Neuroimaging & Brain MeasuresLSDPsilocybin

Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex

This study (2022) applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets. The principal gradient of cortical connectivity was significantly flattened under both drugs relative to their respective placebo conditions. This study is the first to show that macroscale connectivity gradients are sensitive to acute pharmacological manipulation.

Authors

  • Robin Carhart-Harris
  • Leor Roseman
  • Manesh Girn

Published

NeuroImage
individual Study

Abstract

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization.

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Research Summary of 'Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex'

Introduction

Research on serotonergic psychedelics such as LSD and psilocybin has reported substantial changes in whole-brain functional organisation and dynamics, including reduced segregation of large-scale networks, increased global functional connectivity, and greater complexity of regional activity. A recent theoretical account—the RElaxed Beliefs Under Psychedelics (REBUS) model—posits that psychedelics increase the influence of low-level sensory and limbic inputs on high-level representations encoded in transmodal cortex, implying a reduction in hierarchical differentiation between unimodal and transmodal regions. However, whether psychedelics acutely alter macroscale hierarchical organisation has not been directly tested. Girn and colleagues set out to test this idea by applying gradient-mapping techniques to pharmacological resting-state fMRI datasets acquired under LSD and psilocybin. Their primary hypothesis was that both drugs would produce a contraction of the principal cortical connectivity gradient—an axis running from unimodal sensorimotor regions to transmodal association cortex—reflecting reduced hierarchical differentiation and increased unimodal–transmodal crosstalk. Secondary aims included examining drug effects on the second and third gradients, which capture sensory and executive differentiation respectively, and relating gradient changes to self-reported subjective effects such as ego-dissolution and complex imagery. The study therefore investigates whether macroscale connectivity gradients are sensitive to acute serotonergic pharmacological manipulation and whether such changes relate to phenomenology.

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Study Details

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Serotonergic psychedelic drugs LSD and psilocybin... — Research Summary & Context | Blossom