Cortical Excitability: Phenotype and Biomarker in ADHD Therapy

皮质兴奋性：多动症治疗中的表型和生物标志物

• 批准号: 7655838
• 负责人: FLOYD R SALLEE
• 金额: $ 59.22万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655838
• 关键词: 12 year old; Adolescent; Adult; Age; Appearance; Attention; Attention deficit hyperactivity disorder; Behavior; Behavior Disorders; Behavioral; Biological Markers; Brain; Child; Childhood; Clinical; Cognitive; Complex; Corpus striatum structure; Data; Dimensions; Dopamine; Dose; Double-Blind Method; Elements; Emerging Technologies; Etiology; Financial compensation; Functional disorder; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genomics; Hand; Hour; Impairment; Link; Magnetism; Measurement; Measures; Mediating; Modeling; Morbidity - disease rate; Motor Cortex; Outcome; Output; Parietal; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Physiological; Placebo Control; Placebos; Process; Relative (related person); Rest; Safety; Severities; Signal Transduction; Symptoms; Time; Transcranial magnetic stimulation; Transducers; atomoxetine; base; design; disorder subtype; dopamine transporter; endophenotype; follow-up; frontal lobe; improved; mental state; motivational processes; neuroimaging; neurophysiology; neuropsychological; noradrenergic; psychosocial; public health relevance; response; stability testing; treatment response

DESCRIPTION (provided by applicant): Attention-Deficit Hyperactivity Disorder (ADHD) is a behaviorally defined phenotype with patterns of deficits involving attention and inhibition characterized by variability in presentation, pervasiveness, and impairment. Pathophysiologic models of ADHD have advanced through intermediate constructs termed endophenotypes which are quantifiable, grounded in an understanding of the relevant neuro-circuitry, and simplified to be more closely linked to gene expression. We hypothesize that abnormal intracortical inhibition (ICI) functions as a physiologic transducer, a mediating or moderating element underlying many endophenotype constructs in ADHD. A biomarker of GABAergic, dopamine-sensitive, short-interval intracortical inhibition (SICI), is available through emerging technology involving paired-pulse, transcranial magnetic stimulation (pTMS) of motor cortex. Our group has studied SICI in children and adolescents with ADHD with regard to safety, stability, and test-retest reliability. Evidence reveals cortical inhibition (SICI) to be inversely correlated with ADHD symptom severity. As SICI is abnormal in ADHD, our studies suggest SICI change after ATX may signal a physiologic compensation which may mediate subsequent clinical response. We propose these specific aims: 1) To evaluate Intracortical Inhibition (SICI) measured by pTMS, as a marker of the hyperactive-impulsive dimension and symptom severity; 2) To determine cognitive correlates of SICI change relevant to a well characterized ADHD endophenotype of "response suppression/inhibition" by time-locking elements of a Stop Task to pTMS; 3) To characterize the effects of four weeks of atomoxetine (ATX) treatment on ADHD and cortical inhibition. We will assess 120 7-12 year old children with ADHD in a double-blinded, placebo controlled design (ATX vs PLB) evaluating expanded neurophysiological inhibitory markers of transcallosal cortical inhibition (e.g. ISP) along with SICI (aim 3a), and, to follow up on our prior findings related to dopamine transporter polymorphisms, we will assess the contributions of multiple possibly ADHD-related genes (aim 3b). This aim will evaluate whether SICI change following 4 weeks of treatment with ATX predicts treatment response (change from baseline ADHD Rating Scale). Controlling for mental state in this proposal by using the Stop Task may elucidate our seeming paradoxical finding of decreased SICI with ATX response (Gilbert 2007). This aim, though exploratory, has the potential for high clinical impact, determining whether genomic information can be combined with pTMS to more accurately predict clinical response to ATX, as treatment now is delayed, and unpredictable without phenotypic predictors of response. PUBLIC HEALTH RELEVANCE: Attention-deficit, hyperactivity disorder is the most common behavioral disorder of childhood produces significant morbidity in academic, vocational and psychosocial outcomes. ADHD is complex in etiology, with many neurobiologic substrates, one of which is short-interval intracortical inhibition (SICI). SICI measured by transcranial magnetic stimulation (pTMS) of motor cortex has been shown to be inversely correlated with ADHD symptom severity. This proposal will further characterize both the physiologic relevance of SICI for ADHD as well as its utility to predict response to ADHD treatments such as atomoxetine.

描述（由申请人提供）：注意缺陷多动障碍（ADHD）是一种行为定义的表型，其缺陷模式涉及注意力和抑制作用，其特征是表现，普遍性和损害的可变性。 ADHD的病理生理模型已通过称为可量化的中间构建体进行了促进，这些构造是可量化的，基于对相关神经循环的理解，并简化了与基因表达更紧密联系的。我们假设异常内抑制作用（ICI）充当生理传感器，是ADHD中许多内型型构建体的介导或调节元件。 GABA能，多巴胺敏感，短间隔内抑制（SICI）的生物标志物可通过涉及运动皮层的成对脉冲，经颅磁刺激（PTM）的新兴技术获得。我们的小组研究了ADHD儿童和青少年关于安全性，稳定性和测试可靠性的SICI。证据表明皮质抑制（SICI）与多动症症状严重程度成反比。由于SICI在ADHD中是异常的，我们的研究表明，ATX后的SICI变化可能标志着生理补偿，可以介导随后的临床反应。我们提出了这些具体目的：1）评估由PTMS测量的皮质内抑制（SICI），作为多活跃的冲动维度和症状严重程度的标志； 2）通过通过停止任务对PTMS的定时元素来确定与具有良好表征的“响应抑制/抑制”的ADHD内表型相关的SICI变化的认知相关性； 3）表征四个星期的原子氨酸（ATX）治疗对ADHD和皮质抑制的影响。我们将评估120个7-12岁的ADHD儿童，以安慰剂控制设计（ATX与PLB）评估跨国皮质抑制的扩展神经生理学抑制标志物（例如ISP）（例如ISP）以及SICI（AIM 3A）（AIM 3A）（AIM 3A）（AIM 3A），以及与我们的先前发现有关的prositions Transimentions will Will Will Will Will Will tirsiment polymorsions polymorsimens plosimensions pormorsismiss consimensions polymorsiliss consimensions pormorshismins sici抑制作用（ISP）与ADHD相关的基因（AIM 3B）。该目标将评估SICI在使用ATX治疗4周后是否会预测治疗反应（基线ADHD等级量表的变化）是否改变。通过使用停止任务来控制本提案中的精神状态可能会阐明我们通过ATX响应减少SICI的矛盾发现（Gilbert 2007）。该目标虽然探索性，但仍具有高临床影响的潜力，确定是否可以将基因组信息与PTM结合起来，以更准确地预测对ATX的临床反应，因为现在的治疗已被延迟，并且无法预测没有反应的表型预测指标。公共卫生相关性：注意力缺陷，多动症障碍是最常见的儿童行为障碍，在学术，职业和社会心理结局中产生了显着的发病率。 ADHD在病因学上很复杂，具有许多神经生物学底物，其中一种是矮间抑制（SICI）。通过颅磁刺激（PTM）测得的SICI已显示与ADHD症状严重程度成反比。该提案将进一步表征SICI与ADHD的生理相关性，以及预测对ADHD治疗的反应（如阿托莫西汀）的效用。