Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex.
Manesh Girn, Leor Roseman, Boris C. Bernhardt, Jonathan Smallwood, Robin Carhart-Harris, R. Nathan Spreng
Neuroimage April 25, 2022 DOI: 10.1016/j.neuroimage.2022.119220 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Re-analysis of two pharmacological resting-state fMRI datasets Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Healthy volunteers from two previously published studies |
| Interventions | Lysergic acid diethylamide (LSD) psilocybin |
| Topics | LSD Psilocybin Serotonin |
| Keywords | Psychedelics Powerful compounds Brain reorganization Brain's internal hierarchy Brain regions Less specialized Consciousness & perception Conventional mental frameworks |
| Citations | 112 |
| Key points | LSD and psilocybin flatten the principal gradient of cortical connectivity, reducing hierarchical organization between unimodal and transmodal cortex. |
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.