Predictability-mediated pain modulation in context of multiple cues: An event-related fMRI study.

When the pain intensity of an impending stimulus is highly unpredictable, the uncertain expectation of pain may exacerbate the perceived pain intensity of the stimulus, compared to the same stimulus delivered with certain expectation. Here, we address how the perception of physically identical stimuli delivered with different predictability of the pain intensity is influenced by learning. We hypothesized that the difference in perceived pain intensity following high and low predictable cues could be explained by: (1) uncertainty-driven hyperalgesia associated with hippocampal activity; (2) certainty-driven hypoalgesia associated with activity in the periaqueductal gray (PAG) and the rostral anterior cingulate cortex (rACC); and (3) a mixed model of both. To test this hypothesis, two sessions of a delayed conditioning paradigm was employed in conjunction with event-related functional magnetic resonance imaging and trial-by-trial rating of the pain intensity. Participants had to simultaneously learn the outcome association of two cues. One cue was always delivered at the same intensity while the other cue was delivered either at a matched or a substantially higher intensity. As expected, the uncertain condition resulted in higher perceived pain intensity than the certain condition. However, this effect occurred only in the second session and was driven by decreased perceived pain in the certain condition. Furthermore, this effect was associated with decreased activity in the PAG but not the rACC. The changing pain ratings and PAG activity across sessions reflect a dynamic learning process that may mirror decreased perceived threat of and/or decreased attention to pain in the certain condition.