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Background: 1 H-MRS is increasingly used in basic and clinical research to explain brain function and alterations respectively. In psychosis research it is now one of the main tools to investigate imbalances in the glutamatergic system. Interestingly, however, the findings are extremely variable even within patients of similar disease states. One reason may be the variability in analysis strategies, despite suggestions for standardization. Therefore, our study aimed to investigate the extent to which the basis set configuration- which metabolites are included in the basis set used for analysis- would affect the spectral fit and estimated glutamate (Glu) concentrations in the anterior cingulate cortex (ACC), and whether any changes in levels of glutamate would be associated with psychotic-like experiences and autistic traits., Methods: To ensure comparability, we utilized five different exemplar basis sets, used in research, and two different analysis tools, r-based spant applying the ABfit method and Osprey using the LCModel., Results: Our findings revealed that the types of metabolites included in the basis set significantly affected the glutamate concentration. We observed that three basis sets led to more consistent results across different concentration types (i.e., absolute Glu in mol/kg, Glx (glutamate + glutamine), Glu/tCr), spectral fit and quality measurements. Interestingly, all three basis sets included phosphocreatine. Importantly, our findings also revealed that glutamate levels were differently associated with both schizotypal and autistic traits depending on basis set configuration and analysis tool, with the same three basis sets showing more consistent results., Conclusions: Our study highlights that scientific results may be significantly altered depending on the choices of metabolites included in the basis set, and with that emphasizes the importance of carefully selecting the configuration of the basis set to ensure accurate and consistent results, when using MR spectroscopy. Overall, our study points out the need for standardized analysis pipelines and reporting., (© 2024. The Author(s).)

Previous studies reported decreased glutamate levels in the anterior cingulate cortex (ACC) in non-treatment-resistant schizophrenia and first-episode psychosis. However, ACC glutamatergic changes in subjects at high-risk for psychosis, and the effects of commonly experienced environmental emotional/social stressors on glutamatergic function in adolescents remain unclear. In this study, adolescents recruited from the general population underwent proton magnetic resonance spectroscopy (MRS) of the pregenual ACC using a 3-Tesla scanner. We explored longitudinal data on the association of combined glutamate-glutamine (Glx) levels, measured by MRS, with subclinical psychotic experiences. Moreover, we investigated associations of bullying victimization, a risk factor for subclinical psychotic experiences, and help-seeking intentions, a coping strategy against stressors including bullying victimization, with Glx levels. Finally, path analyses were conducted to explore multivariate associations. For a contrast analysis, gamma-aminobutyric acid plus macromolecule (GABA+) levels were also analyzed. Negative associations were found between Glx levels and subclinical psychotic experiences at both Times 1 (n = 219, mean age 11.5 y) and 2 (n = 211, mean age 13.6 y), as well as for over-time changes (n = 157, mean interval 2.0 y). Moreover, effects of bullying victimization and bullying victimization × help-seeking intention interaction effects on Glx levels were found (n = 156). Specifically, bullying victimization decreased Glx levels, whereas help-seeking intention increased Glx levels only in bullied adolescents. Finally, associations among bullying victimization, help-seeking intention, Glx levels, and subclinical psychotic experiences were revealed. GABA+ analysis revealed no significant results. This is the first adolescent study to reveal longitudinal trajectories of the association between glutamatergic function and subclinical psychotic experiences and to elucidate the effect of commonly experienced environmental emotional/social stressors on glutamatergic function. Our findings may deepen the understanding of how environmental emotional/social stressors induce impaired glutamatergic neurotransmission that could be the underpinning of liability for psychotic experiences in early adolescence., (© 2024. The Author(s).)

Background: The histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions., Methods: We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest., Results: We found significant inverse relationships between tracer uptake and Glu (r = -0.66, P = .02) and Glx (r = -0.62, P = .04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P = .56, Glx: r = 0.10, P = .75). We also found a significant difference in striatal (F1,20 = 6.00, P = .02) and ACC (F1,19 = 4.75, P = .04) Glx levels between groups., Conclusions: These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Background: Treatment-resistant schizophrenia (TRS) and non-TRS may be associated with different dopaminergic and glutamatergic regulations. The concept of dysregulated glutamatergic concentrations in specific brain regions remains controversial. Herein, we aimed to assess (i) the distribution of the glutamatergic concentration in the brain, (ii) the association between working memory (WM) differences in TRS and non-TRS patients, and (iii) whether an alteration in the glutamate (Glu) level is associated with WM., Methods: The participants included 38 TRS patients, 35 non-TRS patients, and 19 healthy controls (HCs), all of whom underwent 1.5-Tesla proton magnetic resonance spectroscopy of anterior cingulate cortex (ACC) and medial prefrontal cortex (MPFC). The ratios of glutamatergic neurometabolites to N -acetylaspartate + N -acetyl aspartylglutamate (NAAx) were calculated. Cognitive function was assessed using the Wechsler Adult Intelligence Scales, 4th Edition, which included the working memory index (WMI)., Result: The TRS patients had a higher glutamate + glutamine (Glx)/NAAx ratio compared to the non-TRS patients and HCs in the ACC, but this was not significantly different in the MPFC. WM was negatively correlated with Glx/NAAx in the ACC among the non-TRS patients, but not in the TRS patients or HCs., Conclusions: Our findings were consistent with most studies indicating that the glutamatergic concentration in the ACC plays important roles in the classification of TRS and cognition. Our results may provide potential evidence for predictors and treatment response biomarkers in TRS patients. Further research is needed to probe the value using the relationship between Glu and WM as a potential prognostic predictor of schizophrenia.

A proton magnetic resonance spectroscopy (MRS) technique was used to measure 13 C enrichments of glutamate and glutamine in a 3.5 × 1.8 × 2 cm 3 voxel placed in the dorsal anterior cingulate cortex of five healthy participants after oral administration of [U- 13 C]glucose. Strong pseudo singlets of glutamate and glutamine were induced to enhance the signal strength of glutamate and glutamine. This study demonstrated that 13 C labeling of glutamate and glutamine can be measured with the high sensitivity and spatial resolution of 1 H MRS using a proton-only MRS technique with standard commercial hardware. Furthermore, it is feasible to measure 13 C labeling of glutamate and glutamine in limbic structures, which play major roles in behavioral and emotional responses and whose abnormalities are involved in many neuropsychiatric disorders., (© 2022. The Author(s).)

Methods: Twenty-five newborn piglets were selected and then randomly assigned to the control group ( n = 5) and the model group ( n = 20) subjected to HI. HI was induced by blocking bilateral carotid blood flow under simultaneous inhalation of a 6% oxygen mixture. 1 H-MRS data were acquired from the basal ganglia at the following time points after HI: 6, 12, 24, and 72 h. Changes in protein levels of EAAT2 and GluR2 were determined by immunohistochemical analysis. Correlations among metabolite concentrations, metabolite ratios, and the protein levels of EAAT2 and GluR2 were investigated., Results: The Glu level sharply increased after HI, reached a transient low level of depletion that approached the normal level in the control group, and subsequently increased again. Negative correlations were found between concentrations of Glu and EAAT2 protein levels ( R s = -0.662, P < 0.001) and between the Glu/creatine (Cr) ratio and EAAT2 protein level ( R s = -0.664, P < 0.001). Moreover, changes in GluR2 protein level were significantly and negatively correlated with those in Glu level (the absolute Glu concentration, R s = -0.797, P < 0.001; Glu/Cr, R s = -0.567, P = 0.003)., Conclusions: Changes in Glu level measured by 1 H-MRS were inversely correlated with those in EAAT2 and GluR2 protein levels following HI, and the results demonstrated that 1 H-MRS can reflect the early changes of glutamatergic activity in vivo., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Yuxue Dang and Xiaoming Wang.)

