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Purpose: To develop an experimental approach for determining in vivo transverse relaxation rates (T(2)) of metabolites that are detected by spectral editing without using simulations, and to demonstrate this approach to measure the T(2) of γ-aminobutyric acid (GABA).Materials and Methods: The proposed method first determines the TE-dependence of the edited signals using measurements in a pure phantom solution (10 mM γ-aminobutyric acid; GABA); the phantom T(2) is also determined. Once the editing echo time (TE)-modulation pattern is known, it can then be used to determine T(2) in vivo. The method was applied to measure GABA T(2) in the occipital lobe of five healthy adult subjects at 3T, using a J-difference editing method. Unwanted macromolecular contributions to the GABA signal were also measured.Results: The in vivo T(2) of edited GABA signal was 88 ± 12 ms; this preliminary result is somewhat shorter than other metabolite T(2) values in the literature at this field strength.Conclusion: Spectral editing methods are now widely used to detect low concentration metabolites, such as GABA, but to date no edited acquisition methods have been proposed for the measurement of transverse relaxation times (T(2)). The method described has been successfully applied to measuring the T(2) of GABA. [ABSTRACT FROM AUTHOR]

Alterations in the structure, function, and microcirculation of the thalamus, a key brain region involved in pain pathways, have previously been demonstrated in patients with painless and painful diabetic peripheral neuropathy (DPN). However, thalamic neurotransmitter levels including γ-aminobutyric acid (GABA) (inhibitory neurotransmitter) and glutamate (excitatory neurotransmitter) in different DPN phenotypes are not known. We performed a magnetic resonance spectroscopy study and quantified GABA and glutamate levels within the thalamus, in a carefully characterized cohort of participants with painless and painful DPN. Participants with DPN (painful and painless combined) had a significantly lower GABA:H2O ratio compared with those without DPN (healthy volunteers [HV] and participants with diabetes without DPN [no DPN]). Participants with painless DPN had the lowest GABA:H2O ratio, which reached significance compared with HV and no DPN, but not painful DPN. There was no difference in GABA:H2O in painful DPN compared with all other groups. A significant correlation with GABA:H2O and neuropathy severity was also seen. This study demonstrates that lower levels of thalamic GABA in participants with painless DPN may reflect neuroplasticity due to reduced afferent pain impulses, whereas partially preserved levels of GABA in painful DPN may indicate that central GABAergic pathways are involved in the mechanisms of neuropathic pain in diabetes., (© 2024 by the American Diabetes Association.)

Background: The high co-occurrence of somatic symptom disorder (SSD) in Parkinson's disease (PD) patients suggests overlapping pathophysiology. However, little is known about the neural correlates of SSD and their possible interactions with PD. Existing studies have shown that SSD is associated with reduced task-evoked activity in the medial prefrontal cortex (mPFC), a central node of the default-mode network (DMN). SSD is also associated with abnormal γ-aminobutyric acid (GABA) content, a marker of local inhibitory tone and regional hypoactivity, in the same area when SSD co-occurs with PD., Objectives: To disentangle the individual and shared effects of SSD and PD on mPFC neurotransmission and connectivity patterns and help disclose the neural mechanisms of comorbidity in the PD population., Methods: The study cohort included 18 PD patients with SSD (PD + SSD), 18 PD patients, 13 SSD patients who did not exhibit neurologic disorders, and 17 healthy subjects (HC). Proton magnetic resonance (MR) spectroscopy evaluated GABA levels within a volume of interest centered on the mPFC. Resting-state functional MR imaging investigated the region's functional connectivity patterns., Results: Compared to HC or PD groups, the mPFC of SSD subjects exhibited higher GABA levels and connectivity. Higher mPFC connectivity involved DMN regions in SSD patients without PD and regions of the executive and attentional networks (EAN) in patients with PD comorbidity., Conclusions: Aberrant reconfigurations of connectivity patterns between the mPFC and the EAN are distinct features of the PD + SSD comorbidity. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the human brain and can be measured with magnetic resonance spectroscopy (MRS). Conflicting accounts report decreases and increases in cortical GABA levels across the lifespan. This incompatibility may be an artifact of the size and age range of the samples utilized in these studies. No single study to date has included the entire lifespan. In this study, eight suitable datasets were integrated to generate a model of the trajectory of frontal GABA estimates (as reported through edited MRS; both expressed as ratios and in institutional units) across the lifespan. Data were fit using both a log-normal curve and a nonparametric spline as regression models using a multi-level Bayesian model utilizing the Stan language. Integrated data show that an asymmetric lifespan trajectory of frontal GABA measures involves an early period of increase, followed by a period of stability during early adulthood, with a gradual decrease during adulthood and aging that is described well by both spline and log-normal models. The information gained will provide a general framework to inform expectations of future studies based on the age of the population being studied., Competing Interests: EP, GJ, BF, RE, NP No competing interests declared, (© 2021, Porges et al.)

