Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain’s control energy landscape (original) (raw)
2022, Nature Communications
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. Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin induce a profound but temporary alteration of perception and subjective experience 1. Combined with non-invasive neuroimaging such as functional MRI, these drugs offer a unique window into the function of the human mind and brain, making it possible to relate mental phenomena to their neural underpinnings. A decade of neuroimaging studies has informed novel insights regarding psychedelic action in the brain 2. One model, known as RElaxed Beliefs Under Psychedelics (REBUS) 3 , integrates previous accounts of psychedelic action (the Entropic Brain Hypothesis) 4,5 with the view of the brain as a prediction engine, whereby perception and belief are shaped by both prior knowledge and incoming information. The REBUS model postulates that psychedelics alter conscious experience via their agonist action at serotonin 2a (5-HT2a) receptors, which have especially high expression in higher-order cortical regions. Agonist-induced dysregulation of spontaneous activity in these regions is postulated to translate into decreased precision-weighting on prior beliefs-which has reciprocal (enabling) implications for bottom-up information flow. It is theorized that the observed increase in entropy of brain activity under psychedelics is reflective of reduced
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