244 The amygdala has been consistently implicated in fear-learning 32,74,75, but amygdala involvement may not be an essential feature or necessary prerequisite for nocebo induction. Other brain areas are shown to underlie nocebo hyperalgesia in the absence of an amygdala involvement 76–78. Interestingly, the amygdala seems to be involved when experimental contexts or suggestions are especially negative or frightening, such as in visceral pain studies (Schmid et al., 2015) or studies of a higher threat-load that include extensive conditioning and negative suggestions 73. In line with this, our study with pre-conditioning and negative suggestions showed increased activation of the amygdala on nocebo compared to control trials. Involvement of the amygdala in the more negative experimental contexts could suggest that fear may be a secondary modulatory factor in nocebo hyperalgesia 72,79. Pain-related learning thus seems to potentially take place on two conceptual levels. On one hand, cortical-level associative learning mechanisms may be at the core of acquiring learned pain effects. On the other hand, fearrelated learning, that may take place in subcortical loops involving the amygdala, mediates pain worsening, and may be a secondary modulatory factor in pain chronification 72,80. Distinct learning mechanisms mediated via the vlPFC may also have engaged during nocebo acquisition in our study. The vlPFC is linked to learning, belief formation, and stimulus-response associations 81–85. Neural circuits involving the vlPFC are thought to communicate through oscillations in gamma-band (60–160 Hz) frequency channels. This relates to previous studies implicating gamma-band oscillations as a marker of learning in nocebo acquisition 16,86,87. The vlPFC, as the present study also suggests, may be implicated in sensory stimuli whose properties are processed bottom-up 88. This corresponds to participants engaging in this type of bottom-up processing of nocebo versus control stimuli, only in the acquisition phase of our experiment, before topdown processing based on learned information of nocebo associations begins taking place.
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