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Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy ( 1 H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter implicated in neuropsychiatric disorders. The best method for quantifying GABA is proton magnetic resonance spectroscopy ( 1 H MRS). Considering that accurate measurements of GABA are affected by slight methodological alterations, demonstrating GABA reproducibility in healthy volunteers is essential before implementing the changes in vivo. Thus, our study aimed to evaluate the back-to-back (B2B) and day-to-day (D2D) reproducibility of GABA+ macromolecules (GABA+) using a 3 Tesla MRI scanner, the new 32-channel head coil (CHC), and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) technique with the scan time (approximately 10 min), adequate for psychiatric patients. The dorsomedial pre-frontal cortex/anterior cingulate cortex (dmPFC/ACC) was scanned in 29 and the dorsolateral pre-frontal cortex (dlPFC) in 28 healthy volunteers on two separate days. Gannet 3.1 was used to quantify GABA+. The reproducibility was evaluated by Pearson's r correlation, the interclass-correlation coefficient (ICC), and the coefficient of variation (CV%) (r/ICC/CV%). For Day 1, B2B reproducibility was 0.59/0.60/5.02% in the dmPFC/ACC and 0.74/0.73/5.15% for dlPFC. For Day 2, it was 0.60/0.59/6.26% for the dmPFC/ACC and 0.54/0.54/6.89 for dlPFC. D2D reproducibility of averaged GABA+ was 0.62/0.61/4.95% for the dmPFC/ACC and 0.58/0.58/5.85% for dlPFC. Our study found excellent GABA+ repeatability and reliability in the dmPFC/ACC and dlPFC.

Background: Abnormalities of GABAergic (gamma-aminobutyric acidergic) systems may play a role in schizophrenia and mood disorders. Magnetic resonance spectroscopy allows for noninvasive in vivo quantification of GABA; however, studies of GABA in schizophrenia have yielded inconsistent findings. This may stem from grouping together disparate voxels from functionally heterogeneous regions., Methods: We searched PubMed for magnetic resonance spectroscopy studies of GABA in the medial frontal cortex (MFC) in patients with schizophrenia, bipolar disorder, and depression and in individuals meeting criteria for ultra-high risk for psychosis. Voxel placements were classified as rostral-, rostral-mid-, mid-, or posterior MFC, and meta-analyses were conducted for each group for each subregion., Results: Of 341 screened articles, 23 studies of schizophrenia, 6 studies of bipolar disorder, 20 studies of depression, and 7 studies of ultra-high risk met the inclusion criteria. Meta-analysis revealed lower mid- (standardized mean difference [SMD] = -0.28, 95% CI, -0.48 to -0.07, p < .01) and posterior (SMD = -0.29, 95% CI, -0.49 to -0.09, p < .01) MFC GABA in schizophrenia and increased rostral MFC GABA in bipolar disorder (SMD = 0.76, 95% CI, 0.25 to -1.25, p < .01). In depression, reduced rostral MFC GABA (SMD = -0.36, 95% CI, -0.64 to -0.08, p = .01) did not survive correction for multiple comparisons. We found no evidence for GABA differences in individuals at ultra-high risk for psychosis., Conclusions: While limited by small numbers of published studies, these results substantiate the relevance of GABA in the pathophysiology of psychosis spectrum and mood disorders and underline the importance of voxel placement., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Following surgery, focal seizures relapse in 20% to 50% of cases due to the difficulty of delimiting the epileptogenic zone (EZ) by current imaging or electrophysiological techniques. Here, we evaluate an unbiased metabolomics approach based on ex vivo and in vivo nuclear magnetic resonance spectroscopy (MRS) methods to discriminate the EZ in a mouse model of mesiotemporal lobe epilepsy (MTLE)., Methods: Four weeks after unilateral injection of kainic acid (KA) into the dorsal hippocampus of mice (KA-MTLE model), we analyzed hippocampal and cortical samples with high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Using advanced multivariate statistics, we identified the metabolites that best discriminate the injected dorsal hippocampus (EZ) and developed an in vivo MEGAPRESS MRS method to focus on the detection of these metabolites in the same mouse model., Results: Multivariate analysis of HRMAS data provided evidence that γ-aminobutyric acid (GABA) is largely increased in the EZ of KA-MTLE mice and is the metabolite that best discriminates the EZ when compared to sham and, more importantly, when compared to adjacent brain regions. These results were confirmed by capillary electrophoresis analysis and were not reversed by a chronic exposition to an antiepileptic drug (carbamazepine). Then, using in vivo noninvasive GABA-edited MRS, we confirmed that a high GABA increase is specific to the injected hippocampus of KA-MTLE mice., Significance: Our strategy using ex vivo MRS-based untargeted metabolomics to select the most discriminant metabolite(s), followed by in vivo MRS-based targeted metabolomics, is an unbiased approach to accurately define the EZ in a mouse model of focal epilepsy. Results suggest that GABA is a specific biomarker of the EZ in MTLE., (© 2020 International League Against Epilepsy.)

