7T Proton Magnetic Resonance Spectroscopy of the Anterior Cingulate Cortex in First-Episode Schizophrenia

Recent magnetic resonance spectroscopy (MRS) studies suggest that abnormalities of the glutamatergic system in schizophrenia may be dependent on illness stage, medication status, and symptomatology. Glutamatergic metabolites appear to be elevated in the prodromal and early stages of schizophrenia but unchanged or reduced below normal in chronic, medicated patients. However, few of these studies have measured metabolites with high-field 7T MR scanners, which offer higher signal-to-noise ratio and better spectral resolution than 3T scanners and facilitate separation of glutamate and glutamine into distinct signals. In this study, we examined glutamate and other metabolites in the dorsal anterior cingulate cortex (ACC) of first-episode schizophrenia patients. Glutamate and N-acetylaspartate (NAA) were significantly lower in schizophrenia patients vs controls. No differences were observed in levels of glutamine, GABA, or other metabolites. In schizophrenia patients but not controls, GABA was negatively correlated with the total score on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as well as the immediate memory and language subscales. Our findings suggest that glutamate and NAA reductions in the ACC may be present early in the illness, but additional large-scale studies are needed to confirm these results as well as longitudinal studies to determine the effect of illness progression and treatment. The correlation between GABA and cognitive function suggests that MRS may be an important technique for investigating the neurobiology underlying cognitive deficits in schizophrenia.

[1]  Muhammad G Saleh,et al.  Edited 1H magnetic resonance spectroscopy in vivo: Methods and metabolites , 2017, Magnetic resonance in medicine.

[2]  René S. Kahn,et al.  7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings , 2017, Biological Psychiatry.

[3]  Chunbo Li,et al.  Reduced γ-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk , 2016, Neural plasticity.

[4]  S. A. Wijtenburg,et al.  Elevated brain lactate in schizophrenia: a 7 T magnetic resonance spectroscopy study , 2016, Translational Psychiatry.

[5]  Mark S. Bolding,et al.  Ketamine Modulates Hippocampal Neurochemistry and Functional Connectivity – A Combined Magnetic Resonance Spectroscopy and Resting State fMRI Study in Healthy Volunteers , 2016, Molecular Psychiatry.

[6]  M. Chakravarty,et al.  Glutamatergic Metabolites, Volume and Cortical Thickness in Antipsychotic-Naive Patients with First-Episode Psychosis: Implications for Excitotoxicity , 2016, Neuropsychopharmacology.

[7]  F. Turkheimer,et al.  Treatment-Resistant Schizophrenia Patients Show Elevated Anterior Cingulate Cortex Glutamate Compared to Treatment-Responsive. , 2016, Schizophrenia bulletin.

[8]  Paul G. Unschuld,et al.  Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS Study at 7Tesla , 2016, Schizophrenia Research.

[9]  S. Kühn,et al.  Cross-sectional Study of Glutamate in the Anterior Cingulate and Hippocampus in Schizophrenia. , 2016, Schizophrenia bulletin.

[10]  A. Lahti,et al.  Decreased synaptic and mitochondrial density in the postmortem anterior cingulate cortex in schizophrenia , 2015, Schizophrenia Research.

[11]  Romain Valabregue,et al.  Two‐site reproducibility of cerebellar and brainstem neurochemical profiles with short‐echo, single‐voxel MRS at 3T , 2015, Magnetic resonance in medicine.

[12]  René S. Kahn,et al.  GABA and glutamate in schizophrenia: A 7 T 1H-MRS study , 2014, NeuroImage: Clinical.

[13]  Clifford Qualls,et al.  Increased glutamine in patients undergoing long-term treatment for schizophrenia: a proton magnetic resonance spectroscopy study at 3 T. , 2014, JAMA psychiatry.

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

[15]  A. Lahti,et al.  Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia. , 2013, JAMA psychiatry.

[16]  Rolf Gruetter,et al.  Unedited in vivo detection and quantification of γ‐aminobutyric acid in the occipital cortex using short‐TE MRS at 3 T , 2013, NMR in biomedicine.

[17]  A. Graff-Guerrero,et al.  Glutamate levels in the associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a longitudinal proton magnetic resonance spectroscopy study. , 2013, JAMA psychiatry.

[18]  S. A. Wijtenburg,et al.  In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. , 2013, Schizophrenia bulletin.

[19]  Peter B Barker,et al.  Reproducibility of brain spectroscopy at 7T using conventional localization and spectral editing techniques , 2013, Journal of magnetic resonance imaging : JMRI.

[20]  M. Keshavan,et al.  Brain metabolite alterations in young adults at familial high risk for schizophrenia using proton magnetic resonance spectroscopy , 2013, Schizophrenia Research.

