Cortical Excitability: Phenotype and Biomarker in ADHD Therapy

描述(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，其特征是呈现的变异性、普遍性和损害。ADHD的病理生理学模型通过称为内表型的中间结构得到发展，这种结构是可量化的，建立在对相关神经回路的理解基础上，并被简化为与基因表达更紧密地联系在一起。我们假设异常的皮质内抑制(ICI)起着生理转导的作用，在ADHD的许多内表型结构中起中介或调节作用。GABA能的生物标志物，多巴胺敏感的短间隔皮质内抑制(SICI)，是通过涉及运动皮质的双脉冲经颅磁刺激(PTMS)的新兴技术而获得的。我们小组研究了患有ADHD的儿童和青少年的SICI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ADHD的SICI异常，我们的研究提示，ATX后SICI的改变可能是一种生理代偿信号，可能介导了随后的临床反应。我们提出的具体目标是：1)评估PTMS测量的皮层内抑制(SICI)，作为多动-冲动维度和症状严重程度的标志；2)通过对PTMS的停止任务的时间锁定元素，确定SICI变化与ADHD内表型“反应抑制/抑制”相关的认知相关性；3)表征四周的托莫西汀(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与PLB)评估120名7-12岁的ADHD儿童，评估扩展的神经生理抑制标记物(例如，ISP)和SICI(目标3a)，并且，为了跟进我们先前与多巴胺转运体基因多态相关的发现，我们将评估多个可能与ADHD相关的基因的贡献(目标3b)。这一目的将评估ATX治疗4周后SICI的变化是否可以预测治疗反应(与基线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似乎自相矛盾的发现，即SICI减少与ATX反应(Gilbert 2007)。这个目标虽然是探索性的，但有可能产生很高的临床影响，决定基因组信息是否可以与PTM结合，以更准确地预测对ATX的临床反应，因为治疗现在被推迟，而且如果没有表型反应预测因子，就无法预测。公共卫生相关性：注意力缺陷，多动障碍是儿童最常见的行为障碍，会在学业、职业和心理社会结果中产生显著的发病率。ADHD的病因复杂，有多种神经生物学底物，短程皮质内抑制(SICI)就是其中之一。通过运动皮质的经颅磁刺激(PTMS)测量的SICI已被证明与ADHD症状严重程度呈负相关。这项建议将进一步表征SICI与ADHD的生理学相关性，以及它对预测ADHD治疗(如托莫西汀)反应的有效性。

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.