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.)

Background: γ-Aminobutyric acidergic (GABAergic) dysfunction and immune activation have been implicated in the pathophysiology of schizophrenia. Preclinical evidence suggests that inflammation-related abnormalities may contribute to GABAergic alterations in the brain, but this has never been investigated in vivo in humans. In this multimodal imaging study, we quantified cerebral GABA plus macromolecule (GABA+) levels in antipsychotic-naive people at clinical high risk for psychosis and in healthy volunteers. We investigated for the first time the association between GABA+ levels and expression of translocator protein 18 kDa (TSPO; a marker of microglial activation) using positron emission tomography (PET)., Methods: Thirty-five people at clinical high risk for psychosis and 18 healthy volunteers underwent 3 T proton magnetic resonance spectroscopy to obtain GABA+ levels in the medial prefrontal cortex (mPFC). A subset (29 people at clinical high risk for psychosis and 15 healthy volunteers) also underwent a high-resolution [18F]FEPPA PET scan to quantify TSPO expression. Each participant was genotyped for the TSPO rs6971 polymorphism., Results: We found that GABA+ levels were significantly associated with TSPO expression in the mPFC ( F 1,40 = 10.45, p = 0.002). We found no significant differences in GABA+ levels in the mPFC ( F 1,51 = 0.00, p > 0.99) between people at clinical high risk for psychosis and healthy volunteers. We found no significant correlations between GABA+ levels or residuals of the association with TSPO expression and the severity of prodromal symptoms or cognition., Limitations: Given the cross-sectional nature of this study, we could determine no cause-and-effect relationships for GABA alterations and TSPO expression., Conclusion: Our findings suggest that TSPO expression is negatively associated with GABA+ levels in the prefrontal cortex, independent of disease status., Competing Interests: R. Mizrahi has received speaker fees from Otsuka Lundbeck Canada. No other competing interests declared., (© 2019 Joule Inc. or its licensors)

Background: The role of testosterone (T) in the pathophysiology of affective disorders and anxiety is broadly supported. Evidence suggests that T has anxiolytic and antidepressant properties. One proposed route for the central effects of T is its interaction with the gamma-aminobutyric acid (GABA) system. We explored the relationship between T levels and GABA+ levels in anterior-cingulate (ACC) and the posterior-cingulate (PCC) regions in depressed women, using magnetic resonance spectroscopy ( 1 H-MRS)., Methods: Twenty-one depressed patients with regularly cycling who were not taking hormonal or psychotropic drugs were recruited. We assessed severity of depression using the Hamilton Depression Rating Scale (HDRS). Blood samples were taken for quantification of free (FT) and total testosterone (TT) on the day of the magnetic resonance (MR) scan. We evaluated GABA+ levels in the PCC and ACC, using the Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) sequence. Pearson correlations were used to evaluate the association between FT, TT, GABA+ concentrations, and HDRS scores., Results: TT and FT levels were positively correlated with GABA+ levels in the PCC. No correlation was observed between T levels and GABA+ levels in the ACC. The HDRS total scores correlated negatively with FT levels., Limitations: Limitations include the cross-sectional evaluation and the lack of a comparative healthy group., Conclusions: Our findings suggest that the potential anxiolytic and antidepressant properties of T are related to increased GABA+ levels in the PCC. This observation may contribute to increased understanding of the role of T in depressive and anxiety symptoms in women., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Electroconvulsive therapy (ECT) has often been applied to augment antipsychotics for schizophrenia patients. However, the underpinning mechanism is still unclear. Previous studies of major depressive disorder reported an increase in γ-aminobutyric acid (GABA) after ECT. The present study investigated the effects of ECT on medial prefrontal GABA in schizophrenia using a proton magnetic resonance spectroscopy., Methods: Inpatients fulfilling the diagnostic criteria for schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were assigned to 2 groups, ECT group (n = 14) receiving ECT plus antipsychotic drugs (APD) and drug group (n = 17) only receiving antipsychotic drugs. Medial prefrontal GABA+/Cr concentrations of all patients were measured with magnetic resonance spectroscopy at baseline and after 4-week treatment. Sex- and age-matched healthy comparisons (n = 19) were scanned at baseline., Results: γ-Aminobutyric acid level did not show a significant difference among 3 groups. However, when 2 patient groups were combined, their GABA level was significantly lower than that in healthy comparisons group. For schizophrenia patients, repeated measures analysis of variance revealed that both the group effect and group × time interaction were insignificant, but the time effect of baseline versus after treatment was significant. Exploratory post hoc paired t test found a significant increase of GABA only in ECT group, but not in drug group. No correlation was found between GABA change and clinical symptom improvement in either group., Conclusions: γ-Aminobutyric acid level in the medial prefrontal lobe was reduced in schizophrenia patients. An increase in GABA concentration in the medial prefrontal cortex is more significantly associated with ECT plus antipsychotics than antipsychotics alone, possibly supporting the hypothesis of ECT augmentation for GABA mediated neural inhibition.

