The role of anticipation in nocebo effects on pain

In this study on healthy adult participants, we will use electroencephalography (EEG) to measure neural activity during the anticipation of ‘normal’ and ‘nocebo-augmented’ pain. By exploring the differences in how the brain anticipates pain under these conditions, we aim to better understand how learned expectations shape painful experiences. Nocebo effects on thermal pain will be induced in a single group of 42 participants (sample size derived from a power analysis of Morton et al., 2010) using a verbal suggestion and classical conditioning paradigm while EEG is recorded.

Primary research question: Does the amplitude of late SPN in the 500ms preceding a pain stimulus differ between the anticipation of moderate pain versus heightened, nocebo augmented pain, during the evocation of nocebo effects on pain?
Primary hypothesis: Late SPN amplitudes in response to cues (colored text on a computer screen indicating the activation of a (sham) TENS device), measured in the 500ms preceding cued stimuli, will be increased in anticipation of nocebo trials, as compared to control trials, in the evocation phase.
2. Secondary (exploratory) research questions and hypotheses:
2a. Research question: Does the amplitude of late SPN in the 500ms preceding a pain stimulus differentiate between the anticipation of moderate, control pain and heightened pain, during the acquisition of nocebo effects on pain?
Hypothesis: Late SPN in response to cues 500ms preceding nocebo and control pain stimuli, will be increased during nocebo trials, as compared to control trials, in the acquisition phase.
2b. Research question: Will differences in late SPN amplitude between the first half of nocebo and control evocation trials correlate with the magnitude of self-reported nocebo augmented pain (i.e., noceboe effect) for the evocation phase?
Hypothesis: The magnitude of late SPN (nocebo minus control amplitudes) will correlate with the magnitude of the nocebo effect.
2c. Research question: Does anticipatory neural processing measured with Granger Causality Analysis in the 1000ms preceding pain stimuli differ between moderate pain and heightened, nocebo augmented pain during the acquisition and evocation of nocebo effects?
Hypothesis: Anticipatory neural processing measured 1000ms prior to nocebo pain stimuli in frontal electrodes will predict neural activity in the following 1000ms in temporoparietal electrodes, from the onset of the pain stimulus, modelled with Granger Causality analysis. This model will be compared to a model for control pain stimuli, separately for the acquisition and evocation phases.
2d. Research question: How does fear of pain relate to self-reported nocebo augmented pain during the first half of the evocation phase?

Hypothesis: Higher fear of pain will be correlated with higherself-reported nocebo augmented pain during the first half of the evocation phase. The analysis will be repeated with the entire evocation phase as an exploratory analysis.
2e. Research question: How does fear of pain relate to networks of anticipatory neural processing preceding nocebo-augmented pain during the evocation phase?
Hypothesis: Higher fear of pain will be correlated with a larger difference in SPN and Granger Causality values between? nocebo and control evocation phase trials.

Participants complete the study in a single lab visit of approximately 2 hours in duration, during which the primary and secondary outcomes are measured.

Verbal suggestions: Participants are told at the start of the experiment, and again just prior to the conditioning paradigm, that pulses from an electrical stimulation device attached to their aim via two electrodes will increase the intensity of the thermal pain stimuli when the electrical stimulation device is turned on.

Classical conditioning: Participants undergo a classical conditioning paradigm intended to form an association between the (sham) activation of the electrical stimulation device and increased pain intensity. The acquisition phase of the paradigm, during which time the association is learned, consists of 40 control and 40 reinforced nocebo pain stimuli trials. During control trials, a thermal stimulus calibrated to evoke moderate pain intensity (approximately 4 on a 0-10 pain scale) is paired with a message on a computer screen stating the electrical stimulation device is turned off. During reinforced trials, a thermal stimulus calibrated to evoke moderate pain intensity (approximately 7 on a 0-10 pain scale) is paired with a message on a computer screen stating the electrical stimulation device is turned on. The evocation phase of the paradigm, during which time the learned association is tested, consists of 30 control and 30 nocebo pain stimuli trials. These trials are identical to those of the acquisition phase with the distinction that now the pain stimuli for both trial types are set to the moderate pain intensity previously used only during control trials.