Nearly a third to half of schizophrenia patients are non-responsive to first-line antipsychotics and are labelled treatment resistant schizophrenia (TRS). Neurochemical abnormalities in TRS may not be dopaminergic but possibly glutamate (Glu) related. Studies that have examined glutamatergic abnormalities using proton magnetic resonance spectroscopy ( 1 H-MRS) in TRS, have showed inconsistent results. Hence, we conducted a meta-analysis of 1 H-MRS studies comparing levels of Glu-and its metabolites in the brains of TRS and non-treatment resistant schizophrenia (nTRS) patients. Four eligible studies were included in the analysis. Summary effect size for the group difference between TRS (n = 101, including Ultra-TRS) and nTRS (n = 61) in Glu-levels in the anterior cingulate cortex (ACC) as measured with Hedges's g was 0.21 (95% CI: -0.42 to 0.85; p = 0.5) suggesting absence of significant difference. However, on leave one out analysis, one iteration showed significant difference in Glu-levels between the groups (Hedges's g = 0.46; p = 0.02) with higher Glu-levels in TRS implying significant effect of a single study on the effect size. The higher ACC Glu-in TRS was not associated with symptom severity or antipsychotic administration, indicating a possible trait abnormality. The limited number of datasets comparing Glu-metabolites in other brain regions are narratively described. Our analysis is limited by the significant heterogeneity between studies. Further longitudinal, prospective studies are needed to confirm higher Glu-metabolite levels in ACC in TRS and explore this potential trait abnormality., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A proposed mechanism of chronic pain is dysregulation between the main inhibitory (GABA) and excitatory (glutamate) neurometabolites of the central nervous system. The level of these neurometabolites appears to differ in individual studies of people with pain compared to pain-free controls across different pain conditions. However, this has yet to be systematically investigated., Aims: To establish whether GABA, glutamate, glutamine and Glx levels differ across pain conditions when compared to pain-free controls., Methods: Five databases were searched. Studies were included if they investigated: 1) A pain condition compared to control. 2) Reported GABA, glutamate, glutamine or glutamate/glutamine level. 3) Used 1H-Magnetic Resonance Spectroscopy (Prospero Project ID CRD42018092170). Data extracted included neurometabolite level, pain diagnosis, and spectroscopy parameters. Meta-analyses were conducted to establish the difference in neurometabolite level between participants with pain and pain-free controls for different pain conditions. The MRS-Q was developed from existing clinical consensus to allow for the assessment of quality in the included studies., Results: Thirty-five studies were included investigating combinations of migraine (n = 11), musculoskeletal pain (n = 8), chronic pain syndromes (n = 9) and miscellaneous pain (n = 10). Higher GABA levels were found in participants with migraine compared to controls (Hedge's G 0.499, 95%CI: 0.2 to 0.798). In contrast, GABA levels in musculoskeletal pain conditions (Hedge's G -0.189, 95%CI: 0.530 to 0.153) and chronic pain syndromes (Hedge's G 0.077, 95%CI: 1.612 to 1.459) did not differ from controls. Results for other brain neurometabolites revealed significantly higher levels for glutamate in participants with migraine and Glx in chronic pain syndromes compared to controls., Conclusion: These results support the theory that underlying neurometabolite levels may be unique in different pain conditions and therefore representative of biomarkers for specific pain conditions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy ( 1 H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1 H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance ( 1 H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1 H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.

Impairments in mismatch negativity (MMN) in schizophrenia are well-established; these findings have been extended to show impairments at early illness stages and in bipolar disorder. A substantial literature supports MMN as an index of NMDA receptor output, however, few studies have conducted in vivo assessments to elucidate the neurochemical underpinnings of MMN. Sixty young (16-33 years) participants with bipolar disorder (n = 47) or schizophrenia (n = 13) underwent 1 H-MRS and MMN assessment. Glutamate over creatine (Glu/Cr) levels in the anterior cingulate cortex (ACC) and hippocampus were determined and MMN was measured frontally and temporally. Correlational analyses assessed the relationship between MMN amplitudes and Glu/Cr. Any significant relationships were assessed for specificity with a follow up correlation analysis of MMN and n-acetyleaspartate (NAA/Cr). No associations between frontal or temporal MMN and ACC or hippocampal Glu/Cr were noted in the bipolar group. In the schizophrenia group, frontal and right temporal MMN amplitudes corresponded with increased ACC Glu/Cr at the trend-level. Right temporal MMN was similarly significantly associated with NAA/Cr. MMN was not associated with hippocampal Glu/Cr. This work provides in vivo evidence that glutamatergic processes may underlie MMN generation in early stage schizophrenia but not in early stage bipolar disorder suggesting differences in the MMN mechanism in these groups. The negative association between ACC Glu/Cr and MMN is consistent with findings of reduced MMN and increased in vivo glutamatergic neurometabolite levels in early stage schizophrenia. Furthermore, these results indicate that examining in vivo NAA/Cr may have provide additional insights into the MMN mechanism in schizophrenia., (Copyright © 2019. Published by Elsevier Ltd.)

Ethanol (EtOH) intake leads to modulation of glutamatergic transmission, which may contribute to ethanol intoxication, tolerance and dependence. To study metabolic responses to the hyper glutamatergic status at synapses during ethanol exposure, we used Glud1 transgenic (tg) mice that over-express the enzyme glutamate dehydrogenase in brain neurons and release excess glutamate (Glu) in synapses. We measured neurochemical changes in the hippocampus and striatum of tg and wild-type (wt) mice using proton magnetic resonance spectroscopy before and after the animals were fed with diets within which EtOH constituting up to 6.4% of total calories for 24 weeks. In the hippocampus, the EtOH diet led to significant increases in concentrations of EtOH, glutamine (Gln), Glu, phosphocholine (PCho), taurine, and Gln + Glu, when compared with their baseline concentrations. In the striatum, the EtOH diet led to significant increases in concentrations of GABA, Gln, Gln + Glu, and PCho. In general, neurochemical changes were more pronounced in the striatum than the hippocampus in both tg and wt mice. Overall neurochemical changes due to EtOH exposure were very similar in tg and wt mice. This study describes time courses of neurochemical profiles before and during chronic EtOH exposure, which can serve as a reference for future studies investigating ethanol-induced neurochemical changes.

