Granger Causality during acquisition phase.

Nocebo effects on pain are widely thought to be driven by negative expectations. This suggests that anticipatory processing, or some other form of top-down cognitive activity prior to the experience of pain, takes place to form sensory-augmenting expectations. However, little is known about the neural markers of anticipatory processing for nocebo effects. In this event-related potential study on healthy participants (n = 42), we tested whether anticipatory processing for classically conditioned nocebo-augmented pain differed from pain without nocebo augmentation using stimulus preceding negativity (SPN), and Granger Causality (GC). SPN is a slow-wave ERP component thought to measure top-down processing, and GC is a multivariate time series analysis used to measure functional connectivity between brain regions. Fear of pain was assessed with the Fear of Pain Questionnaire-III and tested for correlation with SPN and GC metrics. We found evidence that both anticipatory processing measured with SPN and functional connectivity from frontal to temporoparietal brain regions measured with GC were increased for nocebo pain stimuli relative to control pain stimuli. Other GC node pairs did not yield significant effects, and a lag in the timing of nocebo pain stimuli limited interpretation of the results. No correlations with trait fear of pain measured after the conditioning procedure were detected, indicating that while differences in neural activity could be detected between the anticipation of nocebo and control pain trials, they likely were not related to fear. These results highlight the role that top-down processes play in augmenting sensory perception based on negative expectations before sensation occurs.

疼痛相关反安慰剂（Nocebo）效应普遍被认为由负面预期所驱动。这提示，在疼痛体验发生前，预期加工或其他形式的自上而下认知活动会参与形成感官增强型预期。然而，目前学界对反安慰剂效应相关预期加工的神经标记物仍知之甚少。本项针对42名健康受试者的事件相关电位（event-related potential, ERP）研究中，我们借助刺激前负波（stimulus preceding negativity, SPN）与格兰杰因果检验（Granger Causality, GC），对比了经典条件化反安慰剂强化疼痛的预期加工与无反安慰剂强化的疼痛预期加工是否存在差异。刺激前负波是一种被认为可用于评估自上而下加工的慢波ERP成分，而格兰杰因果检验则是一种用于测算脑区间功能连接的多变量时间序列分析方法。研究采用疼痛恐惧问卷-III（Fear of Pain Questionnaire-III）评估受试者的疼痛恐惧程度，并检验其与SPN及GC指标的相关性。我们发现，相较于对照疼痛刺激，反安慰剂疼痛刺激的SPN所表征的预期加工，以及经GC测算的额叶至颞顶脑区的功能连接均显著增强。其余GC节点对未显示出显著效应，且反安慰剂疼痛刺激的时间滞后性限制了本研究结果的解读空间。本研究未检测到与条件化程序后测得的特质性疼痛恐惧相关的关联，这表明尽管反安慰剂与对照疼痛试次的预期阶段可观测到神经活动差异，但此类差异大概率与特质性疼痛恐惧无关。上述研究结果凸显了感知发生前，自上而下加工在基于负面预期强化感官知觉过程中所发挥的作用。