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LSD flattens the brain’s energy landscape: evidence from receptor-informed network control theory

View ORCID ProfileS. Parker Singleton, View ORCID ProfileAndrea I. Luppi, View ORCID ProfileRobin L. Carhart-Harris, View ORCID ProfileJosephine Cruzat, View ORCID ProfileLeor Roseman, View ORCID ProfileGustavo Deco, View ORCID ProfileMorten L. Kringelbach, View ORCID ProfileEmmanuel A. Stamatakis, View ORCID ProfileAmy Kuceyeski
doi: https://doi.org/10.1101/2021.05.14.444193
S. Parker Singleton
ADepartment of Computational Biology, Cornell University, Ithaca, USA
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  • For correspondence: sps253@cornell.edu
Andrea I. Luppi
BDivision of Anesthesia, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
CDepartment of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
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  • ORCID record for Andrea I. Luppi
Robin L. Carhart-Harris
DCenter for Psychedelic Research, Department of Brain Science, Imperial College London, London, United Kingdom
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  • ORCID record for Robin L. Carhart-Harris
Josephine Cruzat
ELatin American Brain Health Institute (BrainLat), Universidad Adolfo Ibanez, Santiago, Chile
FCenter for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Roc Boronat 138, Barcelona, Spain
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Leor Roseman
DCenter for Psychedelic Research, Department of Brain Science, Imperial College London, London, United Kingdom
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Gustavo Deco
FCenter for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies, Universitat Pompeu Fabra, Roc Boronat 138, Barcelona, Spain
GInstitució Catalana de la Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, Barcelona, Spain
HDepartment of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
ISchool of Psychological Sciences, Monash University, Melbourne, Clayton, Australia
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Morten L. Kringelbach
JDepartment of Psychiatry, University of Oxford, Oxford, United Kingdom
KCenter of Music in the Brain (MIB), Clinical Medicine, Aarhus University, Denmark
LCentre for Eudaimonia and Human Flourishing, University of Oxford
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Emmanuel A. Stamatakis
BDivision of Anesthesia, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
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  • ORCID record for Emmanuel A. Stamatakis
Amy Kuceyeski
ADepartment of Computational Biology, Cornell University, Ithaca, USA
MDepartment of Radiology, Weill Cornell Medicine, New York, USA
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Abstract

Psychedelics like lysergic acid diethylamide (LSD) offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. The RElaxed Beliefs Under Psychedelics (REBUS) model postulates that 5-HT2a receptor agonism allows the brain to explore its dynamic landscape more readily, as suggested by more diverse (entropic) brain activity. Formally, this effect is theorized to correspond to a reduction in the energy required to transition between different brain-states, i.e. a “flattening of the energy landscape.” However, this hypothesis remains thus far untested. Here, we leverage network control theory to map the brain’s energy landscape, by quantifying the energy required to transition between recurrent brain states. In accordance with the REBUS model, we show that LSD reduces the energy required for brain-state transitions, and, furthermore, that this reduction in 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, we demonstrate the specific role of this receptor in flattening the brain’s energy landscape. Also, in accordance with REBUS, we show that the occupancy of bottom-up states is increased by LSD. In addition to validating fundamental predictions of the REBUS model of psychedelic action, this work highlights the potential of receptor-informed network control theory to provide mechanistic insights into pharmacological modulation of brain dynamics.

Significance Statement We present a multi-modal framework for quantifying the effects of a psychedelic drug (LSD) on brain dynamics by combining functional magnetic resonance imaging (fMRI), diffusion MRI (dMRI), positron emission tomography (PET) and network control theory. Our findings provide support for a fundamental theory of the mechanism of action of psychedelics by showing that LSD flattens the brain’s energy landscape, allowing for more facile and frequent state transitions and more temporally diverse brain activity. We also demonstrate that the spatial distribution of serotonin 2a receptors - the main target of LSD - is key for generating these effects. This approach could be used to understand how drugs act on different receptors in the brain to influence brain function.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 17, 2021.
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LSD flattens the brain’s energy landscape: evidence from receptor-informed network control theory
S. Parker Singleton, Andrea I. Luppi, Robin L. Carhart-Harris, Josephine Cruzat, Leor Roseman, Gustavo Deco, Morten L. Kringelbach, Emmanuel A. Stamatakis, Amy Kuceyeski
bioRxiv 2021.05.14.444193; doi: https://doi.org/10.1101/2021.05.14.444193
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LSD flattens the brain’s energy landscape: evidence from receptor-informed network control theory
S. Parker Singleton, Andrea I. Luppi, Robin L. Carhart-Harris, Josephine Cruzat, Leor Roseman, Gustavo Deco, Morten L. Kringelbach, Emmanuel A. Stamatakis, Amy Kuceyeski
bioRxiv 2021.05.14.444193; doi: https://doi.org/10.1101/2021.05.14.444193

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