Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape
This paper (2022) combines data of the brain’s resting state under the influence of LSD and cortical mapping of 5-HT2A receptors within the framework of network control theory to validate the central tenets of the REBUS model of psychedelics. In accordance with this model, LSD-induced flattening of the brain’s energy landscape, corresponding to greater flexibility for state transitions and more dwell time in brain states than encode bottom-up activity (e.g. salience network) and decreased persistence of states dominated by top-down (frontoparietal) activity.
Authors
- Robin Carhart-Harris
- David Nutt
- Leor Roseman
Published
Abstract
Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states. Using brain states derived from existing functional magnetic resonance imaging (fMRI) datasets, we show that LSD and psilocybin reduce control energy required for brain state transitions compared to placebo. Furthermore, across individuals, reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors (obtained from publicly available positron emission tomography (PET) data under non-drug conditions), we demonstrate an association between the 5-HT2a receptor and reduced control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, we demonstrate that receptor-informed network control theory can model the impact of neuropharmacological manipulation on brain activity dynamics.
Research Summary of 'Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape'
Introduction
Serotonergic psychedelics such as LSD produce profound but transient changes in perception and subjective experience, and recent neuroimaging work has been synthesised in the RElaxed Beliefs Under Psychedelics (REBUS) model. REBUS frames the brain as a prediction engine and proposes that agonism at cortical 5-HT2a receptors relaxes top-down priors, allowing increased influence of bottom-up sensory input and greater temporal diversity (entropy) of brain activity. Formally, this relaxation is hypothesised to correspond to a reduction in the energy required for the brain to move between recurrent functional states — a “flattening” of the brain’s energy landscape — but this specific prediction had not been tested empirically. This study set out to test that prediction by combining resting-state fMRI with diffusion MRI-derived structural connectivity and PET-derived maps of serotonin receptor density, analysed with network control theory. The investigators tested whether LSD lowers the transition energy between empirically derived recurrent brain-states relative to placebo, whether such lowering is associated with increased state switching and entropy of brain dynamics, and whether the spatial distribution of 5-HT2a receptors can mechanistically account for energy reductions.
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Study Details
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Singleton, S. P., Luppi, A. I., Carhart-Harris, R. L., Cruzat, J., Roseman, L., Nutt, D. J., Deco, G., Kringelbach, M. L., Stamatakis, E. A., & Kuceyeski, A. (2022). Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-33578-1
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