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.)

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.)

Metabolite-specific, scalar spin-spin coupling constant (J)-editing 1 H MRS methods have become gold-standard for measuring brain γ-amino butyric acid (GABA) levels in human brain. Localized, two-dimensional (2D) 1 H MRS technology offers an attractive alternative as it significantly alleviates the problem of severe metabolite signal overlap associated with standard 1D MRS and retains spectroscopic information for all MRS-detectable species. However, for metabolites found at low concentration, a direct, in vivo, comprehensive methods comparison is challenging and has not been reported to date. Here, we document an assessment of comparability between 2D 1 H MRS and J-editing methods for measuring GABA in human brain. This clinical study is unique in that it involved chronic administration a GABA-amino transferase (AT) inhibitor (CPP-115), which induces substantial increases in brain GABA concentration, with normalization after washout. We report a qualitative and quantitative comparison between these two measurement techniques. In general, GABA concentration changes detected using J-editing were closely mirrored by the 2D 1 H MRS time courses. The data presented are particularly encouraging considering recent 2D 1 H MRS methodological advances are continuing to improve temporal resolution and spatial coverage for achieving whole-brain, multi-metabolite mapping.

Purpose: To demonstrate simultaneous editing of the two most commonly edited and overlapping signals, γ-aminobutyric acid (GABA), and glutathione (GSH), with Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) using sLASER localization at 7T., Methods: Density matrix simulations of HERMES at 7T were carried out and compared with phantom experiments. Additional phantom experiments were performed to characterize the echo time (TE) -dependent modulation of GABA- and GSH-edited HERMES spectra at TE of 80-160 ms. In vivo experiments were performed in 10 healthy volunteers, comparing HERMES (11 min) to sequentially acquired MEGA-sLASER detection of GABA and GSH (2 × 11 min)., Results: Simulations of HERMES show GABA- and GSH-edited spectra with negligible levels of crosstalk, and give modest agreement with phantom spectra. The TE series of GABA- and GSH-edited HERMES spectra modulate as a result of T 2 relaxation and coupling evolution, with GABA showing a stronger TE-dependence. In vivo HERMES experiments show well-edited GABA and GSH signals. Measured concentrations are not statistically different between HERMES and MEGA-sLASER for GABA (1. 051 ± 0.254 i.u. and 1.053 ± 0.248 i.u; P > 0.985) or GSH (0.300 ± 0.091 i.u. and 0.302 ± 0.093 i.u; P > 0.940)., Conclusion: Simulated, phantom and in vivo measurements of HERMES show excellent segregation of GABA- and GSH-edited signals, and excellent agreement with separately acquired MEGA-sLASER data. HERMES allows two-fold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-sLASER measurements. Magn Reson Med 80:474-479, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: The aim of this study was to compare the gamma-amino butyric acid (GABA) levels in the left basal ganglia (BG) of patients with Parkinson's disease (PD) to those of healthy control (HC) volunteers using proton magnetic resonance spectroscopy ( 1 H MRS)., Materials and Methods: The GABA+ signal-the composite signal from GABA, macromolecules (MMs), and homocarnosine-was detected. GABA+ levels were examined in 21 PD patients and 15 age- and sex-matched HCs. 3T- 1 H-MRS using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence was performed in order to detect GABA+ levels in the left BG, and the spectra were processed using the Gannet software. Differences in GABA+ levels between the two groups were analyzed using independent t-test analysis., Results: The GABA+ levels were significantly lower (P < 0.001) in the left BG of the patients with PD (1.31 ± 0.21 i.u.) than in the left BG of the HCs (1.62 ± 0.26 i.u.)., Conclusion: The lower GABA+ levels in the left BG of the PD patients suggest that GABA plays an important role in the pathogenesis of PD. The reduced GABA+ levels in the PD patients may be associated with GABAergic dysfunction.

