title: Impact of glutamate levels on neuronal response and cognitive abilities in schizophrenia.
abstract: Schizophrenia is characterized by impaired cognitive functioning, and brain regions involved in cognitive control processes show marked glutamatergic abnormalities. However, it is presently unclear whether aberrant neuronal response is directly related to the observed deficits at the metabolite level in schizophrenia. Here, 17 medicated schizophrenia patients and 17 matched healthy participants underwent functional magnetic resonance imaging (fMRI) when performing an auditory cognitive control task, as well as proton magnetic resonance spectroscopy ((1)H-MRS) in order to assess resting-state glutamate in the anterior cingulate cortex. The combined fMRI-(1)H-MRS analysis revealed that glutamate differentially predicted cortical blood-oxygen level-dependent (BOLD) response in patients and controls. While we found a positive correlation between glutamate and BOLD response bilaterally in the inferior parietal lobes in the patients, the corresponding correlation was negative in the healthy control participants. Further, glutamate levels predicted task performance in patients, such that lower glutamate levels were related to impaired cognitive control functioning. This was not seen for the healthy controls. These findings suggest that schizophrenia patients have a glutamate-related dysregulation of the brain network supporting cognitive control functioning. This could be targeted in future research on glutamatergic treatment of cognitive symptoms in schizophrenia.
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Liv E
authors.initials: LE
authors.lastname: Falkenberg
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Haukeland University Hospital, Bergen, Norway ; Division of Psychiatry, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: René
authors.initials: R
authors.lastname: Westerhausen
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Craven
authors.affiliation: Division of Psychiatry, University of Bergen, Haukeland University Hospital, Bergen, Norway ; Department of Clinical Medicine, Psychiatry Section, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Erik
authors.initials: E
authors.lastname: Johnsen
authors.affiliation: Division of Psychiatry, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Rune A
authors.initials: RA
authors.lastname: Kroken
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Haukeland University Hospital, Bergen, Norway ; Division of Psychiatry, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Else-Marie
authors.initials: EM
authors.lastname: L Berg
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Haukeland University Hospital, Bergen, Norway ; Department of Clinical Engineering, University of Bergen, Haukeland University Hospital, Bergen, Norway.
authors.forename: Karsten
authors.initials: K
authors.lastname: Specht
authors.affiliation: Department of Biological and Medical Psychology, University of Bergen, Haukeland University Hospital, Bergen, Norway ; Division of Psychiatry, University of Bergen, Haukeland University Hospital, Bergen, Norway ; Department of Radiology, Haukeland University Hospital, Bergen, Norway ; NORMENT Senter for Fremragende Forskning, Oslo, Norway.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hugdahl
mesh_terms: D000328:Adult; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology*; D056344:Executive Function; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009415:Nerve Net / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods; D012559:Schizophrenia / Q000150:complications / Q000503:physiopathology*
chemical_list: D018698:Glutamic Acid
keywords: 1H-MRS; Anterior cingulate cortex; BOLD; Cognitive control; Combined fMRI–MRS; Connectivity; Glutamate; Inferior parietal lobe
references.citation: Cortex. 1986 Sep;22(3):417-32
references.pmid: 3769494
references.citation: Nat Neurosci. 2009 Jun;12(6):718-24
references.pmid: 19471271
references.citation: Neuropsychologia. 2006;44(14):2836-45
references.pmid: 16879844
references.citation: Biol Psychiatry. 2008 Nov 1;64(9):803-9
references.pmid: 18585682
references.citation: Cereb Cortex. 2014 Jan;24(1):249-60
references.pmid: 23042734
references.citation: NMR Biomed. 2009 Aug;22(7):762-9
references.pmid: 19388001
references.citation: Neuropsychopharmacology. 2011 Jan;36(1):316-38
references.pmid: 20844478
references.citation: Exp Brain Res. 1981;42(3-4):319-30
references.pmid: 6165607
references.citation: Handb Exp Pharmacol. 2012;(213):267-95
references.pmid: 23027419
references.citation: Magn Reson Imaging. 2011 Jan;29(1):19-24
references.pmid: 20884148
references.citation: Science. 2004 Oct 15;306(5695):443-7
references.pmid: 15486290
references.citation: Mol Psychiatry. 2012 Jul;17(7):664-5
references.pmid: 22212598
references.citation: J Magn Reson. 2011 Feb;208(2):210-8
references.pmid: 21130670
references.citation: Schizophr Res. 2007 Dec;97(1-3):215-25
references.pmid: 17851044
references.citation: Nat Rev Neurosci. 2002 Mar;3(3):201-15