Isocitrate dehydrogenase 1 (IDH1) mutational status is an important prognostic biomarker in gliomas. γ-aminobutyric acid (GABA) and reduced glutathione (GSH) play an important role in energy production, which is related to tumor progression. Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy (HERMES) is able to detect GABA and GSH in healthy controls. This study aims to examine GABA and GSH alterations in IDH1-mutated low-grade gliomas using HERMES. We prospectively enrolled 14 suspected low-grade gliomas and 6 healthy control patients in this study, all cases underwent a 3 T MRI scan, including T1-weighted imaging and HERMES acquisition with a volume of interest 3 × 3 × 3 cm 3 . HERMES detects a "GABA+" signal that includes contributions from macromolecules and homocarnosine. GABA+ and GSH in tumor foci (group 1), contralateral cerebral regions (group 2) and healthy controls (group 3) were quantified using Gannet. The fitting errors and SNR of HERMES for GABA+ and GSH were analyzed; FWHM of the unsuppressed water signal was also recorded. The Wilcoxon signed-rank test was performed to test for differences between contralateral GABA+ and GSH levels, and differences in GABA+, GSH and fitting errors/SNR between the three groups were analyzed using analysis of variance (ANOVA). Eleven IDH1-mutant low-grade gliomas (5 Female and 6 Male, age 33-69) and 6 healthy subjects (2 Female and 4 Male, age 35-60) were finally enrolled this study. The mean water linewidth across all subjects was 9.67 ± 2.28 Hz. The Wilcoxon signed-rank test revealed that GABA+ and GSH were decreased significantly in glioma foci compared with contralateral regions, whereas no differences were seen between the left and right regions in healthy controls. ANOVA showed that GABA+ and GSH levels in tumor were lower than contralaterally and in healthy controls, while no differences were observed between the contralateral healthy tissue and healthy controls. No differences of fitting errors or SNR were found between tumors, contralateral regions or healthy controls. Our results suggest that HERMES is a reliable tool to simultaneously measure GABA and GSH alterations in low-grade gliomas with IDH1 mutations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Transcranial direct current stimulation (tDCS) has shown efficacy in augmenting the effects of language therapy in primary progressive aphasia (PPA). The mechanism of action of tDCS is not understood, but preliminary work in healthy adults suggests it modulates γ-aminobutyric acid (GABA) levels to create an environment optimal for learning. It is unknown if this proposed mechanism translates to aging or neurodegenerative conditions. This study tested the hypothesis that tDCS reduces GABA at the stimulated tissue in PPA. We applied GABA-edited magnetic resonance spectroscopy to quantify GABA levels before and after a sham-controlled tDCS intervention with language therapy in PPA. All participants showed improvements but those receiving active tDCS showed significantly greater language improvements compared to sham both immediately after the intervention and at 2-month follow-up. GABA levels in the targeted tissue decreased from baseline after the intervention and remained decreased 2 months after the intervention. This work supports the hypothesis that tDCS modulates GABAergic inhibition to augment learning and is clinically useful for PPA combined with language therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy ( 1 H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p = 0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p = 0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r = +0.661, p = 0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r = +0.522, p = 0.000; left amygdala: r = +0.651, p = 0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p = 0.03) and positively correlated with intra DMPFC connectivity (r = +0.548, p = 0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.

Gambling disorder is characterized by persistent maladaptive gambling behaviors and is now considered among substance-related and addictive disorders. There is still unmet therapeutic need for these clinical populations, however recent advances indicate that interventions targeting the Glutamatergic/GABAergic system hold promise in reducing symptoms in substance-related and addictive disorders, including gambling disorder. There is some data indicating that transcranial direct current stimulation may hold clinical benefits in substance use disorders and modulate levels of brain metabolites including glutamate and GABA. The goal of the present work was to test whether this non-invasive neurostimulation method modulates key metabolites in gambling disorder. We conducted a sham-controlled, crossover, randomized study, blinded at two levels in order to characterize the effects of transcranial direct current stimulation over the dorsolateral prefrontal cortex on neural metabolites levels in sixteen patients with gambling disorder. Metabolite levels were measured with magnetic resonance spectroscopy from the right dorsolateral prefrontal cortex and the right striatum during active and sham stimulation. Active as compared to sham stimulation elevated prefrontal GABA levels. There were no significant changes between stimulation conditions in prefrontal glutamate + glutamine and N-acetyl Aspartate, or in striatal metabolite levels. Results also indicated positive correlations between metabolite levels during active, but not sham, stimulation and levels of risk taking, impulsivity and craving. Our findings suggest that transcranial direct current stimulation can modulate GABA levels in patients with gambling disorder which may represent an interesting future therapeutic avenue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Efficient neural processing depends on regulating responses through suppression and facilitation of neural activity. Utilizing a well-known visual motion paradigm that evokes behavioral suppression and facilitation, and combining five different methodologies (behavioral psychophysics, computational modeling, functional MRI, pharmacology, and magnetic resonance spectroscopy), we provide evidence that challenges commonly held assumptions about the neural processes underlying suppression and facilitation. We show that: (1) both suppression and facilitation can emerge from a single, computational principle - divisive normalization; there is no need to invoke separate neural mechanisms, (2) neural suppression and facilitation in the motion-selective area MT mirror perception, but strong suppression also occurs in earlier visual areas, and (3) suppression is not primarily driven by GABA-mediated inhibition. Thus, while commonly used spatial suppression paradigms may provide insight into neural response magnitudes in visual areas, they should not be used to infer neural inhibition., Competing Interests: MS, AK, RM, AF, ZB, RE, RB, SM No competing interests declared, (© 2018, Schallmo et al.)

The amygdala-medial prefrontal cortex (mPFC) circuit plays a key role in social behavior. The amygdala and mPFC are bidirectionally connected, functionally and anatomically, via the uncinate fasciculus. Recent evidence suggests that GABA-ergic neurotransmission within the mPFC could be central to the regulation of amygdala activity related to emotions and anxiety processing. However, the functional and neurochemical interactions within amygdala-mPFC circuits are unclear. In the current study, multimodal magnetic resonance imaging techniques were combined to investigate effective connectivity within the amygdala-mPFC network and its relationship with mPFC neurotransmission in 22 healthy subjects aged between 41 and 88 years. Effective connectivity in the amygdala-mPFC circuit was assessed on resting-state functional magnetic resonance imaging data using spectral dynamic causal modelling. State and trait anxiety were also assessed. The mPFC was shown to be the target of incoming outputs from the amygdalae and the source of exciting inputs to the limbic system. The amygdalae were reciprocally connected by excitatory projections. About half of the variance relating to the strength of top-down endogenous connection between right amygdala and mPFC was explained by mPFC GABA levels. State anxiety was correlated with the strength of the endogenous connections between right amygdala and mPFC. We suggest that mPFC GABA content predicts variability in the effective connectivity within the mPFC-amygdala circuit, providing new insights on emotional physiology and the underlying functional and neurochemical interactions.

A new approach for simultaneous dual-voxel J-difference spectral editing is described, which uses spatially selective spectral-editing pulses and Hadamard encoding. A theoretical framework for spatial Hadamard editing and reconstruction for parallel acquisition (SHERPA) was developed, applying gradient pulses during the frequency-selective editing pulses. Spectral simulations were performed for either one (gamma-aminobutyric acid, GABA) or two molecules (glutathione and lactate) simultaneously detected in two voxels. The method was tested in a two-compartment GABA phantom, and finally applied to the left and right hemispheres of 10 normal control subjects, scanned at 3 T. SHERPA was successfully implemented at 3 T and gave results in close agreement with conventional MEGA-PRESS scans in both the phantom and in vivo experiments. Simulations for GABA editing for (3 cm) 3 voxels in the left and right hemispheres suggest that both editing efficiency losses and contamination between voxels are about 2%. Compared with conventional single-voxel single-metabolite J-difference editing, two- or fourfold acceleration is possible without significant loss of SNR using the SHERPA method. Unlike some other dual-voxel methods, the method can be used with single-channel receiver coils, and there is no SNR loss due to unfavorable receive-coil geometry factors., (Copyright © 2017 John Wiley & Sons, Ltd.)

