Chapter 8 – General discussion 269 influence the formation of negative associations. In chapter 3, limbic structures such as the hippocampus and amygdala point towards a processing of fear in the brain under nocebo conditions 34,35,41. Our threat manipulations in chapter 5 support the notion that fear can amplify nocebo responses. At the same time, our EEG results in the gamma-band lead us to speculate that nocebo hyperalgesia potentially involves emotional processes such as fear, that have been shown to engage similar patterns of gamma coupling in the amygdala 42. This aligned with our fMRI results that also implicated the amygdala in nocebo hyperalgesia. Both behavioral and brain imaging evidence thus suggests that fear is involved in nocebo, and our project attempted to pinpoint precise mechanisms by which fear of pain may affect pain endurance and chronification. Nocebo attenuation and the challenge of negativity bias Our behavioral study presented in chapter 4 was one of the first studies to show an endurance effect of nocebo, and such a resistance to attenuation aligns well with earlier literature in fear conditioning 9,10. In line with this literature, the resistance effects observed in chapter 4 may be at least partly attributable to negativity bias (i.e., the tendency to attend to and remember negative experiences over neutral or positive ones 45–47). A long line of research indicates that negativity bias is a potent attentional effect that can significantly impact our perception 45– 47. When provided with mixed positive and negative information regarding a given stimulus, individuals are more likely to retain negative knowledge 48. In our study, such a negativity bias may have taken place in the ambiguous learning group that was exposed to a wider range of negative and positive suggestions and associations. In line with previous literature about this type of negativity bias 48, this effect may be of important clinical relevance in pain chronification after exposure to
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