Knocking at the Doors of Perception: Relating LSD Effects on Low-Frequency Fluctuations and Regional Homogeneity to Receptor Densities in fMRI

Despite a renewed scientific interest in lysergic acid diethylamide (LSD), its local neurofunctional effects remain underexplored. This functional Magnetic Resonance Imaging (fMRI) study explored and compared LSD-induced changes in local activity (amplitude of low-frequency fluctuations: ALFF) and local connectivity (regional homogeneity: ReHo), assessing their relationship to regional receptor density. Imaging data of 15 healthy adults from an open dataset were analyzed. For each participant, two pairs of resting-state runs were available (rest1 and rest2), one performed under placebo and one following the intravenous administration of 75μg LSD. Voxel-wise paired t-tests compared ALFF and ReHo in the LSD versus placebo conditions. Rest1*rest2 test-retest reliability and ALFF*ReHo cross-modal associations were assessed with conjunction maps and vertex-wise correlations. Finally, neurochemical enrichment analyses related LSD-induced ALFF and ReHo changes to cortical density maps of LSD-related neurotransmitter receptors and transporters. Both ALFF and ReHo decreased in somatosensory/visual cortices under LSD compared to placebo. Specific decreases were observed for ALFF in associative regions belonging to the Default Mode and Fronto-Parietal networks, and for ReHo in subcortical regions (cluster-based corrected p<0.05). Test-retest reliability was high for ALFF (rho=0.80, p=0.001) and moderate for ReHo (rho=0.46, p=0.001). ALFF*ReHo LSD-induced changes were moderately associated (rest1: rho=0.36, p=0.001; rest2: rho=0.56 p=0.001). Neurochemical enrichment analysis showed that LSD-induced ALFF/ReHo alterations occurred in regions with high density for D2 and 5HT1a receptors (FDR-corrected p<0.05). Together, interactions between reliable neurofunctional indexes and D2 and 5HT1a receptor densities unravel the involvement of novel, complex, and dynamic processes triggered by LSD.