In vivo mapping of pharmacologically induced functional reorganization onto the human brain’s neurotransmitter landscape

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Abstract

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brain’s rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically induced macroscale functional reorganization, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from positron emission tomography, and the regional changes in functional magnetic resonance imaging connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, lysergic acid diethylamide (LSD), psilocybin, N,N-Dimethyltryptamine (DMT), ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA), modafinil, and methylphenidate. Our results reveal a many-to-many mapping between psychoactive drugs’ effects on brain function and multiple neurotransmitter systems. The effects of both anesthetics and psychedelics on brain function are organized along hierarchical gradients of brain structure and function. Last, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganization of the brain’s functional architecture.

Abstract

Anaesthetics and psychedelics systematically engage diverse neurotransmitter systems to perturb consciousness.

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Most cited references 115

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Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

Yoav Benjamini, Yosef Hochberg (1995)

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The organization of the human cerebral cortex estimated by intrinsic functional connectivity.

B T Thomas Yeo, Fenna M Krienen, Jorge Sepulcre … (2011)

Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.

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Local-Global Parcellation of the Human Cerebral Cortex from Intrinsic Functional Connectivity MRI.

Alexander Schaefer, Ru Kong, Evan Gordon … (2018)

A central goal in systems neuroscience is the parcellation of the cerebral cortex into discrete neurobiological "atoms". Resting-state functional magnetic resonance imaging (rs-fMRI) offers the possibility of in vivo human cortical parcellation. Almost all previous parcellations relied on 1 of 2 approaches. The local gradient approach detects abrupt transitions in functional connectivity patterns. These transitions potentially reflect cortical areal boundaries defined by histology or visuotopic fMRI. By contrast, the global similarity approach clusters similar functional connectivity patterns regardless of spatial proximity, resulting in parcels with homogeneous (similar) rs-fMRI signals. Here, we propose a gradient-weighted Markov Random Field (gwMRF) model integrating local gradient and global similarity approaches. Using task-fMRI and rs-fMRI across diverse acquisition protocols, we found gwMRF parcellations to be more homogeneous than 4 previously published parcellations. Furthermore, gwMRF parcellations agreed with the boundaries of certain cortical areas defined using histology and visuotopic fMRI. Some parcels captured subareal (somatotopic and visuotopic) features that likely reflect distinct computational units within known cortical areas. These results suggest that gwMRF parcellations reveal neurobiologically meaningful features of brain organization and are potentially useful for future applications requiring dimensionality reduction of voxel-wise fMRI data. Multiresolution parcellations generated from 1489 participants are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Schaefer2018_LocalGlobal).

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Author and article information

Contributors

Andrea I. Luppi:

ORCID: https://orcid.org/0000-0002-3461-6431

Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Project administrationRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draft

Justine Y. Hansen:

ORCID: https://orcid.org/0000-0003-3142-7480

Role: ConceptualizationRole: MethodologyRole: SoftwareRole: Writing - review & editing

Ram Adapa:

ORCID: https://orcid.org/0000-0002-9845-8532

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing - review & editing

Robin L. Carhart-Harris: Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Leor Roseman:

ORCID: https://orcid.org/0000-0001-9990-6029

Role: Formal analysisRole: InvestigationRole: Writing - review & editing

Christopher Timmermann:

ORCID: https://orcid.org/0000-0002-2281-377X

Role: InvestigationRole: ResourcesRole: Writing - review & editing

Daniel Golkowski: Role: InvestigationRole: ResourcesRole: Validation

Andreas Ranft:

ORCID: https://orcid.org/0000-0002-0530-0796

Role: InvestigationRole: Writing - review & editing

Rüdiger Ilg: Role: InvestigationRole: Resources

Denis Jordan: Role: Formal analysisRole: InvestigationRole: Writing - review & editing

Vincent Bonhomme:

ORCID: https://orcid.org/0000-0001-6356-547X

Role: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Audrey Vanhaudenhuyse:

ORCID: https://orcid.org/0000-0002-4288-9237

Role: ConceptualizationRole: Data curationRole: InvestigationRole: ResourcesRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Athena Demertzi:

ORCID: https://orcid.org/0000-0001-8021-3759

Role: InvestigationRole: Resources

Oceane Jaquet:

ORCID: https://orcid.org/0000-0002-6460-7982

Role: InvestigationRole: Methodology

Mohamed Ali Bahri:

ORCID: https://orcid.org/0000-0002-6919-3360

Role: Methodology

Naji L. N. Alnagger:

ORCID: https://orcid.org/0000-0002-7880-6237

Role: ConceptualizationRole: Data curationRole: Writing - review & editing

Paolo Cardone:

ORCID: https://orcid.org/0000-0002-8537-2123

Role: Investigation

Alexander R. D. Peattie:

