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.

抽象的 我们建议研究中风受试者安慰剂（开放和隐藏）的神经机制。这个提议 建立在我们最近完成的临床试验 NIH R21 (R21HD079048-01A1) 的基础上，该试验表明安慰剂 有助于运动恢复的效果很大并且优于单独使用氟西汀。此外，我们还发现了一个不同的 本次试验中安慰剂和 M1 rTMS 的神经特征得到了我们之前进行的其他试验的支持。此外， 我们的实验室参与了其他大型试验，安慰剂对运动学习有显着的影响。这 该提案将进行一项实验性试验，其中 56 名患有慢性中风的受试者将被随机分为四组 组 (2:2:2:1)：仅使用开放安慰剂（16 名受试者），仅使用假 RTMS（隐藏安慰剂）（16 名受试者），无 治疗（16 名受试者）和单独 M1 rTMS（8 名受试者）。受试者将在考试之前和之后接受评估 使用连接的神经生理学标记进行干预，以测试基于以下内容的特定机制问题 我们的初步数据。我们将使用定量脑电图（EEG）分析前额叶和 感觉运动区和单脉冲 TMS，其次是成对脉冲 TMS，以评估皮质脊髓和皮质内 兴奋性。我们的假设是安慰剂（开放的和隐藏的）将具有特定的脑电图/神经特征 其特征是左额叶 α 不对称 (FAA) 脑电图增强和 β 频带增加 前运动脑电图连接。基于此，我们将测试两个目标： 目标 1：评估是否隐藏 安慰剂（由假 rTMS 索引的临床试验中给出的安慰剂）具有特定的安慰剂脑电图特征 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图 签名与不治疗相比（类似于隐藏的安慰剂）。此外，其次，我们还会评估 与无治疗相比，主动 rTMS 是否与假 rTMS 和 OP 具​​有相似的特征。此举的意义 提案是了解中风患者的安慰剂效应。这将有助于改进未来行程的设计 试验。例如，它可以用于设计具有无与伦比的安慰剂的试验，例如在行为或外科手术中 针对开放安慰剂（无与伦比的安慰剂）进行主动干预的试验。如果神经特征 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， 安慰剂的理解机制也可能为制定干预措施提供见解，这些干预措施将利用 这些效应通过针对奖励激励系统来诱导运动恢复，以增强运动恢复 中风。这个提议很新颖，因为我们正在开发和测试一个新的概念神经模型 中风恢复的期望和动机，我们正在量化安慰剂对运动恢复的影响 一项良好对照试验中的中风。用于运动恢复的开放安慰剂可能为未来治疗开辟新途径 在康复中。我们的团队是一个多学科团队，拥有扎实的研究经验和环境， 不同领域的临床专业知识，如神经病学、电生理学、物理治疗和精神病学。