Neural Substrates of Variability in Attention Deficit Hyperactivity Disorder (ADH

描述(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，方法是将与ADHD儿童体内反应时间变异性增加的更慢和更可变的反应相关联的神经回路联系起来。基于成人和儿童ADHD的大量初步数据，我们假设ADHD相关的功能连接异常(区域时间一致性)在连接右侧背侧前扣带回(DACC)和脾后复合体(RSC；包括楔前和后扣带回)的回路中发挥着关键的病理生理作用，该回路参与了后联结过程和前执行功能的高度整合。我们建议通过扫描100名右撇子儿童来表征这种新的功能障碍部位，这样我们就可以分析至少37名患有混合型ADHD的儿童和37名年龄、智商-社会经济状况、利手和性别匹配的健康对照-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，即与ADHD相关的dACC/RSC功能连接性较弱；以及(2)确定与ADHD相关的逐个试验反应时间变异性的增加是否与dACC/RSC电路功能完整性的差异有关。我们还将进行扩散张量成像(DTI)研究，以检查这一关键电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尖端测量相关的关键神经心理学指标。这一提议将新的方法和假设与大量的初步数据相结合，有可能描绘大脑-行为关系，从而为这种常见和高度损害的疾病的病理生理学翻译模型提供信息。公共卫生相关性：我们建议应用新的神经成像方法来更好地了解儿童注意力缺陷/多动障碍(ADHD)所涉及的大脑机制。ADHD患者的反应一直不一致，我们将研究与这种不一致有关的大脑回路，总共有100名儿童，其中约一半患有ADHD，约一半是健康受试者。这项拟议的研究将使我们能够测试一种新的理论，即ADHD患者特定大脑回路的功能障碍，据信该回路连接和协调大脑的关键前部和后部。获得关于ADHD大脑功能的如此详细的信息将对我们改进诊断ADHD的方法和开发新疗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.