Background: Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy ( 1 H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1 H-MRS during euthymia., Methods: One hundred twenty-eight bipolar I disorder (BDI) euthymic subjects and 80 healthy control subjects underwent 3T brain 1 H-MRS imaging examination including acquisition of an anterior cingulate cortex single voxel (8 cm 3 ) 1 H-MRS, based on a point resolved spectroscopy (PRESS) sequence with an echo time of 80 ms and a repetition time of 1500 ms (BIPUSP MRS study). The Glu system was described by measuring Glu and the sum of Glu and glutamine (Glx) using creatine (Cre) as a reference., Results: Euthymic BDI subjects presented with higher ratios of Glu/Cre and Glx/Cre compared to healthy control subjects. Glu/Cre ratios were lower among patients using anticonvulsants, while Glx/Cre did not differ between the two groups. Lithium, antipsychotics, and antidepressants did not influence Glu/Cre or Glx/Cre., Conclusions: We reported Glu/Cre and Glx abnormalities in the largest sample of euthymic BDI patients studied by 1 H-MRS to date. Our data indicate that both Glu/Cre and Glx/Cre are elevated in BDI during euthymia regardless of medication effects, reinforcing the hypothesis of glutamatergic abnormalities in BD. Furthermore, we found an effect of anticonvulsants on Glu/Cre during euthymia, which might indicate a mechanism of mood stabilization in BD., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, n = 71) and healthy volunteers (n = 60), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (n = 65), then 1 H-MRS was repeated (n = 46). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (P < 0.05). There were longitudinal reductions in Glu/Cr in both the ACC and thalamus over the treatment period (P < 0.05), but these changes were not associated with the therapeutic response. There were no differences in baseline Glu/Cr between patients and controls. These results extend previous evidence linking higher levels of ACC glutamate with a poor antipsychotic response by showing that the association is evident before the initiation of treatment.

Purpose: To simultaneously measure glutamate, glutamine, γ-aminobutyric acid (GABA), and glutathione using spectral editing without subtraction at 7T., Methods: A novel spectral editing approach was proposed to simultaneously measure glutamate, glutamine, GABA, and glutathione using a TE of 56 ms at 7T. By numerical optimization of sequence timing in the presence of an editing pulse, the 4 metabolites all form relatively intense pseudo singlets with maximized peak amplitudes and minimized peak linewidths in 1 of the 3 interleaved spectra. For measuring glutamate, glutamine, and glutathione, the editing pulse targets the H 3 protons of these metabolites near 2.12 parts per million. Both GABA H 2 and H 4 resonances are fully utilized in spectral fitting., Results: Concentration levels (/[total creatine]) of glutamate, glutamine, GABA, and glutathione from an 8 mL voxel in the pregenual anterior cingulate cortex of 5 healthy volunteers were found to be 1.26 ± 0.13, 0.33 ± 0.06, 0.13 ± 0.03, and 0.27 ± 0.03, respectively, with within-subject coefficient of variation at 3.2%, 8.2%, 7.1%, and 10.2%, respectively. The total scan time was less than 4.5 min., Conclusions: The proposed new technique does not require data subtraction. The 3 major metabolites of the glutamatergic and GABAergic systems and the oxidative stress marker glutathione were all measured in 1 short scan with high precision., (© Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

The glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is involved in synaptic plasticity processes, and animal studies have demonstrated altered expression across the sleep wake cycle. Accordingly, glutamate levels are reduced during non-rapid eye movement (NREM) sleep and the rate of this decrease is positively correlated with sleep EEG slow wave activity (SWA). Here, we combined proton magnetic resonance spectroscopy ( 1 H-MRS) and high-density sleep EEG to assess if 1 H-MRS is sensitive to diurnal changes of glutamate + glutamine (GLX) in healthy young adults and if potential overnight changes of GLX are correlated to SWA. 1 H-MRS was measured in the parietal lobe in the evening and in the subsequent morning. High-density sleep EEG was recorded overnight between the evening and morning scans. Our results revealed a significant overnight reduction in GLX, but no significant changes in other metabolites. The decrease in GLX positively correlated with the decrease of SWA. Our study demonstrates that quantification of diurnal changes in GLX is possible by means of 1 H-MRS and indicates that overnight changes in GLX are related to SWA, a marker that is closely linked to the restorative function of sleep. This relationship might be of particular interest in clinical populations in which sleep is disturbed., (© 2018 Wiley Periodicals, Inc.)

Alterations in glutamate neurotransmission have been implicated in the pathophysiology of schizophrenia, as well as in symptom severity and cognitive deficits. The hippocampus, in particular, is a site of key functional and structural abnormalities in schizophrenia. Yet few studies have investigated hippocampal glutamate in antipsychotic-naïve first episode psychosis patients or in individuals at clinical high risk (CHR) of developing psychosis. Using proton magnetic resonance spectroscopy ( 1 H-MRS), we investigated glutamate metabolite levels in the left hippocampus of 25 CHR (19 antipsychotic-naïve), 16 patients with first-episode psychosis (13 antipsychotic-naïve) and 31 healthy volunteers. We also explored associations between hippocampal glutamate metabolites and glial activation, as indexed by [ 18 F]FEPPA positron emission tomography (PET); symptom severity; and cognitive function. Groups differed significantly in glutamate plus glutamine (Glx) levels (F (2, 69)  = 6.39, p = 0.003). Post-hoc analysis revealed that CHR had significantly lower Glx levels than both healthy volunteers (p = 0.003) and first-episode psychosis patients (p = 0.050). No associations were found between glutamate metabolites and glial activation. Our findings suggest that glutamate metabolites are altered in CHR.

Proton magnetic resonance spectroscopy measurements of glutamate and GABA are important in neuropsychiatric research. Some study designs require simultaneous measurement of both metabolites. GABA measurement requires specialized pulse sequences, the most common approach being J-difference spectral editing with MEGA-PRESS. This method enables two different strategies for concurrently measuring glutamate - from either off-resonance or difference spectra. However, it is uncertain how either strategy compares to conventional glutamate measurements. Here we compared these approaches in 49 subjects (28 healthy volunteers and 21 first-episode psychosis patients), in whom both PRESS (TE 80) and MEGA-PRESS (TE 68) spectra were obtained from dorsolateral prefrontal cortex. Glutamate and glx estimates from MEGA-PRESS difference and off-resonance spectra were compared to glutamate and glx estimates from PRESS spectra using correlational analyses. In healthy volunteers, correlations between PRESS and MEGA-PRESS off-resonance values were r ≥ 0.88 and were significantly higher than correlations between PRESS and MEGA-PRESS difference spectrum values (r ≤ 0.36). Patients showed a similar pattern. Lower correlations with difference spectrum values may reflect a disproportionate impact of field instabilities on co-edited glutamate signals. The results suggest that MEGA-PRESS off-resonance spectra can substitute for separately-acquired PRESS spectra in studies requiring simultaneous glutamate and GABA measurements., (Copyright © 2018. Published by Elsevier B.V.)

Background: Cortical glutamatergic dysfunction is thought to be fundamental for psychosis development, and may lead to structural degeneration through excitotoxicity. Glutamate levels have been related to gray matter volume (GMV) alterations in people at ultra-high risk of psychosis, and we previously reported GMV changes in individuals with high schizotypy (HS), which refers to the expression of schizophrenia-like characteristics in healthy people. This study sought to examine whether GMV changes in HS subjects are related to glutamate levels., Methods: We selected 22 healthy subjects with HS and 23 healthy subjects with low schizotypy (LS) based on their rating on a self-report questionnaire for psychotic-like experiences. Glutamate levels were measured in the bilateral anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, and GMV was assessed using voxel-based morphometry., Results: Subjects with HS showed GMV decreases in the rolandic operculum/superior temporal gyrus (pFWE = 0.045). Significant increases in GMV were also detected in HS, in the precuneus (pFWE = 0.043), thereby replicating our previous finding in a separate cohort, as well as in the ACC (pFWE = 0.041). While the HS and LS groups did not differ in ACC glutamate levels, in HS subjects ACC glutamate was negatively correlated with ACC GMV (pFWE = 0.026). Such association was absent in LS., Conclusions: Our study shows that GMV findings in schizotypy are related to glutamate levels, supporting the hypothesis that glutamatergic function may lead to structural changes associated with the expression of psychotic-like experiences.