The amygdala-medial prefrontal cortex (mPFC) circuit plays a key role in emotional processing. GABA-ergic inhibition within the mPFC has been suggested to play a role in the shaping of amygdala activity. However, the functional and neurochemical interactions within the amygdala-mPFC circuits and their relevance to emotional processing remain unclear. To investigate this circuit, we obtained resting-state functional magnetic resonance imaging (rs-fMRI) and proton MR spectroscopy in 21 healthy subjects to assess the potential relationship between GABA levels within mPFC and the amygdala-mPFC functional connectivity. Trait anxiety was assessed using the State-Trait Anxiety Inventory (STAI-Y2). Partial correlations were used to measure the relationships among the functional connectivity outcomes, mPFC GABA levels and STAI-Y2 scores. Age, educational level and amount of the gray and white matters within 1 H-MRS volume of interest were included as nuisance variables. The rs-fMRI signals of the amygdala and the vmPFC were significantly anti-correlated. This negative functional coupling between the two regions was inversely correlated with the GABA+/tCr level within the mPFC and the STAI-Y2 scores. We suggest a close relationship between mPFC GABA levels and functional interactions within the amygdala-vmPFC circuit, providing new insights in the physiology of emotion.

The Proton magnetic resonance ( 1 H-MRS) spectrum contains information about the concentration of tissue metabolites within a predefined region of interest (a voxel). The conventional spectrum in some cases obscures information about less abundant metabolites due to limited separation and complex splitting of the metabolite peaks. One method to detect these metabolites is to reduce the complexity of the spectrum using editing. This review provides an overview of the one-dimensional editing methods available to interrogate these obscured metabolite peaks. These methods include sequence optimizations, echo-time averaging, J-difference editing methods (single BASING, dual BASING, and MEGA-PRESS), constant-time PRESS, and multiple quantum filtering. It then provides an overview of the brain metabolites whose detection can benefit from one or more of these editing approaches, including ascorbic acid, γ-aminobutyric acid, lactate, aspartate, N-acetyl aspartyl glutamate, 2-hydroxyglutarate, glutathione, glutamate, glycine, and serine. Magn Reson Med 77:1377-1389, 2017. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: To investigate the echo time (TE) dependence of J-difference editing of glutathione and to determine the optimal TE for in vivo measurements at 3T., Methods: Spatially resolved density-matrix simulations and phantom experiments were performed at a range of TEs to establish the spatial and TE modulation of glutathione signals in editing-on, editing-off, and difference spectra at 3T. In vivo data were acquired in five healthy subjects to compare a TE of 68 ms and a TE of 120 ms. At the longer TE, high-bandwidth, frequency-modulated, slice-selective refocusing pulses were also compared with conventional amplitude-modulated pulses., Results: Simulations and relaxation-corrected phantom experiments suggest that the maximum edited signal occurs at TE 160 ms, ignoring transverse relaxation. Considering in vivo T 2 relaxation times of 67-89 ms, the optimal in vivo TE is estimated to be 120 ms. In vivo measurements showed that this TE yielded 15% more signal than TE 68 ms. A further gain of 57% resulted from using improved slice-selective refocusing pulses., Conclusion: J-difference editing of glutathione using TE 120 ms delivers increased signal due to improved editing efficiency that more than offsets T 2 losses. The additional TE also allows for use of improved slice-selective refocusing pulses, which results in additional signal gains. Magn Reson Med 77:498-504, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objective: Evidence indicates that thyroid hormones have effects on the inhibitory GABAergic system. The aim of this study was to investigate whether brain GABA levels are altered in patients with hypothyroidism compared with healthy controls., Design/methods: Fifteen patients with primary hypothyroidism and 15 matched healthy controls underwent single-voxel MEGA-PRESS magnetic resonance spectroscopy at 3T, to quantify GABA levels in the median prefrontal cortex (mPFC) and posterior cingulate cortex (PCC). All participants underwent thyroid function test. Neuropsychological performances were evaluated by administration of the Montreal Cognitive Assessment (MoCA) and the 21-item Beck Depression Inventory-II (BDI-II)., Results: The patients with hypothyroidism had significantly lower GABA+ levels in the mPFC compared with healthy controls (P = 0·016), whereas no significant difference (P = 0·214) was observed in the PCC. Exploratory analyses revealed that mPFC GABA+ levels were negatively correlated with the BDI-II scores in patient group (r = -0·60, P = 0·018). No correlations were found between GABA+ levels and TSH or fT3 or fT4 levels in either region (all P > 0·05)., Conclusion: This study suggests that alteration of GABAergic neurotransmission may play an important role in the pathophysiology of primary hypothyroidism, providing intriguing neurochemical clues to understand thyroid-brain interactions., (© 2016 John Wiley & Sons Ltd.)

