Neurology of Deficient Response Control in ADHD

描述（由申请人提供）：注意力缺陷/多动障碍（ADHD）是一种非常普遍的障碍，其中对不良行为的控制受损会影响家庭/社会关系和学校表现。运动反应控制由基底神经节和皮质水平的辅助运动区（SMA）介导，对于选择保留不想要的反应至关重要，因此对于有效抑制冲动、多动和非任务行为是必要的，这些行为是ADHD的特征。最初资助期的研究结果表明，ADHD与运动反应控制异常有关，包括反应抑制受损和受试者内反应变异性（ISV）增加；此外，这些测量的损伤程度在不同认知需求的任务中是相似的，这表明运动反应控制受损是ADHD的主要缺陷。与这些行为观察相一致的是，功能和解剖MRI研究显示，患有ADHD的儿童在基底神经节的SMA和互联区域表现出异常。脑行为相关性的功能性MRI检查提供了进一步的见解，揭示了ADHD儿童，但不是典型发育（TD）儿童，前额叶皮质的募集与较低的ISV相关，反映了反应控制的改善。结合行为和影像学的发现为ADHD的发展模式提供了基础，在这种模式中，在发育早期建立的对运动反应控制至关重要的神经系统功能障碍有助于疾病的病理生理学，而后期发育的前额叶系统的功能促进了代偿。当前提案的目标是：使用新的成像方法来研究涉及SMA和基底神经节的神经回路异常导致ADHD相关的反应控制损伤的假设（目的1），研究一些ADHD儿童成功的运动反应控制依赖于前额叶（而不是典型的前运动）回路的募集的假设（目的2和3），并研究提高警惕性的演示格式是否也能改善反应控制（目标4）。提出的研究不仅有助于确定ADHD的相关中间内表型，而且可能指出潜在有效的治疗策略。

DESCRIPTION (provided by applicant): Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent disorder in which impaired control of unwanted behavior affects family/social relationships and school performance. Motor response control, mediated by the basal ganglia and, at the cortical level, the supplementary motor area (SMA), is crucial for selecting to withhold unwanted responses and thereby necessary for effective inhibition of impulsive, hyperactive and off-task behavior that characterizes ADHD. Findings from the initial grant period established that ADHD is associated with abnormalities in motor response control, including impaired response inhibition and increased intrasubject response variability (ISV); additionally, the degree of impairment on these measures was found to be similar across tasks with differing cognitive demands, suggesting that impaired motor response control is a primary deficit in ADHD. Consistent with these behavioral observations, functional and anatomic MRI studies reveal children with ADHD show abnormalities in the SMA and interconnected regions of the basal ganglia. Functional MRI examination of brain-behavior correlations provided further insight, revealing that for children with ADHD, but not typically developing (TD) children, recruitment of the prefrontal cortex was associated with lower ISV, reflecting improved response control. The combined behavior and imaging findings provide the basis for a shift towards a more developmental model of ADHD in which dysfunction in neural systems critical to motor response control, established early in development, contributes to the pathophysiology of the disorder, while function of later-developing prefrontal systems facilitates compensation. The goals of the current proposal are to: use novel imaging methods to investigate the hypothesis that abnormalities in a neural circuit involving the SMA and basal ganglia contribute to ADHD-associated impairments in response control (Aim 1), investigate the hypothesis that successful motor response control in some children with ADHD depends on recruitment of prefrontal (rather than typical premotor) circuits (Aims 2 and 3), and investigate whether a presentation format that increases vigilance can also result in improved response control (Aim 4). The proposed studies will not only help to identify relevant intermediate endophenotypes of ADHD but also might point to potentially effective treatment strategies.