Background: Whilst robust preclinical and postmortem evidence suggests that altered GABAergic function is central to the development of psychosis, little is known about whether it is altered in subjects at ultra-high risk of psychosis, or its relationship to prodromal symptoms., Methods: Twenty-one antipsychotic naïve ultra-high risk individuals and 20 healthy volunteers underwent proton magnetic resonance imaging at 3T. Gamma-aminobutyric acid levels were obtained from the medial prefrontal cortex using MEGA-PRESS and expressed as peak-area ratios relative to the synchronously acquired creatine signal. Gamma-aminobutyric acid levels were then related to severity of positive and negative symptoms as measured with the Community Assessment of At-Risk Mental States., Results: Whilst we found no significant difference in gamma-aminobutyric acid levels between ultra-high risk subjects and healthy controls (P=.130), in ultra-high risk individuals, medial prefrontal cortex GABA levels were negatively correlated with the severity of negative symptoms (P=.013)., Conclusion: These findings suggest that gamma-aminobutyric acidergic neurotransmission may be involved in the neurobiology of negative symptoms in the ultra-high risk state., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy ( 1 H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p = 0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p = 0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome.

Abnormally low γ-aminobutyric acid (GABA) levels have been consistently reported in adults with major depressive disorder (MDD). Our group extended this finding to adolescents, and documented that GABA deficits were associated with anhedonia. Here we aimed to confirm our prior finding of decreased brain GABA in youth with depression and explore its associations with clinical variables. Forty-four psychotropic medication-free youth with MDD and 36 healthy control (HC) participants (12-21 years) were studied. Participants represent a combined sample of 39 newly recruited youth (MDD=24) and 41 youth from our previously reported study (MDD=20). GABA levels and the combined resonances of glutamate and glutamine (Glx) were measured in vivo in the anterior cingulate cortex using proton magnetic resonance spectroscopy. Youth with depression exhibited significantly lower GABA levels than HC in both the newly reported (P=0.003) and the combined (P=0.003) samples. When depressed participants were classified based on the presence of anhedonia, only the anhedonic MDD subgroup showed reduced GABA levels compared to HC (P=0.002). While there were no associations between any clinical measures and GABA or Glx levels in the new sample, GABA was negatively correlated with only anhedonia severity in the combined MDD group. Furthermore, in the combined sample, hierarchical regression models showed that anhedonia, but not depression severity, anxiety or suicidality, contributed significant variance in GABA levels. This report solidifies the evidence for a GABA deficit early in the course of MDD, which correlates specifically with anhedonia in the disorder.

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.)

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.)

The two-fold benefit of 1 H magnetic resonance spectroscopy (MRS) at high B 0 fields - enhanced sensitivity and increased spectral dispersion - has been used previously to study dynamic changes in metabolite concentrations in the human brain in response to visual stimulation. In these studies, a strong visual on/off stimulus was combined with MRS data acquisition in a voxel location in the occipital cortex determined by an initial functional magnetic resonance imaging experiment. However, 1) to exclude the possibility of systemic effects (heartbeat, blood flow, etc.), which tend to be different for on/off conditions, a modified stimulation condition not affecting the target voxel needs to be employed, and 2) to assess important neurotransmitters of low concentration, in particular γ-aminobutyric acid (GABA), it may be advantageous to analyze steady-state, rather than dynamic, conditions. Thus, the aim of this study was to use short-TE 1 H MRS methodology at 7 T to detect differences in steady-state metabolite levels in response to a varying stimulation paradigm in the human visual cortex. The two different stimulation conditions were termed voxel and control activation. Localized MR spectra were acquired using the SPECIAL (spin-echo full-intensity acquired localized) sequence. Data were analyzed using LCModel. Fifteen individual metabolites were reliably quantified. On comparison of steady-state concentrations for voxel versus control activation, a decrease in GABA of 0.05 mmol/L (5%) and an increase in lactate of 0.04 mmol/L (7%) were found to be the only significant effects. The observed reduction in GABA can be interpreted as reduced neuronal inhibition during voxel activation, whereas the increase in lactate hints at an intensification of anaerobic glycolysis. Differences from previous studies, notably the absence of any changes in glutamate, are attributed to the modified experimental conditions. This study demonstrates that the use of advanced 1 H MRS methodology at 7 T allows the detection of subtle changes in metabolite concentrations involved in neuronal activation and inhibition., (Copyright © 2016 John Wiley & Sons, Ltd.)

