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

Introduction

Previous neuroimaging studies have shown that acute pharmacological perturbations can reveal how physiological state shapes large-scale brain dynamics. Serotonergic hallucinogens such as LSD produce rapid and reproducible changes in consciousness that are linked to widespread, stereotyped disruptions of functional networks. Burt and colleagues note prior findings that LSD-induced alterations in BOLD functional connectivity, operationalised as global brain connectivity (GBC), are abolished by pre-treatment with the selective 5-HT2A antagonist ketanserin and that the regional pattern of LSD-induced GBC change aligns with the spatial expression of HTR2A, the gene encoding the 5-HT2A receptor. Despite these observations, the circuit-level mechanism through which 5-HT2A activation produces the observed topography of functional reorganisation remained unresolved. This study therefore combines brain-wide transcriptomics with a biophysically grounded large-scale cortical model to test whether regionally heterogeneous modulation of neuronal gain, scaled by HTR2A expression, can reproduce LSD-induced GBC topography. The investigators aim to (i) implement a physiologically interpretable model of cortex capable of simulating BOLD signals, (ii) perturb the model by regionally varying gain in proportion to transcriptomic maps, and (iii) determine whether the model reproduces group-level and individual-subject patterns of LSD effects and their relation to altered states of consciousness.