Examining the effect and clinical relevance of targeted memory reactivation during sleep for stroke rehabilitation interventions

中风造成了巨大的医疗保健成本，并使患者的生活质量显著降低（卫生部，2014）。行动障碍是造成长期残疾的主要原因。常用的运动疗法是耗时和昂贵的，并产生不同的结果。因此，人们对开发更有效和可扩展的运动障碍治疗越来越感兴趣。特别是，直接针对参与康复的潜在神经机制可能会产生更好的结果。中风康复需要运动学习。运动技能的学习不仅取决于练习过程中的成绩提高，还取决于练习后的巩固。这种记忆巩固是睡眠的关键功能，与运动表征的神经再激活有关。正在出现直接针对睡眠期间运动巩固过程的方法。一种这样的方法是靶向记忆再激活（TMR）。TMR涉及在最初的学习过程中反复将记忆（如按下按钮）与感官线索（如声音）配对。如果感觉线索在随后的慢波睡眠期间被重新呈现，则这种运动表征的刺激性再激活，从而增强行为巩固（即，与控制听觉线索相比，在一夜TMR之后，学习的运动序列的表现更好）。然而，尽管大规模的荟萃分析表明TMR在健康大脑中的稳健作用（Hu等人，2020年），TMR尚未在临床背景下进行测试。我建议测试TMR是否能有效改善中风后的运动巩固。我还打算通过采用低成本的便携式技术，将TMR带出实验室，进入患者家中。在我目前担任NDCN的RA时，我正在与Tim Denison合作，为此目的调整Dreem头带。研究计划阶段1：在健康人群中进行家庭TMR试验（n=30），以建立促进记忆巩固的最佳方案。参与者将首先在家中进行运动序列任务的训练，其中运动元素与听觉线索配对。在夜间，参与者将佩戴EEG头带，并将在慢波睡眠期间提供相同的听觉线索（TMR组）或不同的线索（对照组）。将测量行为结果（反应时间）和转移到未经培训的任务。第二阶段：使用与第1阶段相似的设计，但具有与康复更相关的延伸任务，在卒中患者（n=10）中测试基于家庭的TMR系统的可行性。半结构化访谈和问卷调查将评估可行性并告知研究修改。第3阶段：TMR作为卒中患者康复辅助治疗的试验（n=40）。患者将从第2阶段开始每天进行运动训练，持续9天，使用夜间EEG加TMR/对照听觉提示。我们将比较TMS与对照组的夜间运动巩固和临床评分变化。结论本研究将为家庭TMR作为脑卒中幸存者运动训练的辅助手段提供依据。这将有助于为更大规模的随机对照试验提供信息，这些随机对照试验可以考虑卒中后运动障碍的新型连续性康复治疗的疗效和成本效益。

Stroke poses significant healthcare costs and leaves patients with significantly lowered quality of life (Department of Health, 2014). Movement impairments are a major contributor to long-term disability. Commonly used movement therapies are time-consuming and expensive and yield variable outcomes. Thus, there is growing interest in development of more effective and scalable treatment of movement impairment. In particular, directly targeting the underlying neural mechanisms involved in rehabilitation might be predicted to result in better outcomes. Stroke rehabilitation requires motor learning. Motor learning depends not only on performance gains made during practice but also on consolidation - performance gains after practice. Such memory consolidation is a key function of sleep and is associated with neural reactivation of the movement representation. Approaches are emerging that target processes of motor consolidation directly during sleep. One such approach is targeted memory reactivation (TMR). TMR involves repeatedly pairing a memory, such as button presses, with sensory cues, such as sounds, during initial learning. If the sensory cues are re-presented during subsequent slow wave sleep this elicits reactivation of the motor representation and thereby enhances behavioural consolidation (i.e. better performance of a learnt motor sequence after a night of TMR compared to control auditory cues). However, although a large-scale meta-analysis suggests robust effects of TMR in the healthy brain (Hu et al., 2020), TMR has yet to be tested in a clinical context. I propose to test whether TMR is effective in improving motor consolidation after stroke. I also aim to take TMR out of the laboratory and into patients' homes by adapting low-cost portable technology. In my current role as an RA at NDCN, I am adapting the Dreem headband for this purpose, in collaboration with Tim Denison. Research Plan Stage 1: Pilot at-home TMR in healthy populations (n=30) to establish optimal protocols for boosting memory consolidation. Participants will first train at home on a motor sequence task, where movement elements are paired with auditory cues. During the night, participants will wear the EEG headband and will be delivered the same auditory cues (TMR group) or different cues (control group), during slow-wave sleep. Behavioural outcomes (reaction time) and transfer to untrained tasks will be measured. Stage 2: Test of feasibility of home-based TMR system in stroke patients (n=10) using similar design to Stage 1 but with a reaching task that is more relevant to rehabilitation. Semi-structured interviews and questionnaires will assess feasibility and inform study modifications. Stage 3: Test of TMR as an adjunct therapy for stroke patient rehabilitation (n=40). Patients will perform the motor training from Stage 2 daily for 9 days with overnight EEG plus TMR/control auditory cues. We will compare overnight motor consolidation, and changes in clinical scores, for TMS versus control group. Conclusion This project will provide evidence on effects of home-based TMR as an adjunct to motor training in stroke survivors. This will help inform larger-scale RCTs that could consider efficacy and cost-effectiveness of a novel adjunctive rehabilitative therapy for motor impairment after stroke.