The aim of this study is to measure GABA levels of perisylvian cortices in schizophrenia and bipolar disorder patients, using proton magnetic resonance spectroscopy ( 1 H-MRS). Patients with schizophrenia (n=25), bipolar I disorder (BD-I; n=28) and bipolar II disorder (BD-II; n=20) were compared with healthy controls (n=30). 1 H-MRS data was acquired using a Siemens 3T whole body scanner to quantify right and left perisylvian structures' (including superior temporal lobes) GABA levels. Right perisylvian GABA values differed significantly between groups [χ 2 =9.62, df: 3, p=0.022]. GABA levels were significantly higher in the schizophrenia group compared with the healthy control group (p=0.002). Furthermore, Chlorpromazine equivalent doses of antipsychotics correlated with right hemisphere GABA levels (r 2 =0.68, p=0.006, n=33). GABA levels are elevated in the right hemisphere in patients with schizophrenia in comparison to bipolar disorder and healthy controls. The balance between excitatory and inhibitory controls over the cortical circuits may have direct relationship with GABAergic functions in auditory cortices. In addition, GABA levels may be altered by brain regions of interest, psychotropic medications, and clinical stage in schizophrenia and bipolar disorder., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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.)

Purpose: To measure in vivo brain gamma-aminobutyric acid (GABA) concentrations, and assess regional and hemispheric differences, using MR spectroscopy ( 1 H-MRS)., Materials and Methods: GABA concentrations were measured bilaterally in the frontal cortex (FC), parietal cortex (PC), and occipital cortex (OC) of 21 healthy young subjects (age range 20-29 years) using 3 Tesla Philips scanner. A univariate general linear model analysis was carried out to assess the effect of region and hemisphere as well as their interaction on GABA concentrations while controlling for sex and gray matter differences., Results: Results indicated a significant regional dependence of GABA levels [F(2,89) = 11.725, P < 0.001, ηp2 = .209] with lower concentrations in the FC compared with both PC (P < 0.001) and OC (P < 0.001) regions. There was no significant hemispheric differences in GABA levels [F(1,89) = .172; P = 0.679; ηp2 = .002]., Conclusion: This study reports the concentrations of GABA in the FC, PC, and OC brain regions of healthy young adults. GABA distribution exhibits hemispheric symmetry, but varies across regions; GABA levels in the FC are lower than those in the PC and OC. J. Magn. Reson. Imaging 2016;44:1619-1623., (© 2016 International Society for Magnetic Resonance in Medicine.)

The quantification of γ-aminobutyric acid (GABA) concentration using localised MRS suffers from partial volume effects related to differences in the intrinsic concentration of GABA in grey (GM) and white (WM) matter. These differences can be represented as a ratio between intrinsic GABA in GM and WM: r M . Individual differences in GM tissue volume can therefore potentially drive apparent concentration differences. Here, a quantification method that corrects for these effects is formulated and empirically validated. Quantification using tissue water as an internal concentration reference has been described previously. Partial volume effects attributed to r M can be accounted for by incorporating into this established method an additional multiplicative correction factor based on measured or literature values of r M weighted by the proportion of GM and WM within tissue-segmented MRS volumes. Simulations were performed to test the sensitivity of this correction using different assumptions of r M taken from previous studies. The tissue correction method was then validated by applying it to an independent dataset of in vivo GABA measurements using an empirically measured value of r M . It was shown that incorrect assumptions of r M can lead to overcorrection and inflation of GABA concentration measurements quantified in volumes composed predominantly of WM. For the independent dataset, GABA concentration was linearly related to GM tissue volume when only the water signal was corrected for partial volume effects. Performing a full correction that additionally accounts for partial volume effects ascribed to r M successfully removed this dependence. With an appropriate assumption of the ratio of intrinsic GABA concentration in GM and WM, GABA measurements can be corrected for partial volume effects, potentially leading to a reduction in between-participant variance, increased power in statistical tests and better discriminability of true effects., (Copyright © 2016 John Wiley & Sons, Ltd.)

