Pharmacological Dissociation of Control Circuits in ADHD and Alcohol Dependence

描述（由申请人提供）：注意力缺陷多动障碍（ADHD）是一种严重和普遍的疾病，大约50%的ADHD成人患有共病的物质使用障碍（SUDS）。有影响力的ADHD模型包括不同的“冷”执行缺陷，包括注意力不集中和分心，以及“热”执行缺陷，包括过度寻求奖励和无法延迟满足，后者在ADHD患者中尤其突出，他们继续发展共病SUDS。虽然前额叶调节的缺陷明显与ADHD和SUDS有关，但前额叶调节并不是一个单一的现象。不同的前额叶回路实现注意力控制、注意力调节和分心抑制，以及食欲控制、动机调节和奖励寻求。此外，已知增强多巴胺和去甲肾上腺素神经传递的兴奋剂可增强注意力控制，而阿片受体拮抗剂纳洛酮已被证明可调节动机和奖励寻求。因此，潜在的可分离形式的前额叶调节失败可能与ADHD和SUDS的不同症状群相关，这些回路可能表现出不同的药理学调节模式。为了研究这些假设，我们将使用fMRI来研究健康对照组和患有ADHD、酒精依赖和ADHD合并酒精依赖的成人对哌醋甲酯、纳洛酮和安慰剂挑战的反应。我们将采用经过充分验证的任务来探测注意力控制和食欲控制回路。我们将使用基于ROI的激活分析，功能连接分析和多变量模式分类方法来分离注意力和食欲控制回路。该项目推进了以下目标：描绘ADHD和SUDS功能障碍的神经基础，开发这些疾病的生物学分类，并促进改进，更有针对性的治疗方法的开发。

DESCRIPTION (provided by applicant): Attention-deficit hyperactivity disorder (ADHD) is a serious and prevalent disorder, and roughly 50% of adults with ADHD have comorbid substance use disorders (SUDS). Influential models of ADHD posit distinct 'cold' executive deficits including inattention and distractibility and 'hot' executive deficits including excess reward- seeking and inability to delay gratification, with the latter especially prominent in ADHD patients who go on to develop comorbid SUDS. Though deficits in prefrontal regulation are clearly implicated in ADHD and SUDS, prefrontal regulation is not a unitary phenomenon. Distinct prefrontal circuits implement attention control, regulation of attention and suppression of distractions, and appetitive control, regulation of motivation and reward seeking. Additionally, stimulants that enhance dopamine and norepinephrine neurotransmission are known to enhance attention control, while naltrexone, an antagonist of opioid receptors, has been shown to modulate motivation and reward seeking. Thus potentially dissociable forms of prefrontal regulatory failure may be associated with distinct clusters of symptoms in ADHD and SUDS, and these circuits may exhibit different patterns of pharmacological modulation. To investigate these hypotheses, we will use fMRI to investigate healthy controls and adults with ADHD, alcohol dependence, and ADHD comorbid with alcohol dependence in response to methylphenidate, naltrexone, and placebo challenge. We will employ well- validated tasks that probe attention control and appetitive control circuits. We will dissociate attention and appetitive control circuits using ROI-based activation analyses, functional connectivity analyses, and multivariate pattern classification methods. This project advances the goals of delineating the neural basis of dysfunction in ADHD and SUDS, developing biologically-based classification in these disorders, and spurring the development of improved, more tailored treatments.