Spatial correspondence of LSD-induced variations of brain functioning at rest with serotonin receptor expression
This analysis of resting-state fMRI (n=15) of LSD (75μg) effects on the brain finds modifications in serotonin receptor-rich areas. The local signal amplitude and functional connectivity (FC) increased in the default mode network (DMN) and attention networks (rich in serotonin 2a receptors). A decrease was seen in limbic areas (with many serotonin 1a receptors).
Authors
- Robin Carhart-Harris
- David Nutt
- Christopher Timmermann
Published
Abstract
Background
Lysergic acid diethylamide (LSD) is an atypical psychedelic compound exerting its effects through pleiotropic actions, mainly involving 1A/2A serotoninergic (5-HT) receptor subtypes. However, the mechanisms by which LSD promotes a reorganization of the brain's functional activity and connectivity are still partially unknown.
Methods
Our study analyzed resting-state functional magnetic resonance imaging (rs-fMRI) data acquired from fifteen healthy volunteers undergoing LSD acute intake. A voxel-wise analysis investigated the alterations of the brain's intrinsic functional connectivity and local signal amplitude induced by LSD or by a placebo. Quantitative comparisons assessed the spatial overlap between these two indices of functional reorganization and the topography of receptor expression obtained from a publicly available collection of in-vivo, whole-brain atlases. Finally, linear regression models explored the relationships between changes in rs-fMRI and behavioral aspects of the psychedelic experience.
Results
LSD elicited modifications of the cortical functional architecture that spatially overlapped with the distribution of serotoninergic receptors. Local signal amplitude and functional connectivity increased in regions belonging to the default mode and attention networks associated with high expression of 5-HT2A receptors. These functional changes correlate with the occurrence of simple and complex visual hallucinations. At the same time, a decrease in local signal amplitude and intrinsic connectivity was observed in limbic areas, which are dense with 5-HT1A receptors.
Conclusions
This study provides new insights into the neural processes underlying the brain network reconfiguration induced by LSD. It also identifies a topographical relationship between opposite effects on brain functioning and the spatial distribution of different 5-HT receptors.
Research Summary of 'Spatial correspondence of LSD-induced variations of brain functioning at rest with serotonin receptor expression'
Introduction
Delli Pizzi and colleagues situate their work within a recent resurgence of experimental research on LSD, noting that psychedelic compounds illuminate the neural bases of perception and selfhood and hold therapeutic promise for mood disorders. While partial agonism at 5-HT2A receptors is widely regarded as central to psychedelic effects, LSD is pharmacologically atypical because it also engages 5-HT1A receptors; how these pleiotropic actions map onto large-scale changes in brain function remains incompletely understood. Previous fMRI studies have reported increased between-network cortical connectivity under LSD and some voxel-wise work has suggested spatial overlap between LSD-induced connectivity changes and cortical 5-HT receptor topography, but questions remain about whether single or multiple receptor subtypes explain bidirectional connectivity effects and how local neuronal activity is affected in parallel. The present study set out to test whether voxel-wise changes in intrinsic functional connectivity and local signal amplitude induced by acute LSD map onto the cortical distribution of 5-HT1A and 5-HT2A receptors. To do so, the investigators analysed resting-state fMRI from a placebo-controlled, within-subject design in healthy volunteers, computing Intrinsic Connectivity Contrast (ICC) as a whole-brain centrality metric and fractional Amplitude of Low-Frequency Fluctuations (fALFF) as a proxy for local signal amplitude. The authors predicted both increases and decreases in connectivity that might parallel increases and decreases in local amplitude, and that these spatial patterns would correspond to receptor density maps obtained from in-vivo PET atlases; they also planned exploratory tests of relationships between rs-fMRI changes and subjective visual hallucinations.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Delli Pizzi, S., Chiacchiaretta, P., Sestieri, C., Ferretti, A., Onofrj, M., Della Penna, S., Roseman, L., Timmermann, C., Nutt, D. J., Carhart-Harris, R. L., & Sensi, S. L. (2023). Spatial correspondence of LSD-induced variations of brain functioning at rest with serotonin receptor expression. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 8(7), 768-776. https://doi.org/10.1016/j.bpsc.2023.03.009
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