LSD flattens the functional hierarchy of the human brain
LSD and psilocybin markedly flatten the brain's principal connectivity gradient—reducing functional differentiation between unimodal (somatomotor) and transmodal (default/frontoparietal) cortex and increasing unimodal–transmodal crosstalk, with LSD-related gradient shifts tracking self-reported ego-dissolution. These results show that macroscale cortical connectivity gradients are sensitive to serotonergic pharmacological modulation and support a mechanistic model linking reduced hierarchical organisation to the psychedelic state.
Authors
- Robin Carhart-Harris
- Leor Roseman
- Manesh Girn
Published
Abstract
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 pharmacological resting-state fMRI data to assess cortical organization in the LSD and psilocybin state. 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 confirmed that this was underpinned by increased unimodal-transmodal crosstalk. In addition, LSD-dependent principal gradient changes tracked changes in self-reported ego-dissolution. 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 a pharmacological manipulation, specifically highlighting an important relationship between cortical organization and serotonergic modulation.
Research Summary of 'LSD flattens the functional hierarchy of the human brain'
Introduction
Classic serotonergic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) are under renewed investigation for therapeutic applications and are known to profoundly alter conscious experience via 5-HT2A receptor agonism. Earlier neuroimaging work using fMRI, MEG and EEG has characterised psychedelic effects on undirected functional connectivity and on some directed measures (for example, Granger causality and travelling waves). A recent theoretical framework, RElaxed Beliefs Under pSychedelics (REBUS), predicts that psychedelics 'flatten' hierarchical information processing by weakening top-down priors encoded in higher-order associative regions and thereby increasing the relative influence of bottom-up sensory signals. Testing REBUS directly is challenging, but one accessible implication is that psychedelics should reduce top-down and/or increase bottom-up directed information flow in the brain. Shinozuka and colleagues set out to operationalise hierarchy as directional asymmetry in interregional signalling and to test whether LSD alters that hierarchy. They applied a measure of temporal irreversibility (INSIDEOUT), together with complementary metrics—hierarchical coherence and hierarchical inhomogeneity, defined from incoming versus outgoing lagged connectivity—to previously acquired MEG recordings in healthy participants who received 75 μg intravenous LSD or placebo. The authors also examined the dynamics of these hierarchy metrics over time, compared their discriminatory power to conventional undirected measures using machine learning, and tested whether regional changes related to serotonin receptor expression maps.
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Study Details
- Study Typeindividual
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- APA Citation
Girn, M., Roseman, L., Bernhardt, B., Smallwood, J., Carhart-Harris, R., & Spreng, R. N. (2020). LSD flattens the functional hierarchy of the human brain. https://doi.org/10.1101/2020.05.01.072314
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