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

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.

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.

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.

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.

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.