Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI
Abstract Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharm...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-02-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-023-02344-2 |
| _version_ | 1827982623994019840 |
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| author | Arnim J. Gaebler Nilüfer Fakour Felix Stöhr Jana Zweerings Arezoo Taebi Mariia Suslova Juergen Dukart Joerg F. Hipp Bhim M. Adhikari Peter Kochunov Suresh D. Muthukumaraswamy Anna Forsyth Thomas Eggermann Florian Kraft Ingo Kurth Michael Paulzen Gerhard Gründer Frank Schneider Klaus Mathiak |
| author_facet | Arnim J. Gaebler Nilüfer Fakour Felix Stöhr Jana Zweerings Arezoo Taebi Mariia Suslova Juergen Dukart Joerg F. Hipp Bhim M. Adhikari Peter Kochunov Suresh D. Muthukumaraswamy Anna Forsyth Thomas Eggermann Florian Kraft Ingo Kurth Michael Paulzen Gerhard Gründer Frank Schneider Klaus Mathiak |
| author_sort | Arnim J. Gaebler |
| collection | DOAJ |
| description | Abstract Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry. |
| first_indexed | 2024-04-09T22:35:47Z |
| format | Article |
| id | doaj.art-2a27b92802e64b309b19055bac2f2fa8 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-04-09T22:35:47Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-2a27b92802e64b309b19055bac2f2fa82023-03-22T12:27:26ZengNature Publishing GroupTranslational Psychiatry2158-31882023-02-0113111210.1038/s41398-023-02344-2Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRIArnim J. Gaebler0Nilüfer Fakour1Felix Stöhr2Jana Zweerings3Arezoo Taebi4Mariia Suslova5Juergen Dukart6Joerg F. Hipp7Bhim M. Adhikari8Peter Kochunov9Suresh D. Muthukumaraswamy10Anna Forsyth11Thomas Eggermann12Florian Kraft13Ingo Kurth14Michael Paulzen15Gerhard Gründer16Frank Schneider17Klaus Mathiak18Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenF. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre BaselF. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre BaselMaryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of MedicineMaryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of MedicineSchool of Pharmacy, Faculty of Medical and Health Sciences, The University of AucklandSchool of Pharmacy, Faculty of Medical and Health Sciences, The University of AucklandInstitute for Human Genetics and Genomic Medicine, Faculty of Medicine, RWTH AachenInstitute for Human Genetics and Genomic Medicine, Faculty of Medicine, RWTH AachenInstitute for Human Genetics and Genomic Medicine, Faculty of Medicine, RWTH AachenDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenCentral Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of HeidelbergUniversity Hospital Düsseldorf, Heinrich-Heine-UniversityDepartment of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH AachenAbstract Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.https://doi.org/10.1038/s41398-023-02344-2 |
| spellingShingle | Arnim J. Gaebler Nilüfer Fakour Felix Stöhr Jana Zweerings Arezoo Taebi Mariia Suslova Juergen Dukart Joerg F. Hipp Bhim M. Adhikari Peter Kochunov Suresh D. Muthukumaraswamy Anna Forsyth Thomas Eggermann Florian Kraft Ingo Kurth Michael Paulzen Gerhard Gründer Frank Schneider Klaus Mathiak Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI Translational Psychiatry |
| title | Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI |
| title_full | Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI |
| title_fullStr | Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI |
| title_full_unstemmed | Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI |
| title_short | Functional connectivity signatures of NMDAR dysfunction in schizophrenia—integrating findings from imaging genetics and pharmaco-fMRI |
| title_sort | functional connectivity signatures of nmdar dysfunction in schizophrenia integrating findings from imaging genetics and pharmaco fmri |
| url | https://doi.org/10.1038/s41398-023-02344-2 |
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