ORCID: https://orcid.org/0000-0003-2115-7640

Role: Data curationRole: Formal analysisRole: ResourcesRole: Writing - review & editing

Anne E. Manktelow:

ORCID: https://orcid.org/0000-0002-2319-1669

Role: InvestigationRole: Writing - review & editing

Draulio B. de Araujo:

ORCID: https://orcid.org/0000-0002-6934-2485

Role: InvestigationRole: Writing - review & editing

Stefano L. Sensi:

ORCID: https://orcid.org/0000-0002-0710-2574

Role: ConceptualizationRole: InvestigationRole: Writing - original draftRole: Writing - review & editing

Adrian M. Owen:

ORCID: https://orcid.org/0000-0002-5738-3765

Role: ConceptualizationRole: Project administrationRole: SupervisionRole: Writing - review & editing

Lorina Naci:

ORCID: https://orcid.org/0000-0001-9630-3978

Role: InvestigationRole: MethodologyRole: Writing - review & editing

David K. Menon:

ORCID: https://orcid.org/0000-0002-3228-9692

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Bratislav Misic:

ORCID: https://orcid.org/0000-0003-0307-2862

Role: ConceptualizationRole: MethodologyRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: Writing - review & editing

Emmanuel A. Stamatakis:

ORCID: https://orcid.org/0000-0001-6955-9601

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: June 2023

Publication date (Electronic, pub): 14 June 2023

Volume: 9

Issue: 24

Electronic Location Identifier: eadf8332

Affiliations

[ ¹ ]Division of Anaesthesia, University of Cambridge, Cambridge, UK.

[ ² ]Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

[ ³ ]Leverhulme Centre for the Future of Intelligence, University of Cambridge, Cambridge, UK.

[ ⁴ ]The Alan Turing Institute, London, UK.

[ ⁵ ]McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

[ ⁶ ]Psychedelics Division - Neuroscape, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

[ ⁷ ]Center for Psychedelic Research, Department of Brain Sciences, Imperial College London, London, UK.

[ ⁸ ]Department of Neurology, Klinikum rechts der Isar, Technical University Munich, München, Germany.

[ ⁹ ]School of Medicine, Department of Anesthesiology and Intensive Care, Technical University of Munich, Munich, Germany.

[ ¹⁰ ]Department of Neurology, Asklepios Clinic, Bad Tölz, Germany.

[ ¹¹ ]Department of Anaesthesiology and Intensive Care Medicine, Klinikum rechts der Isar, Technical University Munich, München, Germany.

[ ¹² ]University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland.

[ ¹³ ]Department of Anesthesia and Intensive Care Medicine, Liege University Hospital, Liege, Belgium.

[ ¹⁴ ]Anesthesia and Perioperative Neuroscience Laboratory, GIGA-Consciousness Thematic Unit, GIGA-Research, Liege University, Liege, Belgium.

[ ¹⁵ ]GIGA-Cyclotron Research Centre-In Vivo Imaging, University of Liege, Liege, Belgium.

[ ¹⁶ ]Brain Institute, Federal University of Rio Grande do Norte, Natal, RN, Brazil.

[ ¹⁷ ]Department of Neuroscience and Imaging and Clinical Science, Center for Advanced Studies and Technology, Institute for Advanced Biomedical Technologies, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.

[ ¹⁸ ]Institute for Memory Impairments and Neurological Disorders, University of California-Irvine, Irvine, CA, USA.

[ ¹⁹ ]Department of Psychology and Department of Physiology and Pharmacology, Western Institute for Neuroscience (WIN), Western University, London, ON, Canada.

[ ²⁰ ]Trinity College Institute of Neuroscience, School of Psychology, Trinity College Dublin, Dublin, Ireland.

[ ²¹ ]Wolfon Brain Imaging Centre, University of Cambridge, Cambridge, UK.

