Chapter 3 – Comprehensive review 89 fMRI has been used to image the function of the entire central nervous system. Because of specialized requirements for spinal MR images, however 80,81, neurobiological nocebo research has predominantly focused on brain mechanisms. Relatively recently, the focus has expanded to the spinal cord, which plays a key role, not only in the afferent transmission of pain signals, but also in the descending modulation of pain 82. In nocebo effects, hyperalgesia may be attributed to sensory and cognitive-emotional brain processes such as those described earlier. However, Benedetti and colleagues (2014) also showed that peripheral biochemical mechanisms may also play a role in nocebo effects. Whether there is an additional early or late source of increased pain perception in the spinal cord, is a question of high relevance and importance. Two studies examined spinal fMRI for nocebo hyperalgesia both induced by conditioning combined with verbal suggestions methods. Geuter & Büchel (2013) investigated thermal conditioning combined with the suggestion that a (sham) capsaicin cream would enhance their perceived pain, while a control cream would have no effect on pain. Significant nocebo effects were reported. The fMRI results revealed that the nocebo manipulation led to increased BOLD signal in the ipsilateral dorsal horn of the spinal cord. Interestingly, the location of the noceboenhanced pain signal largely overlapped with the main effect of pain during heat stimulation. Moreover, response time to painful stimulation differed, with the signal increasing earlier when the nocebo treatment was applied compared to control. Overall, the findings demonstrate nocebo-induced increases in spinal pain signals, indicating that an early pain-facilitating mechanism takes place at the spinal level. Tinnermann et al. (2017) integrated spinal and brain imaging, aiming to unravel whether nocebo hyperalgesia is mediated through corticosubcortico-spinal network interactions, similarly to other forms of cognitive pain modulation. In this study, the impact of perceived value
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