Placebo Treatment Entails Resource-Dependent Downregulation of Negative Inputs

Background Clinical trials of antidepressants show improvements in placebo groups of up to 80% compared to the real treatment arm. The mechanism underlying this clinically important effect has been linked to expectation induced goal-directed control. Here, we investigated how cognitive resources influence the effects of positive expectations on emotional processing. Methods Forty-nine healthy volunteers participated in a cross-over fMRI study, in which expectancy of positive emotional changes was induced by an alleged oxytocin nasal spray combined with verbal instruction. Participants performed a spatial cueing paradigm that manipulated the attention to emotional face distractors in the scanner and were characterized regarding their general ability to control attention. Results Behavioral findings showed placebo treatment to improve mood and to reduce distractibility by fearful over happy faces, specifically when more attentional resources were available to process faces. This aligned with neural changes in activation and functional coupling in lateral prefrontal-limbic networks indicating an expectation induced top-down regulation of aversive inputs. In addition, behavioral effects and prefrontal-parietal engagement directly correlated with trait ability to control attention. Conclusions Our data show that placebo treatment combined with verbal instruction alone can improve mood and recruit top-down attentional selection. Changes in emotional processing critically depended on attentional context and individual control ability (i.e., contextual and general resources). These findings may be particularly relevant in patients with major depressive disorder, who often demonstrate a negativity bias and in whom placebo effects by verbal instructions alone may be limited due to reduced cognitive control capacity. ### Competing Interest Statement The authors have declared no competing interest.