The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

Abstract

Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual-limbic-prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

Keywords: Depression; Dynamic causal modeling; Psilocybin; Serotonin; fMRI.

Fig. 1

Regional effects from the contrast of threat pictures minus shapes within right lateral prefrontal cortex (rLPFC; z = 20) and right amygdala (rAMG; y = −1) and from the contrast of all pictures (threat of non-threat) minus shapes within the right primary visual cortex (rV1; x = 12) across both drug conditions (placebo, psilocybin). SPM{t} overlaid on canonical brain slices (thresholded at p < 0.001 uncorrected for visualization).

Fig. 2

Model specification. A, Basic structure of the three-area model: visual stimulus presentation drives V1 activity, which is bidirectionally connected to AMG, which in turn is bidirectionally connected to the LPFC. B, Bottom-up model: the modulatory effect of threat is only mediated via bottom-up connections from V1 to AMG to LPFC. C, Top-down model: the modulatory effect of threat is only mediated via top-down connections from LPFC to AMG to V1. D, Full model: the modulatory effect of threat is mediated via both bottom-up and top-down connections between V1 and AMG, and between AMG and LPFC.

Fig. 3

Results of Bayesian model selection. Bar charts show the expected model probabilities (A, B) and exceedance probabilities (C, D) of the bottom-up model (1), the top-down model (2), and the full model (3) for the placebo (left) and psilocybin (right) treatment. Notably, the full model with threat-induced modulation of bidirectional connections is the winning model for both the placebo and psilocybin treatment.