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@ARTICLE{Gaebler:1018679,
      author       = {Gaebler, Arnim J. and Fakour, Nilüfer and Stöhr, Felix
                      and Zweerings, Jana and Taebi, Arezoo and Suslova, Mariia
                      and Dukart, Jürgen and Hipp, Joerg F. and Adhikari, Bhim M.
                      and Kochunov, Peter and Muthukumaraswamy, Suresh D. and
                      Forsyth, Anna and Eggermann, Thomas and Kraft, Florian and
                      Kurth, Ingo and Paulzen, Michael and Gründer, Gerhard and
                      Schneider, Frank and Mathiak, Klaus},
      title        = {{F}unctional connectivity signatures of {NMDAR} dysfunction
                      in schizophrenia—integrating findings from imaging
                      genetics and pharmaco-f{MRI}},
      journal      = {Translational Psychiatry},
      volume       = {13},
      number       = {1},
      issn         = {2158-3188},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {FZJ-2023-04973},
      pages        = {59},
      year         = {2023},
      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.},
      cin          = {INM-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-7-20090406},
      pnm          = {5252 - Brain Dysfunction and Plasticity (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5252},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {36797233},
      UT           = {WOS:000935891400001},
      doi          = {10.1038/s41398-023-02344-2},
      url          = {https://juser.fz-juelich.de/record/1018679},
}