Behavioral and Neural Target Engagement for ADHD Executive Working Memory Training

许多研究人员试图证明，通过强化认知训练来提高注意力-- 缺陷/多动障碍(ADHD)患者在WM中存储信息的能力也可能会降低 症状严重或功能受损。这些研究是基于WM行为的强有力的证据 和ADHD的神经功能障碍，人们普遍认为WM相关的脑功能障碍是病因 重要的，并争论说，受损的WM有助于维持这种紊乱。但尽管如此 有希望的早期证据表明WM存储培训的潜在有效性，十年来的模棱两可和负面结果 来自几个精心设计的随机临床试验，让研究人员想知道为什么有意义， 当WM存储容量可靠地增强时，可复制的ADHD临床改善并不总是实现的。 因为很少有调查人员想要错误地放弃这样一个有希望的干预前提，所以有一种搜索 对于关注简单WM存储之外的其他东西的与工作记忆相关的新治疗目标 容量。在这份R61/R33提案中，我们综合了已发表的发现，并提供了我们自己的试点神经成像 有证据表明，更好的WM培训目标可能是高管特定的大脑区域 WM的几个方面。这种执行工作(EWM)记忆操作代表了患者有效使用 在工作记忆中代表的行为和认知控制的信息。这些能力可能比 对ADHD行为障碍有意义的不仅仅是患者一般的WM存储容量有多大。 一个广泛的理论框架支持，工作的工作部分涉及一小部分离散的 灵活地处理WM中的信息或稳定WM中的WM表示的认知操作 面对不同类型的环境干扰。数十项先前的功能磁共振研究可靠地将四种主要疾病联系在一起 这些EWM手术的类型对特定脑区的活动-额上沟和中脑- 外侧前额叶皮质。包括我们的试点证据在内的综合证据表明，这些区域发挥了作用 在ADHD中，异常可以预测ADHD症状的严重程度，并可以通过练习EWM任务来增强。尼姆‘s R61/R33实验治疗学机制是学习典型的5周强化训练课程的理想选择 使用这些EWM练习可以激发与EWM能力和ADHD相关的大脑目标 功能障碍。如果这项由神经科学指导的、最初为期2年的R61研究阶段达到了里程碑，随后的 R33研究阶段将寻求复制，然后展示目标参与与ADHD临床的相关性 功能。如果R61/R33的两个目标都达到了，一系列二次分析将重新检查试验结果 数据。这些努力将为任何后续初步疗效研究的设计提供信息，促进快速 过渡到更大规模的药效测试。

Many investigators have attempted to show that using intensive cognitive training to increase Attention- Deficit/Hyperactivity Disorder (ADHD) patients’ capacity to store information within WM might also reduce symptom severity or functional impairment. Those studies were based on strong evidence for WM behavioral and neural dysfunction in ADHD, a widely-held belief that WM-related brain dysfunction is etiologically significant, and arguments that impaired WM contributes to the maintenance of the disorder. But despite promising early evidence for WM storage training potential efficacy, a decade of equivocal and negative outcomes from several well-designed randomized clinical trials have left investigators wondering why meaningful, replicable ADHD clinical improvements are not always achieved when WM storage capacity is reliably enhanced. Because few investigators want to mistakenly abandon such a promising intervention premise, there is a search for novel working memory-related treatment targets that focus on something other than simple WM storage capacity. In this R61/R33 proposal, we synthesize published findings and provide our own pilot neuroimaging evidence to argue that a better WM training target might be brain regions that specifically underlie the executive aspects of WM. Such executive working (EWM) memory operations represent patients’ ability to effectively use the information represented in WM for behavioral and cognitive control. These abilities likely are more meaningful to ADHD behavioral impairment than merely how large patients’ general WM storage capacity is. An extensive theoretical framework supports that the ‘working’ part of WM involves a small handful of discrete cognitive operations that flexibly manipulate information within WM, or stabilize WM representations in the face of different types of environmental distraction. Dozens of prior fMRI studies reliably link the four primary types of these EWM operations to activity within specific brain regions – the superior frontal sulcus and mid- lateral prefrontal cortex. Converging evidence including our pilot evidence shows these regions function abnormally in ADHD, predict ADHD symptom severity, and can be enhanced by practicing EWM tasks. NIMH’s R61/R33 experimental therapeutics mechanism is ideal to learn if a typical 5-week, course of intensive training that uses these EWM exercises can engage the proposed brain targets linked to both EWM ability and to ADHD dysfunction. If this neuroscience-guided, initial 2-year R61 study phase achieves its milestones, a subsequent R33 study phase will seek to replicate, and then show the relevance of target engagement to ADHD clinical function. If both R61/R33 aims are achieved, a series of secondary analyses will re-examine the trial outcome data. These efforts will inform the design of any subsequent preliminary efficacy study, facilitating a rapid transition into larger-scale efficacy testing.