Chapter 7 – Pharmacological fMRI 243 The learning paradigm induced significant nocebo responses across both groups, as was anticipated. The pharmacological manipulation in this study did not affect learning of verbal pairs or nocebo associations. Although DCS is known to impact neuroplasticity 29 previous findings are mixed. Many studies show effects of DCS on phobia and symptoms that are known to result from aversive learning 29,63–65,65,66. Yet, other studies have shown differential effects of DCS, for example facilitating procedural but not declarative learning 67, and extinction or memory consolidation, but not necessarily acquisition of learned responses 63,68,69. These differential findings could theoretically be related to the dosage used, with doses in the relevant studies mentioned above varying from 50 to 250mg and fixed, rather than measured based on body weight. We choose a moderate dose of 80mg. Generally, there does not seem to be an apparent dose-related efficacy of DCS, with one review of the literature reporting that neither the dose nor the time of administration had an effect on the learning outcomes 65. Interestingly, DCS augmentation effects have mainly been studied in phobic stimuli and for fear memory 29. These results suggest that DCS is effective in modulating limbic NMDA circuits engaged in paradigms with a heavy fear load 70. We did find increased amygdala activation for nocebo trials over control trials during acquisition and extinction of the nocebo effect irrespective of pharmacological group, and there seems to be some involvement of fear in nocebo (Schmid et al., 2015; Thomaidou, Veldhuijzen, et al., 2021; Tinnermann et al., 2017b). Speculatively, the type of pain-learning task employed in our nocebo experiment may potentially not primarily rely on the same fear-learning circuits that DCS has been found to affect in previous studies. DCS not affecting nocebo responding may point to a potential differentiation between the specific mechanisms involved in pain-learning versus fearlearning. In other words, we speculate that learning a negative nocebo association may not involve the NMDA-mediated learning that DCS may be able to augment in more fear-specific contexts.
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