
• 通讯作者: Ewen, Joshua B.

Motor Function and Physiology in Youth With Neurofibromatosis Type 1.

患有 1 型神经纤维瘤病的青少年的运动功能和生理学。

• DOI: 10.1016/j.pediatrneurol.2023.02.014
• 发表时间: 2023
• 期刊: Pediatric neurology
• 影响因子: 3.8
• 作者: Doherty,AlexanderC;Huddleston,DavidA;Horn,PaulS;Ratner,Nancy;Simpson,BrittanyN;Schorry,ElizabethK;Aschbacher-Smith,Lindsey;Prada,CarlosE;Gilbert,DonaldL
• 通讯作者: Gilbert,DonaldL

Altered functional connectivity in children with mild to moderate TBI relates to motor control.

• DOI: 10.3233/prm-150349
• 发表时间: 2015
• 期刊: Journal of pediatric rehabilitation medicine
• 影响因子: 1.9
• 作者: Risen SR;Barber AD;Mostofsky SH;Suskauer SJ
• 通讯作者: Suskauer SJ

Distinct Patterns of Impaired Cognitive Control Among Boys and Girls with ADHD Across Development.

• DOI: 10.1007/s10802-021-00792-2
• 发表时间: 2021-07
• 期刊: Research on child and adolescent psychopathology
• 影响因子: 2.5
• 作者: DeRonda A;Zhao Y;Seymour KE;Mostofsky SH;Rosch KS
• 通讯作者: Rosch KS