Background: The possible role of glutamate in the pathophysiology and treatment of depression is of intense current interest. Proton magnetic resonance spectroscopy (MRS) enables the detection of glutamate in the living human brain and meta-analyses of previous MRS studies in depressed patients have suggested that glutamate levels are decreased in anterior brain regions. Nevertheless, at conventional magnetic field strengths [1.5-3 Tesla (T)], it is difficult to separate glutamate from its metabolite and precursor, glutamine, with the two often being measured together as Glx. In contrast, MRS at 7 T allows clear spectral resolution of glutamate and glutamine., Method: We studied 55 un-medicated depressed patients and 50 healthy controls who underwent MRS scanning at 7 T with voxels placed in anterior cingulate cortex, occipital cortex and putamen (PUT). Neurometabolites were calculated using the unsuppressed water signal as a reference., Results: Compared with controls, depressed patients showed no significant difference in glutamate in any of the three voxels studied; however, glutamine concentrations in the patients were elevated by about 12% in the PUT (p < 0.001)., Conclusions: The increase in glutamine in PUT is of interest in view of the postulated role of the basal ganglia in the neuropsychology of depression and is consistent with elevated activity in the descending cortical glutamatergic innervation to the PUT. The basal ganglia have rarely been the subject of MRS investigations in depressed patients and further MRS studies of these structures in depression are warranted.

Although recent investigations of major depressive disorder (MDD) have focused on the monoaminergic system, accumulating evidences suggest that alternative pathophysiological models of MDD and treatment options for patients with MDD are needed. Animals subjected to chronic forced swim stress (CFSS) develop behavioral despair. The purpose of this study was to investigate the in vivo effects of CFSS on systems other than the monoamine system in the rat prefrontal cortex (PFC) with 7T and short-echo-time (16.3 ms) proton magnetic resonance spectroscopy ( 1 H MRS). Ten male Wistar rats underwent 14 days of CFSS, and in vivo 1 H MRS and forced swim tests were performed before and after CFSS. Point-resolved spectroscopy was used to quantify metabolite levels in the rat PFC. To investigate spectral overlap in glutamate and glutamine, spectral analyses in the spectra obtained in the in vivo 1 H MRS, parametrically matched spectral simulation, and in vitro experiments were performed. The results of the spectral analyses showed that the glutamate/glutamine spectral overlap was not critical, which suggested that in vivo 1 H MRS can be used to reliably assess the glutamate system. The rats showed significantly increased immobility times and decreased climbing times in the FST after CFSS, which suggested that the rats developed behavioral despair. The pre-CFSS and post-CFSS glutamate and glutamine levels did not significantly differ (p > 0.050). The levels of myo-inositol, total choline, and N-acetylaspartate, myo-inositol/creatine, and total choline/creatine increased significantly (p < 0.050). Similar findings have been reported in patients with MDD. Taken together, these results suggest that the CFSS-induced metabolic alterations were similar to those found in patients and that high-field and short-echo-time in vivo 1 H MRS can be used to investigate depression-induced metabolic alterations. Such investigations might provide alternative insights into the nonmonoaminergic pathophysiology and treatment of depression., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Proton functional magnetic resonance spectroscopy ( 1 H fMRS) is a noninvasive neuroimaging technique capable of detecting dynamic changes in glutamate related to task-related demands at a temporal resolution under 1 min. Several recent 1 H fMRS studies demonstrated elevated steady-state levels of glutamate of 2% or greater during different 'task-active' conditions, relative to a 'non-task-active' control condition. However, the 'control' condition from these studies does vary with respect to the degree of constraining behavior, which may lead to different glutamate levels or variability between 'control' conditions. The purpose of this 1 H fMRS study was to compare the steady-state levels and variability of glutamate in the left dorsolateral prefrontal cortex (dlPFC) of 16 healthy adults across four different putative 'non-task-active' conditions: relaxed with eyes closed, passive visual fixation crosshair, visual flashing checkerboard, and finger tapping. Results showed significantly lower glutamate levels during the passive visual fixation crosshair than the visual flashing checkerboard and the finger tapping conditions. Moreover, glutamate was significantly less variable during the passive visual fixation crosshair and the visual flashing checkerboard than the relaxed eyes closed condition. Of the four conditions, the passive visual fixation crosshair condition demonstrated the lowest and least variable glutamate levels potentially reflecting the least dlPFC engagement, but greatest behavioral constraint. These results emphasize the importance of selecting a proper 'control' condition to reflect accurately a 'non-task-active' steady-state level of glutamate with minimal variability during 1 H MRS investigations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Abnormalities of the glutamate system are increasingly implicated in schizophrenia but their exact nature remains unknown. Proton magnetic resonance spectroscopy ( 1 H-MRS), while fundamental in revealing glutamatergic alterations in schizophrenia, has, until recently, been significantly limited and thought to only provide static measures. Functional magnetic resonance spectroscopy (fMRS), which uses sequential scans for dynamic measurement of a range of brain metabolites in activated brain areas, has lately been applied to a variety of task or stimulus conditions, producing interesting insights into neurometabolite responses to neural activation. Here, we summarise the existing 1 H-MRS studies of brain glutamate in schizophrenia. We then present a comprehensive review of research studies that have utilised fMRS, and lastly consider how fMRS methods might further the understanding of glutamatergic abnormalities in schizophrenia.

Introduction: The aim of this study was to investigate the thalamic biochemical profile in patients with essential tremor (ET), using proton magnetic resonance spectroscopy ( 1 H-MRS), and to explore the correlations between clinical and biochemical data., Methods: Sixteen patients with ET and 14 healthy controls participated in this study. After conventional MR imaging, single-voxel 1 H-MRS (TR = 2000 ms; TE = 28 ms) was performed by using a PROBE-SV system implemented on a 3-T scanner. A voxel of 10 × 10 × 15 mm involving the ventrointermediate (Vim) nucleus was acquired in each thalamus of all subjects. Peak areas of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (NAA), creatine + phosphocreatine (Cr), glycerophosphocholine + phosphocholine (Cho), and glutamate + glutamine (Glx) were calculated using a version 6.3-1 K of the fitting program LCModel for each voxel. Comparative and correlation analyses were performed on the NAA, Cr, Cho, and Glx concentrations, as well as on the values of the NAA/Cr, a neural density marker, Cho/Cr, a membrane marker, and Glx/Cr, an intracellular neurotransmitter marker., Results: Patients with ET showed a significant increase in Glx concentration and Glx/Cr ratio values in both thalami, compared to healthy controls, whereas no difference inter-group was found for the other metabolites and NAA/Cr and Cho/Cr ratio values. Of note, the tremor severity was positively related to increased Glx concentrations and Glx/Cr ratio values in ET group., Conclusions: Our study shows that 1 H-MRS can highlight in vivo metabolic abnormalities in the thalami of ET patients, supporting the evidence that the increase of thalamic glutamatergic transmission can play a role in developing of tremor in ET., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Purpose: Glutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy ( 1 H-MRS) protocol composed of semi-localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment., Methods: Participants with amnestic mild cognitive impairment (n = 14; median age = 80) and age- and sex-matched clinically normal controls (n = 32; median age = 79) from the population-based Mayo Clinic Study of Aging were recruited prospectively to the 3T single-voxel 1 H-MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low β-amyloid load on [ 11 C] Pittsburgh Compound B (PiB)-PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high β-amyloid load (SUVr ≥ 1.42)., Results: Glutamate concentration and the glutamate/myo-inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P < .05). Higher global cortical PiB-PET SUVr correlated with lower glutamate/myo-inositol (r = -.3, P = .04)., Conclusions: The advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced 1 H-MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment., (Copyright © 2017 by the American Society of Neuroimaging.)

