The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers

This analysis of a previous double-blind, placebo-controlled, fMRI study (n=15) found that psilocybin increased between-network resting-state functional connectivity (FC) more than MDMA.

Abstract

“Perturbing a system and observing the consequences is a classic scientific strategy for understanding a phenomenon. Psychedelic drugs perturb consciousness in a marked and novel way and thus are powerful tools for studying its mechanisms. In the present analysis, we measured changes in resting-state functional connectivity (RSFC) between a standard template of different independent components analysis (ICA)-derived resting state networks (RSNs) under the influence of two different psychoactive drugs, the stimulant/psychedelic hybrid, MDMA, and the classic psychedelic, psilocybin. Both were given in placebo-controlled designs and produced marked subjective effects, although reports of more profound changes in consciousness were given after psilocybin. Between-network RSFC was generally increased under psilocybin, implying that networks become less differentiated from each other in the psychedelic state. Decreased RSFC between visual and sensorimotor RSNs was also observed. MDMA had a notably less marked effect on between-network RSFC, implying that the extensive changes observed under psilocybin may be exclusive to classic psychedelic drugs and related to their especially profound effects on consciousness. The novel analytical approach applied here may be applied to other altered states of consciousness to improve our characterization of different conscious states and ultimately advance our understanding of the brain mechanisms underlying them.”

Authors: Leor Roseman, Robert Leech, Amanda Feilding, David J. Nutt & Robin L. Carhart-Harris

Summary

Introduction

Psychedelic drugs have been used throughout history to alter consciousness, yet they have been underutilized by modern science. The psychedelic state presents another interesting anomaly, since there is no evidence of reduced wakefulness or awareness, and it is instead referred to as an “expansive” state of consciousness.

The “information integration” theory of Tononi (2012) proposes that consciousness depends on the presence of two key parameters: (1) information and (2) integration.

In recent years, there has been an increasing interest in human fMRI measures of resting state functional connectivity. These measures can be used to describe the integrity and dynamics of resting state networks, which are metastable substates making-up a particular (macro) state of consciousness.

We measured the between-RSN functional connectivity between the default mode network (DMN) and a number of task positive networks (TPNs) during resting conditions, and found that the psilocybin reduces the anticorrelation between DMN and TPNs, which may explain the sense of being apart from or separate from one’s environment.

The primary focus of this paper is on the classic psychedelic state and determining its underlying neurodynamics as measured with fMRI. However, it is useful to compare the psychedelic state with other states of consciousness to see how it relates to these.

Comparing changes in RSFC under psilocybin and MDMA can enable us to isolate and identify effects that are unique to the psychedelic-induced altered state of consciousness produced by classic psychedelics such as psilocybin.

Psilocybin

This is an entirely new analysis on a previously published data set. It was approved by a local NHS Research Ethics Committee and conducted in accordance with Good Clinical Practice guidelines.

MDMA

This study was a within-subjects, double-blind, randomized, placebo-controlled study conducted at Imperial College London. It was approved by several committees and was sponsored by Imperial College London.

Participants Psilocybin

Fifteen healthy subjects took part in the study: 13 males and 2 females. All had used psilocybin at least once before, but not within 6 weeks of the study.

MDMA

13 healthy participants were included in the study, of which 11 gave ratings of 50% for the intensity of MDMA’s effects. All participants were screened for general health, MR-compatibility and present mental health, and none had any history of drug or alcohol dependence.

Psilocybin

All subjects underwent two 12-min eyes-closed resting-state blood oxygen – level dependent (BOLD) fMRI scans: one with placebo and one with psilocybin. Psilocybin was given by injection 6 min after the start of the scans.

MDMA

Two resting-state BOLD scans were performed during each functional scanning session. MDMA peak subjective effects were reported 100 min post administration.

Psilocybin

BOLD-weighted fMRI data were acquired using a gradient echo planar imaging sequence, and were of 5 min (1 min post infusion).

MDMA

BOLD-weighted fMRI data were acquired using a gradient echo planar imaging sequence, and two scans were performed for each condition, 60 min and 113 min post-capsule ingestion.

Resting State Networks (RSN)

We used 10 RSNs that were identified in Smith et al. (2009) using ICA, and 6 non-neural noise components. These networks were likely generated by head motion and non-neural physiological fluctuations.

