Neural mechanisms of psychedelic visual imagery

Abstract

Visual alterations under classic psychedelics can include rich phenomenological accounts of eyes-closed imagery. Preclinical evidence suggests agonism of the 5-HT2A receptor may reduce synaptic gain to produce psychedelic-induced imagery. However, this has not been investigated in humans. To infer the directed connectivity changes to visual connectivity underlying psychedelic visual imagery in healthy adults, a double-blind, randomised, placebo-controlled, cross-over study was performed, and dynamic causal modelling was applied to the resting state eyes-closed functional MRI scans of 24 subjects after administration of 0.2 mg/kg of the serotonergic psychedelic drug, psilocybin (magic mushrooms), or placebo. The effective connectivity model included the early visual area, fusiform gyrus, intraparietal sulcus, and inferior frontal gyrus. We observed a pattern of increased self-inhibition of both early visual and higher visual-association regions under psilocybin that was consistent with preclinical findings. We also observed a pattern of reduced inhibition from visual-association regions to earlier visual areas that indicated top-down connectivity is enhanced during visual imagery. The results were analysed with behavioural measures taken immediately after the scans, suggesting psilocybin-induced decreased sensitivity to neural inputs is associated with the perception of eyes-closed visual imagery. The findings inform our basic and clinical understanding of visual perception. They reveal neural mechanisms that, by affecting balance, may increase the impact of top-down feedback connectivity on perception, which could contribute to the visual imagery seen with eyes-closed during psychedelic experiences.

Fig. 1. Model of effective connectivity change from placebo to psilocybin.

A Estimated mean effective connectivity 70 min post-administration of placebo, (B) estimated change to effective connectivity from placebo to psilocybin and (C) estimated mean effective connectivity 70 minutes post-administration of psilocybin. Brain regions – Early Visual Area (EVA), Fusiform Gyrus (FG), Inferior Frontal Gyrus (IFG), Intraparietal Sulcus (IPS). Cool colours represent inhibition; warm colours represent excitation. For self-connections only, a positive value indicates a move away from excitation, and is represented here as a cool coloured to indicate increased inhibition. Panel (A) displays placebo mean effective connectivity (EC) for reference. Panel (B) shows change from placebo EC which takes into account EC estimates of placebo and psilocybin, 70 min post administration to provide posterior expectations (see Supplementary Fig 3 (A) and (B)). These estimations of EC change from placebo to psilocybin reinforce the general trend of mean EC findings and are displayed to aid visualisation of the connectivity changes induced by psilocybin. Unlike mean EC of the group at (A) placebo and (C) under psilocybin, change in posterior expectation is calculated by using the posterior means of EC of both conditions but calculated as the Bayesian model average at the group level taken over the two conditions. Panel (C) displays mean EC changes under psilocybin. Self-inhibition of the EVA, FG, IFG and IPS was found. Panel (B) reaffirmed the EVA, FG and IFG self-inhibition. Excitation from the EVA to IFG was absent in psilocybin mean EC (Panel (C)) and can be explained by the inhibitory change displayed in panel (B). The strong inhibitory connectivity estimated from the IFG to the FG was diminished. Inhibition is demonstrated across all efferent connections except the FG, which remained at similar effective size values (posterior expectations) under placebo and psilocybin. Panel (C) also demonstrates behavioural associations to mean EC, 70 min post administration of psilocybin and indicates the direction of EC change found under psilocybin. Behavioural scores were measured on a shortform 5D-ASC in-scanner, immediately after scans. A positive behavioural association, indicated by a red value, means the behavioural variable tends to increase when the EC moves in the excitatory direction. Conversely, a negative association, indicated by a blue value, means the behavioural variable tends to decrease when the EC moves in the excitatory direction. Values for EI = elemental imagery, CI = complex imagery, D = disembodiment and U = experience of unity are displayed. The effect sizes (i.e., the posterior expectations) of connections are in Hz except self-connections which are modelled as always inhibitory and are log-scaled (see Supplementary material for more details). Behavioural associations and connections displayed are estimated at posterior probability >0.99, which amounts to very strong evidence. For results inclusive of posterior probability >0.50, see Supplementary Fig S2.

Fig. 2. Coordinates of regions of interest.

The visual and associative regions comprised of the early visual cortex (EVC), fusiform gyrus (FG); inferior parietal sulcus (IPS) and inferior frontal gyrus (IFG).