Efficacy and target engagement of a digital intervention to improve the depression-executive dysfunction syndrome after stroke

项目摘要/摘要 拟议的K23职业发展奖的目标是为PI提供指导、知识、 和技能发展成为研究神经科学启发的、有针对性的治疗的独立调查者 治疗中风后的并发情绪和认知功能障碍。私家侦探的指导团队将为他提供 训练情绪障碍的脑机制，使用功能磁共振检查靶点 参与、临床试验设计和数据分析方法。培训将纳入个性化培训 教程、正式课程、国家和国际讲习班和会议、研究协作、 手稿准备，并资助写作。培训被整合到一项研究提案中，该提案评估 数字干预对抑郁-执行功能障碍综合征的疗效和目标参与度 中风后。中风是世界范围内导致残疾的主要原因。卒中后DED与更多 持续的抑郁症状和执行功能障碍，更差的社会功能，以及更大的损失 与中风后抑郁或执行功能障碍相比，独立更重要。现有的干预措施有限 疗效、副作用的证据，而且中风患者可能很难获得。新颖且可扩展 针对卒中后DED潜在机制的方法可能产生更有效的治疗。至 为了解决这些障碍，PI建议研究一种远程干预中风后DED的方法，该方法结合了 基于iPad的名为Akl-T01的数字疗法，可集中培训快速多任务处理技能，以及虚拟 元认知辅导。AKL-T01旨在针对中风后的常见机制 抑郁症状和执行功能障碍，这是减少内在功能连接 执行控制网络(ECN)。包括虚拟元认知辅导，以解决患者对 赤字，以加强将培训成果转化为日常运作。在这项试点临床试验中，N=70名患者 首次发生卒中和DED的患者将随机接受干预，或接受一般情况下的控制 以及无针对性的认知刺激和元认知辅导。参赛者将完成 在基线、第3周(中期治疗)时测量执行功能障碍、抑郁症状和残疾， 第6周(结束治疗)。参与者将在基线和第6周完成静息状态fMRI扫描。 混合效应模型将检验干预将与更大的 与对照组相比，执行功能、抑郁症状和残疾方面的改善。也是 检验的是这样一种假设，即干预组的内在功能连接性将有更大的变化 在ECN从基线到第6周，相对于对照组。这个项目有可能在一个 可伸缩的方式，这是中风的高度衰弱后果。它将生成可用于优化的数据 治疗效果，进一步细化和个性化干预，并进一步验证治疗目标。

Project Summary/Abstract The goal of the proposed K23 Career Development Award is to provide the PI with the mentorship, knowledge, and skillset to develop into an independent investigator studying neuroscience-inspired, targeted therapeutics for comorbid mood and cognitive dysfunction after stroke. The PI's mentoring team will provide him with training in the brain-based mechanisms of mood disorders, use of functional MRI to examine target engagement, and clinical trial design and data analytic approaches. The training will incorporate individualized tutorials, formal coursework, national and international workshops and conferences, research collaboration, manuscript preparation, and grant writing. The training is integrated in a research proposal that evaluates the efficacy and target engagement of a digital intervention for the depression-executive dysfunction syndrome (DED) after stroke. Stroke is a leading cause of disability worldwide. Post-stroke DED is associated with more persistent depressive symptoms and executive dysfunction, worse social functioning, and greater loss of independence than post-stroke depression or executive dysfunction alone. Existing interventions have limited evidence of efficacy, side effects, and can be difficult for stroke patients to access. Novel and scalable approaches that target the mechanisms underlying post-stroke DED may yield more efficacious treatment. To address these barriers, the PI proposes to study a remote intervention for post-stroke DED that combines an iPad-based digital therapy called AKL-T01 that intensively trains rapid multitasking skills, together with virtual metacognitive coaching. AKL-T01 is designed to target a common mechanism underlying post-stroke depressive symptoms and executive dysfunction, which is reduced intrinsic functional connectivity in the executive control network (ECN). Virtual metacognitive coaching is included to address patient unawareness of deficits to enhance transfer of training gains to daily functioning. In this pilot clinical trial, N=70 patients with a first-time stroke and DED will be randomized to receive the intervention, or to a control condition with general and non-targeted cognitive stimulation together with metacognitive coaching. Participants will complete measures of executive dysfunction, depressive symptoms, and disability at baseline, week 3 (mid treatment), and week 6 (end treatment). Participants will complete resting state fMRI scans at baseline and week 6. Linear mixed-effects models will test the hypotheses that the intervention will be associated with greater improvements in executive function, depressive symptoms, and disability relative to the control group. Also tested is the hypothesis that the intervention group will have greater change in intrinsic functional connectivity in the ECN from baseline to week 6, relative to the control group. This project has the potential to address, in a scalable manner, a highly debilitating consequence of stroke. It will generate data that can be used to optimize treatment efficacy, further refine and personalize the intervention, and further validate a target for treatment.