Psilocybin desynchronizes brain networks

Abstract

1The relationship between the acute effects of psychedelics and their persisting neurobiological and psychological effects is poorly understood. Here, we tracked brain changes with longitudinal precision functional mapping in healthy adults before, during, and for up to 3 weeks after oral psilocybin and methylphenidate (17 MRI visits per participant) and again 6+ months later. Psilocybin disrupted connectivity across cortical networks and subcortical structures, producing more than 3-fold greater acute changes in functional networks than methylphenidate. These changes were driven by desynchronization of brain activity across spatial scales (area, network, whole brain). Psilocybin-driven desynchronization was observed across association cortex but strongest in the default mode network (DMN), which is connected to the anterior hippocampus and thought to create our sense of self. Performing a perceptual task reduced psilocybin-induced network changes, suggesting a neurobiological basis for grounding, connecting with physical reality during psychedelic therapy. The acute brain effects of psilocybin are consistent with distortions of space-time and the self. Psilocybin induced persistent decrease in functional connectivity between the anterior hippocampus and cortex (and DMN in particular), lasting for weeks but normalizing after 6 months. Persistent suppression of hippocampal-DMN connectivity represents a candidate neuroanatomical and mechanistic correlate for psilocybin's pro-plasticity and anti-depressant effects.

Figure 1.. Psilocybin causes dramatic acute brain network changes.

Brain-wide connectivity change (Euclidian distance) was calculated across the cortex and subcortical structures and effects of condition were determined with a linear mixed effects (LME) model. a) Top: psilocybin-associated network change (LME model, t-statistic). Middle: methylphenidate-associated network stimulant. Bottom: day to day FC variability (random effect of day). b) Whole Brain network change magnitude (Euclidian distance between brain-wide connectivity matrices) reveals that psilocybin produces much larger change than methylphenidate, closer in magnitude to between person differences. Vertical bars and asterisks indicate significance (p<0.05) for post-hoc t-test between conditions. c) Change by system (resting-state network), based on individualized Infomap parcellation. Open circles represent individual subjects, bars represent average magnitude. *Disruption was significantly enriched within the default mode network based on rotation permutation testing. d) Psilocybin Network Change across the bilateral hippocampus, basal ganglia, and cerebellum (same color scale as panel a).

Figure 2.. Multi-dimensional Scaling identifies acute and persistent drug effects.

In the scatter plots, each point represents the functional network from a single scan, plotted in a multidimensional space based on the similarity between scans. Replication scans are represented with open circles. a) Dimensions 1 and 4 are plotted for every 15-minute scan. In the top panel, points are colored based on drug condition. In the bottom panel, points are colored based on participant identity. Dimension 1 separates psilocybin from non-drug and MTP scans in most cases. Dimension 4 separates individuals in most cases and shows a small but significant before/after effect. C) Visualization of dimension 1 weights (top 1% of edges are projected onto the brain to show the connections most effected by psilocybin). D) In additional datasets with LSD (top) and psilocybin (bottom), psychedelic causes reliable change along dimension 1.

Figure 3.. Increased spatial entropy (desynchronization of cortical activity) during psilocybin.

a) normalized global spatial complexity (NGSC) captures the ‘complexity’ of brain activity patterns. It is derived from the number of spatial principal components (PCs) used to explain the data. Higher entropy = less desynchronized activity. b) Whole-brain entropy (NGSC) is shown for every fMRI scan for a single participant (P6). Psilocybin scans are shown in red. At right, increases during psilocybin were present in all participants (box and whiskers indicate quartiles and 99.7th percentiles for non-drug scans, red circles indicate psilocybin) c) Entropy within functional brain areas shown similar increases. d) Spatial entropy is visualized on the cortical surface. Psilocybin-associated increase in entropy was largest in association cortices. This was replicated in LSD data (middle; using data from Carhart-Harris et al., 2016) and corresponds spatially to 5ht2A binding density (bottom; borrowed with permission from Beliveau et al., 2017).

Figure 4.. A persisting decrease in anterior hippocampal-DMN connectivity after psilocybin.

a) Group network change (relative to baseline) t-maps, left hippocampus: top=acute psilocybin, bottom = persisting (2 weeks after psilocybin. b) All subjects demonstrated a weakening of anterior hippocampal-cortical FC post-psilocybin (p=5.1e-5; linear mixed effects model accounting for head motion and subject ID). c) Connectivity from an anterior hippocampus seedmap at baseline, post-psilocybin and change for an exemplar (P3). The red border on the right-most brain illustrates individual-defined default mode network. A decrease in hippocampal FC with parietal and frontal components of the DMN is seen. d) Timecourse of anterior hippocampus - DMN for all participants/scans (participant colors as in panel b). A moving average is shown in black. e) schematic of hippocampal-cortical circuits, borrowed from Zheng et al., 2021.