Neuroimage: Clinical Impact of Glutamate Levels on Neuronal Response and Cognitive Abilities in Schizophrenia

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 (1H-MRS) in order to assess resting-state glutamate in the anterior cingulate cortex. The combined fMRI–1H-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.

[1]  Isabell Wartenburger,et al.  Electrophysiological correlates of adult age differences in attentional control of auditory processing. , 2014, Cerebral cortex.

[2]  Parashkev Nachev,et al.  Space and the parietal cortex , 2007, Trends in Cognitive Sciences.

[3]  R. McCarley,et al.  A review of MRI findings in schizophrenia , 2001, Schizophrenia Research.

[4]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[5]  Ravi S. Menon,et al.  Glutamate and glutamine in the anterior cingulate and thalamus of medicated patients with chronic schizophrenia and healthy comparison subjects measured with 4.0-T proton MRS. , 2003, The American journal of psychiatry.

[6]  Daniel C. Javitt,et al.  Glutamatergic abnormalities in schizophrenia: A review of proton MRS findings , 2014, Schizophrenia Research.

[7]  Dimitrios Kapogiannis,et al.  Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network , 2013, NeuroImage.

[8]  S. Provencher.  Estimation of metabolite concentrations from localized in vivo proton NMR spectra , 1993, Magnetic resonance in medicine.

[9]  Alex Fornito,et al.  Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: bridging the gap between neuroimaging and neuropathology. , 2009, Schizophrenia bulletin.

[10]  K. Uğurbil,et al.  Sustained Neuronal Activation Raises Oxidative Metabolism to a New Steady-State Level: Evidence from 1H NMR Spectroscopy in the Human Visual Cortex , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  E. Miller,et al.  THE PREFRONTAL CORTEX AND COGNITIVE CONTROL , 2000 .

[12]  K. Hugdahl,et al.  Left Temporal Lobe Structural and Functional Abnormality Underlying Auditory Hallucinations in Schizophrenia , 2008, Front. Neurosci..

[13]  K. Hugdahl,et al.  The “Forced-Attention Paradigm” in Dichotic Listening to CV-Syllables: A Comparison Between Adults and Children , 1986, Cortex.

[14]  K. Hugdahl,et al.  Resting-state glutamate level in the anterior cingulate predicts blood-oxygen level-dependent response to cognitive control , 2012, Proceedings of the National Academy of Sciences.

[15]  Niall W. Duncan,et al.  Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans , 2013, PloS one.

[16]  William A. Cunningham,et al.  Tools of the Trade Type I and Type II error concerns in fMRI research : rebalancing the scale , 2009 .

[17]  René Westerhausen,et al.  Morphologic asymmetry of the human anterior cingulate cortex , 2007, NeuroImage.

[18]  N. Agarwal,et al.  MR spectroscopy in schizophrenia , 2011, Journal of magnetic resonance imaging : JMRI.

[19]  Huiguang He,et al.  Glutamatergic and Resting-State Functional Connectivity Correlates of Severity in Major Depression – The Role of Pregenual Anterior Cingulate Cortex and Anterior Insula , 2010, Front. Syst. Neurosci..

[20]  Justin L. Vincent,et al.  Evidence for a frontoparietal control system revealed by intrinsic functional connectivity. , 2008, Journal of neurophysiology.

[21]  M. Minzenberg,et al.  Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. , 2009, Archives of general psychiatry.

[22]  K. Hugdahl.  Dichotic Listening in the study of auditory laterality. , 2003 .

[23]  Daniel B. Vigneron,et al.  TE-Averaged two-dimensional proton spectroscopic imaging of glutamate at 3 T , 2006, NeuroImage.

[24]  J. Gore,et al.  Anterior cingulate and cerebellar GABA and Glu correlations measured by ¹H J-difference spectroscopy. , 2011, Magnetic resonance imaging.

[25]  Xiao-Jing Wang,et al.  NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia , 2012, Proceedings of the National Academy of Sciences.

[26]  Dost Öngür,et al.  Quantification of J‐resolved proton spectra in two‐dimensions with LCModel using GAMMA‐simulated basis sets at 4 Tesla , 2009, NMR in biomedicine.

