90 of a nocebo treatment on the magnitude of nocebo responses was also explored. Participants were allocated to one of two groups and received negative suggestions regarding the hyperalgesic effect of inert creams, one labeled as expensive and one as cheap. An additional neutral cream was used as a control. Nocebo effects were successfully induced and participants who received the sham expensive cream reported a significantly higher nocebo effect than participants who received the sham cheap cream. Regions that displayed neural representations of nocebo hyperalgesia irrespective of medication value were identified in the spinal cord at the height of spinal segment C6, slightly more caudal and medial than the pain cluster. This location was almost identical to the results of Geuter & Büchel (2013). Furthermore, compared to the cheap cream group, the expensive cream group had greater activation differences between nocebo and control trials in prefrontal areas, the right amygdala, and the PAG. Moreover, the level of rACC deactivation predicted the strength of reported nocebo hyperalgesia and the spinal cord and rACC revealed coupling with the PAG that correlated with the nocebo magnitude. Taken together, these initial spinal imaging studies on nocebo hyperalgesia showed that both ascending and descending pain modulation at the spinal cord level may be involved in the presentation of nocebo effects. Modulation of the rACC-PAG-spinal axis could represent a mechanism through which the descending pain pathway interacts with higher-cognitive information, such as learned information or negative suggestions, to modulate pain processing. With the pain signal being amplified already at the spinal level, however, interesting questions may be raised regarding the contributing role of the spinal cord in pain amplification under nocebo conditions. While the observed amplification of spinal pain signals suggests a key role for spinal modulatory processes in nocebo hyperalgesia, further modulations at later, cortical areas remain important.
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