The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity

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 randomised, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100 μg 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 predominantly stronger interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of weakened interregional connectivity and increased self-inhibition in occipital brain regions as well as subcortical regions. Together, these findings suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Notably, whole-brain EC did not only provide additional mechanistic insight into the effects of LSD on the Excitation/Inhibition balance of the brain, but EC also correlated with global subjective effects of LSD and discriminated experimental conditions in a machine learning-based analysis with high accuracy (91.11%), highlighting the potential of using whole-brain EC to decode or predict subjective effects of LSD in the future.

LSD Modulates Proteins Involved in Cell Proteostasis, Energy Metabolism and Neuroplasticity in Human Cerebral Organoids

“…Besides the well-established roles of GABA A receptors, emerging evidence has identified this very specific subunit as a promising therapeutic target for addressing a wide spectrum of neurological and neuropsychiatric disorders (65,66). Interestingly, functional magnetic resonance imaging (fMRI) studies suggest that LSD perturbs the excitation/inhibition balance of the brain (67). On the other hand, OGA is an enzyme that mediates the removal of O-GlcNAc from target proteins (68).…”

LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics

“…Other work has also demonstrated that the psychedelic DMT amplifies bottom-up travelling waves while reducing the power of top-down travelling waves. While there have been an abundance of studies on undirected FC under psychedelics (Barrett, Doss, et al, 2020; Barrett, Krimmel, et al, 2020; Bedford et al, 2023; R. L. Carhart-Harris et al, 2016; Dai et al, 2023; Gaddis et al, 2022; Grimm et al, 2018; Madsen et al, 2021; Mason et al, 2020; Palhano-Fontes et al, 2015; Pallavicini et al, 2019; Roseman et al, 2014; Timmermann et al, 2023), there have been relatively few studies on directed FC by comparison (Alamia et al, 2020; Barnett et al, 2020; de Araujo et al, 2011; Timmermann et al, 2023).…”

Synergistic, Multi-level Understanding of Psychedelics: Three Systematic Reviews and Meta-analyses of Their Pharmacology, Neuroimaging and Phenomenology

“…When we initially looked at the pairwise FC matrices from the studies that we included in the meta-analysis, we were surprised to find that the increases in within-DMN FC outnumbered the decreases. This result was mostly driven by three studies that performed whole-brain seed-to-seed FC analyses (Bedford et al, 2023; Dai et al, 2023; Timmermann et al, 2023). However, we subsequently discovered that many of the regions in these studies overlapped with other Yeo networks besides the DMN.…”