Investigating the emotion specificity of placebo effects and their neuronal correlates

Placebo effects in the context of affective processing are still poorly understood. The planned project aims at further elaborating the emotion specificity of placebo treatment and the underlying neuronal correlates. A first functional magnetic resonance imaging (fMRI) investigation of our research group had shown that an inert pill presented with the suggestion that it can reduce disgust symptoms was very effective. The disgust placebo had changed the subjective experience as well as the brain activity and connectivity in a network comprising the insula, the amygdala, prefrontal cognitive control areas, and visual cortex regions during the presentation of disgusting pictures. We now attempt to elucidate the psychophysiological responses to an inert pill presented with the suggestion that it can reduce anxiety, and to compare the effects with those of a disgust placebo. This planned fMRI experiment, during which the participants are exposed to disgusting, fear-inducing and neutral images, allows us to directly analyze the effects of placebo that are coupled with specific affective suggestions. The fMRI recording will be combined with eye tracking in order to study alterations of visual attention associated with placebo treatment. In the second planned experiment, we want to compare placebo treatment that has been conceptualized in the framework of unconscious emotion regulation, with conscious affect control (reappraisal). Within this fMRI study the participants undergo three conditions during the viewing of disgust pictures: (a) they receive a disgust placebo, (b) they are asked to deliberately reduce the negative affective meaning of the disgust images (reappraisal), and (c) they passively view the pictures. This study with a repeated measures design allows us to directly compare the neuronal networks involved in (un)conscious emotion regulation. The planned project has important clinical implications. Individuals suffering from intense and difficult to control negative emotions (anxiety, disgust), especially in the context of particular mental disorders, might profit from the knowledge gained by this investigation. 1

In the context of this research project, the effects of a disgust placebo (supposed homoeopathic medication that reduces disgust symptoms) and a disgust nocebo (fluid with a supposedly aversive smell that increases disgust symptoms) were examined during visually elicited feelings of disgust. Four experiments were conducted. In the first eye-tracking study, the participants looked at affective images, once with and once without the placebo. Here, no placebo effects on eye movements could be identified, although there was a significant decrease of experienced disgust. For this reason, in a second eye-tracking study, the image presentation from the first study was modified, this time with two simultaneously displayed affective scenes (disgust, neutral). The placebo increased the visual attention towards the disgust stimuli. The third study, using functional magnetic resonance imaging (fMRI), was devoted to the direct comparison of the effects of firstly, a placebo (automatic emotion regulation), and secondly, reappraisal (deliberate emotion regulation), on disgust processing. Relative to passive viewing, both reappraisal and placebo treatment effectively reduced experienced disgust. In the placebo condition, this reduction was associated with decreased activation in the insula and the dorsolateral prefrontal cortex (DLPFC). In contrast, reappraisal induced increased activation in both regions. Furthermore, both regulation strategies were associated with opposite patterns of connectivity in a network encompassing the amygdala, the insula and the DLPFC. Only placebo administration led to a reduced coupling in this network. It is a very interesting finding that opposite neuronal activation patterns were associated with comparable subjective disgust states. Finally, in a fourth study with fMRI, the disgust nocebo provoked increased feelings of disgust, as well as enhanced activation of the orbitofrontal cortex and its coupling with the insula (interoception) and the piriform cortex (olfactory imagination), while viewing disgusting images. In addition, the nocebo affected activity and connectivity in the visual cortex, and thus, the sensory processing of the disgust images. Overall, this research project identified significant subjective and neural placebo/nocebo effects in the context of affective processing. These effects should now be investigated in clinical trials with patients who suffer from very intense and difficult-to-control feelings of disgust.