Purpose: To develop J-difference editing with parallel reconstruction in accelerated multivoxel (PRIAM) for simultaneous measurement in two separate brain regions of γ-aminobutyric acid (GABA) or glutathione., Methods: PRIAM separates signals from two simultaneously excited voxels using receiver-coil sensitivity profiles. PRIAM was implemented into Mescher-Garwood (MEGA) edited experiments at 3 Tesla (T), and validated by acquiring dual-voxel MEGA-PRIAM (and compared with conventional single-voxel MEGA-PRESS) spectra from a GABA/glutathione phantom, and 11 healthy participants., Results: MEGA-PRIAM effectively separated phantom spectra with ∼3-4% between-voxel contamination. GABA and glutathione measurements agreed well with those obtained using single-voxel MEGA-PRESS (mean difference was below 2% in GABA levels, and below 7% in glutathione levels). In vivo, GABA- and glutathione-edited spectra were successfully reconstructed with a mean in vivo g-factor of 1.025 (typical voxel-center separation: 7-8 cm). MEGA-PRIAM experiments showed higher signal-to-noise ratio than sequential single-voxel experiments of the same total duration (mean improvement 1.38 ± 0.24)., Conclusions: Simultaneous acquisition of J-difference-edited GABA or glutathione spectra from two voxels is feasible at 3 T. MEGA-PRIAM increases data acquisition rates compared with MEGA-PRESS by a factor of 2. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Background: Gamma-aminobutyric acid (GABA), the brain's principal inhibitory neurotransmitter, has been associated with perceptual and attentional functioning. Recent application of magnetic resonance spectroscopy (MRS) provides in vivo evidence for decreasing GABA concentrations during adulthood. It is unclear, however, how age-related decrements in cerebral GABA concentrations contribute to cognitive decline, or whether previously reported declines in cerebral GABA concentrations persist during healthy aging. We hypothesized that participants with higher GABA concentrations in the frontal cortex would exhibit superior cognitive function and that previously reported age-related decreases in cortical GABA concentrations continue into old age., Methods: We measured GABA concentrations in frontal and posterior midline cerebral regions using a Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) 1 H-MRS approach in 94 older adults without history or clinical evidence of mild cognitive impairment or dementia (mean age, 73 years). We administered the Montreal Cognitive Assessment to assess cognitive functioning., Results: Greater frontal GABA concentrations were associated with superior cognitive performance. This relation remained significant after controlling for age, years of education, and brain atrophy. GABA concentrations in both frontal and posterior regions decreased as a function of age., Conclusions: These novel findings from a large, healthy, older population indicate that cognitive function is sensitive to cerebral GABA concentrations in the frontal cortex, and GABA concentration in frontal and posterior regions continue to decline in later age. These effects suggest that proton MRS may provide a clinically useful method for the assessment of normal and abnormal age-related cognitive changes and the associated physiological contributors., Competing Interests: DISCLOSURES All authors report no biomedical financial interests or potential conflicts of interest.

Purpose: To investigate the effects of B 0 field offsets and drift on macromolecule (MM)-suppressed GABA-editing experiments, and to implement and test a prospective correction scheme. "Symmetric" editing schemes are proposed to suppress unwanted coedited MM signals in GABA editing., Materials and Methods: Full density-matrix simulations of both conventional (nonsymmetric) and symmetric MM-suppressed editing schemes were performed for the GABA spin system to evaluate their offset-dependence. Phantom and in vivo (15 subjects at 3T) GABA-edited experiments with symmetrical suppression of MM signals were performed to quantify the effects of field offsets on the total GABA+MM signal (designated GABA+). A prospective frequency correction method based on interleaved water referencing (IWR) acquisitions was implemented and its experimental performance evaluated during positive and negative drift., Results: Simulations show that the signal from MM-suppressed symmetrical editing schemes is an order of magnitude more susceptible to field offsets than the signal from nonsymmetric editing schemes. The MM-suppressed GABA signal changes by 8.6% per Hz for small field offsets. IWR significantly reduces variance in the field offset and measured GABA levels (both P < 0.001 by F-tests), maintaining symmetric suppression of MM signal., Conclusion: Symmetrical editing schemes substantially increase the dependence of measurements on B 0 field offsets, which can arise due to patient movement and/or scanner instability. It is recommended that symmetrical editing should be used in combination with effective B 0 stabilization, such as that provided by IWR. J. Magn. Reson. Imaging 2016;44:1474-1482., (© 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.)

Various lines of evidence suggest that brain bioenergetics and mitochondrial function may be altered in schizophrenia. On the basis of prior phosphorus-31 ( 31 P)-magnetic resonance spectroscopy (MRS), post-mortem and preclinical studies, this study was designed to test the hypothesis that abnormal glycolysis leads to elevated lactate concentrations in subjects with schizophrenia. The high sensitivity of 7 Tesla proton ( 1 H)-MRS was used to measure brain lactate levels in vivo. Twenty-nine controls and 27 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips 'Achieva' 7T scanner, and spectra were acquired from a voxel in the anterior cingulate cortex. Patients were assessed for psychiatric symptom severity, and all participants completed the MATRICS Consensus Cognitive Battery (MCCB) and University of California, San Diego Performance-Based Skills Assessment (UPSA). The relationship between lactate, psychiatric symptom severity, MCCB and UPSA was examined. Lactate was significantly higher in patients compared with controls (P=0.013). Higher lactate was associated with lower MCCB (r=-0.36, P=0.01) and UPSA total scores (r=-0.43, P=0.001). We believe this is the first study to report elevated in vivo cerebral lactate levels in schizophrenia. Elevated lactate levels in schizophrenia may reflect increased anaerobic glycolysis possibly because of mitochondrial dysfunction. This study also suggests that altered cerebral bioenergetics contribute to cognitive and functional impairments in schizophrenia., Competing Interests: LEH reported receiving or planning to receive research funding or consulting fees from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho Pharmaceutical, Heptares and Pfizer. The remaining authors declare no conflict of interest.

Previous studies have suggested that alterations in excitatory/inhibitory neurotransmitters might play a crucial role in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopy ( 1 H-MRS) can provide valuable information about abnormal brain metabolism and neurotransmitter concentrations. However, few 1 H-MRS studies have been published on the imbalance of the two most abundant neurotransmitters in ASD: glutamate (Glu) and gamma-aminobutyric acid (GABA). Moreover, to our knowledge none of these published studies is performed with a study population consisting purely of high-functioning autism (HFA) adolescents. Selecting only individuals with HFA eliminates factors possibly related to intellectual impairment instead of ASD. This study aims to assess Glu and GABA neurotransmitter concentrations in HFA. Occipital concentrations of Glu and GABA plus macromolecules (GABA+) were obtained using 1 H-MRS relative to creatine (Cr) in adolescents with HFA (n=15 and n=13 respectively) and a healthy control group (n=17). Multiple linear regression revealed significantly higher Glu/Cr and lower GABA+/Glu concentrations in the HFA group compared to the controls. These results imply that imbalanced neurotransmitter levels of excitation and inhibition are associated with HFA in adolescents., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Characterizing how the brain appraises the psychological dimensions of reward is one of the central topics of neuroscience. It has become clear that dopamine neurons are implicated in the transmission of both rewarding information and aversive and alerting events through two different neuronal populations involved in encoding the motivational value and the motivational salience of stimuli, respectively. Nonetheless, there is less agreement on the role of the ventromedial prefrontal cortex (vmPFC) and the related neurotransmitter release during the processing of biologically relevant stimuli. To address this issue, we employed magnetic resonance spectroscopy (MRS), a non-invasive methodology that allows detection of some metabolites in the human brain in vivo, in order to assess the role of the vmPFC in encoding stimulus value rather than stimulus salience. Specifically, we measured gamma-aminobutyric acid (GABA) and, with control purposes, Glx levels in healthy subjects during the observation of appetitive and disgusting food images. We observed a decrease of GABA and no changes in Glx concentration in the vmPFC in both conditions. Furthermore, a comparatively smaller GABA reduction during the observation of appetitive food images than during the observation of disgusting food images was positively correlated with the scores obtained to the body image concerns sub-scale of Body Uneasiness Test (BUT). These results are consistent with the idea that the vmPFC plays a crucial role in processing both rewarding and aversive stimuli, possibly by encoding stimulus salience through glutamatergic and/or noradrenergic projections to deeper mesencephalic and limbic areas., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Sensory processing abnormalities in autism have largely been described by parent report. This study used a multi-method (parent-report and measurement), multi-trait (tactile sensitivity and attention) design to evaluate somatosensory processing in ASD. Results showed multiple significant within-method (e.g., parent report of different traits)/cross-trait (e.g., attention and tactile sensitivity) correlations, suggesting that parent-reported tactile sensory dysfunction and performance-based tactile sensitivity describe different behavioral phenomena. Additionally, both parent-reported tactile functioning and performance-based tactile sensitivity measures were significantly associated with measures of attention. Findings suggest that sensory (tactile) processing abnormalities in ASD are multifaceted, and may partially reflect a more global deficit in behavioral regulation (including attention). Challenges of relying solely on parent-report to describe sensory difficulties faced by children/families with ASD are also highlighted., Competing Interests: Mark Tommerdahl is co-inventor of the tactile stimulator used in the study and is co-founder of Cortical Metrics, which has a license from the University of North Carolina to distribute the device.

