Mechanisms of Open and Hidden Placebo in Stroke Recovery

开放式和隐藏式安慰剂在中风康复中的机制

• 批准号: 10642441
• 负责人: Felipe Fregni
• 金额: $ 22.28万
• 依托单位: SPAULDING REHABILITATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642441
• 关键词: Accounting; Area; Behavioral; Brain; Clinical; Clinical Trials; Data; Development; Electroencephalography; Electrophysiology (science); Environment; Fluoxetine; Future; Intervention; Laboratories; Left; Morbidity - disease rate; Motivation; Motor; Motor Cortex; Multicenter Trials; Neurology; Neuronal Plasticity; Operative Surgical Procedures; Outcome; Performance; Physical therapy; Physiologic pulse; Placebo Effect; Placebos; Prevalence; Procedures; Protocols documentation; Psychiatry; Quality of life; Randomized; Randomized Controlled Clinical Trials; Rehabilitation therapy; Research; Research Personnel; Rewards; Solid; Stroke; System; Testing; Therapeutic; Training; Transcranial magnetic stimulation; United States National Institutes of Health; Work; aged; arm; chronic stroke; design; disability; expectation; experience; four-arm trial; improved; indexing; insight; motor deficit; motor function improvement; motor learning; motor recovery; multidisciplinary; neural; neural circuit; neural model; neuromechanism; neurophysiology; noninvasive brain stimulation; novel; pill; post stroke; role model; stroke clinical trials; stroke patient; stroke recovery; stroke rehabilitation; stroke trials; trial design

ABSTRACT We propose investigating the neural mechanisms of placebo (open and hidden) in stroke subjects. This proposal is built on our recently completed clinical trial NIH R21 (R21HD079048-01A1), which showed that the placebo effect contributing to motor recovery was large and superior to fluoxetine alone. Furthermore, we found a different neural signature of placebo and M1 rTMS in this trial supported by other prior trials we conducted. Additionally, our laboratory was involved in other large trials with significant large placebo effects on motor learning. This proposal will conduct an experimental trial in which 56 subjects with chronic stroke will be randomized into four groups (2:2:2:1): open placebo alone (16 subjects), sham rTMS alone (hidden placebo) (16 subjects), no treatment (16 subjects) and M1 rTMS alone (8 subjects). Subjects will be assessed before and after the intervention using neurophysiological markers of connectivity to test specific mechanistic questions based on our preliminary data. We will use quantitative electroencephalography (EEG) analysis of prefrontal and sensorimotor areas and single and, secondarily, paired-pulse TMS to assess corticospinal and intracortical excitability. Our hypothesis is that placebo (open and hidden) will have a specific EEG/neural signature characterized by an enhancement in left frontal alpha asymmetry (FAA) EEG and an increased beta band premotor-motor EEG connectivity. Based on this, we will test two aims: Aim 1: Evaluate whether a hidden placebo (placebo as given in a clinical trial indexed by sham rTMS) has a specific placebo EEG signature compared to no treatment, and Aim 2: Evaluate whether also the open placebo (OP) has a specific EEG signature compared to no treatment (similar to the hidden placebo). Moreover, secondarily, we will also evaluate if active rTMS has a similar signature to sham rTMS and OP compared to no treatment. The significance of this proposal is understanding the placebo effect in stroke patients. This will help improve the design of future stroke trials. For instance, it could be used to design trials with unmatched placebos such as in a behavioral or surgical trial where the active intervention is given against open placebo (unmatched placebo). If the neural signature of placebo is known, this could be confirmed in the unmatched placebo arm to validate the results. Furthermore, understanding mechanisms of placebo may also provide insights to develop interventions that would harness these effects to induce motor recovery by targeting reward-motivation systems to enhance motor recovery in stroke. This proposal is novel as we are developing and testing a new conceptual neural model of the role of expectation and motivation in stroke recovery, and we are quantifying the placebo effects in motor recovery in stroke in a well-controlled trial. Open placebo for motor recovery may open a new avenue for future treatments in rehabilitation. Our team is a multidisciplinary group with solid research experience and environment, with clinical expertise in different fields, such as neurology, electrophysiology, physical therapy, and psychiatry.

摘要 我们建议研究中风受试者服用安慰剂(公开和隐藏)的神经机制。这项建议 是建立在我们最近完成的临床试验NIH R21(R21HD079048-01A1)的基础上的，这表明安慰剂 运动恢复效果显著，优于单用氟西汀。此外，我们发现了一个不同的 这项试验中安慰剂和M1 rTMS的神经特征得到了我们之前进行的其他试验的支持。另外， 我们的实验室还参与了其他大型试验，这些试验对运动学习有很大的安慰剂效应。这 Proposal将进行一项实验性试验，将56名慢性中风患者随机分为4组 组(2：2：2：1)：单纯开放安慰剂(16人)、单纯假rTMS(隐藏安慰剂)(16人)、无 治疗(16例)和单纯M1 rTMS(8例)。受试者将在考试之前和之后接受评估 使用连接性神经生理学标记物进行干预以测试特定的机械问题 我们的初步数据。我们将使用定量脑电(EEG)分析前额叶和 感觉运动区和单脉冲及配对脉冲TMS评估皮质脊髓和皮质内 兴奋性。我们的假设是，安慰剂(公开的和隐藏的)会有特定的脑电/神经信号 以左额叶阿尔法不对称(FAA)脑电增强和β波段增加为特征 运动前-运动脑电连通性。基于此，我们将测试两个目标：目标1：评估一个隐藏的 安慰剂(由Sham rTMS索引的临床试验中给予的安慰剂)具有特定的安慰剂脑电特征 与不治疗相比，目标2：评估开放安慰剂(OP)是否也有特定的脑电 签名与不治疗相比(类似于隐藏的安慰剂)。此外，第二个方面，我们还将评估 与不治疗相比，活动rTMS具有与假rTMS和OP相似的特征。这件事的意义 提案是了解中风患者的安慰剂效应。这将有助于改进未来冲程的设计 审判。例如，它可以用来设计使用无与伦比的安慰剂的试验，例如在行为或外科手术中 对开放安慰剂(不匹配的安慰剂)进行积极干预的试验。如果大脑的神经信号 安慰剂是已知的，这可以在无与伦比的安慰剂组中得到证实，以验证结果。此外， 了解安慰剂的机制也可能为开发干预措施提供洞察力 这些效应通过靶向奖赏-动机系统促进运动恢复来诱导运动恢复 卒中。这一建议是新颖的，因为我们正在开发和测试一种新的概念性神经模型，它的作用是 中风康复的期望和动机，我们正在量化安慰剂对运动康复的影响 在一项控制良好的试验中中风。用于运动恢复的开放安慰剂可能为未来的治疗开辟一条新的途径 在康复治疗中。我们的团队是一个多学科的团队，拥有坚实的研究经验和环境， 具有不同领域的临床专业知识，如神经学、电生理学、理疗和精神病学。