In this multicenter study, 2D spatial mapping of J-coupled resonances at 3T and 4T was performed using short-TE (15 ms) proton echo-planar spectroscopic imaging (PEPSI). Water-suppressed (WS) data were acquired in 8.5 min with 1-cm 3 spatial resolution from a supraventricular axial slice. Optimized outer volume suppression (OVS) enabled mapping in close proximity to peripheral scalp regions. Constrained spectral fitting in reference to a non-WS (NWS) scan was performed with LCModel using correction for relaxation attenuation and partial-volume effects. The concentrations of total choline (tCho), creatine ؉ phosphocreatine (Cr؉PCr), glutamate (Glu), glutamate ؉ glutamine (Glu؉Gln), myo-inositol (Ins), NAA, NAA؉NAAG, and two macromolecular resonances at 0.9 and 2.0 ppm were mapped with mean Cramer-Rao lower bounds (CRLBs) between 6% and 18% and ϳ150-cm 3 sensitive volumes. Aspartate, GABA, glutamine (Gln), glutathione (GSH), phosphoethanolamine (PE), and macromolecules (MMs) at 1.2 ppm were also mapped, although with larger mean CRLBs between 30% and 44%. The CRLBs at 4T were 19% lower on average as compared to 3T, consistent with a higher signal-to-noise ratio (SNR) and increased spectral resolution. Metabolite concentrations were in the ranges reported in previous studies. Glu concentration was significantly higher in gray matter (GM) compared to white matter ( Key words: magnetic resonance spectroscopic imaging; proton echo planar spectroscopic imaging; glutamate; spectral quantification; human brain Proton magnetic resonance spectroscopic mapping ( 1 H-MRSI) of brain metabolites can identify biomarkers relevant to psychiatric and neurological disease. There is currently increasing interest in extending 1 H-MRSI techniques and processing capabilities to map J-coupled brain metabolite resonances. Glutamate (Glu) and glutamine (Gln) mapping is of particular interest because these metabolites are key components of energy metabolism and nitrogen homeostasis pathways, and are also involved in excitatory synaptic neurotransmission (1). In vivo mapping of Glu in clinically feasible acquisition times may have important diagnostic applications in psychiatric disorders (2,3) and studies of aging (4).Thus far, Glu and Gln have been studied mostly by single-voxel MR spectroscopy (MRS) using a variety of techniques, including model-based fitting of short-TE spectra (4 -7), use of optimized intermediate TE (8) and Carr-Purcell refocusing pulses (9), spectral editing (10), and 2D J-resolved spectroscopy (11,12). MRSI studies of Glu and Gln have used spectral fitting at short TE (13,14), J-refocused coherence transfer (15), and, more recently, 2D J-resolved spectroscopic imaging (16,17). Spectral editing and 2D J-resolved MRSI techniques enable highly selective mapping of Glu and Gln, but they require multistep encoding, which prolongs the acquisition times and limits the sensitivity gains at high field, as metabolite T 2 values have been shown to decrease with field strength (18,19). Short-TE acquisition of single-voxel spect...

Improved detection of J-coupled neurometabolites through the use of modified proton magnetic resonance spectroscopy (1H-MRS) techniques has recently been reported. TE-averaged point-resolved spectroscopy (PRESS) uses the J modulation effects by averaging FIDs with differing echo times to improve detection of glutamate, while standard PRESS detection of glutamate can be improved by using an appropriate single echo determined from J-modulation simulations. In the present study, the reliabilities of TE-averaged PRESS, standard PRESS with TE ‫؍‬ 40 ms, and standard PRESS with TE ‫؍‬ 30 ms in detecting metabolite levels in the cingulate gyrus of the human brain at 3T were compared in six subjects. TE-averaged PRESS measures showed a mean variability of 9% for N-acetyl aspartate, choline, and creatine, compared with < 4% for the 30-and 40-ms PRESS techniques. The coefficients of variation for glutamate were 10%, 7%, and 5% for TE-averaged Glutamate (Glu) is a major excitatory neurotransmitter and has been proposed to play a role in alcohol addiction (1,2), schizophrenia (3-6), epilepsy (7,8), and several other neurodegenerative disorders (for full review, see Mattson) (9). It is not surprising, therefore, that much effort has gone into developing methods to measure neural Glu, and the associated metabolite glutamine (Gln), reliably in both normal subjects and patient population groups. In addition to the role these metabolites may play in central nervous system disorders, Glu and Gln have recently been shown to change during neuronal activity in response to pain (10), visual stimulation (11), and drug administration (12). In studies of this nature, in which rapid changes in Glu are measured, reliable techniques that are optimized for Glu sensitivity are essential.Proton magnetic resonance spectroscopy (1H-MRS) provides a noninvasive technique to measure neurometabolites (13) in both healthy (14) and patient populations (15). Measurement of Glu, however, is complicated by its complex J-coupled spectrum and overlapping peaks from other metabolites, primarily Gln, gamma amino butyric acid (GABA) and N-acetyl aspartate (NAA). Several 1H-MRS acquisition schemes have been proposed to overcome these limitations, ranging from customized two-dimensional (2D) J editing sequences (16 -19) to standard spectroscopic sequences with optimized timing parameters (20,21). Arguments for the use of 2D techniques point to the exploitation of J modulation and coupling within the spectrum to allow for improved spectral separation of the overlapping coupled peaks, and hence more reliable spectral fitting. However, the very J coupling effects that allow for this increased spectral separation can complicate attempts at absolute quantification, due to difficulties in separating relaxation effects on signal intensities from J modulation effects when modeling basis sets for spectral fitting. Alternatively, the J modulation effect may be used to determine a single echo time (TE) at which overlapping peaks are minimized while other peaks of the met...

