Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis

This fMRI study (n=15) found increased functional connectivity (FC) between the default-mode network (DMN) and the task-positive network (TPN) under psilocybin, and suggests that psilocybin may be useful as a brain model for early psychosis.

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.”

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

Summary

Introduction

Psilocybin, the major psychoactive component of magic mushrooms, produces a range of subjective effects from superficial perceptual changes to more profound existential-type experiences. The default-mode network (DMN) is a network of regions in the brain that show greater activity during internally oriented cognition than externally focused attention.

The DMN and TPN are orthogonal in their activity: the DMN serves explorative inner thought, while the TPN serves focused attention. If the DMN and TPN became less orthogonal, this could cause a confusion of states and a disturbance of cognition, such as is seen in early psychosis.

This study sought to test the effect of psilocybin on DMN-TPN and thalamocortical coupling. It found that thalamocortical coupling was preserved after psilocybin but DMN-TPN coupling was increased – consistent with reduced orthogonality between these networks in the psychedelic state.

15 healthy subjects took part, 13 males and 2 females, with a mean age of 32, SD = 8.9. All had used psilocybin at least once before, but not within 6 weeks of the study.

Imaging was performed on a 3T GE HDx system using fast spoiled gradient echo scans with 1-mm isotropic voxel resolution.

Subjects underwent BOLD fMRI scans on 2 separate occasions at least 7 days apart, receiving placebo on 1 occasion and psilocybin on the other. The subjective effects of psilocybin were felt almost immediately after injection and were sustained for the duration of the scan.

Independent Components Analysis

FMRIB’s FSL was used to derive 20 spatiotemporally coherent components from 30 concatenated data sets. These 20 components were registered to the subjects’ T1-weighted high-resolution anatomical scans that were themselves registered to the Montreal Neurological Institute standard brain.

We identified 11 functionally meaningful RSNs, including an anteriorly loaded DMN, a posteriorly loaded DMN, right- and left-lateralized frontoparietal networks, an auditory network, salience network, visual network, precuneus network, dorsal attention network, cerebellar network, and sensorimotor network.

Pearson’s correlational analyses were used to test for relationships between decreased orthogonality between the DMN and TPNs and subjective ratings of disturbed ego boundaries and cognition.

We used seed-based FC to assess DMN-TPN FC. The DMN and TPN were defined using a ventromedial PFC (vmPFC) seed-based resting-state FC analysis, and linear regression was performed to calculate the FC strengths between the DMN and TPN for all of the scanning sessions.

We used linear regression to measure changes in thalamocortical connectivity after psilocybin. Thalamus-DMN and thalamus-TPN FC were calculated in 2 separate regression analyses, and the results were compared before and after psilocybin and placebo.

Subjective Effects

The subjective effects of psilocybin have been documented elsewhere. They include altered visual perception, an altered sense of space and time, and vivified imagination.

The FC between the anteriorly loaded DMN and each of the other 10 networks was compared after placebo and after psilocybin. The FC between the anteriorly loaded DMN and the SAL was significantly increased after psilocybin, as was the FC between the anterior and posterior DMNs.

Positive correlations were found between DMN-TPN FC and ratings of psychedelic effects, but not between DMN-TPN FC and drug effects intensity.

Psilocybin caused nonsignificant increases in thalamocortical FC, but significant increases in thalamic-DMN FC and thalamic-TPN FC. These increases did not correlate with ratings of the intensity of the subjective effects of psilocybin.

We calculated the mean movement per volume for each subject’s scan and compared the psilocybin and placebo scans in a paired t test. No relationships were found between the observed changes in between-network coupling and the differences in movement, so the argument that the observed changes were caused by between-condition differences in movement is not supported.

Increased DMN-TPN coupling was found after psilocybin, implying that DMN-TPN functionality became less distinct under psilocybin. However, psilocybin is often described as “mind expanding” and decreased thalamo-cortical excitation is closely linked to reduced arousal.

We tested to see if the same thalamocortical decoupling occurred under psilocybin as under propofol, and found that thalamic-TPN connectivity was actually increased under psilocybin. This suggests that increased DMN-TPN coupling is not an index of reduced consciousness but rather a change in the specific mode or style of consciousness.

Increased DMN-TPN coupling has been found in experienced mediators, especially those practicing a form of meditation known as “nondual awareness”, and decreased DMN activity has also been found in meditation and the psychedelic state.

This study found increased DMN-TPN coupling in the psychedelic and early psychotic states, and preserved thalamocortical connectivity in the psychedelic and early psychotic states, which may be related to a state in which arousal is preserved but the distinction between inner thought and external focus becomes blurred.

This study assessed the between-network FC after a psychedelic, and found that the drugs may serve as models of the prodrome to psychosis, as well as tools to study mystical-type experiences.