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

AbstractPsychedelics 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 StatementWe 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.