Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

Psilocybin, a classic psychedelic, increases functional connectivity between the default-mode network (DMN) and task-positive network (TPN), reducing the normal orthogonality between these networks. In 15 healthy volunteers, intravenous psilocybin (vs placebo) during resting-state fMRI scans led to greater DMN-TPN connectivity, a pattern also seen in psychosis and meditative states. Thalamocortical connectivity remained unchanged, suggesting it relates to arousal rather than the separateness of internal versus external focus. The findings support psilocybin as a model for early psychosis, where compromised DMN-TPN orthogonality may explain phenomenological overlaps.

Study at a glance

Abstract

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very different functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, independent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.