1 H magnetic resonance spectroscopy (MRS) provides a powerful tool to measure gamma-aminobutyric acid (GABA), the principle inhibitory neurotransmitter in the human brain. We asked whether individual differences in MRS estimates of GABA are uniform across the cortex or vary between regions. In two sessions, resting GABA concentrations in the lateral prefrontal, sensorimotor, dorsal premotor, and occipital cortices were measured in twenty-eight healthy individuals. GABA estimates within each region were stable across weeks, with low coefficients of variation. Despite this stability, the GABA estimates were not correlated between regions. In contrast, the percentage of brain tissue per volume, a control measure, was correlated between the three anterior regions. These results provide an interesting dissociation between an anatomical measure of individual differences and a neurochemical measure. The different patterns of anatomy and GABA concentrations have implications for understanding regional variation in the molecular topography of the brain in health and disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ((1) H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical (1) H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = -0.74, P = 0.001) and in depressed MDD patients (SMD = -0.52, P = 0.005), but not in remitted MDD patients (SMD = -0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = -0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future (1) H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that (1) H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337-3352, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Abnormalities in brain γ-aminobutyric acid (GABA) have been implicated in various neuropsychiatric and neurological disorders. However, in vivo GABA detection by (1) H MRS presents significant challenges arising from the low brain concentration, overlap by much stronger resonances and contamination by mobile macromolecule (MM) signals. This study addresses these impediments to reliable brain GABA detection with the J-editing difference technique on a 3-T MR system in healthy human subjects by: (i) assessing the sensitivity gains attainable with an eight-channel phased-array head coil; (ii) determining the magnitude and anatomic variation of the contamination of GABA by MM; and (iii) estimating the test-retest reliability of the measurement of GABA with this method. Sensitivity gains and test-retest reliability were examined in the dorsolateral prefrontal cortex (DLPFC), whereas MM levels were compared across three cortical regions: DLPFC, the medial prefrontal cortex (MPFC) and the occipital cortex (OCC). A three-fold higher GABA detection sensitivity was attained with the eight-channel head coil compared with the standard single-channel head coil in DLPFC. Despite significant anatomical variation in GABA + MM and MM across the three brain regions (p < 0.05), the contribution of MM to GABA + MM was relatively stable across the three voxels, ranging from 41% to 49%, a non-significant regional variation (p = 0.58). The test-retest reliability of GABA measurement, expressed as either the ratio to voxel tissue water (W) or to total creatine, was found to be very high for both the single-channel coil and the eight-channel phased-array coil. For the eight-channel coil, for example, Pearson's correlation coefficient of test vs. retest for GABA/W was 0.98 (R(2)  = 0.96, p = 0.0007), the percentage coefficient of variation (CV) was 1.25% and the intraclass correlation coefficient (ICC) was 0.98. Similar reliability was also found for the co-edited resonance of combined glutamate and glutamine (Glx) for both coils. 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.

