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Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity

Andrew Gaddis, Daniel E. Lidstone, View ORCID ProfileMary Beth Nebel, Roland Griffiths, View ORCID ProfileStewart H. Mostofsky, Amanda Mejia, View ORCID ProfileFrederick Barrett
doi: https://doi.org/10.1101/2022.02.28.482395
Andrew Gaddis
1Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
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  • For correspondence: gaddis@jhmi.edu fbarrett@jhmi.edu
Daniel E. Lidstone
2Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, Maryland, 21205, USA
3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
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Mary Beth Nebel
2Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, Maryland, 21205, USA
3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
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  • ORCID record for Mary Beth Nebel
Roland Griffiths
1Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
4Center for Psychedelic and Consciousness Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21224, USA
5Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
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Stewart H. Mostofsky
1Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
2Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, Maryland, 21205, USA
3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
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  • ORCID record for Stewart H. Mostofsky
Amanda Mejia
6Department of Statistics, Indiana University Bloomington, Bloomington, IN 47408, USA
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Frederick Barrett
1Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
4Center for Psychedelic and Consciousness Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21224, USA
5Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA
7Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218
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  • ORCID record for Frederick Barrett
  • For correspondence: gaddis@jhmi.edu fbarrett@jhmi.edu
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ABSTRACT

Background Serotonin 2A receptor (5-HT2AR) agonist psychedelics including psilocybin and LSD (“classic” psychedelics) evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been proposed to underlie these effects, which is supported by some functional MRI (fMRI) studies. Likely due to sample size limitations, these studies have treated the thalamus as a unitary structure, despite known differential 5-HT2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been employed to generate functional subdivisions of the thalamus from resting state fMRI (rsfMRI) data. This report utilizes a novel data-sparing ICA approach in order to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity.

Methods Baseline rsfMRI data (n=38) was utilized to generate a template, which was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in a smaller sample (n=18). Correlations with subjective reports of drug effect and comparisons with a previously reported analytic approach (treating the thalamus as a single functional unit) were conducted.

Results Several intrathalamic components showed significant psilocybin-induced alterations in intrathalamic spatial organization, largely localized to the mediodorsal and pulvinar nuclei, and correlated with reported subjective effects. These same components demonstrated alterations in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance.

Conclusions Utilization of a novel analytic approach demonstrated changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT2AR. Given that these changes were not observed using whole-thalamus analyses, it seems that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.

Competing Interest Statement

RRG is a board member of the Heffter Research Institute. No other authors have competing interests.

Footnotes

  • https://github.com/mandymejia/templateICA

  • https://github.com/mandymejia/templateICAr

  • https://github.com/KKI-CNIR/CNIR-fmri_preproc_toolbox

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 02, 2022.
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Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity
Andrew Gaddis, Daniel E. Lidstone, Mary Beth Nebel, Roland Griffiths, Stewart H. Mostofsky, Amanda Mejia, Frederick Barrett
bioRxiv 2022.02.28.482395; doi: https://doi.org/10.1101/2022.02.28.482395
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Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity
Andrew Gaddis, Daniel E. Lidstone, Mary Beth Nebel, Roland Griffiths, Stewart H. Mostofsky, Amanda Mejia, Frederick Barrett
bioRxiv 2022.02.28.482395; doi: https://doi.org/10.1101/2022.02.28.482395

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