[21]  Hans-Jochen Heinze,et al.  Systematic Regional Variations of GABA, Glutamine, and Glutamate Concentrations Follow Receptor Fingerprints of Human Cingulate Cortex , 2013, The Journal of Neuroscience.

[22]  A. Lahti,et al.  Regional Decoupling of N-acetyl-aspartate and Glutamate in Schizophrenia , 2012, Neuropsychopharmacology.

[23]  A. Egerton,et al.  Anterior Cingulate Glutamate Levels Related to Clinical Status Following Treatment in First-Episode Schizophrenia , 2012, Neuropsychopharmacology.

[24]  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.

[25]  R. Yoshimura,et al.  Six-month treatment with atypical antipsychotic drugs decreased frontal-lobe levels of glutamate plus glutamine in early-stage first-episode schizophrenia , 2012, Neuropsychiatric disease and treatment.

[26]  David A. Lewis,et al.  Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia , 2012, Trends in Neurosciences.

[27]  Ravi S. Menon,et al.  Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia , 2011, British Journal of Psychiatry.

[28]  J. Walecki,et al.  Proton Magnetic Resonance Spectroscopy Study of Brain Metabolite Changes after Antipsychotic Treatment , 2011, Pharmacopsychiatry.

[29]  A. Graff-Guerrero,et al.  Higher Levels of Glutamate in the Associative-Striatum of Subjects with Prodromal Symptoms of Schizophrenia and Patients with First-Episode Psychosis , 2011, Neuropsychopharmacology.

[30]  S. Leucht,et al.  Proton Magnetic Resonance Spectroscopy and Illness Stage in Schizophrenia—A Systematic Review and Meta-Analysis , 2011, Biological Psychiatry.

[31]  Robert C. Knowlton,et al.  Assessments of Function and Biochemistry of the Anterior Cingulate Cortex in Schizophrenia , 2010, Biological Psychiatry.

[32]  Tyrone D. Cannon,et al.  Proton MRS in twin pairs discordant for schizophrenia , 2010, Molecular Psychiatry.

[33]  Philip K. McGuire,et al.  Glutamate Dysfunction in People with Prodromal Symptoms of Psychosis: Relationship to Gray Matter Volume , 2009, Biological Psychiatry.

[34]  A. Schleicher,et al.  Receptor architecture of human cingulate cortex: Evaluation of the four‐region neurobiological model , 2009, Human brain mapping.

[35]  Ravi S. Menon,et al.  Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia , 2007, British Journal of Psychiatry.

[36]  Dennis Velakoulis,et al.  Evidence for neuronal dysfunction in the anterior cingulate of patients with schizophrenia: A proton magnetic resonance spectroscopy study at 3 T , 2007, Schizophrenia Research.

[37]  R. Kahn,et al.  What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. , 2007, Schizophrenia bulletin.

[38]  E. Bullmore,et al.  Effects of gamma-aminobutyric acid-modulating drugs on working memory and brain function in patients with schizophrenia. , 2007, Archives of general psychiatry.

[39]  Arvind Caprihan,et al.  Use of tissue water as a concentration reference for proton spectroscopic imaging , 2006, Magnetic resonance in medicine.

[40]  F. Benes,et al.  A cross-study meta-analysis and three-dimensional comparison of cell counting in the anterior cingulate cortex of schizophrenic and bipolar brain , 2005, Schizophrenia Research.

[41]  J. Lauriello,et al.  Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. , 2005, The American journal of psychiatry.

[42]  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.

[43]  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.

[44]  K Ugurbil,et al.  In vivo 1H NMR spectroscopy of the human brain at 7 T , 2001, Magnetic resonance in medicine.

[45]  J. Newcomer,et al.  NMDA receptor hypofunction model of schizophrenia. , 1999, Journal of psychiatric research.

[46]  B. Moghaddam,et al.  Corticolimbic Dopamine Neurotransmission Is Temporally Dissociated from the Cognitive and Locomotor Effects of Phencyclidine , 1998, The Journal of Neuroscience.

[47]  C. Randolph,et al.  The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. , 1998, Journal of clinical and experimental neuropsychology.

[48]  Bita Moghaddam,et al.  Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex , 1997, The Journal of Neuroscience.

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

[50]  Danny J. J. Wang,et al.  Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study , 2017, Neuropsychopharmacology.

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

[52]  H. Holcomb,et al.  Correlations Between rCBF and Symptoms in Two Independent Cohorts of Drug-Free Patients with Schizophrenia , 2006, Neuropsychopharmacology.

[53]  T L Patterson,et al.  UCSD Performance-Based Skills Assessment , 2016 .