94 Egorova and colleagues (2015) discuss that the dlPFC involves downstream circuits to, amongst others, the anterior insula, hypothalamus, and PAG, which are known to be involved in pain modulation 92. Each of these areas has been implicated in nocebo hyperalgesia in the studies included in this review. Moreover, previous research does indicate a specific involvement of the rDLPFC in pain perception and cognitive evaluation of incoming stimuli 58,93. Importantly, in visceral pain studies, the involvement of the insula in nocebo hyperalgesia also marks mechanisms of sensory integration and cognitive pain evaluation 69–71. Thus, cognitive processing in frontal areas may interact with primary control centers for descending pain inhibition such as the PAG 94 thereby modulating pain under hyperalgesic conditions. Findings involving the ACC deserve special attention, as they are most consistent across studies and indicate that higher order cognitive controls also play an important role in efferent pain modulation. The ACC is highlighted as a key region involved in cognitive pain processing 19,57,59,63. Kong et al. (2008) showed that nocebo hyperalgesia was predominantly produced through a modulatory pain pathway involving the bilateral ACC. Based on the findings by Tinnermann and colleagues (2017) a modulatory function of the rACC on the descending pain system under hyperalgesic conditions is also evident. Notably, studies that include elaborate suggestions with a heavy negative load and hyperalgesic treatments, such as that of Kong et al. (2008), found an extensive involvement of cognitive pain processing, mediated through the ACC. Studies that did not employ extensive negative suggestions or sham treatments, however 8,58,60, showed a main involvement of painmodulatory processes, but not affective processes, with a notable lack of ACC involvement. A possibility to replicate nocebo findings and evaluate the role of the ACC in hyperalgesia may exist, for example in patient studies or subdural electrode techniques that have been found to be powerful in locating sources of deep brain activity 95.
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