PMID- 36797233
OWN - NLM
STAT- MEDLINE
DCOM- 20230222
LR  - 20230523
IS  - 2158-3188 (Electronic)
IS  - 2158-3188 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Feb 16
TI  - Functional connectivity signatures of NMDAR dysfunction in 
      schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.
PG  - 59
LID - 10.1038/s41398-023-02344-2 [doi]
LID - 59
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Gaebler, Arnim J
AU  - Gaebler AJ
AUID- ORCID: 0000-0002-8816-3415
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany. agaebler@ukaachen.de.
AD  - JARA - Translational Brain Medicine, Aachen, Germany. agaebler@ukaachen.de.
AD  - Department of Physiology, Faculty of Medicine, RWTH Aachen, Aachen, Germany. 
      agaebler@ukaachen.de.
FAU - Fakour, Nilufer
AU  - Fakour N
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany.
AD  - JARA - Translational Brain Medicine, Aachen, Germany.
FAU - Stohr, Felix
AU  - Stohr F
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany.
AD  - JARA - Translational Brain Medicine, Aachen, Germany.
FAU - Zweerings, Jana
AU  - Zweerings J
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany.
AD  - JARA - Translational Brain Medicine, Aachen, Germany.
FAU - Taebi, Arezoo
AU  - Taebi A
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany.
AD  - JARA - Translational Brain Medicine, Aachen, Germany.
FAU - Suslova, Mariia
AU  - Suslova M
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany.
AD  - JARA - Translational Brain Medicine, Aachen, Germany.
AD  - Department of Physiology, Faculty of Medicine, RWTH Aachen, Aachen, Germany.
FAU - Dukart, Juergen
AU  - Dukart J
AD  - F. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre 
      Basel, Basel, Switzerland.
AD  - Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research 
      Centre Julich, Julich, Germany.
AD  - Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University 
      Dusseldorf, Dusseldorf, Germany.
FAU - Hipp, Joerg F
AU  - Hipp JF
AUID- ORCID: 0000-0002-7875-2988
AD  - F. Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre 
      Basel, Basel, Switzerland.
FAU - Adhikari, Bhim M
AU  - Adhikari BM
AD  - Maryland Psychiatric Research Center, Department of Psychiatry, University of 
      Maryland School of Medicine, Baltimore, MD, USA.
FAU - Kochunov, Peter
AU  - Kochunov P
AD  - Maryland Psychiatric Research Center, Department of Psychiatry, University of 
      Maryland School of Medicine, Baltimore, MD, USA.
FAU - Muthukumaraswamy, Suresh D
AU  - Muthukumaraswamy SD
AUID- ORCID: 0000-0001-7042-3920
AD  - School of Pharmacy, Faculty of Medical and Health Sciences, The University of 
      Auckland, Auckland, New Zealand.
FAU - Forsyth, Anna
AU  - Forsyth A
AD  - School of Pharmacy, Faculty of Medical and Health Sciences, The University of 
      Auckland, Auckland, New Zealand.
FAU - Eggermann, Thomas
AU  - Eggermann T
AUID- ORCID: 0000-0002-8419-0264
AD  - Institute for Human Genetics and Genomic Medicine, Faculty of Medicine, RWTH 
      Aachen, Aachen, Germany.
FAU - Kraft, Florian
AU  - Kraft F
AD  - Institute for Human Genetics and Genomic Medicine, Faculty of Medicine, RWTH 
      Aachen, Aachen, Germany.
FAU - Kurth, Ingo
AU  - Kurth I
AD  - Institute for Human Genetics and Genomic Medicine, Faculty of Medicine, RWTH 
      Aachen, Aachen, Germany.
FAU - Paulzen, Michael
AU  - Paulzen M
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany.
AD  - JARA - Translational Brain Medicine, Aachen, Germany.
AD  - Alexianer Hospital, Aachen, Germany.
FAU - Grunder, Gerhard
AU  - Grunder G
AD  - Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical 
      Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
FAU - Schneider, Frank
AU  - Schneider F
AD  - University Hospital Dusseldorf, Heinrich-Heine-University, Dusseldorf, Germany.
FAU - Mathiak, Klaus
AU  - Mathiak K
AUID- ORCID: 0000-0002-2276-7726
AD  - Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, 
      RWTH Aachen, Aachen, Germany.
AD  - JARA - Translational Brain Medicine, Aachen, Germany.
LA  - eng
GR  - R01 EB015611/EB/NIBIB NIH HHS/United States
GR  - RF1 MH123163/MH/NIMH NIH HHS/United States
GR  - S10 OD023696/OD/NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20230216
PL  - United States
TA  - Transl Psychiatry
JT  - Translational psychiatry
JID - 101562664
RN  - 690G0D6V8H (Ketamine)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - R60L0SM5BC (Midazolam)
SB  - IM
MH  - Humans
MH  - *Schizophrenia/diagnostic imaging/genetics/metabolism
MH  - Magnetic Resonance Imaging/methods
MH  - *Ketamine/pharmacology
MH  - Receptors, N-Methyl-D-Aspartate/genetics
MH  - Genome-Wide Association Study
MH  - Midazolam
PMC - PMC9935542
COIS- MP has received speaker's fees from the following pharmaceutical companies: 
      Neuraxpharm, Lundbeck. GG has served as a consultant for Allergan (Dublin, 
      Ireland), Boehringer Ingelheim (Ingelheim, Germany), Institute for Quality and 
      Efficiency in Health Care (IQWiG, Cologne, Germany) Janssen-Cilag (Neuss, 
      Germany), Lundbeck (Copenhagen, Denmark), Otsuka (Chiyoda, Japan), Recordati 
      (Milan, Italy), Sage (Cambridge, USA), and Takeda (Osaka, Japan). He has served 
      on the speakers' bureau of Gedeon Richter (Budapest, Hungary), Janssen Cilag, 
      Lundbeck, Otsuka, Recordati. He has received grant support from Boehringer 
      Ingelheim, Lundbeck, and Saladax (Bethlehem, USA). He is co-founder and/or 
      shareholder of Mind and Brain Institute GmbH (Zornheim, Germany), Brainfoods GmbH 
      (Zornheim, Germany), InMediCon GmbH (Pentling, Germany), OVID Health Systems GmbH 
      (Berlin, Germany) and MIND Foundation gGmbH (Berlin, Germany). The Authors have 
      declared that there are no conflicts of interest in relation to the subject of 
      this study.
EDAT- 2023/02/17 06:00
MHDA- 2023/02/22 06:00
PMCR- 2023/02/16
CRDT- 2023/02/16 23:13
PHST- 2022/01/02 00:00 [received]
PHST- 2023/01/30 00:00 [accepted]
PHST- 2023/01/26 00:00 [revised]
PHST- 2023/02/16 23:13 [entrez]
PHST- 2023/02/17 06:00 [pubmed]
PHST- 2023/02/22 06:00 [medline]
PHST- 2023/02/16 00:00 [pmc-release]
AID - 10.1038/s41398-023-02344-2 [pii]
AID - 2344 [pii]
AID - 10.1038/s41398-023-02344-2 [doi]
PST - epublish
SO  - Transl Psychiatry. 2023 Feb 16;13(1):59. doi: 10.1038/s41398-023-02344-2.