[27]  Aysenil Belger,et al.  Attention deficits in schizophrenia — Preliminary evidence of dissociable transient and sustained deficits , 2010, Schizophrenia Research.

[28]  Kenneth Hugdahl,et al.  The effect of stimulus intensity on the right ear advantage in dichotic listening , 2008, Neuroscience Letters.

[29]  D. Veltman,et al.  The association between cingulate cortex glutamate concentration and delay discounting is mediated by resting state functional connectivity , 2012, Brain and behavior.

[30]  G. Barker,et al.  Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology , 2012, Molecular Psychiatry.

[31]  Jack L. Lancaster,et al.  Clustered pixels analysis for functional MRI activation studies of the human brain , 1995 .

[32]  M. Carli,et al.  Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex , 2011, Psychopharmacology.

[33]  Antipsychotic drug effects in schizophrenia: a review of longitudinal FMRI investigations and neural interpretations. , 2013, Current medicinal chemistry.

[34]  A. Mechelli,et al.  Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis. , 2011, Archives of general psychiatry.

[35]  F. Benes,et al.  Increased density of glutamate-immunoreactive vertical processes in superficial laminae in cingulate cortex of schizophrenic brain. , 1992, Cerebral cortex.

[36]  Bita Moghaddam,et al.  From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment , 2012, Neuropsychopharmacology.

[37]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[38]  Charles Fernyhough,et al.  Auditory hallucinations in schizophrenia and nonschizophrenia populations: a review and integrated model of cognitive mechanisms. , 2012, Schizophrenia bulletin.

[39]  Georg Northoff,et al.  Involvement of glutamate in rest‐stimulus interaction between perigenual and supragenual anterior cingulate cortex: A combined fMRI‐MRS study , 2011, Human brain mapping.

[40]  Mark Slifstein,et al.  Elevated prefrontal cortex γ-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. , 2012, Archives of general psychiatry.

[41]  Jean-Luc Anton,et al.  Region of interest analysis using an SPM toolbox , 2010 .

[42]  M. Woldorff,et al.  The neural circuitry underlying the executive control of auditory spatial attention , 2007, Brain Research.

[43]  Karl J. Friston,et al.  Stochastic Designs in Event-Related fMRI , 1999, NeuroImage.

[44]  M. Tohen,et al.  An excitement subscale of the Positive and Negative Syndrome Scale , 2004, Schizophrenia Research.

[45]  Kenneth Hugdahl,et al.  A new verbal reports fMRI dichotic listening paradigm for studies of hemispheric asymmetry , 2008, NeuroImage.

[46]  Fahmeed Hyder,et al.  In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. , 2003, Annual review of physiology.

[47]  O. Salonen,et al.  Brain networks of bottom-up triggered and top-down controlled shifting of auditory attention , 2009, Brain Research.

[48]  Jacob Cohen,et al.  Applied multiple regression/correlation analysis for the behavioral sciences , 1979 .

[49]  E. Torrey,et al.  Schizophrenia and the inferior parietal lobule , 2007, Schizophrenia Research.

[50]  S. Petersen,et al.  Development of distinct control networks through segregation and integration , 2007, Proceedings of the National Academy of Sciences.

[51]  P. Fransson.  How default is the default mode of brain function? Further evidence from intrinsic BOLD signal fluctuations , 2006, Neuropsychologia.

[52]  Cameron S Carter,et al.  Cognitive Control Deficits in Schizophrenia: Mechanisms and Meaning , 2011, Neuropsychopharmacology.

[53]  J. Rauschecker,et al.  Maps and streams in the auditory cortex: nonhuman primates illuminate human speech processing , 2009, Nature Neuroscience.

[54]  J. Badcock.  The cognitive neuropsychology of auditory hallucinations: a parallel auditory pathways framework. , 2010, Schizophrenia bulletin.

[55]  T. Goschke,et al.  Executive control emerging from dynamic interactions between brain systems mediating language, working memory and attentional processes. , 2004, Acta psychologica.

