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Purpose: Idiopathic generalized epilepsies (IGE) comprise a group of clinical syndromes associated with spike wave discharges, putatively linked to alterations in neurotransmission. The purpose of this study was to investigate whether patients with IGE have altered glutamine and γ-aminobutyric acid (GABA) levels indicative of altered excitatory and inhibitory neurotransmission in frontal regions., Materials and Methods: Single-voxel MEGA-edited PRESS magnetic resonance imaging (MRI) spectra were acquired from a 30-mL voxel in the dorsolateral prefrontal cortex in 13 patients with IGE (8 female) and 16 controls (9 female) at 3T. Metabolite concentrations were derived using LCModel. Differences between groups were investigated using an unpaired t-test., Results: Patients with IGE were found to have significantly higher glutamine than controls (P = 0.02). GABA levels were also elevated in patients with IGE (P = 0.03)., Conclusion: Patients with IGE have increased frontal glutamine and GABA compared with controls. Since glutamine has been suggested to act as a surrogate for metabolically active glutamate, it may represent a marker for excitatory neurotransmission., (© 2014 Wiley Periodicals, Inc.)

Sensory perception, including 2-point discrimination (2 ptD), is tightly linked to cortical processing of tactile stimuli in primary somatosensory cortices. While the role of cortical activity in response to a tactile stimulus has been widely investigated, the role of baseline cortical activity is largely unknown. Using resting state fMRI we investigated the relationship between local BOLD fluctuations in the primary somatosensory cortex (the representational field of the hand) and 2 ptD of the corresponding index finger (right and left). Cortical activity was measured using fractional amplitudes of the low frequency BOLD fluctuations (fALFF) and synchronicity using regional homogeneity (ReHo) of the S1 hand region during rest. 2 ptD correlated with higher ReHo values in the representational areas of the contralateral S1 cortex (left hand: p = .028; right hand: p = .049). 2 ptD additionally correlated with higher fALFF in the representational area of the left hand (p = .007) and showed a trend for a significant correlation in the representational area of the right hand (p = .051). Thus, higher BOLD amplitudes and synchronicity at rest, as measures of cortical activity and synchronicity, respectively, are related to better tactile discrimination abilities of the contralateral hand. Our findings extend the relationship seen between spontaneous BOLD fluctuations and sensory perception., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no-go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and region dependent manner., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Several recent studies have reported an inter-individual correlation between regional GABA concentration, as measured by MRS, and the amplitude of the functional blood oxygenation level dependent (BOLD) response in the same region. In this study, we set out to investigate whether this coupling generalizes across cortex. In 18 healthy participants, we performed edited MRS measurements of GABA and BOLD-fMRI experiments using regionally related activation paradigms. Regions and tasks were the: occipital cortex with a visual grating stimulus; auditory cortex with a white noise stimulus; sensorimotor cortex with a finger-tapping task; frontal eye field with a saccade task; and dorsolateral prefrontal cortex with a working memory task. In contrast to the prior literature, no correlation between GABA concentration and BOLD activation was detected in any region. The origin of this discrepancy is not clear. Subtle differences in study design or insufficient power may cause differing results; these and other potential reasons for the discrepant results are discussed. This negative result, although it should be interpreted with caution, has a larger sample size than prior positive results, and suggests that the relationship between GABA and the BOLD response may be more complex than previously thought.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central auditory system. Altered GABAergic neurotransmission has been found in both the inferior colliculus and the auditory cortex in animal models of presbycusis. Edited magnetic resonance spectroscopy (MRS), using the MEGA-PRESS sequence, is the most widely used technique for detecting GABA in the human brain. However, to date there has been a paucity of studies exploring changes to the GABA concentrations in the auditory region of patients with presbycusis. In this study, sixteen patients with presbycusis (5 males/11 females, mean age 63.1 ± 2.6 years) and twenty healthy controls (6 males/14 females, mean age 62.5 ± 2.3 years) underwent audiological and MRS examinations. Pure tone audiometry from 0.125 to 8 kHz and tympanometry were used to assess the hearing abilities of all subjects. The pure tone average (PTA; the average of hearing thresholds at 0.5, 1, 2 and 4 kHz) was calculated. The MEGA-PRESS sequence was used to measure GABA+ concentrations in 4 × 3 × 3 cm(3) volumes centered on the left and right Heschl's gyri. GABA+ concentrations were significantly lower in the presbycusis group compared to the control group (left auditory regions: p = 0.002, right auditory regions: p = 0.008). Significant negative correlations were observed between PTA and GABA+ concentrations in the presbycusis group (r = -0.57, p = 0.02), while a similar trend was found in the control group (r = -0.40, p = 0.08). These results are consistent with a hypothesis of dysfunctional GABAergic neurotransmission in the central auditory system in presbycusis and suggest a potential treatment target for presbycusis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The biomarker potential of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) for the in vivo characterization of preclinical stages in Alzheimer's disease has not yet been explored. We measured GABA, glutamate + glutamine (Glx), and N-acetyl-aspartate (NAA) levels by single-voxel MEGA-PRESS magnetic resonance spectroscopy in the posterior cingulate cortex of 21 elderly subjects and 15 patients with amnestic mild cognitive impairment. Participants underwent Pittsburgh Compound B positron emission tomography, apolipoprotein E (APOE) genotyping, and neuropsychological examination. GABA, Glx, and NAA levels were significantly lower in patients. NAA was lower in Pittsburgh Compound B-positive subjects and APOE ε4 allele carriers. GABA, Glx, and NAA levels were positively correlated to CERAD word learning scores. Reductions in GABA, Glx, and NAA levels may serve as metabolic biomarkers for cognitive impairment in amnestic mild cognitive impairment. Because GABA and Glx do not seem to reflect amyloid β deposition or APOE genotype, they are less likely biomarker candidates for preclinical Alzheimer's disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aberrant function of glutamatergic pathways is likely to underlie the pathology of schizophrenia. Evidence of oxidative stress in the disease pathology has also been reported. N-Acetylaspartate (NAA) is metabolically linked to both cascades and may be a key marker in exploring the interconnection of glutamatergic pathways and oxidative stress. Several studies have reported positive correlation between the levels of NAA and Glx (the sum of glutamate and glutamine) in several brain regions in healthy subjects, by using proton magnetic resonance spectroscopy ([(1)H]MRS). Interestingly, one research group recently reported decoupling of the relationship between NAA and Glx in the hippocampus of patients with schizophrenia. Here we report levels of NAA and Glx measured using [(1)H]MRS, relative to the level of creatine (Cr) as an internal control. The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in 25 patients with schizophrenia and 17 matched healthy controls were studied. In DLPFC, NAA/Cr and Glx/Cr were significantly positively correlated in healthy controls after correction for the effect of age and smoking status and after correction for multiple comparisons (r= 0.627, P= 0.017). However, in patients with schizophrenia, the positive correlation between NAA/Cr and Glx/Cr was not observed even after correcting for these two variables (r= -0.330, P= 0.124). Positive correlation between NAA/Cr and Glx/Cr was not observed in the ACC in both groups. Decoupling of NAA and Glx in the DLPFC may reflect the interconnection of glutamatergic pathways and oxidative stress in the pathology of schizophrenia, and may possibly be a biomarker of the disease.

