Chapter 7 – Pharmacological fMRI 245 The insula and more broadly the operculum are also thought to be central cognitive features of sensory perception 89–91. Opercular involvement is consistently found in nocebo hyperalgesia and marks mechanisms of sensory discrimination and cognitive pain modulation 78,92–94. We also found differences in insular and opercular activations between nocebo and control stimuli. It is perhaps unsurprising that sensory modulation is involved in the acquisition of nocebo hyperalgesia. Crucially, however, we found a persistence of insular activations even when all heat administrations were equal in intensity, during extinction, albeit this was only a small cluster of activations. This may indicate that the brain continues engaging in cognitive pain discrimination during nocebo responding, when nocebo stimuli were generally perceived as more painful while all heat intensities were actually identical. Indeed, this is in line with findings of the present study indicating that nocebo responses were not completely attenuated. We also found further differences in opercular activations between evoked nocebo responses and baseline pain. Before learning took place, we administered participants with baseline high pain stimuli. Our results show increased activation of the operculum during nocebo-augmented high pain in the evocation phase, as compared to the baseline high pain stimuli. The operculum was significantly less engaged in experiencing high pain before learning took place, while increased cognitive sensory processing seems to take place when pain sensitivity is increased under nocebo hyperalgesic conditions. The consistent involvement of subregions of the operculum, ACC, and PFC in nocebo responding may underscore a primary role of cognitive and sensory integration and modulation in nocebo hyperalgesia. A limitation of this study was in analyzing the small number of initial nocebo evocation trials, before prolonged extinction, which underpowered the evocation results. Given that extinction begins soon after the pairing of the cues and varying stimulus intensities is
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