Cortical Excitability: Phenotype and Biomarker in ADHD Therapy

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，其特征是表现、普遍性和损害的可变性。注意缺陷多动障碍的病理生理模型已经通过被称为内表型的中间结构得到了发展，这些内部表型是可量化的，基于对相关神经回路的理解，并且简化为与基因表达更密切相关。我们假设异常皮质内抑制（ICI）作为一种生理传感器，是ADHD中许多内表型构建的中介或调节因素。一种gaba能、多巴胺敏感、短间隔皮质内抑制（SICI）的生物标志物，通过涉及运动皮质成对脉冲、经颅磁刺激（pTMS）的新兴技术可获得。本小组研究了SICI在儿童和青少年ADHD患者中的安全性、稳定性和重测可靠性。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中是异常的，我们的研究表明，ATX后SICI的改变可能预示着一种生理补偿，这种补偿可能介导随后的临床反应。我们提出了以下具体目标：1)评估通过pTMS测量的皮质内抑制（SICI）作为多动-冲动维度和症状严重程度的标志；2)通过pTMS停止任务的时间锁定要素，确定SICI变化与ADHD“反应抑制/抑制”内表型相关的认知相关性；3)观察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）对120名7-12岁ADHD儿童进行评估，评估经胼胝体皮层抑制（如ISP）和SICI的扩展神经生理抑制标志物（目的3a），并且，为了跟进我们先前有关多巴胺转运体多态性的发现，我们将评估多种可能与ADHD相关的基因的贡献（目的3b）。该目的将评估使用ATX治疗4周后SICI变化是否预测治疗反应（从基线ADHD评定量表的变化）。在这个建议中，通过使用停止任务来控制精神状态可能会解释我们看似矛盾的发现，即随着ATX反应，SICI下降（Gilbert 2007）。这一目的虽然是探索性的，但具有很高的临床影响潜力，确定基因组信息是否可以与pTMS相结合，以更准确地预测ATX的临床反应，因为现在的治疗是延迟的，而且没有表型预测反应是不可预测的。公共卫生相关性：注意缺陷、多动障碍是儿童最常见的行为障碍，在学业、职业和社会心理方面产生了显著的发病率。ADHD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）。运动皮质经颅磁刺激（pTMS）测量的SICI与ADHD症状严重程度呈负相关。这一建议将进一步表征SICI与ADHD的生理相关性，以及它在预测对ADHD治疗（如托莫西汀）的反应方面的效用。

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.