Purpose: The purpose of this study is to describe the Gannet toolkit for the quantitative batch analysis of gamma-aminobutyric acid (GABA) -edited MRS data., Materials and Methods: Using MEGA-PRESS editing and standard acquisition parameters, four MEGA-PRESS spectra were acquired in three brain regions in 10 healthy volunteers. These 120 datasets were processed without user intervention with Gannet, a Matlab-based tool that takes raw time-domain data input, processes it to generate the frequency-domain edited spectrum, and applies a simple modeling procedure to estimate GABA concentration relative to the creatine or, if provided, the unsuppressed water signal. A comparison of four modeling approaches is also presented., Results: All data were successfully processed by Gannet. Coefficients of variation across subjects ranged from 11% for the occipital region to 17% for the dorsolateral prefrontal region. There was no clear difference in fitting performance between the simple Gaussian model used by Gannet and the other more complex models presented., Conclusion: Gannet, the GABA Analysis Toolkit, can be used to process and quantify GABA-edited MRS spectra without user intervention.

Purpose: To investigate the quantitative impact of frequency drift on Gamma-Aminobutyric acid (GABA+)-edited MRS of the human brain at 3 Tesla (T)., Methods: Three sequential GABA+-edited MEGA-PRESS acquisitions were acquired in fifteen sessions; in ten of these, MRS was preceded by functional MRI (fMRI) to induce frequency drift, which was estimated from the creatine resonance at 3.0 ppm. Simulations were performed to examine the effects of frequency drift on the editing efficiency of GABA and co-edited macromolecules (MM) and of subtraction artifacts on GABA+ quantification. The efficacy of postprocessing frequency correction was also investigated., Results: Gradient-induced frequency drifts affect GABA+ quantification for at least 30 min after imaging. Average frequency drift was low in control sessions and as high as -2 Hz/min after fMRI. Uncorrected frequency drift has an approximately linear effect on GABA+ measurements with a -10 Hz drift resulting in a 16% decrease in GABA+, primarily due to subtraction artifacts., Conclusion: Imaging acquisitions with high gradient duty cycles can impact subsequent GABA+ measurements. Postprocessing can address subtraction artifacts, but not changes in editing efficiency or GABA:MM signal ratios; therefore, protocol design should avoid intensive gradient sequences before edited MRS Magn Reson Med 72:941-948, 2014. © 2013 Wiley Periodicals, Inc., (Copyright © 2013 Wiley Periodicals, Inc.)

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.)

