Frontal P3 event-related potential is related to brain glutamine/glutamate ratio measured in vivo

BACKGROUND The auditory P3 event-related potential (ERP) is thought to index cognitive processing relevant to attention and working memory processes. Drug challenge studies suggest that glutamate neurotransmission plays an important role in modulating P3 ERP. However, while direct links between glutamate activity and P3 ERP response in humans are suspected, mechanistic details remain largely unknown. We investigated here the relationships between P3 ERP and indices of glutamatergic processing measured in vivo with proton magnetic resonance spectroscopy ((1)H MRS). We hypothesized that a higher index of glutamatergic processing (glutamine/glutamate ratio; abbreviated Gln/Glu) in the anterior cingulate (ACC) and in the parietal-occipital (POC) cortices would associate with larger frontal P3a and parietal P3b amplitudes, respectively. METHODS Frontal P3a (Fz) and parietal P3b (Pz) were collected from 32 healthy participants who performed an auditory oddball task. Resting glutamate (Glu), glutamine (Gln), and Gln/Glu (an index of glutamatergic processing) measures were obtained on a 4T MR scanner using J-resolved MR spectroscopy. Linear regression and partial correlations were used for statistical analysis. RESULTS Significant positive correlations were found between frontal P3a amplitude and ACC Gln/Glu ratio (partial R=0.57; P=0.001) and between frontal P3a amplitude and ACC Gln concentration (partial R=0.43; P=0.02). Relationships between parietal P3b and the glutamate indices in the POC were not significant. CONCLUSIONS These results indicate a specific connection between an index of glutamate neurotransmitter function in ACC and frontal P3 ERP, providing a novel insight into the neurochemistry underlying scalp recorded EEG response. Abnormalities in glutamate neurotransmission have been observed in schizophrenia and other psychiatric conditions and may underlie illness related deficits of P3 ERP.

[1]  J. Coyle.  NMDA receptor and schizophrenia: a brief history. , 2012, Schizophrenia bulletin.

[2]  D. Senkowski,et al.  Hippocampal glutamate concentration predicts cerebral theta oscillations during cognitive processing , 2006, Psychopharmacology.

[3]  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.

[4]  E Donchin,et al.  A new method for off-line removal of ocular artifact. , 1983, Electroencephalography and clinical neurophysiology.

[5]  Dost Öngür,et al.  Abnormal Glutamatergic Neurotransmission and Neuronal-Glial Interactions in Acute Mania , 2008, Biological Psychiatry.

[6]  Kelvin O. Lim,et al.  Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized 1H MRS study , 2009, NMR in biomedicine.

[7]  J. Polich.  Updating P300: An integrative theory of P3a and P3b , 2007, Clinical Neurophysiology.

[8]  B. Mueller,et al.  Proton echo‐planar spectroscopic imaging of J‐coupled resonances in human brain at 3 and 4 Tesla , 2007, Magnetic resonance in medicine.

[9]  D. Javitt,et al.  Neurophysiological biomarkers for drug development in schizophrenia , 2008, Nature Reviews Drug Discovery.

[10]  J. Polich,et al.  Neuropsychology and neuropharmacology of P3a and P3b. , 2006, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[11]  Richard Needleman,et al.  Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS , 2010, Journal of the Neurological Sciences.

[12]  Daniel H. Mathalon,et al.  Glutamatergic Modulation of Auditory Information Processing in the Human Brain , 2012, Biological Psychiatry.

[13]  D. Friedman,et al.  The novelty P3: an event-related brain potential (ERP) sign of the brain's evaluation of novelty , 2001, Neuroscience & Biobehavioral Reviews.

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

[15]  Darren Price,et al.  Glutamatergic correlates of gamma-band oscillatory activity during cognition: A concurrent ER-MRS and EEG study , 2014, NeuroImage.

[16]  Dost Öngür,et al.  Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole , 2010, Neuropsychopharmacology.

[17]  R. Knight,et al.  Contributions of temporal-parietal junction to the human auditory P3 , 1989, Brain Research.

[18]  C. Tenke,et al.  Principal components analysis of Laplacian waveforms as a generic method for identifying ERP generator patterns: II. Adequacy of low-density estimates , 2006, Clinical Neurophysiology.

[19]  P. Bottomley.  Spatial Localization in NMR Spectroscopy in Vivo , 1987, Annals of the New York Academy of Sciences.

[20]  S. Provencher.  Automatic quantitation of localized in vivo 1H spectra with LCModel , 2001, NMR in biomedicine.

[21]  Thomas E. Nichols,et al.  Anterior cingulate gyrus dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance. , 1997, The American journal of psychiatry.

[22]  Adolf Pfefferbaum,et al.  Trait and state aspects of p300 amplitude reduction in schizophrenia: a retrospective longitudinal study , 2000, Biological Psychiatry.

[23]  Jun Shen,et al.  Metabolic alterations in focally activated primary somatosensory cortex of α-chloralose-anesthetized rats measured by 1H MRS at 11.7 T , 2005, NeuroImage.

[24]  Rolf Gruetter,et al.  Quantitative proton spectroscopic imaging of the neurochemical profile in rat brain with microliter resolution at ultra‐short echo times , 2008, Magnetic resonance in medicine.

[25]  Fbirn,et al.  A multi-site resting state fMRI study on the amplitude of low frequency fluctuations in schizophrenia , 2013, Front. Neurosci..

[26]  Bob Oranje,et al.  The Effects of a Sub-Anaesthetic Dose of Ketamine on Human Selective Attention , 2000, Neuropsychopharmacology.

[27]  E. Bramon,et al.  Are auditory P300 and duration MMN heritable and putative endophenotypes of psychotic bipolar disorder? A Maudsley Bipolar Twin and Family Study , 2009, Psychological Medicine.

[28]  E. Donchin,et al.  Parsing the late positive complex: mental chronometry and the ERP components that inhabit the neighborhood of the P300. , 2004, Psychophysiology.

[29]  Jonathan D. Cohen,et al.  Decision making, the P3, and the locus coeruleus-norepinephrine system. , 2005, Psychological bulletin.

[30]  Barry Fowler,et al.  Biological determinants of P300: the effects of a barbiturate on latency and amplitude , 1997, Biological Psychology.

[31]  Pierre J Magistretti,et al.  Neuroenergetics: Calling Upon Astrocytes to Satisfy Hungry Neurons , 2004, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[32]  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.

[33]  E. Donchin,et al.  Is the P300 component a manifestation of context updating? , 1988, Behavioral and Brain Sciences.

[34]  Tsutomu Nakada,et al.  1H magnetic resonance spectroscopic imaging of permanent focal cerebral ischemia in rat: longitudinal metabolic changes in ischemic core and rim , 2001, Brain Research.

[35]  E. Halgren,et al.  Generators of the late cognitive potentials in auditory and visual oddball tasks. , 1998, Electroencephalography and clinical neurophysiology.

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

[37]  Arne Schousboe,et al.  Role of astrocytes in glutamate homeostasis: Implications for excitotoxicity , 2005, Neurotoxicity Research.

[38]  E. Donchin,et al.  Spatiotemporal analysis of the late ERP responses to deviant stimuli. , 2001, Psychophysiology.

[39]  John H Krystal,et al.  Modulation of the cortical processing of novel and target stimuli by drugs affecting glutamate and GABA neurotransmission. , 2009, The international journal of neuropsychopharmacology.

[40]  E. Donchin,et al.  Localization of the event-related potential novelty response as defined by principal components analysis. , 2003, Brain research. Cognitive brain research.