In the past, nocebo manipulations have been found to modulate pain perception and influence long-term habituation to pain. Recently, neural correlates accompanying this finding have been identified: habituation over days is mirrored by decreased activity in pain processing brain areas whereas nocebo-specific modulation specifically involves the opercular cortex.Focusing on duration and central network characteristics of nocebo information in a longitudinal heat pain paradigm we investigated 40 healthy participants over a period of 21 consecutive days, whereof sessions on day 1, 8, 14, and 21 were performed during functional MRI scanning. Negative context information was given to half of the participants, inducing a nocebo manipulation through verbal suggestions. The analysis was focused on brain areas associated with habituation and nocebo effects and identified coupled brain regions using functional connectivity analysis.Decreased pain perception over days was reflected in reduced BOLD-signal in pain processing areas, such as the insula and somatosensory cortices, whereas increased rACC activation reflected the central correlate for habituation over time. Habituation was significantly less pronounced in the nocebo group. Consistent with previous results, the nocebo manipulation not only modulated pain perception but was accompanied by activation of the operculum over an extended period of time. Importantly, the operculum exhibited changes in coupling during nociceptive input over time, as demonstrated by decreased connectivity with the basal ganglia, and pinpoints differences, depending on whether a nocebo context was given or not. These data suggest that negative verbal suggestions prognosticating increasing pain may prevail by modulating basal ganglia-thalamocortical loops.