Impaired responses to tactile stimulation are a commonly reported symptom among children with autism spectrum disorder (ASD). Furthermore, impairments in filtering or habituation to tactile input have been described in ASD. This study measured different aspects of tactile processing to investigate atypical touch sensitivity in children with ASD, methodology that has not been previously used in this population. Sixty-seven typically developing children (TDC) and 32 children with ASD (ages 8-12) completed vibrotactile tasks assessing: reaction time (RT); static and dynamic detection threshold (DT); amplitude discrimination with and without single-site adaptation; frequency discrimination; and temporal order judgment (TOJ) with and without concurrent stimulation. Children with ASD showed raised static detection thresholds and an absence of the effect of a dynamically increasing subthreshold stimulus on static detection threshold. Children with ASD also showed poorer amplitude discrimination than TDC, as well as decreased adaptation. There were no significant differences in frequency discrimination or TOJ performance between the groups. Differences in the effect of dynamic stimulation on detection threshold suggest impaired feed-forward inhibition in autism, which may be linked to poor sensory filtering. Increased baseline amplitude discrimination thresholds in ASD suggest that lateral inhibitory connections are weaker in ASD, and an absence of the effect of adaptation suggests impaired modulation of lateral inhibitory connections in ASD, which may relate to aberrant habituation. These results suggest a functional deficit in the somatosensory inhibitory system in autism. Understanding the specific mechanisms underlying sensory symptoms in autism may allow for more specific therapeutic or drug targeting in the near future.

Overexposure to manganese (Mn) may lead to parkinsonian symptoms including motor deficits. The main inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is known to play a pivotal role in the regulation and performance of movement. Therefore this study was aimed at testing the hypothesis that an alteration of GABA following Mn exposure may be associated with fine motor performance in occupationally exposed workers and may underlie the mechanism of Mn-induced motor deficits. A cohort of nine Mn-exposed male smelter workers from an Mn-iron alloy factory and 23 gender- and age-matched controls were recruited and underwent neurological exams, magnetic resonance spectroscopy (MRS) measurements, and Purdue pegboard motor testing. Short-echo-time MRS was used to measure N-Acetyl-aspartate (NAA) and myo-inositol (mI). GABA was detected with a MEGA-PRESS J-editing MRS sequence. The mean thalamic GABA level was significantly increased in smelter workers compared to controls (p = 0.009). Multiple linear regression analysis reveals (1) a significant association between the increase in GABA level and the duration of exposure (R(2) = 0.660, p = 0.039), and (2) significant inverse associations between GABA levels and all Purdue pegboard test scores (for summation of all scores R(2) = 0.902, p = 0.001) in the smelter workers. In addition, levels of mI were reduced significantly in the thalamus and PCC of smelter workers compared to controls (p = 0.030 and p = 0.009, respectively). In conclusion, our results show clear associations between thalamic GABA levels and fine motor performance. Thus in Mn-exposed subjects, increased thalamic GABA levels may serve as a biomarker for subtle deficits in motor control and may become valuable for early diagnosis of Mn poisoning.

There is increasing interest in the use of edited proton magnetic resonance spectroscopy for the detection of GABA in the human brain. At a recent meeting held at Cardiff University, a number of spectroscopy groups met to discuss the acquisition, analysis and interpretation of GABA-edited MR spectra. This paper aims to set out the issues discussed at this meeting, reporting areas of consensus around parameters and procedures in the field and highlighting those areas where differences remain. It is hoped that this paper can fulfill two needs, providing a summary of the current 'state-of-the-art' in the field of GABA-edited MRS at 3T using MEGA-PRESS and a basic guide to help researchers new to the field to avoid some of the pitfalls inherent in the acquisition and processing of edited MRS for GABA., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are needed, given the clinical heterogeneity of the disease. Here, we provide proof-of-concept for using multimodal magnetic resonance imaging (MRI) as a diagnostic biomarker for ALS. Specifically, we evaluated the added diagnostic utility of proton magnetic resonance spectroscopy (MRS) to diffusion tensor imaging (DTI)., Methods: Twenty-nine patients with ALS and 30 age- and gender-matched healthy controls underwent brain MRI which used proton MRS including spectral editing techniques to measure γ-aminobutyric acid (GABA) and DTI to measure fractional anisotropy of the corticospinal tract. Data were analyzed using logistic regression, t-tests, and generalized linear models with leave-one-out analysis to generate and compare the resulting receiver operating characteristic (ROC) curves., Results: The diagnostic accuracy is significantly improved when the MRS data were combined with the DTI data as compared to the DTI data only (area under the ROC curves (AUC) = 0.93 vs. AUC = 0.81; P = 0.05). The combined MRS and DTI data resulted in sensitivity of 0.93, specificity of 0.85, positive likelihood ratio of 6.20, and negative likelihood ratio of 0.08 whereas the DTI data only resulted in sensitivity of 0.86, specificity of 0.70, positive likelihood ratio of 2.87, and negative likelihood ratio of 0.20., Interpretation: Combining multiple advanced neuroimaging modalities significantly improves disease discrimination between ALS patients and healthy controls. These results provide an important step toward advancing a multimodal MRI approach along the diagnostic test development pathway for ALS.

