Pain processing and pain perception in the human brain: a neural signals approach

疼痛几乎是一种普遍的体验。它对健康、福祉和疾病进程的重要性是不可否认的。一个人可以经历或多或少的疼痛，测量疼痛强度在诊断、评估和治疗中非常重要。然而，这项测量出人意料地困难，因为疼痛程度取决于复杂的因素，如期望、注意力，甚至个性。此外，强健、有效的疼痛强度测量方法也难以捉摸。目前的方法，如数字疼痛分级量表，强烈依赖患者的语言理解-例如，短语“可以想象到的最严重的疼痛”通常被用来定义量表的顶端。也许正是由于这些原因，评分与有害刺激的能量以及大脑中假定的“疼痛中心”或“疼痛网络”的激活之间的相关性是出了名的差。这个项目开发了一种新的方法来理解疼痛感知。使用最先进的反馈控制激光刺激器，我们将健康志愿者手背的皮肤暴露在短暂的、量化的辐射热脉冲中，导致剧烈的针刺疼痛。这反映了特定的神经生理疼痛通路(“A-Delta通路”)中的信号。参与者被随机地用两种能量中的一种进行刺激，这两种能量都高于个体的阈值，以激活A-Delta通路。他们判断自己经历的强度是“更高”还是“更低”。我们使用标准方法来计算疼痛感知的两个截然不同的方面：一个人的判断跟踪实际刺激能量的敏感度，以及他们无论实际刺激能量如何，都偏向于更高或更低的反应。例如，仅仅害怕强烈疼痛的人可能会判断所有疼痛刺激的强度都较高：它们会显示出强烈的偏向和低敏感性。我们还使用非侵入性放置在头皮上的脑电电极来记录激光刺激引起的大脑活动。通过将不同截止点的脑电幅值分布一分为二，我们可以模拟该特定时刻的脑电信号在区分高强度和低强度刺激方面的效果。因此，我们将确定大脑对伤害性刺激的反应组件，这些组件最接近疼痛感知的敏感度和偏差组件。这为寻找痛觉的神经基础提供了一种新的、可控的、生理特异性的、完全客观的方法。它不需要任何主观的定义或关于什么是“疼痛”的指导，只需要参与者判断刺激是更强烈还是更弱。通过对大样本参与者的测试，我们解决了人与人之间在疼痛感知方面的个体差异。我们可以确定与高和低疼痛倾向以及高和低疼痛敏感度相关的心理特征。两个进一步的大型实验利用了这些重要的方法学发展。实验2旨在展示我们的方法如何用于量化和了解一种流行的止痛药(瑞芬太尼)的效力。对药物或安慰剂的双盲注射进行比较，以确定药物是否影响偏见或敏感性，以及这种变化背后的脑电成分。实验3使用这些新的测量方法来调查众所周知的安慰剂效应的基础-这可能是疼痛研究中最引人注目的发现。参与者了解到，在激光刺激之前呈现的特定视觉刺激，预测下一次刺激是更强烈还是更弱。再一次，我们评估这个预测性线索是否改变了敏感性或偏向。我们将确定负责线索如何影响这两个方面的疼痛感知的脑电成分。总体而言，这一结果为疼痛感知提供了一种新的客观方法，对未来疼痛和止痛的临床研究有用。

Pain is an almost universal experience. Its importance for health, well-being and disease processes is undeniable. One can experience more or less pain, and measuring pain intensity is important in diagnosis, assessment and therapy. However, this measurement is surprisingly difficult, because pain levels depend on complex factors such as expectation, attention, and even personality. Moreover, robust, valid measures of pain intensity are elusive. Current methods, such as numerical pain rating scales, rely strongly on patients' verbal understanding - e.g., the phrase "worst pain imaginable" is generally used to define the top of the scale. Perhaps for these reasons, ratings show notoriously poor correlation with the energy of a noxious stimulus, and also with activation of putative 'pain centres' or 'pain networks' in the brain.This project develops a novel approach to understanding pain perception. Using a state-of-the-art feedback-controlled laser stimulator, we expose the skin on the back of the hand of healthy volunteers to brief, quantified pulses of radiant heat, causing a sharp 'pinprick' pain. This reflects signals in a specific neurophysiological pain pathway ("A-delta pathway"). Participants are stimulated randomly with either of two energies, both above the individual's threshold to activate the A-delta pathway. They judge whether they experienced 'higher' or 'lower' intensity. We use standard methods to calculate two distinct aspects of pain perception: the SENSITIVITY with which a person's judgements track the actual stimulation energy, and their BIAS in preferring to respond 'higher', or 'lower', irrespective of actual stimulation energy. For example, someone who simply fears strong pain might judge ALL pain stimuli as 'higher' intensity: they would then show strong bias and low sensitivity.We also record the brain activity evoked by laser stimulation, using EEG electrodes non-invasively placed on the scalp. By dividing the distribution of EEG amplitudes in two at different cutoff points, we can simulate how effective the EEG signal at that particular moment would be in classifying the higher and lower intensity stimuli. We will thus identify the components of the brain's response to noxious stimulation that best approximate the sensitivity and bias components of pain perception. This provides a novel, well-controlled, physiologically-specific, and fully objective method to search for the neural basis of pain perception. It does not require any subjective definition or instruction regarding what counts as 'pain', and merely requires participants to judge whether a stimulus is more or less intense. By testing a large sample of participants, we address individual differences between people in pain perception. We may identify psychological profiles associated with high and low pain bias, and with high and low pain sensitivity.Two further large experiments leverage these important methodological developments. Experiment 2 aims to show how our method can be used to quantify and understand the potency of a popular analgesic drug (remifentanil). Double-blind infusions of drug or placebo are compared to address whether the drug influences bias or sensitivity, and which EEG components underlie this change.Experiment 3 uses these new measurement approaches to investigate the basis of the well-known placebo effect - perhaps the most striking finding in pain research. Participants learn that a specific visual stimulus, presented before laser stimulation, predicts whether the next stimulus will be more or less intense. Again, we assess whether this predictive cue changes sensitivity or bias. We will identify the EEG components that are responsible for how the cue influences these two aspects of pain perception.Overall, the results provide a novel and objective approach to pain perception, useful for future clinical studies of pain and analgesia.