Between placebo and nocebo: response to control treatment is mediated by amygdala activity and connectivity

N Egorova, F Benedetti, RL Gollub… - European journal of …, 2020 - Wiley Online Library
European journal of pain, 2020Wiley Online Library
Background In experimental placebo and nocebo studies, neutral control treatments are
often administered for comparison with active treatments, but are of little interest, as, on
average, they result in little change. Yet, when considered at an individual level, they
fluctuate between baseline and subsequent measurements and may reveal important
information about participants' placebo/nocebo responding tendencies. Methods In a
paradigm involving application of creams paired with positive, negative and neutral …
Background
In experimental placebo and nocebo studies, neutral control treatments are often administered for comparison with active treatments, but are of little interest, as, on average, they result in little change. Yet, when considered at an individual level, they fluctuate between baseline and subsequent measurements and may reveal important information about participants' placebo/nocebo responding tendencies.
Methods
In a paradigm involving application of creams paired with positive, negative and neutral expectations, some subjects rated identical stimuli in the neutral condition as more painful while others as less painful after treatment with inert cream. We divided subjects into two groups based on the median split in these pre‐post responses in the neutral control condition, and investigated (a) fMRI signal differences (post minus pre) between the two groups in neutral condition, and (b) seed‐based resting state connectivity of the bilateral amygdala, known to be involved in emotional self‐regulation, as well as ambiguous stimulus processing and aversive learning.
Results
The results suggested that subjects who rated the same pain stimuli after treatment with explicitly neutral cream as more painful showed stronger fMRI activation of the amygdala during the experiment and had higher connectivity between the left amygdala and the striatum at rest. Neutral pre‐post changes predicted behavioural placebo/nocebo response in this and two independent datasets.
Conclusion
These findings suggest that measuring pre‐post change in the neutral control condition might provide important information about subjects' individual differences in placebo/nocebo response.
Significance
Pre‐post changes in pain ratings in neutral conditions are modulated by amygdala activity and connectivity and can be used to predict placebo/nocebo responses.
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