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 我们建议研究中风主体中安慰剂（开放和隐藏）的神经机制。这个建议 建于我们最近完成的临床试验NIH R21（R21HD079048-01A1）上，该试验表明安慰剂 导致运动恢复的效果很大，仅优于氟西汀。此外，我们发现了另一种 在这项试验中，安慰剂和M1 RTM的神经特征由我们进行的其他先前试验支持。此外， 我们的实验室参与了其他大型试验，对运动学习具有重大安慰剂作用。这 提案将进行实验试验，其中56名患有慢性中风的受试者将被随机分为4个 小组（2：2：2：1）：单独开放安慰剂（16个主题），单独的rtms（隐藏安慰剂）（16个科目），没有 仅处理（16名受试者）和M1 RTMS（8个受试者）。受试者将在 使用连通性的神经生理学标志物进行干预，以测试基于 我们的初步数据。我们将对前额叶和 感觉运动区域和单一，其次是配对的脉冲TM，以评估皮质脊髓和心脏内部 兴奋性。我们的假设是安慰剂（开放和隐藏）将具有特定的脑电图/神经特征 以左额叶不对称性（FAA）脑电图增强的特征和增加的β频段 运动前运动EEG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（安慰剂在临床试验中给出，由假RTMS索引）具有特定的安慰剂eeg签名 与未治疗相比，目标2：评估开放安慰剂（OP）是否具有特定的脑电图 签名与没有治疗相比（类似于隐藏的安慰剂）。此外，其次，我们还将评估 如果主动RTM具有与假RTMS和OP相似的签名，则与无治疗相比。这一点的意义 建议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 试验。例如，它可用于设计无与伦比的安慰剂的试验，例如行为或外科手术 对开放安慰剂（无与伦比的安慰剂）进行主动干预的试验。如果神经签名 已知安慰剂，可以在无与伦比的安慰剂组中确认这一点以验证结果。此外， 了解安慰剂的机制也可能提供见解，以制定可以利用的干预措施 这些效果通过靶向奖励动机系统来诱导运动恢复 中风。当我们开发和测试一种新的概念神经模型时，该提议是新颖的 中风恢复的期望和动机，我们正在量化运动恢复中的安慰剂效应 在经过良好控制的试验中中风。开放式安慰剂进行运动恢复可能会为未来治疗的新途径开放 在康复中。我们的团队是一个具有扎实的研究经验和环境的跨学科小组， 不同领域的临床专业知识，例如神经病学，电生理学，物理疗法和精神病学。