Author notes

[* ]Corresponding author. Email: al857@ 123456cam.ac.uk

Author information

Andrea I. Luppi https://orcid.org/0000-0002-3461-6431

Justine Y. Hansen https://orcid.org/0000-0003-3142-7480

Ram Adapa https://orcid.org/0000-0002-9845-8532

Leor Roseman https://orcid.org/0000-0001-9990-6029

Christopher Timmermann https://orcid.org/0000-0002-2281-377X

Andreas Ranft https://orcid.org/0000-0002-0530-0796

Vincent Bonhomme https://orcid.org/0000-0001-6356-547X

Audrey Vanhaudenhuyse https://orcid.org/0000-0002-4288-9237

Athena Demertzi https://orcid.org/0000-0001-8021-3759

Oceane Jaquet https://orcid.org/0000-0002-6460-7982

Mohamed Ali Bahri https://orcid.org/0000-0002-6919-3360

Naji L. N. Alnagger https://orcid.org/0000-0002-7880-6237

Paolo Cardone https://orcid.org/0000-0002-8537-2123

Alexander R. D. Peattie https://orcid.org/0000-0003-2115-7640

Anne E. Manktelow https://orcid.org/0000-0002-2319-1669

Draulio B. de Araujo https://orcid.org/0000-0002-6934-2485

Stefano L. Sensi https://orcid.org/0000-0002-0710-2574

Adrian M. Owen https://orcid.org/0000-0002-5738-3765

Lorina Naci https://orcid.org/0000-0001-9630-3978

David K. Menon https://orcid.org/0000-0002-3228-9692

Bratislav Misic https://orcid.org/0000-0003-0307-2862

Emmanuel A. Stamatakis https://orcid.org/0000-0001-6955-9601

Article

Publisher ID: adf8332

DOI: 10.1126/sciadv.adf8332

PMC ID: 10266734

PubMed ID: 37315149

SO-VID: 783f55a1-af47-433d-bc4f-0b4b2157404c

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 15 November 2022

Date accepted : 10 May 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000913, James S. McDonnell Foundation;

Funded by: FundRef http://dx.doi.org/10.13039/100007631, Canadian Institute for Advanced Research;

Award ID: RCZB/072 RG93193

Funded by: FundRef http://dx.doi.org/10.13039/100007631, Canadian Institute for Advanced Research;

Funded by: FundRef http://dx.doi.org/10.13039/100008069, University of California, San Francisco;

Funded by: FundRef http://dx.doi.org/10.13039/100014735, Royal College of Physicians and Surgeons of Canada;

Funded by: FundRef http://dx.doi.org/10.13039/501100000038, Natural Sciences and Engineering Research Council of Canada;

Award ID: 017-04265

Funded by: FundRef http://dx.doi.org/10.13039/100018382, Beckley Foundation;

Funded by: FundRef http://dx.doi.org/10.13039/100013057, Heffter Research Institute;

Funded by: FundRef http://dx.doi.org/10.13039/100018491, Health Sciences, University of Arizona;

Funded by: FundRef http://dx.doi.org/10.13039/100015904, Alexander Mosley Charitable Trust;

Funded by: FundRef http://dx.doi.org/10.13039/100010269, Wellcome;

Funded by: Helmholtz International BigBrain Analytics and Learning Laboratory the Natural Sciences and Engineering Research Council of Canada and Fonds;

Funded by: Oreal Unesco for Women in Science Excellence Research Fellowship to LN;

Funded by: FundRef http://dx.doi.org/10.13039/501100002661, Fonds De La Recherche Scientifique - FNRS;

Funded by: Human Brain Project to NLNA;

Funded by: Neuropsychoanalysis Foundation;

Funded by: Multidisplinary Association for Psychedelic Studies;

Funded by: Bernard Wolfe Health Neuroscience Fund;

Funded by: Technical University Munich;

Funded by: Pain management BeSARPP Brussels Belgium;

Funded by: Belgian National Funds for Scientific Research Brussels Belgium;

Funded by: FundRef http://dx.doi.org/10.13039/501100018942, Centro Singular de Investigación de Galicia;

Funded by: FundRef http://dx.doi.org/10.13039/501100000272, National Institute for Health Research;

Funded by: FundRef http://dx.doi.org/10.13039/501100000038, Natural Sciences and Engineering Research Council of Canada;

Funded by: FundRef http://dx.doi.org/10.13039/501100002661, Fonds De La Recherche Scientifique - FNRS;

Funded by: FundRef http://dx.doi.org/10.13039/501100014602, GIGA German Institute of Global and Area Studies;

Funded by: FundRef http://dx.doi.org/10.13039/501100020643, Medical Research Centre;

Funded by: Mind Science Foundation San Antonio Texas;

Funded by: Travail Brussels Belgium;

Funded by: Fondazione Europea di Ricerca Biomedica Milan Italy;

Funded by: University Hospital of Liege Liege Belgium;

Funded by: European Commission Brussels Belgium;

Funded by: European Space Agency Brussels Belgium;

Funded by: Physical Sciences Research Council;

Award ID: EP/T022159/1

Funded by: FundRef http://dx.doi.org/10.13039/501100000271, Science and Technology Facilities Council;

Funded by: FundRef http://dx.doi.org/10.13039/501100020643, Medical Research Centre;

Award ID: MR/M009041/1

Funded by: FundRef http://dx.doi.org/10.13039/501100005370, Gates Cambridge Trust;

Award ID: OPP 1144

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In vivo mapping of pharmacologically induced functional reorganization onto the human brain’s neurotransmitter landscape

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Most cited references 115

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

The organization of the human cerebral cortex estimated by intrinsic functional connectivity.

Local-Global Parcellation of the Human Cerebral Cortex from Intrinsic Functional Connectivity MRI.

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Cited by 6

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