Psilocybin induces time-dependent changes in global functional connectivity
Psi-induced changes in brain connectivity
Affiliations
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Lenggstr. 31, 8032 Zurich, Switzerland
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
Correspondence
- Corresponding Author: Katrin H. Preller, PhD Neuropsychopharmacology and Brain Imaging Department of Psychiatry, Psychotherapy and Psychosomatics Zürich University Hospital for Psychiatry Lenggstrasse 31 CH-8032 Zürich, Switzerland Tel.: +41-44-384-2625 .
Correspondence information about the author Katrin H. PrellerAffiliations
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Lenggstr. 31, 8032 Zurich, Switzerland
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
Correspondence
- Corresponding Author: Katrin H. Preller, PhD Neuropsychopharmacology and Brain Imaging Department of Psychiatry, Psychotherapy and Psychosomatics Zürich University Hospital for Psychiatry Lenggstrasse 31 CH-8032 Zürich, Switzerland Tel.: +41-44-384-2625 .
Affiliations
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Lenggstr. 31, 8032 Zurich, Switzerland
Affiliations
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
- Department of Physics, Yale University, 40 Temple Street, New Haven, CT, 06511, United States
Affiliations
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
Affiliations
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
Affiliations
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Lenggstr. 31, 8032 Zurich, Switzerland
Affiliations
- Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Lenggstr. 31, 8032 Zurich, Switzerland
Affiliations
- Mind and Brain Lab, Department of Psychology, University of Ljubljana, Aškerčeva 2, 1000 Ljubljana, Slovenia
Affiliations
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
Affiliations
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
- Department of Physics, Yale University, 40 Temple Street, New Haven, CT, 06511, United States
- Department of Neuroscience, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
Affiliations
- Department of Psychiatry, Yale University School of Medicine, 40 Temple Street, New Haven, CT, 06511, United States
Affiliations
- Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, Lenggstr. 31, 8032 Zurich, Switzerland
Article Info
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Figure 1
Psilocybin induces changes in Global Brain Connectivity and Subjective Drug Effects. (A) Z-score map for the main effect of Psi condition vs. Pla condition across assessment times (TFCE type I error protected). Red/orange areas indicate regions where participants exhibited stronger GBC in the Psi condition, whereas blue areas indicate regions where participants exhibited reduced GBC condition, compared with the Pla. (B) Distribution plots show the distributions of connectivity strength (Fz) values within grayordinates showing significant hyper- and hypo-connectivity in the main effect of drug. Dashed lines indicate the mean connectivity strength (Fz) for hyper- and hypo-connected areas averaged across grayordinates showing a significant main effect of drug. (C) Psi – Pla condition change scores of mean Fz values within grayordinates showing significant hyper- and hypo-connectivity in the main effect of drug (see Fig. 1A ) for each time point. (D) Scatterplot showing significant negative relationship evident between averaged hyper- and hypo- connected voxels (see Fig. 1A and inlet) across subjects (black data points) for Psi – Pla condition change scores. Grey background indicates the 95% confidence interval. (E) Retrospectively assessed (360 min after drug administration) subjective drug-induced effects. Effects were assessed with the Five Dimension Altered States of Consciousness Questionnaire. EU: Experience of Unity; SE: Spiritual Experience; BS: Blissful State; I: Insightfulness; D: Disembodiment; ICC: Impaired Control and Cognition; A: Anxiety; CI: Complex Imagery; EI: Elementary Imagery; AVS: Audio-Visual Synesthesia; CMP: Changed Meaning of Percepts. (F) Average subjective effect scores in the Pla and Psi condition assessed after each scan (N=22). For all other analyses: N=23. * indicates significant difference between Psi and Pla conditions, p<0.05, Bonferroni corrected.
