Exploring the Neural Mechanisms Underlying Pain Modulation by Positive and Negative Expectations

Abstract

Besides the nociceptive input, the percept of pain is shaped by many factors. One prominent factor is expectations, as observed in placebo hypoalgesia and nocebo hyperalgesia. There are indications that this influence can even last over longer periods of time. On a neurobiological level, the descending pain modulatory system (DPMS) may partially mediate placebo and nocebo effects. Although they appear crucial for the initiation of expectations for the subsequent modulation of pain, only few studies investigated the neural processes during the anticipation phase.

This dissertation consists of three studies aimed at (1) assessing similarities and differences between the neuronal representations of positive and negative expectations during the anticipation and pain phase, (2) evaluating the temporal stability of expectation effects on pain perception and identifying neural predictors for the persistence of effects, and (3) testing whether a conscious modulation of expectations without deceptive information affects pain perception.

In all studies, expectations regarding an upcoming pain stimulus were manipulated on a trial-by-trial basis. In the first study, EEG and fMRI data were recorded while participants supposedly received real-time feedback on their pain sensitivity on every trial. In the second study, the same sample of participants was re-invited to the lab one week later to test for the stability of effects. Participants in the third study were instructed to consciously modulate their expectations in line with a visual cue, while, as in the second study, EEG data were recorded.

The first study revealed that positive and negative expectations were similarly represented in neural activity during the anticipation phase, and activity only differentiated during the actual pain processing. Strikingly, this pattern was mirrored in the anterior insula and areas of the DPMS including the ACC, DLPFC, and vmPFC. The combined EEG-fMRI analysis showed an earlier onset of activity in the prefrontal cortex and anterior insula compared to activity in the ACC during the anticipation phase. In the second study, it was shown that both positive and negative expectations had lasting effects on pain perception over one week. The stability of effects could be predicted by neural activity recorded during the initial day of expectation induction, with activity in the DLPFC, anterior insula, and amygdala being related to the stability of positive expectations, while activity in the thalamus predicted the stability of negative expectations. Moreover, expectations were reflected in theta-to-alpha oscillatory activity. The third study showed that pain ratings could be modulated when participants consciously adjusted their expectations, which also led to changes in high-frequency oscillatory activity during the pain phase.

The results presented here highlight the relevance of unique anticipatory processes for the subsequent modulation of pain perception. It was shown that areas of the DPMS, especially the prefrontal cortex, and the anterior insula play an important role in the generation of expectations and their longer-term stabilization. The results bear clinical implications, particularly in regard to the high stability of both placebo and nocebo effects and the efficacy of conscious expectation modulations.