Proton-Magnetic Resonance Spectroscopy ( 1 H-MRS) may serve as an important tool for identifying biomarkers that aid the understanding of early psychosis, as development of this condition may be associated with metabolite concentration changes that reflect an alteration in glutamatergic mechanisms. The current study explored 1 H-MRS metabolite concentrations in the striatum and anterior cingulate cortex (ACC) as potential biomarkers of psychosis-risk symptom severity. In a sample of 12 adolescents at clinical high-risk for psychosis, the subclinical symptom of grandiosity significantly correlated with glutamate in the ACC. Striatal glutathione, a marker of oxidative stress linked to the glutamatergic system, significantly correlated with grandiosity. Anterior cingulate glutathione significantly correlated with grandiosity and disorganized communication. These findings suggest that within a small sample of young people at clinical high-risk, glutamatergic metabolites are correlated with symptomatology generally predictive of conversion to psychosis. These mechanisms may serve as relevant biomarkers for facilitating prediction of symptom severity and providing insight into the etiology of early psychosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains' left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to account for confounding factors that could contaminate the measurement of neurometabolite levels due to disease, such as the macromolecule signal, partial volume effects, and relaxation effects. Glutamate levels in both regions of interest were lower in people with multiple sclerosis. In the sensorimotor (though not the parietal) region, GABA concentration was higher in the multiple sclerosis group compared to controls. Lower magnetization transfer ratio within grey and white matter regions from which spectroscopy data were acquired was linked to neurometabolite levels. When adjusting for age, normalized brain volume, MTR, total N-acetylaspartate level, and glutamate level, significant relationships were found between lower sensorimotor GABA level and worse performance on several tests, including one of upper limb motor function. This work highlights important methodological considerations relevant to analysis of spectroscopy data, particularly in the afflicted human brain. These findings support that regional neurotransmitter levels are linked to local microstructural integrity and specific behavioral abilities that can be affected in diseases such as multiple sclerosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Single prolonged stress (SPS) is one of the preclinical models of posttraumatic stress disorder (PTSD) in humans. Not every traumatized person develops PTSD and the onset of the disease varies from months to many years after exposure to life-threatening events. The pathogenetic neurometabolites in PTSD have not been investigated to date, and could provide a means for therapeutic interventions. Therefore the present study aimed to evaluate neurochemical changes in the frontal cortex in the SPS model during time-dependent sensitization using in vivo and ex vivo proton magnetic spectroscopy ( 1 H-MRS). Twenty-one male Sprague-Dawley rats (200-220 g) were randomly assigned into two groups (Control, n = 10; SPS, n = 11). SPS consists of three consecutive stressors (restraint, forced swimming, and ether exposure) followed by 7 days without disturbance. In vivo 1 H-MRS scans were conducted at baseline, immediately after SPS, and 3 and 7 days after SPS to quantify time-dependent alterations in the frontal cortex. On day 7, all animals were sacrificed and ex vivo 1 H-MRS was performed. After SPS exposure, the SPS group showed signs of excitatory activities (glutamate) and cellular membrane turnover (choline and total choline) for 7 days. After the time-sensitization period, the SPS group showed lower glutamate and creatine levels and higher choline and lactate levels than the control group. These results indicate that SPS induces sustained adaptation of glutamatergic neuronal activity in the frontal cortex. Therefore, we conclude that SPS-induced stress reduces glutamatergic metabolism in the frontal cortex.

Although postpartum depression (PPD) is a prevalent subtype of major depressive disorder, neuroimaging studies on PPD are rare, particularly those identifying neurochemical abnormalities obtained by proton magnetic resonance spectroscopy (¹H-MRS). The dorsolateral prefrontal (DLPF) and the anterior cingulate gyrus (ACG) are part of the neural pathways involved in executive functions and emotional processing, and both structures have been implicated in the neurobiology of depressive disorders. This study aimed to evaluate brain metabolites abnormalities in women with PPD compared with healthy postpartum (HP) women. Thirty-six PPD (34 without antidepressants) and 25 HP women underwent a ¹H-MRS acquired on a 3-T MRI system, with the volume of interest positioned in ACG and DLPF. An ANCOVA was conducted with age, postpartum time, and contraceptive type as covariates. PPD group presented significantly lower Glutamate+Glutamine (Glx, -0.95mM) and N-acetylaspartate+N-acetylaspartylglutamate (NAA, -0.60mM) values in DLPF. There were no significant differences between groups in ACG, but we found a significant increase of Glutamate (Glu, 2.18mM) and Glx (1.84mM) in participants using progestogen-only contraceptives. These findings suggest glutamatergic dysfunction and neuronal damage in the DLPF of PPD patients, similarly to other subtypes of depressive disorders. Progestogens seem to interfere in the neurochemistry of ACG., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The diagnosis of psychoactive substance use disorders has been based primarily on descriptive, symptomatic checklist criteria. In opioid addiction, there are no objective biological indicators specific enough to guide diagnosis, monitor disease status, and evaluate efficacy of therapeutic interventions. Proton magnetic resonance spectroscopy ( 1 H MRS) of the brain has potential to identify and quantify biomarkers for the diagnosis of opioid dependence. The purpose of this study was to detect the absolute glutamate concentration in the nucleus accumbens (NAc) of patients with prescription opioid dependence using 1 H MRS, and to analyze its clinical associations., Methods: Twenty patients with clinically diagnosed definitive prescription opioid dependent (mean age = 26.5 ± 4.3 years) and 20 matched healthy controls (mean age = 26.1 ± 3.8 years) participated in this study. Patients were evaluated with the Barratt Impulsiveness Scale (BIS-11), the Self-Rating Anxiety Scale (SAS), and the opiate Addiction Severity Inventory (ASI). We used point-resolved spectroscopy to quantify the absolute concentrations of metabolites (glutamate, choline, N -acetylaspartate, glutamine, creatine) within the NAc. The difference between metabolite levels of groups and Pearson's correlation between glutamate levels and psychometric scores in patients were analyzed statistically., Results: Glutamate concentrations in the NAc were significantly higher in prescription opiate addicts than in controls ( t  =   3.84, p  =   .001). None of the other metabolites differed significantly between the two groups (all p s > .05). The glutamate concentrations correlated positively with BIS-11 scores in prescription opiate addicts ( r  =   .671, p  =   .001), but not with SAS score and ASI index., Conclusions: Glutamate levels in the NAc measured quantitatively with in vivo 1 H MRS could be used as a biomarker to evaluate disease condition in opioid-dependent patients.

Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds (NAAc, N-acetylaspartate plus N-acetyl-aspartyl-glutamate), a marker of neuronal viability, can be quantified with proton magnetic resonance spectroscopy (1H-MRS). We used 1H-MRS imaging to assess Glx and NAAc, as well as total-choline (glycerophospho-choline plus phospho-choline), myo-inositol and total-creatine (creatine plus phosphocreatine) from an axial supraventricular slab of gray matter (GM, medial-frontal and medial-parietal) and white matter (WM, bilateral-frontal and bilateral-parietal) voxels. Schizophrenia subjects (N = 104) and healthy controls (N = 97) with a broad age range (16 to 65) were studied. In schizophrenia, Glx was increased in GM (P < .001) and WM (P = .01), regardless of age. However, with greater age, NAAc increased in GM (P < .001) but decreased in WM (P < .001) in schizophrenia. In patients, total creatine decreased with age in WM (P < .001). Finally, overall cognitive score correlated positively with WM neurometabolites in controls but negatively in the schizophrenia group (NAAc, P < .001; and creatine [only younger], P < .001). We speculate the results support an ongoing process of increased glutamate metabolism in schizophrenia. Later in the illness, disease progression is suggested by increased cortical compaction without neuronal loss (elevated NAAc) and reduced axonal integrity (lower NAAc). Furthermore, this process is associated with fundamentally altered relationships between neurometabolite concentrations and cognitive function in schizophrenia., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To investigate possible metabolic changes in vitreous of patients with diabetes mellitus with or without diabetic retinopathy using proton magnetic resonance spectroscopy., Material and Methods: Twenty-eight healthy control subjects (group 1), 18 patients with diabetes mellitus without diabetic retinopathy (group 2) and 18 patients with diabetic retinopathy (group 3) were included. Proton magnetic resonance spectroscopy was performed in left vitreous of all subjects; amounts of Glutamate, Choline, Lactate and Creatine values were measured. Choline/Creatine, Glutamate/Creatine and Lactate/Creatine ratios were calculated., Results: Glutamate/Creatine and Lactate/Creatine ratios were significantly higher in group 2 and 3 when compared to group 1. Both Glutamate/Creatine and Lactate/Creatine ratios did not show any difference in group 2 when compared to group 3., Conclusions: Our results suggest that when compared to healthy subjects, Glutamate and Lactate are the main metabolites of vitreous in diabetes mellitus patients. This may help us to better understand the metabolic factors in pathogenesis of diabetic retinopathy.

The consistency and reliability of proton magnetic resonance spectroscopy ( 1 H-MRS) assessments of neurotransmitter concentration has not been widely examined over multiple days. The purpose of this study was to determine the reliability of glutamate and GABA measures using a single-voxel 1 H-MRS protocol in healthy men and women. Glutamate and GABA quantitations were obtained from the primary motor cortex (M1) and the dorsolateral prefrontal cortex (DLPFC) in 13 healthy individuals across 3 data collection sessions, including a baseline (Visit 1), 2-week (Visit 2), and 2-month time point (Visit 3). Glutamate concentrations were similar across visits in M1 (p=0.72) and the DLPFC (p=0.52). Reliability across days was excellent in M1 (R=0.93), and in the DLPFC (R=0.99). GABA concentrations were similar across visits in M1 (p=0.44) and in the DLPFC (p=0.59). Reliability of GABA concentration across days was excellent in M1 (R=0.93), and in the DLPFC (R=0.97). 1 H-MRS is a reliable method for quantifying glutamate and GABA concentration in M1 and the DLPFC in humans., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Repeated exposure to dizocilpine (MK-801) can be used as a model of schizophrenia that incorporates disease progression. Proton magnetic resonance spectroscopy ( 1 H MRS) has been widely used to investigate schizophrenia-related alterations in glutamate (Glu). The purpose of this study was to investigate metabolic alterations in the prefrontal cortex (PFC) in an animal model of schizophrenia by using in vivo 1 H MRS. Because of the spectral overlap of Glu and glutamine (Gln), high-field 1 H MRS with short echo time (TE) was used. A point-resolved spectroscopy sequence was used to measure the levels of Glu and Gln, and the brain metabolites in a volume of interest (22.5μL) located in the PFC region of rats (n=13) before and after 6days of MK-801 (0.5mg/kg) treatment. Analysis of the spectra showed that the cross-contamination of Glu and Gln can be considered to comparably low. No metabolic parameters were altered (p>0.05). However, differences in Glu and N-acetylaspartate (NAA) levels between two times were significantly correlated (p<0.01). The results showed both decreased (in 6 of the 13 rats) and increased (7 of the 13 rats) levels of Glu and NAA, which suggested that these opposite metabolic alterations reflect two stage of disease progression. The results suggest that high-field and short TE in vivo 1 H MRS can quantify Glu and Gln with reliably low level of cross-contamination and that repeated exposure to MK-801 induces the progressive development of schizophrenia., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Previous studies reported decreased N-acetyl aspartate and increased Glx (the sum of glutamate plus glutamine) in bipolar disorder. Since these studies included patients at different stages of illness, it is unknown whether these changes have a causal role or a consequence of multiple episodes and treatments. The studies in early-stage bipolar disorder patients have the potential to provide answers to these issues. Therefore, we evaluated N-acetyl aspartate and Glx levels in hippocampi of first-episode bipolar disorder patients and health subjects at baseline and at 12 months, and examined the impact of episode recurrence on these measures., Method: We used single-voxel proton magnetic resonance spectroscopy to compare the hippocampal neurometabolites ( N-acetyl aspartate and Glx) levels between 41 patients with bipolar disorder following recovery from their first-manic episode and 27 matched healthy subjects at recruitment and 12 months later. We also compared N-acetyl aspartate and Glx levels between patients who had a recurrence of a mood episode and those who did not., Results: There was no main effect of either group (diagnosis) or time for hippocampal N-acetyl aspartate and Glx levels in bipolar disorder patients and healthy subjects. We also did not find any group-by-time interaction for the levels of these metabolites. There were also no differences in N-acetyl aspartate and Glx between patients who experienced a recurrence of a mood episode and those who did not over 12-month follow-up., Conclusion: Our data suggest that N-acetyl aspartate and Glx levels are not altered in early stage bipolar disorder. Further, these data suggest that episode recurrence in early stages does not have a significant impact on the levels of these metabolites. These may suggest that there may be an early window for intervention to potentially arrest neuroprogression of the disease.