Figure 2
Effect of Psilocybin on Global Brain Connectivity Increase Over Time From T1 toT3. (A) Left panel shows the unthresholded Z-score map for the Psi vs. Pla condition 20 minutes after substance administration (T1). Red/orange areas indicate regions where participants exhibited stronger GBC in the Psi condition, whereas blue areas indicate regions where participants exhibited reduced GBC in the Psi condition, compared with Pla condition. Histograms show the distribution of Z-scores. Dashed lines indicate the most extreme values. Right panel displays the corresponding significant (TFCE type I error protected) areas showing increased (red) and decreased (blue) GBC in the Psi condition compared to Pla. (B) Distribution plots show the distributions of connectivity strength (Fz) values at T1 within grayordinates showing significant hyper- and hypo-connectivity in the main effect of drug (see Fig. 1A ). Dashed lines indicate the mean connectivity strength (Fz) at T1 for hyper- and hypo-connected areas averaged across grayordinates showing a significant main effect of drug. (C) Scatterplot showing significant negative relationship evident between averaged hyper- and hypo- connected voxels (see Fig. 1A ) across subjects (black data points) for Psi – Pla condition change scores at T1. Grey background indicates the 95% confidence interval. (D) Left panel shows the unthresholded Z-score map for the Psi vs. Pla condition 40 minutes after substance administration (T2). Red/orange areas indicate regions where participants exhibited stronger GBC in the Psi condition, whereas blue areas indicate regions where participants exhibited reduced GBC in the Psi condition, compared with Pla condition. Histograms show the distribution of Z-scores. Dashed lines indicate the most extreme values at T1. Right panel displays the corresponding significant (TFCE type I error protected) areas showing increased (red) and decreased (blue) GBC in the Psi condition compared to Pla. (E) Distribution plots show the distributions of connectivity strength (Fz) values at T2 within grayordinates showing significant hyper- and hypo-connectivity in the main effect of drug (see Fig. 1A ). Dashed lines indicate the mean connectivity strength (Fz) at T2 for hyper- and hypo-connected areas averaged across grayordinates showing a significant main effect of drug. (F) Scatterplot showing significant negative relationship evident between averaged hyper- and hypo- connected voxels (see Fig. 1A ) across subjects (black data points) for Psi – Pla condition change scores at T2. Grey background indicates the 95% confidence interval. (G) Left panel shows the unthresholded Z-score map for the Psi vs. Pla condition 70 minutes after substance administration (T3). Red/orange areas indicate regions where participants exhibited stronger GBC in the Psi condition, whereas blue areas indicate regions where participants exhibited reduced GBC in the Psi condition, compared with Pla condition. Histograms show the distribution of Z-scores. Dashed lines indicate the most extreme values at T1. Right panel displays the corresponding significant (TFCE type I error protected) areas showing increased (red) and decreased (blue) GBC in the Psi condition compared to Pla. (H) Distribution plots show the distributions of connectivity strength (Fz) values at T3 within grayordinates showing significant hyper- and hypo-connectivity in the main effect of drug (see Fig. 1A ). Dashed lines indicate the mean connectivity strength (Fz) at T3 for hyper- and hypo-connected areas averaged across grayordinates showing a significant main effect of drug. (I) Scatterplot showing significant negative relationship evident between averaged hyper- and hypo- connected voxels (see Fig. 1A ) across subjects (black data points) for Psi – Pla condition change scores at T3. Grey background indicates the 95% confidence interval. N=23.
Figure 3
Intra-individual Psilocybin-induced Effects are Correlated Over Time. (A) The left panel shows the Pearson correlation coefficient of reported values on each 5D-ASC short scale, and the mean across scales, between different time points in the Psi condition. The scatterplots show the correlations between time points for the mean of all 5D-ASC short scales. Data points are color coded for each individual and rank-ordered according to their value on the mean 5D-ASC short score at T1. Grey background indicates the 95% confidence interval. N=22. (B) The left panel shows Pearson’s r for the relationships between the unthresholded Z-maps for Psi vs. Pla conditions at T1, T2, and T3 (see Fig. 2 ). The scatterplots illustrate the correlations between Z-maps. Plotted are Z-scores for all grayordinates for the Psi vs. Pla comparison at respective time points (black data points). Ellipse marks the 95% confidence interval. The red line represents the linear regression line. (C) Barplots show average intra-individual correlations between conditions and time points. The left panels show average Pearson’s r. The right panels show average η2. Green bars display mean intra-individual relationships between assessment time points in the Pla condition. Purple bars show mean intra-individual relationships between the mean Pla and Psi time points, as well as each time point in the Psi condition. Error bars represent the standard error of the mean. N=23.
