SEYED HOSSEINI (2019-05-16 to 2021-03-31) A Novel Neuromonitoring Guided Cognitive Intervention for Targeted Enhancement of Working Memory. Amount: $671125
Working memory (WM) is one of the core components of executive functions essential for everyday life activities. It is one of the central cognitive constructs included in the NIMH Research Domains Criteria (RDoC) that depends critically on sustained active maintenance in the prefrontal cortex which interacts with parietal regions in a task dependent manner. Accumulating evidence suggest that WM deficits present in a wide range of brain disorders including attention deficit hyperactivity disorder (ADHD). Without early intervention, WM deficits will continue to reduce the likelihood of academic and occupational success. In line with NIMH's emphasis on developing personalized interventions that focus on operationally defined functional domains of mental disorders, particularly intervention targets related to RDoC constructs, we are proposing a novel intervention to enhance WM by probing the individualized neural systems underlying WM. Particularly, the proposed intervention integrates computerized WM training with real-time neuromonitoring and neurofeedback to guide the intervention through reinforcement of a strategy that maximizes the engagement of the target WM network. We will particularly focus on the frontal-parietal circuit (target) which is the core system underlying WM. We will test the proposed intervention on children with ADHD with WM deficits, given a wealth of data demonstrating prevalence of WM impairment in this population that is often associated with hypoactivation in the frontal and parietal circuits indicated by fMRI and fNIRS studies. In the R61 proof-of-concept phase, we will assess target engagement, effective dose and feasibility. Sixty children with ADHD with WM deficits will be randomized to treatment (N = 30) or control (N = 30). Both groups will be assessed using a set of neuroimaging, clinical and behavioral assessments. Particularly, we will test if the intervention results in normalized activity (reduced hypoactivity) in the frontal-parietal network and improved WM performance during N-back task. If the intervention results in improvement in target engagement and WM performance based on the proposed criteria, we will advance to the R33 phase to replicate and validate the effects of the optimal dose of the proposed intervention, versus an active comparison intervention, in a larger sample of children with ADHD (N = 100) with WM deficits. We will also test if enhanced activity in the frontal-parietal network is associated with improvement in BRIEF WM scale (clinical outcome) and N-back performance (functional outcome). Finally, we will assess retention, adherence, satisfaction and acceptability of randomization and will develop and standardize the protocols for a larger trial if the milestones for (a) target engagement, (b) association between target engagement and clinical WM outcomes, and (c) feasibility are met. Validation of the proposed approach will provide a foundation for developing personalized, pathology- focused, cross-diagnostic interventions and could significantly enhance patient outcomes and public health.
工作记忆（WM）是日常生活活动必不可少的执行功能的核心组成部分之一。它是NIMH研究领域标准（RDoC）中包含的中心认知结构之一，其主要依赖于前额皮质中的持续主动维持，其以任务依赖性方式与顶叶区域相互作用。越来越多的证据表明，WM缺陷存在于广泛的脑部疾病中，包括注意力缺陷多动障碍（ADHD）。如果没有早期干预，WM缺陷将继续降低学业和职业成功的可能性。根据NIMH强调开发个性化干预措施，侧重于操作定义的精神障碍功能领域，特别是与RDoC结构相关的干预目标，我们提出了一种新的干预措施，通过探测WM的个体化神经系统来增强WM。特别是，拟议的干预措施将计算机化的WM训练与实时神经监测和神经反馈相结合，通过强化最大化目标WM网络参与的策略来指导干预。我们将特别关注正面 - 顶叶电路（目标），它是WM的核心系统。我们将测试针对患有WM缺陷的ADHD儿童的建议干预措施，因为大量数据显示该人群中WM损伤的患病率通常与fMRI和fNIRS研究所指示的额叶和顶叶回路中的低活化有关。在R61概念验证阶段，我们将评估目标参与度，有效剂量和可行性。 60名患有多发性肝炎缺陷的ADHD儿童将被随机分配到治疗组（N = 30）或对照组（N = 30）。将使用一组神经影像学，临床和行为评估来评估两组。特别地，我们将测试干预是否导致额叶顶层网络中的标准化活动（降低的活动减少）以及在N-back任务期间改善的WM性能。如果干预导致基于拟议标准的目标参与度和WM性能改善，我们将进入R33阶段以复制和验证拟议干预的最佳剂量的影响，而不是主动比较干预，在更大的样本中患有ADHD（N = 100）且患有WM缺陷的儿童。我们还将测试额叶 - 顶叶网络中的增强活动是否与简要WM量表（临床结果）和N-back性能（功能结果）的改善相关。最后，我们将评估随机化的保留，依从性，满意度和可接受性，并且如果（a）目标参与，（b）目标参与和临床WM结果之间的关联（c）的里程碑，将开发和标准化更大规模试验的方案。 ）可行性得到满足。验证所提出的方法将为开发个性化，以病理学为重点的交叉诊断干预提供基础，并可显着提高患者的治疗效果和公共健康。
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