Psilocybin modulation of dynamic functional connectivity is associated with plasma psilocin and subjective effects

Abstract Background Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state dynamic functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects.

Aim: Evaluate the association between resting-state dynamic functional connectivity (dFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans.

Methods: Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis.

Results: Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state was positively associated with PPL and SDI.

Conclusion: Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs in exchange for increases in a uniform connectivity structure. We apply and argue for a modified approach to modeling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics. Highlights We examined psilocybin effects on resting-state fMRI dynamic functional connectivity Diametrical clustering described as improved strategy for LEiDA-defined brain states Individual brain state dynamics defined by fractional occurrence and dwell time Two frontoparietal states and a fully connected brain state affected by psilocybin Brain state dynamics associated with psilocin level and subjective experience