Stratifying Chronic Pain Patients By Pathological Mechanism- A Multimodal Investigation Using Functional MRI, Psychometric And Clinical Assessment

大约五分之一的人每天都会遭受疼痛的折磨。尽管我们尽了最大的努力，但我们常常挣扎着甚至部分地减轻他们的痛苦。其中一个原因是，目前的诊断是基于症状的，但相同的症状可能会因不同的原因而发生。如果我们能根据“机制”来诊断疼痛，也就是症状背后的生物过程，那么患者可能会更早地得到更精确的治疗。当身体中探测到危险的传感器不断地通过脊髓向大脑发送信息时，它们可以是“外围”的。有时，脊椎会出现“交叉连接”，代表触摸的信息变得混乱，导致不正确或放大的疼痛信号--“中枢敏感化”。这些过程可能是由于疾病(如骨关节炎)或由于神经损伤--“神经病变”。大脑成像告诉我们，大脑各部分之间沟通方式的变化--即连通性--预示着过渡到慢性疼痛，但我们不知道连通性差异是否会导致疼痛，或者是其他部位功能障碍的连锁反应；可能是外周或脊髓功能障碍。最后，位于大脑底部(脑干)的疼痛控制系统--“下行调节系统”--可能会失灵，产生类似中枢敏感化的症状。这些机制中的一种或全部可能与慢性疼痛患者有关。由于症状可能是相同的，我们目前还不知道是哪种。该项目旨在预测面部或上肢慢性疼痛患者个体的潜在机制。我们将使用计算机化的模式识别(PR)技术来确定临床评估(检查、访谈、问卷)的哪种组合；专门的神经系统测试和脑/脊柱成像技术最能检测潜在的病理生理机制。从历史上看，在休息和刺激时，很难获得脑干和脊柱的清晰“功能”图像，但我们现在有了新的方法来帮助解决这些问题。首先，我们将在健康、无痛的人的手臂上使用电刺激，看看外周是如何传递正常的持续疼痛信号的。通过改变刺激的特征，我们还可以暂时在脊柱中产生中枢敏感化。在面部，我们可以检查智齿手术后由于外周和中枢敏感化而引起的疼痛。我们可以使用麻醉剂注射来‘阻断’外周信号，只在这些患者中观察中枢敏感化。智齿手术很少见，但有时会导致神经损伤，导致慢性面部疼痛。我们也将对这些患者进行研究，再次使用麻醉剂注射来分别观察外周和中枢信号。我们还将研究由骨性关节炎引起的慢性手臂疼痛的患者。从历史上看，骨性关节炎被认为是一种“外周”疾病，但一些患者也可能有“中枢”变化，我们将在大脑和脊柱确定这一点。最后，我们将使用一种名为“条件性疼痛调制”(CPM)的技术来评估所有患者和健康人的“下行调节”疼痛控制系统的工作情况。我们将利用所有这些临床数据(成像、检查、问卷调查)，并使用PR来开发不同的“指纹”，对外周和中枢疼痛机制进行分类。我们将在每个慢性面部和手臂患者中应用该分类器，以预测他们个人潜在的病理生理。同样，将对第二个分类器进行训练，以识别每个慢性疼痛患者的“正常”和“异常”下行调节疼痛控制。这个项目的成功将帮助我们获得最好的治疗，更快地满足每一位持续性疼痛患者的需求。我们产生的关于大脑和脊柱如何代表这些机制的新知识也将刺激急需的新治疗方法的发展。

Approximately one person in five suffers with pain every day. Despite our best efforts we often struggle even to partly alleviate their pain. One reason is that current diagnoses are based upon symptoms, but the same symptoms can occur for different reasons. If we could diagnose pain based upon 'mechanisms', the biological processes underlying symptoms, then patients might get more precise treatment earlier.Several mechanisms can be faulty in chronic pain. They can be 'peripheral'- when sensors in the body that detect danger persistently send messages via the spinal cord to the brain. Sometimes 'crossed-wires' occur in the spine, where messages representing touch become scrambled, resulting in an incorrect or amplified pain signal- 'central sensitisation'. These processes might be due to disease (e.g. osteoarthritis (OA)) or because of nerve damage-'neuropathy'. Brain imaging has told us that changes in the way parts of the brain communicate with one another -'connectivity'- predicts transition to chronic pain, but we don't know whether connectivity differences cause pain or are a 'knock-on' effect of dysfunction elsewhere; perhaps peripherally or in the cord. Finally, pain control systems in the base of the brain (brainstem)- the 'descending modulatory system'- can fail, producing symptoms similar to central sensitisation. One or all these mechanisms might be involved in patients with chronic pain. As the symptoms can look the same we don't currently know which.This project aims to predict the mechanisms underlying individual patients with chronic pain of the face or upper limb. We will use computerised pattern recognition (PR) techniques to determine which combination of clinical assessments (examinations, interviews, questionnaires); specialised nervous system tests and brain/spine imaging techniques best detect the underlying pathophysiological mechanisms. Historically it has been difficult to get clear 'functional' images of the brainstem and spine during rest and stimulation but we now have new methods to help solve these problems. First, we will use electrical stimulation in the arms of healthy, pain-free people to see how the periphery transmits a normal ongoing pain signal. By changing the characteristics of the stimulation we can also temporarily create central sensitisation in the spine. In the face, we can examine pain due to peripheral and central sensitisation after wisdom tooth surgery. We can use an anaesthetic injection to 'block' the peripheral signal to look at central sensitisation only in these patients. Rarely, but sometimes wisdom tooth surgery produces nerve damage, leading to chronic facial pain. We will also study these patients too, again using anaesthetic injections to look at the peripheral and central signals separately. We will also study patients with chronic arm pain due to OA. Historically OA was considered a 'peripheral' disease, but some patients may also have 'central' changes, which we will determine in the brain and spine. Finally, we will use a technique called 'Conditioned Pain Modulation' (CPM) to assess, in all patients and healthy people, how well their 'descending modulatory' pain control systems are working.We will capitalise on all of these clinical data (imaging, examination, questionnaires) and use PR to develop distinct 'fingerprints' that classify peripheral and central pain mechanisms. We will apply the classifier in each chronic face and arm patient to make predictions about their individual underlying pathophysiology. Similarly, a second classifier will be trained to recognise 'normal' versus 'abnormal' descending modulatory pain control in each chronic pain patient. Success in this project will help us get the best treatment, more quickly to suit the needs of each patient in persistent pain. The new knowledge that we generate about how the brain and spine represent these mechanisms will also stimulate the development of much-needed new treatments.