Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD

A computational model that simulates how LSD affects human brain activity shows that the drug alters communication between cortical areas by increasing the sensitivity of pyramidal neurons via the serotonin-2A receptor. The model accurately reproduced changes in functional connectivity observed in brain scans, and fitting it to individual participants captured personal differences in drug response related to altered consciousness. This approach links molecular drug actions to large-scale brain network changes, offering a path toward personalized medicine.

Study at a glance

Abstract

Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically induced effects. Previously, using pharmacological neuroimaging, we found that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to agonism of the serotonin-2A receptor (Preller et al., 2018). Here, we integrate brain-wide transcriptomics with biophysically based circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical large-scale spatiotemporal dynamics. Our model captures the inter-areal topography of LSD-induced changes in cortical blood oxygen level-dependent (BOLD) functional connectivity. These findings suggest that serotonin-2A-mediated modulation of pyramidal-neuronal gain is a circuit mechanism through which LSD alters cortical functional topography. Individual-subject model fitting captures patterns of individual neural differences in pharmacological response related to altered states of consciousness. This work establishes a framework for linking molecular-level manipulations to systems-level functional alterations, with implications for precision medicine.