This study is the first to show a relationship between in-vivo brain gamma-amino butyric acid (GABA) levels and auditory inhibitory electrophysiological measures in schizophrenia. Results revealed a strong association between GABA levels and gating of the theta-alpha and beta activities in schizophrenia.

Purpose: To investigate factors that influence the multiplet pattern observed in J-difference editing of gamma-aminobutyric acid (GABA)., Methods: Density matrix simulations were applied to investigate the shape of the 3 ppm GABA multiplet as a function of the editing sequence's slice-selective refocusing pulse properties, in particular bandwidth, transition width, and flip angle. For comparison to the calculations, experimental measurements were also made at 3 T on a 10 mM GABA solution using the MEGA-PRESS sequence at various refocusing pulse flip angles., Results: Good agreement was found between experiments and simulations. The edited multiplet consists of two outer lines of slightly unequal intensity due to strong coupling, and a smaller central line, the result of the unequal J-couplings between the C4 and C3 protons. The size of the center peak increases with increasing slice-selective refocusing pulse transition width, and deviation of the flip angle from 180°., Conclusion: The 3 ppm GABA multiplet pattern observed in the MEGA-PRESS experiment depends quite strongly on the properties of the slice-selective refocusing pulses used. Under some circumstance, the central peak can be quite large; this does not necessarily indicate inefficient editing, or a subtraction artifact, but should be recognized as a property of the pulse sequence itself., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To measure in vivo transverse relaxation times (T2 ) of gamma-aminobutyric acid (GABA) at 7T using the experimental spectral-editing method., Materials and Methods: Experiments were performed at 7T in a 10 mM GABA phantom to determine the intrinsic TE-dependence of the edited signal. Then the same method was applied with editing-based suppression of coedited macromolecular signals to five healthy volunteers to determine T2 of GABA in vivo., Results: From in vivo data acquired at multiple echo times, the in vivo GABA T2 relaxation time was estimated to be 63 ± 19 msec., Conclusion: We present a measurement of the T2 of edited GABA signal at 7T by first using phantom measurements to determine the echo time-dependence of edited signal. The method is purely experimental and does not rely on prior knowledge of coupling constants or simulation of realistic experiments. J. Magn. Reson. Imaging 2013;38:1224-1229. © 2013 Wiley Periodicals, Inc., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: To compare the repeatability of γ-aminobutyric acid (GABA) measurements using J-difference editing, before and after spectral realignment-a technique which has previously been demonstrated to improve the quality of J-difference GABA spectra., Materials and Methods: We performed in vivo measurements in three brain regions (occipital, sensorimotor, and dorsolateral prefrontal cortex [DLPFC]), and analyzed these using alternative alignment approaches to evaluate the impact of alignment on repeatability: "Independent alignment" (aligning each subspectrum independently) and "Pairwise alignment" (aligning each on and off subspectrum as a pair) were compared., Results: Pairwise alignment improved the group mean coefficient of variation in all regions; 0.4% in occipital, 1.1% in sensorimotor, and 1.1% in DLPFC. Independent alignment resulted in subtraction artifacts in the majority of cases, and increased the coefficient of variation in the DLPFC by 9.4%. Simulations demonstrate that the GABA quantification error in datasets with high B0 drift, is 4.5% without alignment, but <1% with optimal alignment., Conclusion: Pairwise alignment improves the repeatability of GABA spectroscopy data. However, independently aligning all on and off subspectra can lead to artifacts and worse repeatability when compared with nonaligned data., (Copyright © 2012 Wiley Periodicals, Inc.)

The major excitatory and inhibitory neurotransmitters, glutamate (Glu) and gamma-aminobutyric acid (GABA), respectively, are implicated in the pathophysiology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide that modulates the Glu system, may also be altered in schizophrenia. This study investigated GABA, Glu + glutamine (Glx), and NAAG levels in younger and older subjects with schizophrenia. Forty-one subjects, 21 with chronic schizophrenia and 20 healthy controls, participated in this study. Proton magnetic resonance spectroscopy ((1)H-MRS) was used to measure GABA, Glx, and NAAG levels in the anterior cingulate (AC) and centrum semiovale (CSO) regions. NAAG in the CSO was higher in younger schizophrenia subjects compared with younger control subjects. The opposite pattern was observed in the older groups. Glx was reduced in the schizophrenia group irrespective of age group and brain region. There was a trend for reduced AC GABA in older schizophrenia subjects compared with older control subjects. Poor attention performance was correlated to lower AC GABA levels in both groups. Higher levels of CSO NAAG were associated with greater negative symptom severity in schizophrenia. These results provide support for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia. The study also highlights the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia.

Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. Although measurements of GABA levels in vivo in the human brain using edited proton magnetic resonance spectroscopy ((1)H-MRS) have been established for some time, it is has not been established how regional GABA levels vary with age in the normal human brain. In this study, 49 healthy men and 51 healthy women aged between 20 and 76 years were recruited and J-difference edited spectra were recorded at 3T to determine the effect of age on GABA levels, and to investigate whether there are regional and gender differences in GABA in mesial frontal and parietal regions. Because the signal detected at 3.02 ppm using these experimental parameters is also expected to contain contributions from both macromolecules (MM) and homocarnosine, in this study the signal is labeled GABA+ rather than GABA. Significant negative correlations were observed between age and GABA+ in both regions studied (GABA+/Cr: frontal region, r=-0.68, p<0.001, parietal region, r=-0.54, p<0.001; GABA+/NAA: frontal region, r=-0.58, p<0.001, parietal region, r=-0.49, p<0.001). The decrease in GABA+ with age in the frontal region was more rapid in women than men. Evidence of a measureable decline in GABA is important in considering the neurochemical basis of the cognitive decline that is associated with normal aging., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The cortical dynamics of somatosensory processing can be investigated using vibrotactile psychophysics. It has been suggested that different vibrotactile paradigms target different cortical mechanisms, and a number of recent studies have established links between somatosensory cortical function and measurable aspects of behavior. The relationship between cortical mechanisms and sensory function is particularly relevant with respect to developmental disorders in which altered inhibitory processing has been postulated, such as in ASD and ADHD. In this study, a vibrotactile battery consisting of nine tasks (incorporating reaction time, detection threshold, and amplitude- and frequency discrimination) was applied to a cohort of healthy adults and a cohort of typically developing children to assess the feasibility of such a vibrotactile battery in both cohorts, and the performance between children and adults was compared. These results showed that children and adults were both able to perform these tasks with a similar performance, although the children were slightly less sensitive in frequency discrimination. Performance within different task-groups clustered together in adults, providing further evidence that these tasks tap into different cortical mechanisms, which is also discussed. This clustering was not observed in children, which may be potentially indicative of development and a greater variability. In conclusion, in this study, we showed that both children and adults were able to perform an extensive vibrotactile battery, and we showed the feasibility of applying this battery to other (e.g., neurodevelopmental) cohorts to probe different cortical mechanisms., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus a relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the reproducibility of spectroscopic measurements from the anterior cingulate (AC) and the dorsolateral prefrontal cortex (DLPFC) regions at 7T using a 32-channel head coil., Materials and Methods: Spectra were acquired in four healthy subjects each scanned twice using a stimulated echo acquisition mode (STEAM) sequence, and a MEGA-PRESS-IVS sequence for gamma-aminobutyric acid (GABA) editing. STEAM spectra were quantified using LCModel, whereas MEGA-PRESS-IVS data were analyzed using peak integrals determined using in-house software. Mean coefficient of variation (CV) and mean absolute difference between visits were calculated., Results: For the AC STEAM dataset, the mean CV between visits was 6.2% for prominent metabolites such as N-acetylaspartate (NAA), total creatine (tCr), and total choline (tCho) and 6.3% for low signal-to-noise ratio (SNR) metabolites such as glutamate (Glu), glutamine (Gln), and GABA. The mean CV between visits for the DLPFC STEAM dataset was 8.5% for prominent metabolites and 21% for lower SNR metabolites. In the AC, the reproducibility measures for GABA were superior for STEAM compared to MEGA-PRESS-IVS (mean CV of 3.5% vs. 13.6%), but the opposite pattern was observed in the DLPFC region (mean CV of 16.2% vs. 13.4%)., Conclusion: 7T MR spectroscopy of the AC and DLPFC using both short TE STEAM and MEGA-PRESS-IVS sequences provide excellent reproducibility of 12 metabolites, including GABA., (Copyright © 2012 Wiley Periodicals, Inc.)

Importance: A lack of neuroinhibitory function may result in unopposed excitotoxic neuronal damage in amyotrophic lateral sclerosis (ALS)., Objective: To determine whether there are reductions in γ-aminobutyric acid (GABA) levels and elevations in glutamate-glutamine (Glx) levels in selected brain regions of patients with ALS by use of proton magnetic resonance spectroscopy., Design: Case-control study using short echo time and GABA-edited proton magnetic resonance spectroscopy at 3 T with regions of interest in the left motor cortex, left subcortical white matter, and pons; data analyzed using logistic regression, t tests, and Pearson correlations; and post hoc analyses performed to investigate differences between riluzole-naive and riluzole-treated patients with ALS., Setting: Tertiary referral center., Participants: Twenty-nine patients with ALS and 30 age- and sex-matched healthy controls., Exposure: Fifteen patients were taking 50 mg of riluzole twice a day as part of their routine clinical care for ALS., Main Outcomes and Measures: Levels of GABA, Glx, choline (a marker of cell membrane turnover), creatine (a marker of energy metabolism), myo-inositol (a marker of glial cells), and N-acetylaspartate (a marker of neuronal integrity)., Results: Patients with ALS had significantly lower levels of GABA in the motor cortex than did healthy controls (P < .01). Patients with ALS also had significantly lower levels of N-acetylaspartate in the motor cortex (P < .01), subcortical white matter (P < .05), and pons (P < .01) and higher levels of myo-inositol in the motor cortex (P < .001) and subcortical white matter (P < .01) than did healthy controls. Riluzole-naive patients with ALS had higher levels of Glx than did riluzole-treated patients with ALS (P < .05 for pons and motor cortex) and healthy controls (P < .05 for pons and motor cortex). Riluzole-naive patients with ALS had higher levels of creatine in the motor cortex (P < .001 for both comparisons) and subcortical white matter (P ≤ .05 for both comparisons) than did riluzole-treated patients with ALS and healthy controls. Riluzole-naive patients with ALS had higher levels of N-acetylaspartate in the motor cortex than did riluzole-treated patients with ALS (P < .01)., Conclusions and Relevance: There are reduced levels of GABA in the motor cortex of patients with ALS. There are elevated levels of Glx in riluzole-naive patients with ALS compared with riluzole-treated patients with ALS and healthy controls. These results point to an imbalance between excitatory and inhibitory neurotransmitters as being important in the pathogenesis of ALS and an antiglutamatergic basis for the effects of riluzole, although additional research efforts are needed.

