Chapter 8 – General discussion 271 and this effect was fully mediated by pain-related fear. For the first time in a nocebo study, we manipulated and measured fear levels directly and precisely (see also chapter 2), by obtaining self-reported levels as well as imaging startle responses via EMG. Startle responses are thought to represent a more direct biobehavioral fear response, as compared to selfreported fear 56,57. Our results may thus add to a more complete picture of nocebo responses, that may be shaped through a process of learning pain associations by experience, in combination with the cooccurrence of adverse emotional factors such as fear. This involvement of emotional factors in pain perception highlights the top-down features of pain processing. However, our research shows that nocebo effects do not always involve fear processing and the amygdala. Rather, it seems that only when a stimulus such as pain is identified as emotive to some level, meaning that it may be especially negative or frightening, brain regions concerned with the emotional and cognitive components of pain, such as the amygdala, hippocampus, insula, and ACC become involved 39. Indeed, this seems to be the case in patients with chronic pain, who may have formed emotive associations with pain and for whom often it is fear of pain that is particularly disabling 58. A recent study comparing young chronic pain patients and healthy peers indicated that in patients only, increased pain catastrophizing was associated with enhanced threat-safety learning and found resting-state functional connectivity alterations between the amygdala and the inferior parietal lobe, including the insula 59. These findings are aligned with our fMRI results implicating the amygdala and insula in pain that is aggravated through learning. Insular activity is indeed not only involved in subjective pain experiences, but is also associated with fear processing, and conditions such as irritable bowel syndrome, chronic fatigue, and persisting or insufficiently explained pain symptoms 39,60,61. Thus, based on our current understanding of the physiological underpinnings of emotional elements that can influence pain processing, learning often seems to take place on two levels. On one hand, a cortical-
RkJQdWJsaXNoZXIy MTk4NDMw