The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity
Using regression dynamic causal modelling of resting-state fMRI in a randomized placebo-controlled crossover (n=45), LSD produced widespread increases in interregional effective connectivity and reduced self-inhibition — except in occipital regions where interregional connectivity decreased and self-inhibition increased — consistent with a perturbation of the brain's excitation/inhibition balance. Both effective connectivity and functional connectivity distinguished LSD from placebo with high accuracy (EC 91.11%, FC 85.56%), indicating their promise as clinically relevant biomarkers.
Authors
- Patrick Vizeli
- Stefan Borgwardt
- Felix Müller
Published
Abstract
Psychedelics have emerged as promising candidate treatments for various psychiatric conditions, and given their clinical potential, there is a need to identify biomarkers that underlie their effects. Here, we investigate the neural mechanisms of lysergic acid diethylamide (LSD) using regression dynamic causal modelling (rDCM), a novel technique that assesses whole-brain effective connectivity (EC) during resting-state functional magnetic resonance imaging (fMRI). We modelled data from two randomized, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100 μ g LSD and placebo in two resting-state fMRI sessions. We compared EC against whole-brain functional connectivity (FC) using classical statistics and machine learning methods. Multivariate analyses of EC parameters revealed widespread increases in interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of primarily decreased interregional connectivity and increased self-inhibition in occipital brain regions. This finding suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Moreover, random forests classified LSD vs. placebo states based on FC and EC with comparably high accuracy (FC: 85.56%, EC: 91.11%) suggesting that both EC and FC are promising candidates for clinically-relevant biomarkers of LSD effects.
Research Summary of 'The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity'
Introduction
Bedford and colleagues frame the study within growing clinical interest in psychedelics such as psilocybin and LSD as potential treatments for several psychiatric disorders. They note that both functional connectivity (FC) and effective connectivity (EC) have shown promise as biomarkers of psychedelic effects, but that FC is an undirected, correlational measure that does not capture connection asymmetry or within-region gain (self-connections). By contrast, EC is derived from mechanistic generative models and can estimate directed influences and local gain, potentially offering greater interpretability about neural mechanisms. Against this background, the investigators set out to examine LSD-induced changes in whole-brain EC during resting-state fMRI, using regression dynamic causal modelling (rDCM), a recently developed variant of dynamic causal modelling that enables whole-brain EC estimation in resting-state data. They also compared EC to conventional FC in multivariate and machine-learning analyses, and tested whether connectivity measures related to retrospective subjective effects, with the objective of assessing EC's potential as a mechanistic biomarker that could decode or predict subjective responses to LSD.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topic
- Authors
- APA Citation
Bedford, P., Hauke, D. J., Wang, Z., Roth, V., Nagy-Huber, M., Holze, F., Ley, L., Vizeli, P., Liechti, M. E., Borgwardt, S., Müller, F., & Diaconescu, A. O. (2022). The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity. https://doi.org/10.1101/2022.11.01.514687
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