Increased global functional connectivity correlates with LSD-induced ego dissolution

This seminal fMRI, double-blind, placebo-controlled study (n=15) found that LSD (75µg) increased global connectivity in the brain, which correlated with ‘ego dissolution’ and which overlapped significantly with where serotonin (5-HT2a) receptors are found.

Abstract

“Lysergic acid diethylamide (LSD) is a non-selective serotonin-receptor agonist that was first synthesized in 1938 and identified as (potently) psychoactive in 1943. Psychedelics have been used by indigenous cultures for millennia; however, because of LSD’s unique potency and the timing of its discovery (coinciding with a period of major discovery in psychopharmacology), it is generally regarded as the quintessential contemporary psychedelic. LSD has profound modulatory effects on consciousness and was used extensively in psychological research and psychiatric practice in the 1950s and 1960s. In spite of this, however, there have been no modern human imaging studies of its acute effects on the brain. Here we studied the effects of LSD on intrinsic functional connectivity within the human brain using fMRI. High-level association cortices (partially overlapping with the default-mode, salience, and frontoparietal attention networks) and the thalamus showed increased global connectivity under the drug. The cortical areas showing increased global connectivity overlapped significantly with a map of serotonin 2A (5-HT2A) receptor densities (the key site of action of psychedelic drugs). LSD also increased global integration by inflating the level of communication between normally distinct brain networks. The increase in global connectivity observed under LSD correlated with subjective reports of “ego dissolution.” The present results provide the first evidence that LSD selectively expands global connectivity in the brain, compromising the brain’s modular and “rich-club” organization and, simultaneously, the perceptual boundaries between the self and the environment.”

Authors: Enzo Tagliazucchi, Leor Roseman, Mendel Kaelen, Csaba Orban, Suresh D. Muthukumaraswamy, Kevin Murphy, Helmut Laufs, Robert Leech, John McGonigle, Nicolas Crossley, Edward Bullmore, Tim M. Williams, Mark Bolstridge, Amanda Feilding, David J. Nutt & Robin L. Carhart-Harris

Notes

Highlights from the authors:

• High-level cortical regions and the thalamus show increased connectivity under LSD
• The brain’s modular and rich-club organization is altered under LSD
• Increased global connectivity under LSD correlates with ego dissolution scores

This study was funded in part by the Beckley Foundation.

This study used the same participants as Carhart-Harris et al. (2016), which looked at the immediate and long-term psychological effects of this dose of LSD.

The supplemental information (graphs and procedures) can be found here.

Summary

RESULTS

We used fMRI to investigate changes in functional connectivity following intravenous injection of lysergic acid diethylamide (LSD) versus placebo in 15 healthy volunteers. We hypothesized that these changes would implicate high-level cortical networks such as the default-mode network and salience network.

We measured the functional connectivity density of 401 regions of interest (ROIs) covering cortical and sub-cortical gray matter under LSD and placebo. The FCD values were globally increased under LSD compared with placebo.

The global connectivity of the brain increased under LSD, with the largest increases observed in the frontal, parietal, and inferior temporal cortices, as well as in the bilateral thalamus. These increases were correlated with increases in the 5-HT2A receptors, and with increased connectivity of the brain under psilocybin.

We correlated regional FCD increases under LSD with the intensity of ego dissolution reported by the participants across all ROIs, and identified four regions presenting correlations with ego dissolution scores and uncorrelated to all other VAS scores.

The FCD increases indicated that the overall global connectivity of the regions in Figure 1C increased under LSD relative to placebo. Four RSNs were identified as becoming more engaged with the globally connected regions under LSD: a sensorimotor RSN, two visual RSNs, and an auditory RSN.

We evaluated whether LSD only scaled the magnitude of the coupling or also rearranged connectivity patterns in the brain, independent of the coupling strength. We observed increased between-module communication in frontal and midline regions, suggesting that these areas serve as conduits for increased between-module communication under LSD.

We investigated changes in the level of integration between highly coupled regions by means of the so-called ”rich-club” coefficient F(k). The results show that LSD decreases the level of communication between the brain’s dominant hub regions, indicating that LSD impairs within-module communication of highly coupled nodes.

DISCUSSION

The present results indicate that LSD enhances global and between-module communication while diminishing the integrity of individual modules, and that this effect is mediated by the brain’s key integration centers such as those that are rich in 5-HT2A receptors.

A formal analysis revealed that regions of increased global connectivity under LSD expressed the 5-HT2A receptors in especially high concentrations, which may explain the increased glucose metabolism observed in these regions.

Studies performed during the 1950s and 1960s revealed decreased oscillatory power under LSD and psilocybin, and recent studies have revealed diminished power in a broad range of frequency bands after psilocybin infusion. Alpha oscillations are linked to a number of cognitive processes, including attention, memory, executive control, and conscious access.

The areas of the brain that displayed increased global connectivity under LSD have different functional roles, such as the frontoparietal cortex, the precuneus, the temporo-parietal junction, and the bilateral insular cortex. This increased communication between these areas and other brain systems may explain the psychedelic experience of ego dissolution.

The boundaries between lower-level systems anchored to the external world and higher-level systems operating more autonomously from sensory information might be blurred in the brain during psychedelic experiences.

Our exploratory imaging analysis revealed significant correlations with only one out of six VAS items, i.e., feelings of ego dissolution. This suggests that the whole brain may be involved in this phenomenon.

The neurophysiology of the psychedelic state contrasts with that of the unconscious state on many levels, including increased frontoparietal FCD, increased between-module cross-talk, and decreased modularity. This study supports the hypothesis that the level of entropy in the brain is predictive of the subjective quality of consciousness.

While we attempted to reduce the impact of head motion in our results, significant differences in head motion persisted between conditions. Additionally, we used a small sample of 15 ”clean” datasets and our analysis of ego dissolution was based on a single numerical report by experienced psychedelic drug users.

The present study explored one of the most remarkable and least understood domains of the psychedelic experience, known both colloquially and academically as ”ego dissolution”. It revealed an increase in global integration within the brain, seemingly mediated by high-level cortical association regions that are rich in 5-HT2A receptors.