Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape
Combining PET maps of 19 neurotransmitter receptors and transporters with fMRI connectivity changes produced by ten psychoactive drugs, the authors show that pharmacological effects arise from engagement of multiple neurotransmitter systems and are organised along hierarchical gradients of brain structure and function. They further show that regional co‑susceptibility to drugs mirrors co‑susceptibility to disorder‑related structural alterations, linking molecular chemoarchitecture to macroscale functional reorganisation.
Authors
- Robin Carhart-Harris
- Leor Roseman
- Draulio Araújo
Published
Abstract
To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain’s rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brain’s functional architecture.
Research Summary of 'Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape'
Introduction
Luppi and colleagues frame the study around the challenge of understanding how psychoactive compounds—ranging from anaesthetics to psychedelics and cognitive enhancers—produce profound but reversible alterations of brain function. Earlier work has shown that many such drugs target specific neurotransmitter systems (for example, propofol acting on GABA-A), and that acute pharmacological manipulations combined with non-invasive imaging can probe causally how brain organisation supports cognition and consciousness. However, it remains unclear how the brain's full, high-dimensional ‘‘neurotransmitter landscape’’ maps onto macroscale, drug-induced reorganisation of functional connectivity, and whether common topographic or hierarchical patterns underlie diverse drug effects. This study set out to bridge microscale molecular chemoarchitecture and macroscale functional reorganisation by relating PET-derived cortical maps of 18 receptors and transporters (across nine neurotransmitter systems) to regional changes in resting-state fMRI connectivity induced by seven mind-altering drugs (including anaesthetics, psychedelics, and cognitive enhancers). The investigators aimed to (i) test whether regions with similar receptor/transporter profiles respond similarly to pharmacological perturbation, (ii) identify multivariate receptor–drug associations using Partial Least Squares (PLS), and (iii) determine how drug-induced reorganisation aligns with canonical cortical hierarchies and with region-to-region co-susceptibility to disease-related structural abnormalities.
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Study Details
- Study Typeindividual
- Journal
- Compounds
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- APA Citation
Luppi, A. I., Hansen, J. Y., Adapa, R., Carhart-Harris, R. L., Roseman, L., Timmermann, C., Golkowski, D., Ranft, A., Ilg, R., Jordan, D., Bonhomme, V., Vanhaudenhuyse, A., Demertzi, A., Jaquet, O., Bahri, M. A., Alnagger, N. L., Cardone, P., Peattie, A. R. D., Manktelow, A. E., . . . Stamatakis, E. A. (2022). Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape. https://doi.org/10.1101/2022.07.12.499688
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