Placebo-induced pain reduction is associated with inverse network coupling at rest

Placebos can reduce pain by inducing beliefs in the effectiveness of an actually inert treatment. Such top-down effects on pain typically engage lateral and medial prefrontal regions, the insula, somatosensory cortex, as well as the thalamus and brainstem during pain anticipation or perception. Considering the level of large-scale brain networks, these regions spatially align with fronto-parietal/executive control, salience, and sensory-motor networks, but it is unclear if and how placebos alter interactions between them during rest. Here, we investigated how placebo analgesia affected intrinsic network coupling. Ninety-nine human participants were randomly assigned to a placebo or control group and underwent resting-state fMRI after pain processing. Results revealed inverse coupling between sensory-motor and salience-like networks in placebo but not control participants. Specifically, networks were centered on the bilateral somatosensory cortex, as well as on the brainstem, thalamus, striatal regions, dorsal and rostral anterior cingulate cortex, and the insula, respectively. Across participants, more negative between-network coupling was associated with lower individual pain intensity as assessed during a preceding pain task, but was unrelated to expectations of medication effectiveness in the placebo group. Altogether, these findings provide initial evidence that placebo analgesia affects the intrinsic communication between large-scale brain networks, even in the absence of pain. We suggest a model where placebo analgesia increases activation within a descending pain-modulatory network, segregating it from somatosensory regions that might code for painful experiences.\n\nHighlightsO_LIPlacebo analgesia affects resting-state connectivity between networks.\nC_LIO_LISalience-related and somatosensory regions are negatively coupled at rest.\nC_LIO_LIThis coupling is negative following placebo, but not in control participants.\nC_LIO_LIMore negative between-network coupling is related to lower pain intensity.\nC_LI