Neural Substrates of Variability in Attention Deficit Hyperactivity Disorder (ADH

描述（由申请人提供）：在这份修订后的申请中，我们提出了一种新的方法来理解注意缺陷/多动障碍（ADHD）的病理生理学，通过将神经回路与ADHD儿童中更慢和更可变的反应联系起来，以增加受试者内反应时间的可变性。基于成人和儿童ADHD的大量初步数据，我们假设ADHD相关的功能连通性（区域时间一致性）异常在连接右背前扣带皮层（dACC）和脾后复核（RSC，包括楔前叶和后扣带皮层）的电路中，参与后关联过程和前执行功能之间的高水平整合，在ADHD中起着关键的病理生理作用。我们建议通过扫描100名右撇子来描述这种新的功能障碍位点，这样我们就可以分析至少37名患有复合型ADHD的儿童和37名年龄、智商、社会经济地位、惯用手和性别匹配的健康比较的完整成像和神经心理学数据。我们将(1)使用fMRI来证实我们的初步发现，即较弱的dACC/RSC功能连接与ADHD相关；(2)确定adhd相关的每次试验反应时间变异性的增加是否与dACC/RSC回路功能完整性的差异有关。我们还将进行弥散张量成像（DTI）研究，以检查这一关键回路的功能和结构完整性之间的关系，并探索与我们的功能连接的前沿测量相关的关键神经心理学测量。该建议结合了新颖的方法和假设以及大量的初步数据，有可能描述大脑-行为关系，这将为这种常见和高度损害的疾病的病理生理学的翻译模型提供信息。公共卫生相关性：我们建议应用新的神经影像学方法来更好地了解儿童注意力缺陷/多动障碍（ADHD）的大脑机制。患有多动症的人在他们的反应中总是不一致的，我们将研究与这种不一致有关的大脑回路，总共有100个孩子，其中大约一半患有多动症，大约一半是健康的受试者。这项提议的研究将允许我们测试一种新的理论，该理论是关于多动症中特定大脑回路功能障碍的，该回路被认为连接和协调大脑的关键前部和后部。获得关于多动症大脑功能的如此详细的信息，将对我们改进多动症诊断方法和开发新治疗方法的能力产生重大影响。

DESCRIPTION (provided by applicant): In this revised application, we propose a novel approach to understanding the pathophysiology of Attention- Deficit/Hyperactivity Disorder (ADHD) by linking a neural circuit that has been associated with slower and more variable responses to increased intra-subject response time variability in children with ADHD. Based on extensive preliminary data in adults and children with ADHD, we hypothesize that ADHD-related abnormalities in functional connectivity (regional temporal coherence) in a circuit linking the right dorsal anterior cingulate cortex (dACC) to the retrosplenial complex (RSC; comprising precuneus and posterior cingulate cortex) which is involved in high level integration between posterior association processes and anterior executive functions, plays a key pathophysiological role in ADHD. We propose to characterize this novel locus of dysfunction by scanning 100 right-handed children so that we can analyze full imaging and neuropsychological data from at least 37 children with combined-type ADHD and 37 age-, IQ- socioeconomic status, handedness- and sex- matched healthy comparisons. We will (1) use fMRI to confirm our preliminary findings of weaker dACC/RSC functional connectivity associated with ADHD; and (2) determine whether ADHD-related increases in trial-by- trial response time variability are related to differences in the functional integrity of the dACC/RSC circuit. We will also conduct diffusion tensor imaging (DTI) studies to examine the relationship between functional and structural integrity of this key circuit, and explore key neuropsychological measures in relation to our cutting- edge measures of functional connectivity. This proposal, which combines novel methods and hypotheses with substantial preliminary data, has the potential to delineate brain-behavior relationships that will inform translational models of pathophysiology of this common and highly impairing disorder. PUBLIC HEALTH RELEVANCE: We propose to apply novel neuroimaging methods to better understand the brain mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Individuals with ADHD are consistently inconsistent in their responses, and we will study a brain circuit that is associated with such inconsistency in a total of 100 children, about half of whom have ADHD and about half of whom are healthy subjects. The proposed study will allow us test a new theory about a the dysfunction of a specific brain circuit in ADHD which is believed to connect and coordinate key front and back parts of the brain. Achieving such a level of detailed information about brain functioning in ADHD would have major impact on our ability to improve methods of diagnosing ADHD and of developing new treatments.