Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD
Joshua B Burt, Katrin H Preller, Murat Demirtas, Jie Lisa Ji, John H Krystal, Franz X Vollenweider, Alan Anticevic, John D Murray, Joshua B Burt, Katrin H Preller, Murat Demirtas, Jie Lisa Ji, John H Krystal, Franz X Vollenweider, Alan Anticevic, John D Murray
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.
Trial registration: ClinicalTrials.gov NCT02451072.
Keywords: computational model; functional connectivity; gene expression; human; neuroscience; pharmacological neuroimaging.
Conflict of interest statement
JB JBB is currently an employee of RBNC Therapeutics. KP KHP is currently an employee of Hoffmann-La Roche. MD, FV No competing interests declared, JJ JJ has a consulting agreement with BlackThorn Therapeutics. JK JHK has consulting agreements (less than US$10,000 per year) with the following: AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, COMPASS Pathways, Limited, United Kingdom, Concert Pharmaceuticals, Inc, Epiodyne, Inc, EpiVario, Inc, Heptares Therapeutics, Limited (UK), Janssen Research \& Development, Otsuka America, Pharmaceutical, Inc, Perception Neuroscience Holdings, Inc, Spring Care, Inc, Sunovion Pharmaceuticals, Inc, Takeda Industries and Taisho Pharmaceutical Co., Ltd. JHK serves on the scientific advisory boards of Bioasis Technologies, Inc, Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc (Clinical Advisory Board), BlackThorn Therapeutics, Inc, Cadent Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, LLC., EpiVario, Inc, Lohocla Research Corporation, PsychoGenics, Inc; is on the board of directors of Inheris Biopharma, Inc; has stock options with Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, Inc, EpiVario, Inc and Terran Life Sciences; and is editor of Biological Psychiatry with income greater than $10,000. AA AA has a consulting agreement with BlackThorn Therapeutics. AA is co-inventor of United States patent 10950327 "Methods and systems for computer-generated predictive application of neuroimaging and gene expression mapping data". JM JDM has a consulting agreement with BlackThorn Therapeutics. JDM is co-inventor of United States patent 10950327 "Methods and systems for computer-generated predictive application of neuroimaging and gene expression mapping data".
© 2021, Burt et al.
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Source: PubMed