无先兆偏头痛患者针刺安慰剂疗效影像学预测研究

Positive medical responses to placebo treatments are a well-recognized phenomenon observed in much pathology, with a higher prevalence for neurological and painful conditions. Placebo analgesia is observed ubiquitously in pain treatment trials, especially in chronic pain populations, in which it often exhibits sustained effectiveness rivaling in magnitude that of the active treatment. Yet, interpretation of placebo response in clinical observations remains questionable because of experimental design weaknesses, as repeatedly pointed out in the past. Here we identified and validated that clinical placebo response is predictable from brain magnetic resonance imaging (MRI). Patients with migraine without aura underwent pretreatment brain scans in a clinical trial. It is an 8-wk single-blinded placebo acupuncture treatment trial. We hypothesize that the structural and functional properties of pain processing pathways could identify the placebo response. We reasoned that if we could uncover a brain marker prior to the start of the trials that forecasts how individual subjects will perform during these trials, and then we could conclude that clinical placebo response is a predetermined brain process. If future similar studies can further expand and eventually provide a brain based predictive best-therapy option for individual patients, it would dramatically decrease unnecessary exposure of patients to ineffective therapies and decrease the duration and magnitude of pain suffering. Moreover, if placebo response can be predictably removed/reduced in clinical trials, then, besides reducing the cost of clinical trials, the efficacy and neurobiology of therapies can be identified more accurately and at the level of the individual.

如何有效预防偏头痛的发展，减轻因偏头痛发作导致的身心损害，是患者和临床工作者最关心的问题。在临床干预偏头痛的各种手段中，安慰剂可有效降低偏头痛头疼发作次数。研究者若能将安慰剂镇痛机制游刃有余的应用到临床干预实践当中，这对慢性疼痛病人症状的改善，尤其是偏头痛病人的康复具有十分重要的意义。本项目拟在申请人团队多年偏头痛个体差异神经影像学研究基础上，采用假针刺诱发安慰剂治疗效果，设计16周单盲法安慰剂干预纵向实验设计，借助多模态磁共振成像技术采集被试治疗前后影像学数据，探索在安慰剂治疗前偏头痛患者中枢神经系统个体差异特性与未来安慰剂疗效的关系；借助多元回归的分析方法，试图建立大脑疼痛感知、抑制、情感通路预测安慰剂临床疗效的影像学标记。本项目的顺利实施不仅可以精准的定义安慰剂预防偏头痛的脑影像学标记、为安慰剂治疗偏头痛的临床应用提供更多参考依据，同时为针刺预防偏头痛发作脑机制研究提供新的研究。

偏头痛在全球致残原因中位居第二，在年轻女性中居首位。虽然多种药物可用于偏头痛急性期治疗和间歇期预防，但药物引起的不良反应不容忽视。针刺已成为一种便携、易操作、安全的偏头痛常规非药物治疗手段，但受偏头痛患者人群异质性的影响，针刺疗效存在较大个体差异。若能明确针刺适宜人群影像学特征，可优化针刺预防偏头痛临床方案，提高偏头痛预防综合疗效。在本项目的支持下，项目负责人研究团队首先根据临床试验指南，将患者分为高、低偏头痛发作频率组。研究结果发现：患者静息态下大脑功能连接特征可有效预测偏头痛患者头痛发作频率，且预测特征主要位于大脑的边缘叶、额叶、颞叶等区域。研究结果表明大脑功能连接可作为一种客观评估偏头痛发作频率的神经影像学指标。此外，慢性疼痛患者受长期疼痛影响，患者疼痛情绪、疼痛行为较健康对照表现出异常模式，且异常表现可反作用疼痛慢性化。借助多变量分析方法，研究团队发现慢性疼痛患者疼痛情绪、疼痛共情行为在疼痛期下和非疼痛期下均异于健康对照，且慢性疼痛会改变疼痛人群大脑结构特性。改变的大脑结构在疼痛与疼痛共情的相互影响中起到中介作用，一方面可能加重了疼痛强度，一方面导致疼痛共情的异常。在上述数据分析过程中，为了更好的分析大脑纤维束白质微结构变化与慢性疼痛症状、疗效之间的关系，团队提出了一种基于图谱的白质纤维束分析方法及大脑白质纤维束白质微结构计算方法，实现了沿着纤维束的白质微结构计算与分析。研究方法与现有方法相比在检测和理解白质微结构差异上存在优势。本项目已有研究结果已应用在偏头痛针刺适应人群影像学筛选研究工作中，为偏头痛针刺疗效预测提供了影像学参考及方法支持。