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）是一种行为定义的表型，其缺陷模式涉及注意力和抑制，其特征是表现的可变性、普遍性和损伤。 ADHD 的病理生理学模型已经通过称为内表型的中间结构取得了进展，这些中间结构是可量化的，基于对相关神经回路的理解，并简化为与基因表达更紧密地联系。我们假设异常皮质内抑制（ICI）充当生理传感器，是 ADHD 中许多内表型结构的中介或调节元件。 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层的配对脉冲、经颅磁刺激 (pTMS) 的新兴技术获得。我们小组研究了 ADHD 儿童和青少年 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 SICI 在 ADHD 中是异常的，我们的研究表明 ATX 后 SICI 的变化可能发出生理代偿的信号，从而可能介导随后的临床反应。我们提出以下具体目标：1）评估 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元素，确定与明确描述的 ADHD 内表型“反应抑制/抑制”相关的 SICI 变化的认知相关性； 3) 表征阿托西汀 (ATX) 治疗 4 周对 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 ADHD 儿童，评估经胼胝体皮质抑制的扩展神经生理学抑制标志物（例如 ISP）以及 SICI（目标 3a），并且为了跟进我们之前与多巴胺转运蛋白多态性相关的发现，我们将评估多个可能与 ADHD 相关的基因的贡献（目标 3b）。该目的将评估 ATX 治疗 4 周后 SICI 的变化是否可以预测治疗反应（ADHD 评定量表基线的变化）。在本提案中，通过使用“停止任务”来控制精神状态可能会阐明我们看似矛盾的发现，即 SICI 随 ATX 反应而减少（Gilbert 2007）。这一目标虽然是探索性的，但具有产生巨大临床影响的潜力，确定基因组信息是否可以与 pTMS 相结合，以更准确地预测对 ATX 的临床反应，因为现在治疗被延迟，并且在没有反应表型预测因子的情况下无法预测。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、职业和社会心理方面产生显着的发病率。 ADHD 的病因很复杂，有许多神经生物学基础，其中之一是短间隔皮质内抑制（SICI）。通过运动皮层经颅磁刺激 (pTMS) 测量的 SICI 已被证明与 ADHD 症状严重程度呈负相关。该提案将进一步描述 SICI 对 ADHD 的生理相关性及其预测 ADHD 治疗（如阿托西汀）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.