Cortical Excitability: Phenotype and Biomarker in ADHD Therapy

描述（由申请人提供）：注意力缺陷多动障碍（ADHD）是一种行为学定义的表型，其缺陷模式涉及注意力和抑制，特征为表现、普遍性和损伤的变异性。ADHD的病理生理学模型已经通过称为内表型的中间结构而发展，内表型是可量化的，基于对相关神经回路的理解，并且简化为与基因表达更紧密地联系在一起。我们假设异常皮质内抑制（ICI）功能作为一个生理传感器，一个介导或调节因素的基础上许多内表型结构在ADHD。GABA能、多巴胺敏感、短间隔皮质内抑制（SICI）的生物标志物可通过涉及运动皮质的成对脉冲、经颅磁刺激（pTMS）的新兴技术获得。我们的小组研究了SICI在儿童和青少年多动症的安全性，稳定性和重测信度。有证据表明，皮质抑制（SICI）与ADHD症状严重程度呈负相关。由于SICI在ADHD中异常，我们的研究表明ATX后SICI的变化可能是生理补偿的信号，可能介导随后的临床反应。我们提出了这些具体的目标：1）评估皮质内抑制（SICI）测量的pTMS，作为一个标记的多动-冲动的维度和症状的严重程度; 2）确定认知相关的SICI变化相关的一个良好的表征ADHD内表型的“反应抑制/抑制”的时间锁定元素的停止任务的pTMS; 3）表征4周托莫西汀（ATX）治疗对ADHD和皮质抑制的影响。我们将采用双盲、安慰剂对照设计（ATX vs PLB）评估120名7-12岁ADHD儿童，评价经胼胝体皮质抑制（例如ISP）的扩展神经生理学抑制标志物沿着SICI（目标3a），并且为了随访我们先前与多巴胺转运蛋白多态性相关的发现，我们将评估多种可能的ADHD相关基因的贡献（目标3b）。该目的将评价ATX治疗4周后的SICI变化是否可预测治疗应答（相对于基线ADHD评定量表的变化）。在这个提议中，通过使用停止任务来控制心理状态，可能会阐明我们看似矛盾的发现，即ATX反应降低了SICI（吉尔伯特，2007）。这一目标虽然是探索性的，但具有高度临床影响的潜力，确定基因组信息是否可以与pTMS组合以更准确地预测对ATX的临床应答，因为现在的治疗是延迟的，并且在没有应答的表型预测因子的情况下是不可预测的。公共卫生相关性：注意力缺陷多动障碍是儿童期最常见的行为障碍，在学业、职业和心理社会结果方面产生显著的发病率。ADHD的病因复杂，有许多神经生物学基础，其中之一是短间隔皮质内抑制（SICI）。通过经颅磁刺激（pTMS）运动皮层测量的SICI已被证明与ADHD症状严重程度呈负相关。该提案将进一步表征SICI与ADHD的生理相关性及其预测ADHD治疗（如托莫西汀）反应的效用。

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.