Background: Studies have reported that transcranial direct current stimulation (tDCS) can modulate human behaviors, symptoms, and neural activity; however, the neural effects during stimulation are unknown. Most studies compared the effects of tDCS before and after stimulation. The objective of our study was to measure the neurobiological effect of a single tDCS dose during stimulation., Methods: We conducted an online and offline protocol combining tDCS and magnetic resonance spectroscopy (MRS) in 17 healthy participants. We applied anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) and cathodal tDCS over the right DLPFC for 30 minutes, one of the most common montages used with tDCS. We collected MRS measurements in the left DLPFC and left striatum during tDCS and an additional MRS measurement in the left DLPFC immediately after the end of stimulation., Results: During stimulation, active tDCS, as compared with sham tDCS, elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine but did not induce significant differences in prefrontal or striatal gamma-aminobutyric acid level. Immediately after stimulation, active tDCS, as compared with sham tDCS, did not significantly induce differences in glutamate + glutamine, N-acetylaspartate, or gamma-aminobutyric acid levels in the left DLPFC., Conclusions: These observations indicate that tDCS over the DLPFC has fast excitatory effects, acting on prefrontal and striatal transmissions, and these effects are short lived. One may postulate that repeated sessions of tDCS might induce similar longer lasting effects of elevated prefrontal N-acetylaspartate and striatal glutamate + glutamine levels, which may contribute to its behavioral and clinical effects., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: It is increasingly being recognized that alterations of the GABAergic system are implicated in the pathophysiology of depression. This study aimed to explore in vivo gamma-aminobutyric acid (GABA) levels in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and posterior-cingulate cortex (PCC) of postmenopausal women with depression using magnetic resonance spectroscopy (H-MRS)., Methods: Nineteen postmenopausal women with depression and thirteen healthy controls were enrolled in the study. All subjects underwent H-MRS of the ACC/mPFC and PCC using the "MEGA Point Resolved Spectroscopy Sequence" (MEGA-PRESS) technique. The severity of depression was assessed by 17-item Hamilton Depression Scale (HAMD). Quantification of MRS data was performed using Gannet program. Differences of GABA+ levels from patients and controls were tested using one-way analysis of variance. Spearman correlation coefficients were used to evaluate the linear associations between GABA+ levels and HAMD scores, as well as estrogen levels., Results: Significantly lower GABA+ levels were detected in the ACC/mPFC of postmenopausal women with depression compared to healthy controls (P = 0.002). No significant correlations were found between 17-HAMD/14-HAMA and GABA+ levels, either in ACC/mPFC (P = 0.486; r = 0.170/P = 0.814; r = -0.058) or PCC (P = 0.887; r = 0.035/ P = 0.987; r = -0.004) in the patients; there is also no significant correlation between GABA+ levels and estrogen levels in patients group (ACC/mPFC: P = 0.629, r = -0.018; PCC: P = 0.861, r = 0.043)., Conclusion: Significantly lower GABA+ levels were found in the ACC/mPFC of postmenopausal women with depression, suggesting that the dysfunction of the GABAergic system may also be involved in the pathogenesis of depression in postmenopausal women., Competing Interests: The authors have no conflicts of interest to disclose.

Purpose: To investigate a novel Hadamard-encoded spectral editing scheme and evaluate its performance in simultaneously quantifying N-acetyl aspartate (NAA) and N-acetyl aspartyl glutamate (NAAG) at 3 Tesla., Methods: Editing pulses applied according to a Hadamard encoding scheme allow the simultaneous acquisition of multiple metabolites. The method, called HERMES (Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy), was optimized to detect NAA and NAAG simultaneously using density-matrix simulations and validated in phantoms at 3T. In vivo data were acquired in the centrum semiovale of 12 normal subjects. The NAA:NAAG concentration ratio was determined by modeling in vivo data using simulated basis functions. Simulations were also performed for potentially coedited molecules with signals within the detected NAA/NAAG region., Results: Simulations and phantom experiments show excellent segregation of NAA and NAAG signals into the intended spectra, with minimal crosstalk. Multiplet patterns show good agreement between simulations and phantom and in vivo data. In vivo measurements show that the relative peak intensities of the NAA and NAAG spectra are consistent with a NAA:NAAG concentration ratio of 4.22:1 in good agreement with literature. Simulations indicate some coediting of aspartate and glutathione near the detected region (editing efficiency: 4.5% and 78.2%, respectively, for the NAAG reconstruction and 5.1% and 19.5%, respectively, for the NAA reconstruction)., Conclusion: The simultaneous and separable detection of two otherwise overlapping metabolites using HERMES is possible at 3T. Magn Reson Med 76:11-19, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

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.)