Background: Magnetic resonance spectroscopy (MRS) studies have consistently demonstrated reduced cortical γ-aminobutyric acid (GABA) concentrations in individuals with major depression. However, evidence for a persistent deficit during remission, which would suggest that GABA dysfunction is a possible trait marker of depression, is equivocal. Although MRS measures total concentration of GABA, magneto-encephalography provides direct measures of neural activity, with cortical γ oscillations shaped by the activity of GABAergic inhibitory interneurons. In this study we investigated whether γ oscillations and GABA concentrations would differ in individuals with remitted depression (RD) compared with never depressed control subjects (ND)., Methods: Thirty-seven healthy, unmedicated female volunteers (n = 19 RD, and n = 18 ND) were recruited. The γ oscillation frequencies and amplitudes in the visual cortex, induced by simple grating stimuli, were quantified with time-frequency analyses. Distinct GABA/glutamate + glutamine MRS peaks were resolved from MEGA-PRESS difference spectra in prefrontal, occipital, and subcortical volumes., Results: The RD and ND individuals did not differ in the frequency of subclinical depressive symptoms. The ND were slightly older (mean = 23 years vs. 21 years), but age did not correlate with dependent measures. There were no group differences in GABA levels or induced cortical γ measures, but RD individuals had markedly reduced M80 (C1) components of the pattern-onset evoked response (46% reduction, Cohen's d = 1.01, p = .006)., Conclusions: Both MRS and magneto-encephalography measures of the GABA system are normal in RD. However, the early visual evoked response is a potential trait marker of the disorder., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: To measure the in vivo longitudinal relaxation time T1 of GABA at 3 Tesla (T)., Materials and Methods: J-difference edited single-voxel MR spectroscopy was used to isolate γ-aminobutyric acid (GABA) signals. An increased echo time (80 ms) acquisition was used, accommodating the longer, more selective editing pulses required for symmetric editing-based suppression of co-edited macromolecular signal. Acquiring edited GABA measurements at a range of relaxation times in 10 healthy participants, a saturation-recovery equation was used to model the integrated data., Results: The longitudinal relaxation time of GABA was measured as T(1,GABA) = 1.31 ± 0.16 s., Conclusion: The method described has been successfully applied to measure the T1 of GABA in vivo at 3T., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To demonstrate the feasibility of measuring the temporal dynamics of cerebral lactate concentration and examine these dynamics in human subjects using magnetic resonance spectroscopy (MRS) during hypoxia., Materials and Methods: A respiratory protocol consisting of 10-minute baseline normoxia, 20-minute inspiratory hypoxia, and ending with 10-minute normoxic recovery was used, throughout which lactate-edited MRS was performed. This was repeated four times in three subjects. A separate session was performed to measure blood lactate. Impulse response functions using end-tidal oxygen and blood lactate as system inputs and cerebral lactate as the system output were examined to describe the dynamics of the cerebral lactate response to a hypoxic challenge., Results: The average lactate increase was 20% ± 15% during the last half of the hypoxic challenge. Significant changes in cerebral lactate concentration were observed after 400 seconds. The average relative increase in blood lactate was 188% ± 95%. The temporal dynamics of cerebral lactate concentration was reproducibly demonstrated with 200-second time bins of MRS data (coefficient of variation 0.063 ± 0.035 between time bins in normoxia). The across-subject coefficient of variation was 0.333., Conclusion: The methods for measuring the dynamics of the cerebral lactate response developed here would be useful to further investigate the brain's response to hypoxia., (Copyright © 2012 Wiley Periodicals, Inc.)