references.pmid: 11994752
references.citation: Neuroimage. 2007 Feb 1;34(3):888-95
references.pmid: 17161625
references.citation: Schizophr Bull. 2010 May;36(3):576-84
references.pmid: 18835839
references.citation: Soc Cogn Affect Neurosci. 2009 Dec;4(4):423-8
references.pmid: 20035017
references.citation: Neuroscience. 2012 Dec 27;227:102-9
references.pmid: 23022216
references.citation: Neuroimage. 2008 Apr 1;40(2):902-911
references.pmid: 18234509
references.citation: Neuropsychopharmacology. 2012 Jan;37(1):4-15
references.pmid: 21956446
references.citation: Am J Psychiatry. 2002 Nov;159(11):1944-6
references.pmid: 12411236
references.citation: Neuroimage. 2002 Jan;15(1):273-89
references.pmid: 11771995
references.citation: Brain Res. 2007 Feb 23;1134(1):187-98
references.pmid: 17204249
references.citation: J Magn Reson Imaging. 2011 Dec;34(6):1251-61
references.pmid: 22102558
references.citation: Ann N Y Acad Sci. 2003 Nov;1003:318-27
references.pmid: 14684455
references.citation: Arch Gen Psychiatry. 2011 Sep;68(9):881-90
references.pmid: 21536967
references.citation: Schizophr Res. 2014 Feb;152(2-3):325-32
references.pmid: 24418122
references.citation: Psychiatry Res. 2009 Apr 30;172(1):44-8
references.pmid: 19239984
references.citation: Schizophr Bull. 2013 Jan;39(1):120-9
references.pmid: 21746807
references.citation: Neuropsychologia. 2010 Jun;48(7):2075-81
references.pmid: 20363236
references.citation: Neuroimage. 1996 Dec;4(3 Pt 1):223-35
references.pmid: 9345513
references.citation: Front Neurosci. 2009 May 01;3(1):34-45
references.pmid: 19753095
references.citation: Biol Psychiatry. 2011 May 15;69(10):967-73
references.pmid: 21193174
references.citation: Schizophr Bull. 1987;13(2):261-76
references.pmid: 3616518
references.citation: Brain Cogn. 2011 Jul;76(2):276-85
references.pmid: 21398015
references.citation: Neuroimage. 2013 Jan 1;64:112-9
references.pmid: 23000786
references.citation: PLoS One. 2013;8(4):e60312
references.pmid: 23573246
references.citation: Schizophr Bull. 2009 Sep;35(5):973-93
references.pmid: 18436528
references.citation: Annu Rev Physiol. 2003;65:401-27
references.pmid: 12524459
references.citation: Magn Reson Med. 1993 Dec;30(6):672-9
references.pmid: 8139448
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5069-73
references.pmid: 22411802
references.citation: Schizophr Res. 2001 Apr 15;49(1-2):1-52
references.pmid: 11343862
references.citation: Schizophr Bull. 2012 Jun;38(4):683-93
references.pmid: 22446568
references.citation: Front Syst Neurosci. 2010 Jul 15;4:
references.pmid: 20700385
references.citation: J Neurosci. 2009 Jan 28;29(4):1175-90
references.pmid: 19176826
references.citation: Psychopharmacology (Berl). 2011 Apr;214(3):639-52
references.pmid: 21052982
references.citation: Biol Psychiatry. 2010 May 15;67(10):912-8
references.pmid: 20060103
references.citation: J Neurophysiol. 2008 Dec;100(6):3328-42
references.pmid: 18799601
references.citation: Acta Psychol (Amst). 2004 Feb-Mar;115(2-3):105-21
references.pmid: 14962396
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16720-5
references.pmid: 23012427
references.citation: Schizophr Res. 2012 Sep;140(1-3):136-42
references.pmid: 22831772
references.citation: Schizophr Bull. 2013 Sep;39(5):1087-95
references.pmid: 23070537
references.citation: Neuroimage. 1999 Nov;10(5):607-19
references.pmid: 10547338
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13507-12
references.pmid: 17679691
references.citation: Cereb Cortex. 1992 Nov-Dec;2(6):503-12
references.pmid: 1282404
references.citation: Am J Psychiatry. 2003 Dec;160(12):2231-3
references.pmid: 14638596
references.citation: Arch Gen Psychiatry. 2009 Aug;66(8):811-22
references.pmid: 19652121
references.citation: Trends Cogn Sci. 2007 Jan;11(1):30-6
references.pmid: 17134935
references.citation: J Cereb Blood Flow Metab. 2007 May;27(5):1055-63
references.pmid: 17033694
references.citation: Neuroimage. 2006 May 1;30(4):1171-8
references.pmid: 16431138
references.citation: Schizophr Res. 2010 Sep;122(1-3):104-12
references.pmid: 20554160
references.citation: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references.pmid: 15803162
references.citation: Am J Psychiatry. 2007 Mar;164(3):467-73
references.pmid: 17329472
references.citation: Hum Brain Mapp. 2007 Nov;28(11):1213-22
references.pmid: 17266108
references.citation: Neurosci Lett. 2008 Jan 24;431(1):90-4
references.pmid: 18162310
references.citation: Nat Rev Neurosci. 2000 Oct;1(1):59-65
references.pmid: 11252769
references.citation: Hum Brain Mapp. 2011 Dec;32(12):2172-82
references.pmid: 21305662
references.citation: Schizophr Res. 1998 Mar 10;30(2):115-25
references.pmid: 9549774
references.citation: Arch Gen Psychiatry. 2012 May;69(5):449-59
references.pmid: 22213769
references.citation: Brain Res. 2009 Aug 25;1286:155-64
references.pmid: 19577551
references.citation: Brain Behav. 2012 Sep;2(5):553-62
references.pmid: 23139901
references.citation: Curr Med Chem. 2013;20(3):428-37
references.pmid: 23157635