The ventromedial prefrontal cortex (vmPFC) plays a key role in emotion processing and regulation. vmPFC dysfunction may lead to disinhibition of amygdala causing high anxiety levels. γ-Aminobutyric acid (GABA) inter-neurons within vmPFC shape the information flow to amygdala. Thus, we hypothesize that GABA content within vmPFC could be relevant to trait anxiety. Forty-three healthy volunteers aged between 20 and 88 years were assessed for trait anxiety with the Subscale-2 of the State-Trait-Anxiety Inventory (STAI-Y2) and were studied with proton magnetic resonance spectroscopy to investigate GABA and Glx (glutamate+glutamine) contents within vmPFC. Total creatine (tCr) was used as internal reference. Partial correlations assessed the association between metabolite levels and STAI-Y2 scores, removing the effect of possible nuisance factors including age, educational level, volumes of gray matter and white matter within magnetic resonance spectroscopy voxel. We observed a positive relationship between GABA/tCr and STAI-Y2 scores. No significant relationships were found between Glx/tCr and STAI-Y2 and between tCr/water and STAI-Y2. No differences were found between males and females as regards to age, STAI-Y2, GABA/tCr, Glx/tCr, tCr/water, gray matter and white matter volumes. We suggest a close relationship between GABA content within vmPFC and trait anxiety providing new insights in the physiology of emotional brain., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Altered γ -aminobutyric acid (GABA), glutamate (Glu) levels, and an imbalance between GABAergic and glutamatergic neurotransmissions have been involved in the pathophysiology of schizophrenia. However, it remains unclear how these abnormalities impact the onset and course of psychosis. In the present study, 21 drug-naïve subjects at ultrahigh risk for psychosis (UHR), 16 drug-naïve patients with first-episode schizophrenia (FES), and 23 healthy controls (HC) were enrolled. In vivo GABA and glutamate+glutamine (Glx) levels in the medial prefrontal cortex were measured using proton magnetic resonance spectroscopy. Medial prefrontal GABA and Glx levels in FES patients were significantly lower than those in HC and UHR, respectively. GABA and Glx levels in UHR were comparable with those in HC. In each group, there was a positive correlation between GABA and Glx levels. Reduced medial prefrontal GABA and Glx levels thus may play an important role in the early stages of schizophrenia., Competing Interests: The authors report no competing interests related to this manuscript.

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 Magnetic Resonance Spectroscopy (MRS) has been widely used to study the healthy and diseased brain in vivo. The availability of whole body MR scanners with a field strength of 3 Tesla and above permit the quantification of many metabolites including the neurotransmitters glutamate (Glu) and γ-aminobutyric acid (GABA). The potential link between neurometabolites identified by MRS and cognition and behavior has been explored in numerous studies both in healthy subjects and in patient populations. Preliminary findings suggest direct or opposite associations between GABA or Glu with impulsivity, anxiety, and dexterity. This chapter is intended to provide an overview of basic principles of MRS and the literature reporting correlations between GABA or Glu and results of neuropsychological assessments.

γ-Aminobutyric acid (GABA) has been implicated in several pain conditions, yet no study has systematically evaluated GABA levels in migraine using (1) H-MRS. The accurate detection, separation and quantification of GABA in individuals with migraine could elucidate the role of this neurotransmitter in migraine pathophysiology. Such information may eventually be useful in the diagnosis and development of more effective treatments for migraine. The aims of this study were therefore to compare the concentration of GABA+ in individuals with migraine with that in asymptomatic individuals, and to determine the diagnostic potential of GABA+ in the classification of those with or without migraine. In this case-control study, GABA+ levels in the brain were determined in 19 participants with migraine and 19 matched controls by (1) H-MRS using Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence. The diagnostic accuracy of GABA+ for the detection of migraine and the optimal cut-off value were determined by receiver operating characteristic analysis. GABA+ levels were significantly higher (p = 0.002) in those with migraine [median, 1.41 institutional units (IU); interquartile range, 1.31-1.50 IU] than in controls (median, 1.18 IU; interquartile range, 1.12-1.35 IU). The GABA+ concentration appears to have good accuracy for the classification of individuals with or without migraine [area under the curve (95% confidence interval), 0.837 (0.71-0.96); p < 0.001]. The optimal GABA+ cut-off value for migraine was 1.30 IU, with a sensitivity of 84.2%, specificity of 68.4% and positive likelihood ratio of +2.67. The outcomes of this study suggest altered GABA metabolism in migraine. These results add to the scarce evidence on the putative role of GABA in migraine and provide a basis to further explore the causal relationship between GABA+ and the pathophysiology of migraine. This study also demonstrates that GABA+ concentration has good diagnostic accuracy for migraine. These findings offer new research and practice directions for migraine diagnosis., (Copyright © 2015 John Wiley & Sons, Ltd.)