Alterations in the balance between excitatory and inhibitory neurotransmission have been implicated in several neurodevelopmental disorders. Neurofibromatosis type 1 is one of the most common monogenic disorders causing cognitive deficits for which studies on a mouse model (Nfl(+/-)) proposed increased γ-aminobutyric acid-mediated inhibitory neurotransmission as the neural mechanism underlying these deficits. To test whether a similar mechanism translates to the human disorder, we used magnetic resonance spectroscopy to measure γ-aminobutyric acid levels in the visual cortex of children and adolescents with neurofibromatosis type 1 (n = 20) and matched control subjects (n = 26). We found that patients with neurofibromatosis type 1 have significantly lower γ-aminobutyric acid levels than control subjects, and that neurofibromatosis type 1 mutation type significantly predicted cortical γ-aminobutyric acid. Moreover, functional imaging of the visual cortex indicated that blood oxygen level-dependent signal was correlated with γ-aminobutyric acid levels both in patients and control subjects. Our results provide in vivo evidence of γ-aminobutyric acidergic dysfunction in neurofibromatosis type 1 by showing a reduction in γ-aminobutyric acid levels in human patients. This finding is relevant to understand the physiological profile of the disorder and has implications for the identification of targets for therapeutic strategies.

Edited magnetic resonance spectroscopy makes possible noninvasive studies of the role of the inhibitory neurotransmitter GABA in the healthy brain and in disease processes. A major limitation of the methodology is coediting of macromolecular signals. Although it has previously been shown that macromolecular signal can be suppressed using a symmetrical editing scheme, this approach is rarely applied at field strength of 3T as insufficiently selective pulses result in loss of GABA signal (in addition to the intended suppression of macromolecular signal). In this article, the authors show that increasing the echo time to 80 ms lets more selective editing pulses be used, allowing for symmetric editing-based suppression of coedited macromolecular signal without loss of GABA signal. The method is applied to acquire macromolecule-suppressed GABA-edited spectra in 10 healthy participants., (Copyright © 2012 Wiley Periodicals, Inc.)

Huntington's disease (HD) is a neurodegenerative disorder characterized by early cognitive decline that progresses at later stages to dementia and severe movement disorder. HD is caused by a cytosine-adenine-guanine triplet-repeat expansion mutation in the Huntingtin gene, allowing early diagnosis by genetic testing. This study aimed to identify the relationship of N-acetylaspartate and other brain metabolites to cognitive function in HD-mutation carriers by using high-field-strength magnetic resonance spectroscopy (MRS) at 7 Tesla. Twelve individuals with the HD mutation in premanifest or early-stage disease versus 12 healthy controls underwent (1)H magnetic resonance spectroscopy (7.2 mL voxel in the posterior cingulate cortex) at 7 Tesla, and also T1-weighted structural magnetic resonance imaging. All participants received standardized tests of cognitive functioning including the Montreal Cognitive Assessment and standardized quantified neurological examination within an hour before scanning. Individuals with the HD mutation had significantly lower posterior cingulate cortex N-acetylaspartate (-9.6%, P = .02) and glutamate (-10.1%, P = .02) levels than did controls. In contrast, in this small group, measures of brain morphology including striatal and ventricle volumes did not differ significantly. Linear regression with Montreal Cognitive Assessment scores revealed significant correlations with N-acetylaspartate (r(2) = 0.50, P = .01) and glutamate (NAA) (r(2) = 0.64, P = .002) in HD subjects. Our data suggest a relationship between reduced N-acetylaspartate and glutamate levels in the posterior cingulate cortex with cognitive decline in the early stages of HD. N-acetylaspartate and glutamate magnetic resonance spectroscopy signals of the posterior cingulate cortex region may serve as potential biomarkers of disease progression or treatment outcome in HD and other neurodegenerative disorders with early cognitive dysfunction, when structural brain changes are still minor., (Copyright © 2012 Movement Disorder Society.)

Rationale and Objectives: To assess differences in excitatory (glutamate/glutamine or Glx) and inhibitory (γ-Aminobutyric acid or GABA) neurotransmitter levels using MR spectroscopy in pain processing regions of the brain in patients diabetic neuropathy (DN) and positive sensory symptoms and age-matched healthy control (HC) subjects., Materials and Methods: Seven diabetic patients (5 males, 2 females, mean age = 57.0 ± 8.5 years) with confirmed DN and positive sensory symptoms and 7 age and sex matched HC subjects (mean age = 57.7 ± 3.2 years) underwent 3 Tesla MR spectroscopy. Glx and GABA levels were quantified in the right anterior and posterior insula, anterior cingulate cortex and right thalamus., Results: Mean Glx levels were significantly higher and mean GABA levels were significantly lower within the posterior insula in the DN patients compared to HC (P = 0.005 and 0.012 respectively)., Conclusions: This pilot data demonstrates an excitatory/inhibitory neurotransmitter imbalance in the brain of in patients with DN and positive sensory symptoms compared to pain free HC subjects., (Copyright © 2012 AUR. All rights reserved.)