[56]  D. Goff,et al.  Converging Evidence of NMDA Receptor Hypofunction in the Pathophysiology of Schizophrenia , 2003, Annals of the New York Academy of Sciences.

[57]  M. Rushworth,et al.  Behavioral / Systems / Cognitive Connectivity-Based Parcellation of Human Cingulate Cortex and Its Relation to Functional Specialization , 2008 .

[58]  Ravi S. Menon,et al.  Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. , 2002, The American journal of psychiatry.

[59]  M. Corbetta,et al.  Control of goal-directed and stimulus-driven attention in the brain , 2002, Nature Reviews Neuroscience.

[60]  K. Hugdahl,et al.  Cognitive Control of Auditory Laterality , 2010 .

[61]  E. Miller,et al.  The prefontral cortex and cognitive control , 2000, Nature Reviews Neuroscience.

[62]  D. Pandya,et al.  Efferent connections of the cingulate gyrus in the rhesus monkey , 1981, Experimental Brain Research.

[63]  Niall W. Duncan,et al.  Glutamate modulates resting state activity in the perigenual anterior cingulate cortex – A combined fMRI–MRS study , 2012, Neuroscience.

[64]  William A. Cunningham,et al.  Type I and Type II error concerns in fMRI research: re-balancing the scale. , 2009, Social cognitive and affective neuroscience.

[65]  E. Nick.  Applied multiple regression , 1977 .

[66]  Mark S. Bolding,et al.  Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging , 2012, Schizophrenia Research.

[67]  André Aleman,et al.  Auditory Hallucinations in Schizophrenia Are Associated with Reduced Functional Connectivity of the Temporo-Parietal Area , 2010, Biological Psychiatry.

[68]  M. Posner,et al.  Attention and cognitive control. , 1975 .

[69]  D. Barch,et al.  Brain Network Connectivity in Individuals with Schizophrenia and Their Siblings , 2011, Biological Psychiatry.

[70]  Karsten Specht,et al.  Attention and cognitive control networks assessed in a dichotic listening fMRI study , 2011, Brain and Cognition.

[71]  Karl J. Friston,et al.  Detecting Activations in PET and fMRI: Levels of Inference and Power , 1996, NeuroImage.

[72]  K. R. Ridderinkhof,et al.  The Role of the Medial Frontal Cortex in Cognitive Control , 2004, Science.

[73]  D. Long.  The Two Halves of the Brain , 2011 .

[74]  Paul Allen,et al.  Misattribution of speech and impaired connectivity in patients with auditory verbal hallucinations , 2007, Human brain mapping.

[75]  T. Woo,et al.  N-Methyl-D-Aspartate Receptor and Calbindin-Containing Neurons in the Anterior Cingulate Cortex in Schizophrenia and Bipolar Disorder , 2008, Biological Psychiatry.

[76]  Derek K. Jones,et al.  A diffusion tensor imaging study of fasciculi in schizophrenia. , 2007, The American journal of psychiatry.

[77]  Karl J. Friston.  The disconnection hypothesis , 1998, Schizophrenia Research.

[78]  J. Coyle,et al.  Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications. , 2012, Handbook of experimental pharmacology.

[79]  Marte Swart,et al.  When Broca goes uninformed: reduced information flow to Broca's area in schizophrenia patients with auditory hallucinations. , 2013, Schizophrenia bulletin.

[80]  Peter R Luijten,et al.  Glutamate in schizophrenia: a focused review and meta-analysis of ¹H-MRS studies. , 2013, Schizophrenia bulletin.

[81]  Kenneth Hugdahl,et al.  Identification of attention and cognitive control networks in a parametric auditory fMRI study , 2010, Neuropsychologia.

[82]  Dost Öngür,et al.  Creatine abnormalities in schizophrenia and bipolar disorder , 2009, Psychiatry Research: Neuroimaging.

[83]  P. Renshaw,et al.  Accuracy and stability of measuring GABA, glutamate, and glutamine by proton magnetic resonance spectroscopy: a phantom study at 4 Tesla. , 2011, Journal of magnetic resonance.

[84]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.