LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory
Year: 2021
Type: preprint
Abstract: Psychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by 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 measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSD’s 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 from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing 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, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics. Significance Statement We present a multi-modal framework for quantifying the effects of two psychedelic drugs (LSD and psilocybin) on brain dynamics by combining functional magnetic resonance imaging (fMRI), diffusion MRI (dMRI), positron emission tomography (PET) and network control theory. Our findings provide evidence that psychedelics flatten the brain’s control energy landscape, allowing for more facile state transitions and more temporally diverse brain activity. We also demonstrate that the spatial distribution of serotonin 2a receptors - the main target of LSD and psilocybin - is optimized for generating these effects. This approach could be used to understand how drugs act on different receptors in the brain to influence brain activity dynamics.
Authors: S. Parker Singleton, Andrea I. Luppi, Robin L. Carhart-Harris, Josephine Cruzat, Leor Roseman, David J. Nutt, Gustavo Deco, Morten L. Kringelbach, Emmanuel A. Stamatakis, Amy Kuceyeski
Institutions: Cornell University, University of Cambridge, University of California, San Francisco, Imperial College London, Universitat Pompeu Fabra, Adolfo Ibáñez University, Institució Catalana de Recerca i Estudis Avançats, Max Planck Institute for Human Cognitive and Brain Sciences, Monash University, Aarhus University, University of Oxford, Weill Cornell Medicine
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: green
Funders: National Science Foundation, Ministerio de Ciencia, Innovación y Universidades, Alexander Mosley Charitable Trust, Beckley Foundation, Imperial College London, National Research Foundation, Danmarks Grundforskningsfond, Cambridge Trust, Ministerio de Ciencia e Innovación, Gates Cambridge Trust, National Institutes of Health, University of California, San Francisco, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Agencia Estatal de Investigación
Awards: G3026416681, G3529715140, G3690828678, G3742369756, G3936970252, G4199552044, G4293036456, Heritability and cognitive implications of structural-functional connectome coupling, G495187929, G4989108295, G5175525644, G5242404030, G534784824, G5374962834, G5554424168, G5555131222, Center for Music in the Brain (MIB), G6299396884, G683931746, G6966048999, Graduate Research Fellowship Program (GRFP), G8229174675, G8684520763, G8858395165, G9000094943
OpenAlex ID: W3159984005