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 我们建议调查安慰剂（开放和隐藏）在中风受试者的神经机制。这项建议 是建立在我们最近完成的临床试验NIH R21（R21 HD 079048 - 01 A1），该试验表明，安慰剂 促进运动恢复的作用大，且上级优于单独的氟西汀。此外，我们发现了一个不同的 本试验中安慰剂和M1 rTMS的神经特征得到了我们先前进行的其他试验的支持。此外，本发明还 我们的实验室参与了其他大型试验，这些试验对运动学习有显著的安慰剂效应。这 一项提案将进行一项实验性试验，其中56名慢性中风患者将被随机分为四组， 组（2：2：2：1）：仅开放安慰剂组（16例受试者），仅假rTMS组（隐藏安慰剂组）（16例受试者），无 治疗组（16例受试者）和M1 rTMS单独治疗组（8例受试者）。受试者将在 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（开放和隐藏）将有一个特定的脑电图/神经签名 特征为左额叶α不对称（FAA）EEG增强和β带增加 前运动-运动脑电连接基于此，我们将测试两个目标：目标1：评估是否隐藏 安慰剂（在通过假rTMS索引的临床试验中给予的安慰剂）具有特定的安慰剂EEG特征 目的2：评价开放式安慰剂（OP）是否也具有特异性EEG 与未治疗相比，签名（类似于隐藏的安慰剂）。此外，其次，我们还将评估 如果活性rTMS与假rTMS和OP相比与无治疗具有相似的特征。其意义 这项研究的目的是了解中风患者的安慰剂效应。这将有助于改善未来中风的设计 审判例如，它可以用于设计具有不匹配的安慰剂的试验，例如在行为或手术中， 试验中，给予活性干预与开放安慰剂（不匹配的安慰剂）。如果神经信号 如果已知安慰剂，则可以在不匹配的安慰剂组中证实这一点，以验证结果。此外，委员会认为， 了解安慰剂的机制也可能为开发干预措施提供见解， 这些影响，以诱导运动恢复的目标奖励激励系统，以提高运动恢复， 中风这一建议是新颖的，因为我们正在开发和测试一个新的概念神经模型的作用， 期望和动机，我们正在量化运动恢复中的安慰剂效应， 在一个良好的对照试验中中风。运动恢复的开放安慰剂可能为未来的治疗开辟新途径 在康复中。我们的团队是一个多学科小组，具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。