Psilocybin shapes the slow, global propagation of brain activity over the cortical layout of 5HT2a receptors

Uncovering the neural basis of psychedelics’ potent effects on brain activity and conscious experience has great potential for understanding their therapeutic effects. Numerous studies using functional magnetic resonance imaging (fMRI) uncovered a strong effect of psychedelics on global properties of fMRI signal, but how they map to underlying neural phenomena remains to be further explored. In this article, we aimed to relate commonly reported findings from functional connectivity studies of psychedelics to changes in the spatio-temporal propagation of activity over the unimodal-transmodal cortical axis. We used data from an openly available dataset including baseline sessions, a control session with administration of methylphenidate, and psilocybin, a 5HT2a agonist. We found that faster propagation speed was related to increased total functional connectivity and a contraction of the principal gradient. The results support the view that these functional connectivity indices obtained from entire signal time courses reflect the modulation of specific global events of propagation. Furthermore, we found that the cortical distribution of 5HT2a receptors could contribute to the modulation of travelling wave propagation by psilocybin. These findings provide a link between macroscopic signatures of neuromodulatory activity, global brain events and receptor action, with relevance for understanding the mechanisms of psychedelic effects. The psychedelic substance psilocybin modifies the temporo-spatial aspects of global infraslow cortical activity across the serotonin receptor landscapes. These findings provide a link between macroscopic signatures of neuromodulatory activity, global brain events and receptor action, with relevance for understanding the mechanisms of psychedelic effects.