Preprocessing

We used the Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) to analyze the data. We used the standard imaging preprocessing pipeline that involved brain extraction, motion correction, spatial smoothing, and a high-pass filter.

Between Networks Functional Connectivity(FC) Psilocybin

We back-projected the components from Smith et al. (2009) into each 4D fMRI dataset using a general linear model, and applied a dual regression pipeline to each dataset to extract timecourses for each component. We then presented the between-RSN coupling graphically using a 13 x 13 correlation matrix.

To further partial out non-neural noise confounds, six motion time courses and motion outliers were entered as confounds, and a general linear model was estimated twice for each RSN pair. A symmetrical connectivity matrix was created by averaging together each subject’s two values for each RSN pair.

MDMA

The MDMA resting state functional connectivity was analyzed using the same procedure described above. The mean head motion under MDMA and its placebo condition were 0.083 mm and 0.061 0.019 mm, respectively.

Psilocybin

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

Psilocybin

The coupling strengths for each condition can be seen in Figure 3 and are corrected for multiple comparisons using FDR with q = 0.05 and q = 0.1. The following RSN pairs showed a significant decrease in coupling under psilocybin: SM-VisM, SM-VisL and SM-VisO. The following RSN pairs showed a significant increase in coupling: VisM-lFP, VisM-DAN, VisM-rFP, VisM-DAN2, VisM-Cerebellum and AUD-DMN.

MDMA

We repeated the analysis for the MDMA condition and found that only one RSN pair showed a significant change in coupling.

Differences in Movement

Both drugs increased head motion between conditions, but the increase was relatively modest. Power et al. (2012) suggest that head motion can change the results of RSFC, so they added several motion confounds to the regression analysis. However, some RSN pairs still showed significant differences in coupling strength, so these results should be approached with caution.

Discussion

To our knowledge, this is the first analysis to use a standard ICA-derived template of RSNs to construct between-network functional connectivity matrixes for different drug states. This may have wider application, allowing us to categorize different states of consciousness.

The present study found that psilocybin increased the coupling between brain networks, especially between networks with high 5-HT2A receptor density, and between networks that were already positively coupled at baseline.

The pattern of increased between-network RSFC under psilocybin did not apply universally for the whole brain, and decreased RSFC was observed between the three visual RSNs and the sensorimotor network.

Previous neuroimaging studies with psychedelics have failed to reveal a simple and compelling explanation for their characteristic hallucinogenic effects. This study suggests that increased communication between the visual system and other systems may lead to erroneous perceptual associations.

Given reports of synesthesia-like experiences under psychedelics, one may have expected increased cross-modality communication, but instead was surprised by the decreased coupling that was observed here.

A dynamical systems theory approach to the present results suggests that RSNs are “attractors” into which the brain tends to gravitate for short periods of time. The depth of “basins of attraction” reflect the stability of particular RSNs or metastable “sub-states”. The increased RSFC observed between different RSNs could be interpreted as a flattening of the attractor landscape, which would imply that the global system will move more easily between different metastable sub-states, and therefore have a greater repertoire of metastable states. Psilocybin increased between-RSN RSFC, but decreased between-RSN RSFC. This suggests that the ease of transition between RSNs/metastable sub-states is facilitated under the drug.

Only one RSN-pair showed a significant change in RSFC under MDMA, i.e., increased ECN-DMN2 RSFC. This result is difficult to interpret in isolation, but may relate to a shared aspect of these drugs’ subjective effects.

The present analysis has focused on understanding the neural correlates of the psychedelic state as produced by the classic psychedelic, psilocybin. The findings that MDMA has a less marked effects on between-network RSFC have merely served to emphasize that the psychedelic state rests on a particularly profound disturbance of brain function.

The significant change in head movement under psilocybin implies that some results should be interpreted with caution, in particular the decreases in coupling strength. However, the significant correlation between changes in mean motion and changes in subjective intensity rating suggests that disambiguating the two effects is problematic.

This new analysis used between-network functional connectivity to determine the effects of two distinct serotonergic compounds on spontaneous brain function. Psilocybin produced marked changes in between-network RSFC, while MDMA had a notably less marked effect.