18 known to play a crucial role in learning and memory formation 76–79. More specifically, the amygdala and hippocampus, structures sometimes implicated in nocebo effects 20,21, play essential roles in the formation of new memories based on past experiences 80–82. At the same time, the consistent involvement of the ACC in nocebo effects may be drawing together prior memories, expectations, and information processing. The ACC is an area that is largely interconnected to the limbic system and may play a key role in cognitive control and conflict monitoring 83,84. These neuroscientific similarities may indicate that nocebo hyperalgesia involves a complex cognitive network that is responsible both for memory formation and for the recall and integration of learned expectations and incoming sensory information. Brain plasticity, learning, and cognitive-emotional factors, seem to form an interconnected, cortical-subcortical network that may be involved in nocebo hyperalgesia and in pain processing 21,60,62,85 (Figure 2). Yet, inconsistencies and a lack of replicability between nocebo studies do not permit for firm conclusions to be drawn. Cognitive and emotional components, such as learning and fear, seem have a critical role in the formation of nocebo hyperalgesia. Nevertheless, there is uncertainty regarding the specific learning mechanisms that may be involved, how they affect brain plasticity, and how learning networks may integrate with pain processing. This is evident in the large disparity in neurophysiological findings of fMRI and EEG studies. Inconsistencies in the literature also lead to uncertainty regarding the impact of fear, as compared to related cognitive-emotional responses such as anxiety. It is important for systematic experimental research to actively manipulate states of brain plasticity, learning, memory, and other cognitive processes. While a comprehensive overview of the state-ofthe-art in nocebo research is valuable, pharmacological manipulations and other methods that directly manipulate cognitive states may be central components in the strive to unravel the specific neurocognitive mechanisms of nocebo hyperalgesia.
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