Figure 4
Relationship of Baseline Global Brain Connectivity with Psilocybin-induced Changes in Global Brain Connectivity Increases Over Time. (A) Psi-induced hyper-connectivity (Psi-Pla, left panel) at T3 was significantly correlated with (Pla GBC+Psi GBC)/2 (OH) across individuals. (B) Psi-induced hypo-connectivity (Psi-Pla, left panel) at T3 was significantly correlated with OH across individuals. (C) Psi-induced changes in Fz in hypo and hyper-connected (Psi-Pla, left panel, absolute values) at T3 were significantly correlated with OH across individuals. The right panel shows Pearson’s r vales for the correlation between OH and the Psi-Pla Fz change scores at each time point corresponding to the scatterplots displayed in each panel. Data points are color coded for each individual and rank-ordered according to theirOH score at T1 in hyper-connected areas (panel A). Grey background in scatterplots indicates the 95% confidence interval. N=23.
Figure 5
Correlation between Psilocybin-induced Changes in Global Brain Connectivity and Cortical Gene Expression Topography Over Time. (A) The brain maps illustrate the cortical gene expression levels averaged in the left hemisphere (lateral and medial view) for five receptor genes of interest. On the right, correlations (Pearson’s r) between gene expression maps are shown. (B) The brain maps on the y-axis represent the cortical gene expression levels (see A). The brain maps on the x-axis show the unthresholded Z-score maps for Psi>Pla conditions at T1, T2, and T3 (see Fig. 2 ).Red/orange areas indicate regions where participants exhibited stronger GBC in the Psi condition, whereas blue areas indicate regions where participants exhibited reduced GBC in the Psi condition, compared with Pla. Values are the respective correlation coefficients (Pearson’s r) between Z-score maps and gene expression maps. All correlations were significant (p<0.05, Bonferroni corrected). (C) The histogram depicts the correlation between all gene expression maps and the unthresholded Z-score map for Psi>Pla condition at T1, T2, and T3. The colored lines highlight the HTR1A and HTR2A gene expression maps. (D) The barplot depicts the averaged difference (HTR2A-HTR1A) of correlation values (Pearson’s r) between each individual’s Psi>Pla map at T1, T2, and T3 and the HTR2A and HTR1A gene expression map. N=23.
Abstract
Background
The use of Psilocybin in scientific and experimental clinical contexts has triggered renewed interest in the mechanism of action of psychedelics. However, its time-dependent systems-level neurobiology remains sparsely investigated in humans.
Methods
We therefore conducted a double-blind, randomized, counterbalanced, cross-over study during which 23 healthy human participants received placebo and 0.2 mg/kg of psilocybin p.o. on two different test days. Participants underwent MRI scanning at three time points between administration and peak effects: 20 mins, 40 mins, and 70 mins after administration. Resting-state functional connectivity was quantified via a data-driven global brain connectivity method and compared to cortical gene expression maps.
Results
Psilocybin reduced associative, but concurrently increased sensory brain-wide connectivity. This pattern emerged over time from administration to peak-effects. Furthermore, we show that baseline connectivity is associated with the extent of Psilocybin-induced changes in functional connectivity. Lastly, Psilocybin induced changes correlated time-dependently with spatial gene expression patterns of the 5-HTR2A and 5-HTR1A.
Conclusions
These results suggest that the integration of functional connectivity in sensory and the disintegration in associative regions may underlie the psychedelic state and pinpoint the critical role of the serotonin 2A and 1A receptor systems. Furthermore, baseline connectivity may represent a predictive marker of the magnitude of changes induced by psilocybin and may therefore contribute to a personalized medicine approach within the potential framework of psychedelic treatment.
Keywords:
Serotonin, psilocybin, fMRI, global brain connectivity, functional connectivity, receptor gene expressionTo access this article, please choose from the options below
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This study was registered as a clinical trial at ClinicalTrials.gov, NCT03736980, https://clinicaltrials.gov/ct2/show/NCT03736980
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