The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7 T, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, N-acetylaspartylglutamic acid, myo-inositol, GABA, glutathione, total creatine, and total choline. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

N-acetyl-aspartate (NAA) is responsible for the majority of the most prominent peak in (1)H-MR spectra, and has been used as diagnostic marker for several pathologies. However, ~10% of this peak can be attributed to N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide whose release may be triggered by intense neuronal activation. Separate measurement of NAA and NAAG using MRS is difficult due to large superposition of their spectra. Specifically, in functional MRS (fMRS) experiments, most work has evaluated the sum NAA+NAAG, which does not appear to change during experiments. The aim of this work was to design and perform an fMRS experiment using visual stimulation and a spectral editing sequence, MEGA-PRESS, to further evaluate the individual dynamics of NAA and NAAG during brain activation. The functional paradigm used consisted of three blocks, starting with a rest (baseline) block of 320 s, followed by a stimulus block (640 s) and a rest block (640 s). Twenty healthy subjects participated in this study. On average, subjects followed a pattern of NAA decrease and NAAG increase during stimulation, with a tendency to return to basal levels at the end of the paradigm, with a peak NAA decrease of -(21±19)% and a peak NAAG increase of (64±62)% (Wilcoxon test, p<0.05). These results may relate to: 1) the only known NAAG synthesis pathway is from NAA and glutamate; 2) a relationship between NAAG and the BOLD response., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: Complex motor stereotypies are rhythmic, repetitive, fixed, purposeful but purposeless movements that stop with distraction. They can occur in otherwise normal healthy children (primary stereotypies) as well in those with autism spectrum disorders (secondary stereotypies). The underlying neurobiologic basis for these movements is unknown but is thought to involve cortical-striatal-thalamo-cortical pathways. To further clarify potential neurochemical alterations, gamma-aminobutyric acid (GABA), glutamate, glutamine, N-acetylaspartate, and choline levels were measured in 4 frontostriatal regions by using (1)H MRS at 7T., Materials and Methods: A total of 18 children with primary complex motor stereotypies and 24 typically developing controls, ages 5-10 years, completed MR spectroscopy at 7T. Single voxel STEAM acquisitions from the anterior cingulate cortex, premotor cortex, dorsolateral prefrontal cortex, and striatum were obtained, and metabolites were quantified with respect to Cr by using LCModel., Results: The 7T scan was well tolerated by all the participants. Compared with the controls, children with complex motor stereotypies had lower levels of GABA in the anterior cingulate cortex (GABA/Cr, P = .049; GABA/Glu, P = .051) and striatum (GABA/Cr, P = .028; GABA/Glu, P = .0037) but not the dorsolateral prefrontal cortex or the premotor cortex. Glutamate, glutamine, NAA, and Cho levels did not differ between groups in any of the aforementioned regions. Within the complex motor stereotypies group, reduced GABA to Cr in the anterior cingulate cortex was significantly associated with greater severity of motor stereotypies (r = -0.59, P = .021)., Conclusions: These results indicate possible GABAergic dysfunction within corticostriatal pathways in children with primary complex motor stereotypies., (© 2016 by American Journal of Neuroradiology.)

Learning mechanisms are based on synaptic plasticity processes. Numerous studies on synaptic plasticity suggest that the regulation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a central role maintaining the delicate balance of inhibition and excitation. However, in humans, a link between learning outcome and GABA levels has not been shown so far. Using magnetic resonance spectroscopy of GABA prior to and after repetitive tactile stimulation, we show here that baseline GABA+ levels predict changes in perceptual outcome. Although no net changes in GABA+ are observed, the GABA+ concentration prior to intervention explains almost 60% of the variance in learning outcome. Our data suggest that behavioral effects can be predicted by baseline GABA+ levels, which provide new insights into the role of inhibitory mechanisms during perceptual learning., (© The Author 2015. Published by Oxford University Press.)

Purpose: The conventional spectral-editing experiment used to measure GABA in the human brain also contains a contribution from macromolecules (MM), and the combined GABA plus MM signal is often referred to as "GABA+". More recently, methods have been developed to estimate GABA free from MM contamination. In this study, the relationship between GABA acquired with MM suppression and conventional GABA+ measurements was examined., Methods: GABA-edited MEGA-PRESS experiments with and without MM suppression were performed in the sensorimotor and occipital cortex of 12 healthy subjects at 3 Tesla. The correlation between GABA+ and MM-suppressed GABA measures was then determined., Results: Across all data, a significant correlation between GABA+ and MM-suppressed GABA was found (r = 0.48; P = 0.02). Regionally, the sensorimotor voxel showed a trend toward a correlation of r = 0.53, P = 0.07 and the occipital voxel did not show a correlation, r = 0.058, P = 0.9., Conclusion: GABA+ and MM-suppressed GABA are moderately correlated, but statistical power to reveal this relationship may vary regionally. The MM signal, while often assumed to be functionally irrelevant, appears to show inter-individual and inter-regional variance that impacts the correlation of GABA+ and MM-suppressed GABA., (© 2014 Wiley Periodicals, Inc.)

It is not known why tinnitus occurs in some cases of hearing damage but not others. Abnormalities of excitation-inhibition balance could influence whether tinnitus develops and its severity if it does. Animal models of hearing damage, which also produce tinnitus based on behavioral evidence, have identified abnormalities of GABAergic inhibition, both cortically and subcortically. However, the precise relationships of GABA inhibitory changes to tinnitus itself, as opposed to other consequences of hearing damage, remain uncertain. Here, we used magnetic resonance spectroscopy to non-invasively quantify GABA in the left (LAC) and right (RAC) auditory cortices of a group of 14 patients with lateralized tinnitus (eight left ear) and 14 controls matched for age, sex, and hearing. We also explored the potential relationships with other brain metabolites (i.e., choline, N-acetylaspartate, and creatine). The presence of tinnitus was associated with a reduction in auditory cortex GABA concentration. Regardless of tinnitus laterality, post hoc testing indicated reductions that were significant in RAC and nonsignificant in LAC. Tinnitus severity and hearing loss were correlated positively with RAC choline but not GABA. We discuss the results in the context of current models of tinnitus and methodological constraints., Significance Statement: Permanently affecting one in seven adults, tinnitus lacks both widely effective treatments and adequate understanding of its brain mechanisms. Existing animal models represent tinnitus that may not be distinguishable from homeostatic responses to the auditory insults used to induce it. Human studies can be well controlled in this regard but are usually not (with few even matching control subjects for hearing loss) and are limited in scope as a result of relying solely on non-invasive recording techniques. Here, we exploit recent advances in non-invasive spectroscopic techniques to establish, in a human study tightly controlled for hearing loss and hyperacusis, that tinnitus is associated with a significant reduction in auditory cortex GABA concentration, which has implications for understanding and treatment of the condition., (Copyright © 2015 Sedley et al.)

