Central correlates of placebo effects in nausea differ between men and women.

INTRODUCTION: Despite growing evidence validating placebo effects in nausea, little is known about the underlying cortical mechanisms in women and men. Therefore, the present study examined sex differences and electroencephalography (EEG) characteristics of the placebo effect on nausea. METHODS: On 2 consecutive days, 90 healthy subjects (45 females) were exposed to a nauseating visual stimulus. Nausea was continuously rated on an 11-point numeric rating scale, and 32 EEG channels were recorded. On day 2, subjects were randomly allocated to either placebo treatment or no treatment: the placebo group received sham acupuncture, whereas the control group did not receive any intervention. RESULTS: In contrast to the control group, both sexes in the placebo group showed reduced signs for anticipatory nausea in the EEG, indexed by increased frontal lobe and anterior cingulate activity. Among women, the improvement in perceived nausea in the placebo group was accompanied by decreased activation in the parietal, frontal, and temporal lobes. In contrast, the placebo-related improvement of perceived nausea in men was accompanied by increased activation in the limbic and sublobar (insular) lobes. CONCLUSION: Activation of the parietal lobe in women during the placebo intervention may reflect altered afferent activity from gastric mechanoreceptors during nausea-induced tachyarrhythmia, whereas in men, altered interoceptive signals in the insular cortex might play a role. Thus, the results suggest different cerebral mechanisms underlying the placebo effects in men and women, which could have implications for the treatment of nausea.

Molecular classification of the placebo effect in nausea.

In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and (in females) gastric activity could be verified. Using label-free tandem mass spectrometry, 74 differentially regulated proteins were identified as correlates of the placebo effect. Gene ontology (GO) enrichment analyses identified acute-phase proteins and microinflammatory proteins to be involved, and the identified GO signatures predicted day-adjusted scores of nausea indices in the placebo group. We also performed GO enrichment analyses of specific plasma proteins predictable by the experimental factors or their interactions and identified 'grooming behavior' as a prominent hit. Finally, Receiver Operator Characteristics (ROC) allowed to identify plasma proteins differentiating placebo responders from non-responders, comprising immunoglobulins and proteins involved in oxidation reduction processes and complement activation. Plasma proteomics is a promising tool to identify molecular correlates and predictors of the placebo effect in humans.