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

Robin L. Carhart-Harris, Robert Leech, David Erritzoe, Tim M. Williams, James M. Stone, John Evans,
David J. Sharp, Amanda Feilding, Richard G. Wise, and David J. Nutt

Schizophrenia Bulletin, 2012, Volume 39, Issue 6, November 2013, Pages 1343–1351

doi : 10.1093/schbul/sbs117

 

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamo-cortical 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 thalamo-cortical 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.

Key words : serotonin/5-HT/resting-state networks/ default-mode network/psychedelic /consciousness/
psychosis/at-risk mental state

 

Introduction

Background :

Psilocybin is a tryptamine psychedelic and the prodrug of the major psychoactive component of magic mushrooms, psilocin. Psilocybin and psilocin were first isolated and synthesized by Albert Hofmann1 after which they were used in psychotherapy before this was curtailed by political pressure.2 Classic psychedelics like psilocybin produce a range of subjective effects from superficial perceptual changes to more profound existential- type experiences.3 Much has been written about the phenomenology of the psychedelic state, but we have only a limited understanding of how it is produced in the brain.

Functional MRI Measures of Spontaneous Brain Activity

There has been an increased interest in measures of spontaneous brain activity in recent years.4 In humans, fMRI measures of task-free- or “resting-state” functional connectivity (FC) have become popular. Measures of resting-state FC using independent components analysis (ICA) have identified a number of spatiotemporally coherent networks5 that closely resemble stimulus-evoked activation maps.6 Of particular interest is the defaultmode network (DMN), a network of regions (including the posterior cingulate cortex; medial prefrontal cortex, mPFC; and lateral inferior parietal cortex) that show greater activity during internally oriented cognition than externally focused attention.7 The DMN receives brain regions, has undergone significant evolutionary expansion,9 and serves as an important convergence zone or “connector hub” in the cortex.10 The DMN is activated during high-level cognitions such as predicting the future11; making personal, social, and moral judgments12,13; and contemplating the past.14 These properties have led to speculations that the DMN is the biological system upon which our psychological notions of self15 or “ego”16 are based.

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