Purpose: To develop a tissue correction for GABA-edited magnetic resonance spectroscopy (MRS) that appropriately addresses differences in voxel gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) fractions., Materials and Methods: Simulations compared the performance of tissue correction approaches. Corrections were then applied to in vivo data from 16 healthy volunteers, acquired at 3T. GM, WM, and CSF fractions were determined from T1 -weighted images. Corrections for CSF content, GM/WM GABA content, and water relaxation of the three compartments are combined into a single, fully corrected measurement., Results: Simulations show that CSF correction increases the dependence of GABA measurements on GM/WM fraction, by an amount equal to the fraction of CSF. Furthermore, GM correction substantially (and nonlinearly) increases the dependence of GABA measurements on GM/WM fraction, for example, by a factor of over four when the voxel GM tissue fraction is 50%. At this tissue fraction, GABA is overestimated by a factor of 1.5. For the in vivo data, correcting for voxel composition increased measured GABA values (P < 0.001 for all regions), but did not reduce intersubject variance (P > 0.5 for all regions). Corrected GABA values differ significantly based on the segmentation procedure used (P < 0.0001) and tissue parameter assumptions made (P < 0.0001)., Conclusion: We introduce a comprehensive tissue correction factor that adjusts GABA measurements to correct for different voxel compositions of GM, WM, and CSF., (© 2015 Wiley Periodicals, Inc.)

Purpose: The purpose of this study was to compare magnetic resonance spectroscopy (MRS) of three different regions of the human brain between 3 and 7 Tesla, using the same subjects and closely matched methodology at both field strengths., Methods: A semi-LASER (sLASER) pulse sequence with TE 32ms was used to acquire metabolite spectrum along with the water reference at 3T and 7T using similar experimental parameters and hardware at both field strengths (n=4 per region and field). Spectra were analyzed in LCModel using a simulated basis set., Results: Signal-to-noise ratio (SNR) at 7T was higher compared to 3T, and linewidths (in ppm) at both field strengths were comparable in ppm scale. Of the 13 metabolites reported in the paper, most metabolites were measured with higher precision at 7T in all three regions., Conclusion: The study confirms gains in SNR and measurement precision at 7T in all three representative brain regions using the sLASER pulse sequence coupled with a 32-channel phased-array head coil., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: In proton MR spectra of the human brain, relatively broad macromolecule (MM) resonances underlie the narrower signals from metabolites. The purpose of this study was to quantify the MM profile in healthy human brain at 3T and 7T, both in gray matter (anterior cingulate cortex [ACC]) and white matter (centrum semiovale [CSO])., Methods: A water-suppressed, inversion-recovery pulse sequence was used to null metabolite signals and acquire MM spectra in 20 healthy volunteers using very similar methodology at both field strengths (n = 5 per region and field). The MM spectra were fitted with multiple Gaussian functions and quantified relative to the unsuppressed water signal from the same volume., Results: MM proton concentration values were in the range of 5-20 mmol/kg. No significant differences were found between the MM proton concentration measurements by region (P ≈ 0.8) nor by field strength (P ≈ 0.5). Linewidths of the well-resolved M1 peak were slightly more than double at 7T (43.0 ± 4.7 Hz in ACC, 45.6 ± 4.1 Hz in CSO) compared with 3T (19.8 ± 3.5 Hz in ACC, 20.0 ± 4.3 Hz in CSO)., Conclusion: The absence of differences in MM concentrations between white and gray matter implies that a single MM "baseline" may be adequate for spectral fitting of multiple brain regions when determining metabolite concentrations. Visibility of MM signals is similar at 3T and 7T., (© 2014 Wiley Periodicals, Inc.)

Introduction: Paired associative stimulation (PAS), is a novel non-invasive technique where two neural substrates are employed in a temporally coordinated manner in order to modulate cortico-motor excitability within the motor cortex (M1). In swallowing, combined pharyngeal electrical and transcranial-magnetic-stimulation induced beneficial neurophysiological and behavioural effects in healthy subjects and dysphagic stroke patients. Here, we aimed to investigate the whole-brain changes in neural activation during swallowing using functional magnetic resonance imaging (fMRI) following PAS application and in parallel assess associated GABA changes with magnetic resonance spectroscopy (MRS)., Methods: Healthy adults (n=11, 38±9years old) were randomised to receive real and sham PAS to the 'stronger' motor cortex pharyngeal representation, on 2 separate visits. Following PAS, event-related fMRI was performed to assess changes in brain activation in response to water and saliva swallowing and during rest. Data were analysed (SPM8) at P<.001. MRS data were acquired using MEGA-PRESS before and after the fMRI acquisitions on both visits and GABA concentrations were measured (AMARES, jMRUI)., Results: Following real PAS, BOLD signal changes (group analyses) increased at the site of stimulation during water and saliva swallowing, compared to sham PAS. It is also evident that PAS induced significant increases in BOLD signal to contralateral (to stimulation) hemispheric areas that are of importance to the swallowing neural network. Following real PAS, GABA:creatine ratio showed a trend to increase contralateral to PAS., Conclusion: Targeted PAS applied to the human pharyngeal motor cortex induces local and remote changes in both primary and non-primary areas for water and saliva tasks. There is a possibility that changes of the inhibitory neurotransmitter, GABA, may play a role in the changes in BOLD signal. These findings provide evidence for the mechanisms underlying the beneficial effects of PAS on the brain swallowing network., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS often report difficulty with ignoring (habituating to) tactile sensations, and some patients perceive that this contributes to a "premonitory urge" to tic. While common, the physiological basis of impaired tactile processing in TS, and indeed tics themselves, remain poorly understood. It has been well established that GABAergic processing plays an important role in shaping the neurophysiological response to tactile stimulation. Furthermore, there are multiple lines of evidence suggesting that a deficit in GABAergic transmission may contribute to symptoms found in TS. In this study, GABA-edited magnetic resonance spectroscopy (MRS) was combined with a battery of vibrotactile tasks to investigate the role of GABA and atypical sensory processing in children with TS. Our results show reduced primary sensorimotor cortex (SM1) GABA concentration in children with TS compared with healthy control subjects (HC), as well as patterns of impaired performance on tactile detection and adaptation tasks, consistent with altered GABAergic function. Moreover, in children with TS SM1 GABA concentration correlated with motor tic severity, linking the core feature of TS directly to in vivo brain neurochemistry. There was an absence of the typical correlation between GABA and frequency discrimination performance in TS as was seen in HC. These data show that reduced GABA concentration in TS may contribute to both motor tics and sensory impairments in children with TS. Understanding the mechanisms of altered sensory processing in TS may provide a foundation for novel interventions to alleviate these symptoms., (Copyright © 2015 the American Physiological Society.)

