Enhanced repertoire of brain dynamical states during the psychedelic experience

Abstract

The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasing interest in neuroimaging. Brain states departing from normal waking consciousness are expected to be accompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experience produced by psilocybin (a substance found in "magic mushrooms") is characterized by unconstrained cognition and profound alterations in the perception of time, space and selfhood. Considering the spontaneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psychedelic experience can be found in the dynamics and variability of spontaneous brain activity fluctuations and connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy subjects were scanned before, during and after intravenous infusion of psilocybin and an inert placebo. Blood-Oxygen Level Dependent (BOLD) temporal variability was assessed computing the variance and total spectral power, resulting in increased signal variability bilaterally in the hippocampi and anterior cingulate cortex. Changes in BOLD signal spectral behavior (including spectral scaling exponents) affected exclusively higher brain systems such as the default mode, executive control, and dorsal attention networks. A novel framework enabled us to track different connectivity states explored by the brain during rest. This approach revealed a wider repertoire of connectivity states post-psilocybin than during control conditions. Together, the present results provide a comprehensive account of the effects of psilocybin on dynamical behavior in the human brain at a macroscopic level and may have implications for our understanding of the unconstrained, hyper-associative quality of consciousness in the psychedelic state.

Keywords: Psilocybin; fMRI; functional connectivity; psychedelic state; resting state.

Figure 1

Psilocybin infusion modifies the temporal variability of BOLD signal in a network comprising anterior cingulate cortex (ACC) and bilateral hippocampus. A) Maps of statistical significance for variance (σ ²) and total spectral power (TP) increases after psilocybin infusion. Results are shown overlaid separately into an anatomical MNI152 template, overlaid together and also rendered together into a three‐dimensional anatomical image. In all cases only clusters surviving a threshold of P < 0.05, Family Wise Error (FWE) cluster corrected (after passing an uncorrected threshold of P < 0.005) are shown. B) BOLD Variance time courses (obtained over a 1 min. sliding window) into the four regions of peak statistical significance defined in Table 1 for the psilocybin and the placebo infusion. C) Variance of the time course of intra‐hippocampal correlations (computed over a range of non‐overlapping window lengths) before and after psilocybin infusion. Results for placebo infusion are shown as insets (before and after in blue and red, respectively). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Psilocybin infusion modifies BOLD spectral content in a distributed fronto‐parietal network. A) Maps of statistical significance for decreased low frequency power (LFP) and power spectrum scaling exponent α after psilocybin infusion. Results are shown overlaid separately into an anatomical MNI152 template, overlaid together and also rendered together into a three‐dimensional anatomical image. Notice that in all cases only clusters surviving a threshold of P < 0.05, FWE cluster corrected (after passing an uncorrected threshold of P < 0.005) are shown. B) Maps of statistical significance of increased power point rate (PPR) and decreased point process interval (PPI) after psilocybin infusion (same renderings and statistical thresholds as in A). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

BOLD spectral changes after psilocybin infusion are located in higher order brain networks and leave primary sensory areas unaffected. A) Overlap between statistical significance maps presented in Figure 2 and a group of well‐established cortical RSN (from Beckmann et al. [2005]) together with the average overlap obtained after 100 spatial randomizations preserving first order statistics (image phase shuffling). (*) indicates an empirical P value smaller than 0.05, Bonferroni corrected. This P value is defined as the ratio of instances in which the real maps yield a higher overlap than the randomized versions. B) Whole brain grey matter average probability distributions for α, LFP, PPR, and PPI, before and after psilocybin infusion. In the inset, the same distributions are shown before and after the placebo infusion. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

Entropy of the dynamical functional connectivity states. Illustration of the procedure to estimate the temporal evolution of the collective states (i.e. all possible 64 motifs) in the network of regions associated with increased temporal variability (bilateral hippocampi and ACC). After selecting the four regions of interest demonstrating enhanced variability after psilocybin infusion (left and right hippocampus, left and right ACC), the partial correlation between all variables is computed (including also the mean head displacement time series as a partial regressor). After thresholding (with P < 0.05, corrected) a series of up to 64 discrete connectivity states are obtained from which the probability distribution can be computed. Finally, from this information, histograms of states (provided here as an illustration) and their corresponding Shannon's entropy (H) can be computed. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 5

Dynamical functional connectivity entropy increased after psilocybin infusion. A) Entropy of connectivity states (H, defined following the procedure outlined in Figure 4 and computed at different time window lengths) are plotted for the comparisons placebo before versus after, psilocybin before versus after and psilocybin after versus placebo after (mean $\pm$ SEM). B) The probability distributions for the (ranked) dynamical functional connectivity states across all conditions. Histograms were obtained pooling states across subjects and window sizes. C) First row: five most frequent connectivity states before the infusion of psilocybin. Second row: five most frequent states after the infusion of psilocybin. Third row: states observed only after the infusion of psilocybin, but absent before the infusion and in the placebo condition. In all cases the lines are used to indicate a significant transient functional connectivity between two nodes. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]