Background-Cognitive deficits in schizophrenia may be related to glutamatergic dysfunction, but in-vivo measurement of glutamate metabolism has been challenging. We examined the relationship between glutamate metabolism and cognitive function in schizophrenia.

IMPORTANCE The N-methyl-D-aspartic acid receptor hypofunction model of schizophrenia predicts a paradoxical increase in synaptic glutamate release. In vivo measurement of glutamatergic neurotransmission in humans is challenging, but glutamine, the principal metabolite of synaptic glutamate, can be quantified with proton magnetic resonance spectroscopy (1 H-MRS). Although a few studies have measured glutamate, glutamine, and glutamine to glutamate ratio, it is not clear which of these 1 H-MRS indices of glutamatergic neurotransmission is altered in schizophrenia. OBJECTIVE To examine glutamine, glutamate, and glutamine to glutamate ratio in the dorsal anterior cingulate, as well as their relationships with symptoms and cognition in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional design using 3-T 1 H-MRS in participants recruited from university-based psychiatric outpatient clinics who underwent neuroimaging at an affiliated research facility. Participants were 84 patients with a DSM-IV-TR diagnosis of schizophrenia and 81 psychiatrically healthy volunteers, matched in age, sex, ethnicity, and occupational level to the head of household of family of origin. MAIN OUTCOMES AND MEASURES Glutamine, glutamate, and glutamine to glutamate ratio. Also symptoms and cognition. RESULTS Glutamine was increased in the schizophrenia group (P = .01) as well as the glutamine to glutamate ratio (P = .007) but not glutamate (P = .89). Glutamine levels were positively correlated with severity of psychotic symptoms (P = .02). Choline was also increased in schizophrenia (P = .002). CONCLUSIONS AND RELEVANCE Elevated glutamine, which was directly related to psychotic symptoms, is consistent with increased glutamatergic synaptic release in schizophrenia, as predicted by the N-methyl-D-aspartic acid receptor hypofunction model. Further understanding the underlying mechanism of glutamatergic dysfunction in schizophrenia may lead to new pharmacological strategies to treat psychosis.

A 1 H magnetic resonance spectroscopic imaging study at 3T and short echo time was conducted to evaluate both the reproducibility, as measured by the interscan coefficient of variation (CV), and test-retest reliability, as measured by the intraclass correlation coefficient (ICC), of measurements of glutamate (Glu), combined glutamate and glutamine (Glx), myo-inositol (mI), N-acetylaspartate, creatine, and choline in 21 healthy subjects. The effect of partial volume correction on these measures and the relationship of reproducibility and reliability to data quality were also examined. A 1 H magnetic resonance spectroscopic imaging slice was prescribed above the lateral ventricles and single repeat scans were performed within 30 min to minimize physiologic variability. Interscan CVs based on all the voxels varied from 0.05 to 0.07 for N-acetylaspartate, creatine, and choline to 0.10-0.13 for mI, Glu, and Glx. Findings on the reproducibility of gray and white matter estimates of N-acetylaspartate, creatine, and choline are consistent with previous studies using longer echo times, with CVs in the range of 0.02-0.04 and ICC in the range of 0.65-0.90. CVs for Glu, Glx, and mI are much lower than reported in previous studies at 1.5T, while white matter mI (CV 5 0.04, ICC 5 0.93) and gray matter Glx (CV 5 0.04, ICC 5 0.68) demonstrated both high reproducibility and test-retest reliability. Magn Reson Med 66:324-332,