Purpose: To determine the reproducibility of a comprehensive single-session measurement of glutathione (GSH), γ-aminobutyric acid (GABA), glutamate, and other biochemicals implicated in the pathophysiology of multiple sclerosis (MS) in the human brain with 1 H magnetic resonance spectroscopy (MRS)., Materials and Methods: Five healthy subjects were studied twice in separate 1-hour sessions at 7T. One MS patient was also scanned once. GSH and GABA were measured with J-difference editing using a semilocalized by adiabatic selective refocusing sequence (semi-LASER, TE = 72 msec). A stimulated echo acquisition mode sequence (STEAM, TE = 10 msec) was used to detect glutamate along with the overall biochemical profile. Spectra were quantified with LCModel. Quantification accuracy was assessed through Cramer-Rao lower bounds (CRLB). Reproducibility of the metabolite quantification was tested using coefficients of variation (CoV)., Results: CRLB were ≤7% for GSH, GABA, and glutamate and average CoV of 7.8 ± 3.2%, 9.5 ± 7.0%, and 3.2 ± 1.7% were achieved, respectively. The average test/retest concentration differences at this measurement reproducibility and quantification accuracy were smaller for GABA and glutamate than intersubject variations in metabolite content with CoV ratios of 0.6 and 0.8, respectively. As proof of principle, GSH, GABA, and glutamate were also detected in an MS patient., Conclusion: GSH, GABA, glutamate, and other metabolites relevant in MS can be quantified at 7T with high accuracy and reproducibility in a single 1-hour session. This methodology might serve as a clinical research tool to investigate biochemical markers associated with MS., Level of Evidence: 2 J. Magn. Reson. Imaging 2017;45:187-198., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objective: Both Tourette's disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently investigated in prior studies., Method: We used proton magnetic resonance spectroscopy (1H-MRS) in children between 8 and 12 years of age (TD n  = 15, ADHD n  = 39, TD + ADHD n  = 29, and healthy controls n  = 53) as an in vivo method of evaluating glutamate concentrations in the fronto-striatal circuit. Spectra were collected on a 3 Tesla Siemens scanner from two voxels in each participant: the anterior cingulate cortex (ACC) and the left dorsal striatum. LC-model was used to process spectra and generate glutamate concentrations in institutional units. A one-way analysis of variance was performed to determine significant effects of diagnostic group on glutamate concentrations., Results: We did not find any group differences in glutamate concentrations in either the ACC (F (3132)  = 0.97, p  = 0.41) or striatum (F (3121)  = 0.59, p  = 0.62). Furthermore, variation in glutamate concentration in these regions was unrelated to age, sex, medication use, IQ, tic, or ADHD severity. Obsessive-compulsive (OC) symptoms were positively correlated with ACC glutamate concentration within the participants with TD (rho = 0.35, p uncorrected  = 0.02)., Conclusion: We found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive and psychiatric symptoms. Atrophy of the striatum has been proposed for several years as a biomarker to assess disease progression in HD gene carriers. However, it does not provide any information about the biological mechanisms linked to HD pathogenesis. Changes in brain metabolites have been also consistently seen in HD patients and animal models using Magnetic Resonance Spectroscopy (MRS), but metabolite measurements are generally limited to a single voxel. In this study, we used Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) in order to map glutamate distribution in the brain of a knock-in mouse model (Ki140CAG) with a precise anatomical resolution. We demonstrated that both heterozygous and homozygous mice with pathological CAG repeat expansion in gene encoding huntingtin exhibited an atrophy of the striatum and a significant alteration of their metabolic profile in the striatum as compared to wild type littermate controls. The striatal decrease was then confirmed by gluCEST imaging. Surprisingly, CEST imaging also revealed that the corpus callosum was the most affected structure in both genotype groups, suggesting that this structure could be highly vulnerable in HD. We evaluated for the first time gluCEST imaging as a potential biomarker of HD and demonstrated its potential for characterizing metabolic defects in neurodegenerative diseases in specific regions., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Previous studies have examined the relationship of brain metabolic changes in patients with attention deficit hyperactivity disorder (ADHD) and internet gaming disorder (IGD). However, these studies have been limited by a small number of subjects, a large variance in subject age, and different brain regions of interest. The present study assessed the effects of chronic internet game play in ADHD children. Twenty eight ADHD adolescents with IGD (IGD+ADHD), 27 ADHD adolescents without problematic internet game playing (ADHD only) and 42 healthy comparison adolescents (HC) were included in the study. Magnetic resonance spectroscopy (MRS) was performed on a 3T MRI scanner. Our results indicate that the levels of NAA in both ADHD groups were lower than those observed in the HC group. The levels of Glu+Gln in the ADHD only group were increased, compared to those observed in the control group. However, Glu+Gln was not increased in the IGD+ADHD group. In addition, the levels of Glu+Gln in the IGD+ADHD group were positively correlated with K-ARS total and inattention scores. ADHD and IGD subjects were both characterized by decreased NAA levels within the frontal lobe, consistent with hypofrontality., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Short-TE (1) H MRS has great potential for brain cancer diagnostics. A major difficulty in the analysis of the spectra is the contribution from short-T2 signal components, mainly coming from mobile lipids. This complicates the accurate estimation of the spectral parameters of the resonance lines from metabolites, so that a qualitative to semi-quantitative interpretation of the spectra dominates in practice. One solution to overcome this difficulty is to measure and estimate the short-T2 signal component and to subtract it from the total signal, thus leaving only the metabolite signals. The technique works well when applied to spectra obtained from healthy individuals, but requires some optimisation during data acquisition. In the clinical setting, time constraints hardly allow this. Here, we propose an iterative estimation of the short-T2 signal component, acquired in a single acquisition after measurement of the full spectrum. The method is based on QUEST (quantitation based on quantum estimation) and allows the refinement of the estimate of the short-T2 signal component after measurement. Thus, acquisition protocols used on healthy volunteers can also be used on patients without further optimisation. The aim is to improve metabolite detection and, ultimately, to enable the estimation of the glutamine and glutamate signals distinctly. These two metabolites are of great interest in the characterisation of brain cancer, gliomas in particular. When applied to spectra from healthy volunteers, the new algorithm yields similar results to QUEST and direct subtraction of the short-T2 signal component. With patients, up to 12 metabolites and, at least, seven can be quantified in each individual brain tumour spectrum, depending on the metabolic state of the tumour. The refinement of the short-T2 signal component significantly improves the fitting procedure and produces a separate short-T2 signal component that can be used for the analysis of mobile lipid resonances. Thus, in brain tumour spectra, distinct estimates of signals from glutamate and glutamine are possible. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The MEGA-PRESS pulse sequence was used for determination of overlapping signals in the (1)H-MRS spectra of the human brain. For the first time, the balance of GABA glutamate/glutamine concentrations was estimated quantitatively in the human brain of patients with ultra-high risk of schizophrenia. It was found that GABA concentration and GABA/GLX ratios were significantly reduced in the left frontal lobe of UHR subjects.

