The influence of variability of prior experience and pain on placebo responses

尽管先前的神经影像学研究已经确定了皮质（rACC， PFC），皮质下（RVM， PAG）和脊柱（背角）部位参与安慰剂镇痛，但期望和先前经验如何塑造疼痛感知的机制目前尚不清楚。与多感觉整合类似，我们假设大脑以贝叶斯的方式将先前的经验和期望与传入的疼痛刺激整合在一起。在这个框架中，先前的经验和期望被认为是“先验”，然后与可能性（即疼痛刺激）相结合。重要的是，该框架考虑了初始经验/期望的不确定性，因此对后验进行了预测，即安慰剂反应的效应大小。本质上，如果先前的经验保持在相似的平均强度，但具有不同程度的方差，则在高度可变的期望的情况下，传入的数据将获得更多的权重，从而导致较弱的安慰剂反应。相反，如果经验保持不变，但传入的刺激具有高水平的可变性，则经验将获得更多的权重，这将导致更强的安慰剂效应。我们将用两个系列的实验来检验这个模型。在第一个系列中，我们将改变先前经验的方差，在第二个系列中，我们将改变经验数据的方差（即可能性）。使用一种新的皮质-脊髓功能磁共振成像方案，我们不仅能够评估在安慰剂镇痛的情况下皮层和脊髓对疼痛刺激的反应，而且还能够研究皮层、皮层下和脊髓区域之间的连通性。

Although previous neuroimaging studies have identified cortical (rACC, PFC), subcortical (RVM, PAG), and spinal (dorsal horn) sites involved in placebo analgesia, the mechanism of how expectation and prior experience can shape pain perception is currently unknown. In analogy to multisensory integration we hypothesize that the brain integrates prior experience and expectation with incoming pain stimuli in a Bayesian sense. In this framework prior experience and expectation are considered as a ‘prior’ that is then combined with a likelihood (i.e., pain stimulus). Importantly, this framework takes uncertainty of the initial experience/expectation into account and therefore makes predictions about the posterior, i.e., the effect size of the placebo response. In essence, if the prior experience is kept at a similar mean strength but with different degrees of variance, the incoming data will gain more weight in the case of a highly variable expectation and thus result in a weaker placebo response. Conversely, if the experience is kept constant, but the incoming stimulus has a high level of variability, the experience will gain more weight, which will result in a stronger placebo effect.We will test this model in two experimental series. In the first series we will vary the variance of prior experience and in the second series we will vary the variance of the experienced data (i.e., likelihood). Using a novel cortico-spinal fMRI protocol, we will be able not only to assess cortical and spinal responses to painful stimuli in the context of placebo analgesia, but will also be in a position to investigate the connectivity between cortical, subcortical, and spinal areas.