Electrophysiological markers for anticipatory processing of nocebo-augmented pain

Abstract

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.

Fig 1. Mean pain ratings for nocebo and control evocation trials.

Pain ratings were made on a computerized 0–10 NRS. Error bars represent standard deviations. Dots indicate individual participant data.

Fig 2. Mean SPN at Cz during nocebo and control evocation trials.

Mean amplitudes for SPN at electrode Cz for nocebo and control evocation trials. The gray bar indicates the adjusted late SPN window, -500 to 0ms relative to the pain stimulus onset (time 0). Auditory cues were to be presented at -3500, -2500, and -1500ms.

Fig 3. Mean SPN at Cz during nocebo and control acquisition trials.

Mean amplitudes for SPN at electrode Cz for nocebo and control acquisition trials. The gray bar indicates the late SPN window, -500 to 0ms relative to the pain stimulus onset. Auditory cues were presented at -3500, -2500, and -1500ms, but for the nocebo trials they were erroneously presented 400ms earlier.

Fig 4. GC time series during evocation phase.

Evocation phase Granger Causality estimates from -1000ms to +1000ms relative to pain stimulus onset. The shaded area around the plotted lines indicates +/- 1 SEM. A: Frontal left to temporoparietal left. B: Frontal left to temporoparietal right. C: Frontal right to temporoparietal left. D: Frontal right to temporoparietal right.

Fig 5. GC time series during acquisition phase.

Acquisition phase Granger Causality estimates from -1000ms to +1000ms relative to pain stimulus onset. The shaded area around the plotted lines indicates +/- 1 SEM. A: Frontal left to temporoparietal left. B: Frontal left to temporoparietal right. C: Frontal right to temporoparietal left. D: Frontal right to temporoparietal right.