Introduction: Resistance to antipsychotic treatment is a significant clinical problem in patients with schizophrenia with approximately 1 in 3 showing limited or no response to repeated treatments with antipsychotic medication. The neurobiological basis for treatment resistance is unknown but recent evidence implicates glutamatergic function in the anterior cingulate cortex. We examined glutamate levels of chronically ill treatment-resistant patients directly compared to treatment-responsive patients., Methods: We acquired proton magnetic resonance spectroscopy (1H-MRS) at 3 Tesla from 21 treatment-resistant and 20 treatment-responsive patients. All participants had a DSM-IV diagnosis of schizophrenia. Treatment-resistant patients were classified using the modified Kane criteria. The groups were matched for age, sex, smoking status, and illness duration., Results: Glutamate to creatine ratio levels were higher in treatment-resistant patients (Mean [SD] = 1.57 [0.24]) than in treatment-responsive patients (Mean[SD] = 1.38 [0.23]), (T[35] = 2.34, P = .025, 2-tailed), with a large effect size of d = 0.76. A model assuming 2 populations showed a 25% improvement in the fit of the Akaike weights (0.55) over a model assuming 1 population (0.44), producing group values almost identical to actual group means., Discussion: Increased anterior cingulate glutamate level is associated with treatment-resistant schizophrenia. This appears to be a stable neurobiological trait of treatment-resistant patients. We discuss possible explanations for glutamatergic dysfunction playing a significant role in resistance to conventional antipsychotic treatments, which are all dopamine-2 receptor blockers. Our findings suggest that glutamatergic treatments may be particularly effective in resistant patients and that 1H-MRS glutamate indices can potentially have clinical use., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Abnormalities in glutamate neurotransmission may have a role in the pathophysiology of adolescent depression. The present pilot study examined changes in cortical glutamine/glutamate ratios in depressed adolescents receiving high-frequency repetitive transcranial magnetic stimulation. Ten adolescents with treatment-refractory major depressive disorder received up to 30 sessions of 10-Hz repetitive transcranial magnetic stimulation at 120% motor threshold with 3000 pulses per session applied to the left dorsolateral prefrontal cortex. Baseline, posttreatment, and 6-month follow-up proton magnetic resonance spectroscopy scans of the anterior cingulate cortex and left dorsolateral prefrontal cortex were collected at 3T with 8-cm(3) voxels. Glutamate metabolites were quantified with 2 distinct proton magnetic resonance spectroscopy sequences in each brain region. After repetitive transcranial magnetic stimulation and at 6 months of follow-up, glutamine/glutamate ratios increased in the anterior cingulate cortex and left dorsolateral prefrontal cortex with both measurements. The increase in the glutamine/glutamate ratio reached statistical significance with the TE-optimized PRESS sequence in the anterior cingulate cortex. Glutamine/glutamate ratios increased in conjunction with depressive symptom improvement. This reached statistical significance with the TE-optimized PRESS sequence in the left dorsolateral prefrontal cortex. High-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex may modulate glutamate neurochemistry in depressed adolescents., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy ((1) H-MRS) can noninvasively measure glutamatergic function. Evidence suggests that aberrant glutamatergic signaling plays a role in numerous psychopathologies. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined., Materials and Methods: At 7T MR, we acquired (1) H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (n = 26) twice on two separate days. An adapted echo time optimized point-resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 ppm, was used to excite and acquire the spectra. In-house software was used to model glutamate, glutamine, and glutathione, among other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements., Results: Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). A negative correlation was observed between glutathione concentration and age (r(24)  = -0.37; P < 0.05), and a gender effect was noted on glutamine and glutathione., Conclusion: The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals., (© 2015 Wiley Periodicals, Inc.)

Developmental adjustments in the balance of excitation and inhibition are thought to constrain the plasticity of sensory areas of the cortex. It is unknown however, how changes in excitatory or inhibitory neurochemical expression (glutamate, γ-aminobutyric acid (GABA)) contribute to skill acquisition during development. Here we used single-voxel proton magnetic resonance spectroscopy (1H-MRS) to reveal how differences in cortical glutamate vs. GABA ratios relate to face proficiency and working memory abilities in children and adults. We show that higher glutamate levels in the inferior frontal gyrus correlated positively with face processing proficiency in the children, but not the adults, an effect which was independent of age-dependent differences in underlying cortical gray matter. Moreover, we found that glutamate/GABA levels and gray matter volume are dissociated at the different maturational stages. These findings suggest that increased excitation during development is linked to neuroplasticity and the acquisition of new cognitive skills. They also offer a new, neurochemical approach to investigating the relationship between cognitive performance and brain development across the lifespan., (© 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.)

Proton MR spectroscopy ((1)H-MRS) complements other brain research methods by providing measures of neurometabolites noninvasively in a localized brain area. Improvements in MR scanner technologies, and data acquisition and analysis methods should allow functional (1)H-MRS (fMRS) to measure neurometabolite concentration changes during task-induced brain activation. The aim of the current study was to further develop event-related fMRS at 3T to investigate glutamate dynamics in response to repetition suppression. A secondary aim was to investigate the relationship between blood-oxygen-level-dependent (BOLD) responses and glutamate dynamics in the same paradigm at the same time. A novel approach of interleaved water-suppressed (metabolite) and unsuppressed (water) fMRS was used to simultaneously detect the event-related dynamics of glutamate and BOLD signal to repetition suppression in the lateral occipital cortex of thirteen (N=13) volunteers. On average, (1)H-MRS-visible glutamate increased after novel visual stimuli presentations by 12% and decreased by 11-13% on repeated compared to novel presentations. The BOLD signal, as measured by water peak amplitude changes, showed significant difference between Task and Rest trials, and, on a GLM based analysis of the time series, demonstrated a significant difference between the novel and repeated trials, however appeared to be decoupled from the glutamate response as no correlation was found between the two. These results are the first demonstration that reductions in neuronal activity typical of repetition suppression effects are reflected by reduced glutamatergic and BOLD measures, that glutamate and BOLD responses may not be coupled as previously thought, and that these changes and relationships can be measured simultaneously using event-related fMRS at 3T., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The pathophysiology of bipolar disorder (BD) mostly remains unclear. However, some findings argue for a dysfunction in glutamatergic neurotransmission in BD. Proton magnetic resonance spectroscopy at 3T was used to determine glutamate concentrations in the anterior cingulate cortex (ACC) and the hippocampus (HC) of euthymic outpatients with BP-I disorder and age- and sex-matched healthy controls. In patients with BD, glutamate concentrations were significantly increased in the ACC and decreased in the HC compared with concentrations in controls. Significant group differences were also measured for N-acetyl aspartate and choline; no differences were found for other metabolites examined. An inverse correlation was observed for glutamate concentrations in the ACC and number of episodes. The findings of the study add to the concept of abnormalities in glutamatergic regulation in the ACC and HC in patients with BD., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Posttraumatic stress disorder (PTSD) patients have low cortical concentrations of γ-aminobutyric acid (GABA) and elevated glutamate (Glu) as measured by proton magnetic resonance spectroscopy ((1)H MRS). Alcohol use disorder (AUD) is highly comorbid with PTSD, but the neurobiological underpinnings are largely unknown. We wanted to determine if PTSD patients with AUD have normalized cortical GABA and Glu levels in addition to metabolite alterations common to AUD. We compared brain metabolite concentrations in 10 PTSD patients with comorbid AUD (PAUD) with concentrtations in 28 PTSD patients without AUD and in 20 trauma-exposed controls (CON) without PTSD symptoms. We measured concentrations of GABA, Glu, N-acetylaspartate (NAA), creatine- (Cr) and choline-containing metabolites (Cho), and myo-Inositol (mI) in three cortical brain regions using (1)H MRS and correlated them with measures of neurocognition, insomnia, PTSD symptoms, and drinking severity. In contrast to PTSD, PAUD exhibited normal GABA and Glu concentrations in the parieto-occipital and temporal cortices, respectively, but lower Glu and trends toward higher GABA levels in the anterior cingulate cortex (ACC). Temporal NAA and Cho as well as mI in the ACC were lower in PAUD than in both PTSD and CON. Within PAUD, more cortical GABA and Glu correlated with better neurocognition. Heavy drinking in PTSD is associated with partially neutralized neurotransmitter imbalance, but also with neuronal injury commonly observed in AUD., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: While the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N-Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx)., Methods: Fifty-three young adults (age range 15-33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine., Results: Neither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity., Conclusions: This study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment.