Chapter 8 – General discussion 267 nocebo-augmented pain compared to a baseline pain stimulus. In line with the literature, this finding reflects the role of alpha-band oscillations in the formation of expectations 31,32 and in the cognitive regulation of pain through the integration of past experiences in pain processing 32,33. Taken together, our EEG findings went beyond merely implicating associative learning in nocebo, by providing a more detailed neurophysiological characterization of a potential cortical integration between learned effects and the processing of noxious stimuli. Findings that point towards long-range temporal correlations in neural dynamics as feature of learning negative associations are crucial because they suggest a potential involvement of integrative learning in nocebo hyperalgesia. In chapter 7 we reported an fMRI study designed to examine more precise implications of brain plasticity in pain processing, utilizing a targeted pharmacological manipulation of NMDA-dependent learning. We used induction methods consistent with our previous experiments in chapters 4 to 6 and comparable to some existing fundamental nocebo fMRI studies 5,34–36. The results supported findings of an integration of learned associations with sensory inputs under nocebo hyperalgesic conditions. Particularly, results that implicated regions such as the ACC and insula in learning nocebo associations, which are generally in line with the literature as reviewed in chapter 3, suggest that the most prominent difference between nocebo and control cues can be seen in brain areas that are thought to synthesize sensory perception based on beliefs and expectations 37. Activity in the ACC has been related to the graded encoding of pain based on the magnitude of expected pain 37,38. Brain mechanisms that involve the insula and ACC may thus reflect the meaning of learned negative cues 39. This type of meaning-related processing of pain through learned expectations could be critical for preparing the sensory system to optimally process noxious information. 37”.
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