Purpose: To determine whether there are in vivo differences of γ-aminobutyric acid (GABA) levels in frontal and parietal regions of Alzheimer's disease (AD) patients, compared with healthy controls using magnetic resonance spectroscopy ((1) H-MRS)., Materials and Methods: Fifteen AD patients and fifteen age- and gender-matched healthy controls underwent (1) H-MRS of the frontal and parietal lobes using the "MEGA-Point Resolved Spectroscopy Sequence" (MEGA-PRESS) technique, and cognitive levels of subjects were evaluated using Mini-Mental State Examination (MMSE) tests. MRS data were processed using the Gannet program. Because the signal detected by MEGA-PRESS includes contributions from GABA, macromolecules and homocarnosine, it is labeled as "GABA+" rather than GABA. Differences of GABA+/Cr ratios between AD patients and controls were tested using covariance analysis, adjusting for gray matter fraction. The relationship between GABA+/Cr and MMSE scores was also analyzed., Results: Significant lower GABA+/Cr ratios were found in the parietal region of AD patients compared with controls (P = 0.041). In AD patients, no significant correlations between GABA+/Cr and MMSE scores were found in either the frontal (r = -0.164; P = 0.558) or parietal regions (r = 0.025; P = 0.929)., Conclusion: Decreased GABA+/Cr levels were present in the parietal region of patients with AD in vivo, suggesting that abnormalities of the GABAergic system may be present in the pathogenesis of AD., (© 2014 Wiley Periodicals, Inc.)

Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy ((1)H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate-glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T (1)H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD., (Copyright © 2014 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: Empathy is a multidimensional construct referring to the capacity to understand and share the emotional and affective states of another person. Cerebral γ-aminobutyric acid (GABA)-ergic levels are associated with a variety of neurological and psychiatric disorders. However, the role of the GABA system in different dimensions of empathy has not been investigated., Materials and Methods: Thirty-two right-handed healthy volunteers took part in this study. We used proton magnetic resonance spectroscopy to determine GABA concentrations in the anterior insula (AI) and the anterior cingulate cortex (ACC) and to examine the relationship between the GABA concentrations and the subcomponents of empathy evaluated by the Interpersonal Reactivity Index (IRI)., Result: Pearson correlation analyses (two-tailed) showed that AI GABA was significantly associated with the empathy concern score (r = 0.584, p<0.05) and the personal distress score (r = 0.538, p<0.05) but not significantly associated with other empathy subscales. No significant correlation was found between ACC GABA and empathy subscores., Conclusion: Left AI GABA was positively correlated with the emotional aspects of empathy. These preliminary findings call into question whether AI GABA alterations might predict empathy dysfunction in major psychiatric disorders such as autism and schizophrenia, which have been described as deficits in emotional empathic abilities.

The (1)H resonances of γ-aminobutyric acid (GABA) in the human brain in vivo are extensively overlapped with the neighboring abundant resonances of other metabolites and remain indiscernible in short-TE MRS at 7 T. Here we report that the GABA resonance at 2.28 ppm can be fully resolved by means of echo time optimization of a point-resolved spectroscopy (PRESS) scheme. Following numerical simulations and phantom validation, the subecho times of PRESS were optimized at (TE, TE2) = (31, 61) ms for detection of GABA, glutamate (Glu), glutamine (Gln), and glutathione (GSH). The in vivo feasibility of the method was tested in several brain regions in nine healthy subjects. Spectra were acquired from the medial prefrontal, left frontal, medial occipital, and left occipital brain and analyzed with LCModel. Following the gray and white matter (GM and WM) segmentation of T1 -weighted images, linear regression of metabolite estimates was performed against the fractional GM contents. The GABA concentration was estimated to be about seven times higher in GM than in WM. GABA was overall higher in frontal than in occipital brain. Glu was about twice as high in GM as in WM in both frontal and occipital brain. Gln was significantly different between frontal GM and WM while being similar between occipital GM and WM. GSH did not show significant dependence on tissue content. The signals from N-acetylaspartylglutamate were clearly resolved, giving the concentration more than 10 times higher in WM than in GM. Our data indicate that the PRESS TE = 92 ms method provides an effective means for measuring GABA and several challenging J-coupled spin metabolites in human brain at 7 T., (Copyright © 2014 John Wiley & Sons, Ltd.)

Proton magnetic resonance spectroscopy ((1)H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if (1)H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, (1)H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. Here, we thoroughly addressed these matters with a three-pronged approach. Firstly, we determined the sensitivity and reproducibility of (1)H-MRS in rat at 9.4 Tesla for detecting changes in GABA and glutamate levels in the striatum and the prefrontal cortex, respectively. Secondly, we evaluated the neuropharmacological and neurobiological relevance of the MRS readouts by pharmacological interventions with five well-characterized drugs (vigabatrin, 3-mercaptopropionate, tiagabine, methionine sulfoximine, and riluzole), which target key nodes in GABAergic and glutamatergic neurotransmission. Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, (1)H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm(3) volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative (1)H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders.

Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission., (© 2014 Wiley Periodicals, Inc.)