While the neurobiological basis and developmental course of attention-deficit/hyperactivity disorder (ADHD) have not yet been fully established, an imbalance between inhibitory/excitatory neurotransmitters is thought to have an important role in the pathophysiology of ADHD. This study examined the changes in cerebral levels of GABA+, glutamate and glutamine in children and adults with ADHD using edited magnetic resonance spectroscopy. We studied 89 participants (16 children with ADHD, 19 control children, 16 adults with ADHD and 38 control adults) in a subcortical voxel (children and adults) and a frontal voxel (adults only). ADHD adults showed increased GABA+ levels relative to controls (P = 0.048), while ADHD children showed no difference in GABA+ in the subcortical voxel (P > 0.1), resulting in a significant age by disorder interaction (P = 0.026). Co-varying for age in an analysis of covariance model resulted in a nonsignificant age by disorder interaction (P = 0.06). Glutamine levels were increased in children with ADHD (P = 0.041), but there was no significant difference in adults (P > 0.1). Glutamate showed no difference between controls and ADHD patients but demonstrated a strong effect of age across both groups (P < 0.001). In conclusion, patients with ADHD show altered levels of GABA+ in a subcortical voxel which change with development. Further, we found increased glutamine levels in children with ADHD, but this difference normalized in adults. These observed imbalances in neurotransmitter levels are associated with ADHD symptomatology and lend new insight in the developmental trajectory and pathophysiology of ADHD.

Objective: We aimed to determine the effect of an open-label 8 week Vitamin D3 supplementation on manic symptoms, anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid (GABA) in youth exhibiting symptoms of mania; that is, patients with bipolar spectrum disorders (BSD). We hypothesized that an 8 week Vitamin D3 supplementation would improve symptoms of mania, decrease ACC glutamate, and increase ACC GABA in BSD patients. Single time point metabolite levels were also evaluated in typically developing children (TD)., Methods: The BSD group included patients not only diagnosed with BD but also those exhibiting bipolar symptomology, including BD not otherwise specified (BD-NOS) and subthreshold mood ratings (Young Mania Rating Scale [YMRS] ≥8 and Clinical Global Impressions - Severity [CGI-S] ≥3). Inclusion criteria were: male or female participants, 6-17 years old. Sixteen youth with BSD exhibiting manic symptoms and 19 TD were included. BSD patients were asked to a take daily dose (2000 IU) of Vitamin D3 (for 8 weeks) as a supplement. Neuroimaging data were acquired in both groups at baseline, and also for the BSD group at the end of 8 week Vitamin D3 supplementation., Results: Baseline ACC GABA/creatine (Cr) was lower in BSD than in TD (F[1,31]=8.91, p=0.007). Following an 8 week Vitamin D3 supplementation, in BSD patients, there was a significant decrease in YMRS scores (t=-3.66, p=0.002, df=15) and Children's Depression Rating Scale (CDRS) scores (t=-2.93, p=0.01, df=15); and a significant increase in ACC GABA (t=3.18, p=0.007, df=14)., Conclusions: Following an 8 week open label trial with Vitamin D3, BSD patients exhibited improvement in their mood symptoms in conjunction with their brain neurochemistry.

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.)

Objective: An imbalance of excitatory and inhibitory neurotransmission in autism spectrum disorder (ASD) has been proposed. We compared glutamate (Glu), glutamine (Gln), and γ-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) of 13 males with ASD and 14 typically developing (TD) males (ages 13-17), and correlated these levels with intelligence quotient (IQ) and measures of social cognition., Methods: Social cognition was evaluated by administration of the Social Responsiveness Scale (SRS) and the Reading the Mind in the Eyes Test (RMET). We acquired proton magnetic resonance spectroscopy ((1)H-MRS) data from the bilateral ACC using the single voxel point resolved spectroscopy sequence (PRESS) to quantify Glu and Gln, and Mescher-Garwood point-resolved spectroscopy sequence (MEGA-PRESS) to quantify GABA levels referenced to creatine (Cr)., Results: There were higher Gln levels (p=0.04), and lower GABA/Cre levels (p=0.09) in the ASD group than in the TD group. There was no difference in Glu levels between groups. Gln was negatively correlated with RMET score (rho=-0.62, p=0.001) and IQ (rho=-0.56, p=0.003), and positively correlated with SRS scores (rho=0.53, p=0.007). GABA/Cre levels were positively correlated with RMET score (rho=0.34, p=0.09) and IQ (rho=0.36, p=0.07), and negatively correlated with SRS score (rho=-0.34, p=0.09)., Conclusions: These data suggest an imbalance between glutamatergic neurotransmission and GABA-ergic neurotransmission in ASD. Higher Gln levels and lower GABA/Cre levels were associated with lower IQ and greater impairments in social cognition across groups.

Transcranial magnetic stimulation (TMS) is a widely used tool for noninvasive modulation of brain activity, that is thought to interact primarily with excitatory and inhibitory neurotransmitter systems. Neurotransmitters such as glutamate and GABA can be measured by magnetic resonance spectroscopy (MRS). An important prerequisite for studying the relationship between MRS neurotransmitter levels and responses to TMS is that both modalities should examine the same regions of brain tissue. However, co-registration of TMS and MRS has been little studied to date. This study reports on a procedure for the co-registration and co-visualization of MRS and TMS, successfully localizing the hand motor cortex, as subsequently determined by its functional identification using TMS. Sixteen healthy subjects took part in the study; in 14 of 16 subjects, the TMS determined location of motor activity intersected the (2.5cm)(3) voxel selected for MRS, centered on the so called 'hand knob' of the precentral gyrus. It is concluded that MRS voxels placed according to established anatomical landmarks in most cases agree well with functional determination of the motor cortex by TMS. Reasons for discrepancies are discussed., (Copyright © 2015 Elsevier B.V. All rights reserved.)