Objective: Recent scientific findings have reinvigorated interest in examining the role of γ-aminobutyric acid (GABA), the major inhibitory central nervous system neurotransmitter, in chronic pain conditions. Decreased inhibitory neurotransmission is a proposed mechanism in the pathophysiology of chronic pain syndromes such as fibromyalgia (FM). The purpose of this study was to test the hypothesis that decreased levels of insular and anterior cingulate GABA would be present in FM patients, and that the concentration of this neurotransmitter would be correlated with pressure-pain thresholds., Methods: Sixteen FM patients and 17 age- and sex-matched healthy controls underwent pressure-pain testing and a 3T proton magnetic resonance spectroscopy session in which the right anterior insula, right posterior insula, anterior cingulate, and occipital cortex were examined in subjects at rest., Results: GABA levels in the right anterior insula were significantly lower in FM patients compared with healthy controls (mean ± SD 1.17 ± 0.24 arbitrary institutional units versus 1.42 ± 0.32 arbitrary institutional units; P = 0.016). There was a trend toward increased GABA levels in the anterior cingulate of FM patients compared with healthy controls (P = 0.06). No significant differences between groups were detected in the posterior insula or occipital cortex (P > 0.05 for all comparisons). Within the right posterior insula, higher levels of GABA were positively correlated with pressure-pain thresholds in the FM patients (Spearman's rho = 0.63; P = 0.02)., Conclusion: Diminished inhibitory neurotransmission resulting from lower concentrations of GABA within the right anterior insula may play a role in the pathophysiology of FM and other central pain syndromes., (Copyright © 2012 by the American College of Rheumatology.)

It has previously been demonstrated that there is a negative correlation between the amplitude of the BOLD response and resting γ amino-butyric acid (GABA) concentration in visual cortex. The work here is the first to empirically characterize individual variability in the haemodynamic response functions (HRFs) in response to a simple visual stimulus and baseline GABA concentration in a population of young adult males (n = 15, aged 20-28 years). The results demonstrate that GABA concentration is negatively correlated with BOLD response amplitude (r = -0.64, P < 0.02) and positively correlated with HRF width (r = 0.67, P < 0.002), that is, individuals with higher resting GABA concentration tend to exhibit smaller and wider HRFs. No correlations were observed with resting cerebral blood flow and GABA concentration and similarly, no correlations were observed between GABA and the proportional tissue content of the MRS voxel. We argue that correlation of the height of the HRF is supportive of the view that the previously observed correlations between BOLD amplitudes and GABA are reflective of differences in neuronal activity. However, the changes in HRF shape in individuals with higher baseline GABA levels are suggestive that differing vascular response characteristics may also make a significant contribution. Our results reinforce the view that variability in endogenous factors, such as neurotransmitter concentration, can have a profound effect on the vascular haemodynamic response. This has important implications for between-cohort fMRI studies in which variation in parameters such as GABA concentration may lead to group differences in the BOLD signal., (Copyright © 2011 Wiley Periodicals, Inc.)

The neural mechanisms underlying variability in human sensory perception remain incompletely understood. In particular, few studies have attempted to investigate the relationship between in vivo measurements of neurochemistry and individuals' behavioral performance. Our previous work found a relationship between GABA concentration in the visual cortex and orientation discrimination thresholds (Edden et al., 2009). In the present study, we used magnetic resonance spectroscopy of GABA and psychophysical testing of vibrotactile frequency thresholds to investigate whether individual differences in tactile frequency discrimination performance are correlated with GABA concentration in sensorimotor cortex. Behaviorally, individuals showed a wide range of discrimination thresholds ranging from 3 to 7.6 Hz around the 25 Hz standard. These frequency discrimination thresholds were significantly correlated with GABA concentration (r = -0.58; p < 0.05) in individuals' sensorimotor cortex, but not with GABA concentration in an occipital control region (r = -0.04). These results demonstrate a link between GABA concentration and frequency discrimination in vivo, and support the hypothesis that GABAergic mechanisms have an important role to play in sensory discrimination.

Background: Impulsivity is a multifaceted personality construct associated with numerous psychiatric disorders. Recent research has characterized four facets of impulsivity: "urgency" (the tendency to act rashly especially in the context of distress or cravings); "lack of premeditation" (not envisaging the consequences of actions); "lack of perseverance" (not staying focused on a task); and "sensation seeking" (engaging in exciting activities). Urgency is particularly associated with clinical populations and problematic disinhibited behavior., Methods: We used magnetic resonance spectroscopy to measure concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the dorsolateral prefrontal cortex (DLPFC) in two cohorts of 12 and 13 participants., Results: We find that variation in trait urgency in healthy men correlates with GABA concentration in the DLPFC. The result was replicated in an independent cohort. More GABA predicted lower urgency scores, consistent with a role in self-control for GABA-mediated inhibitory mechanisms in DLPFC., Conclusions: These findings help account for individual differences in self-control and thus clarify the relationship between GABA and a wide range of psychiatric disorders associated with impaired self-control., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Group comparisons of indices derived from diffusion tensor imaging are common in the literature. An increasingly popular approach to performing such comparisons is the skeleton-projection based approach where, for example, fractional anisotropy (FA) values are projected onto a skeletonized version of the data to minimize differences due to spatial misalignment. In this work, we examine the spatial heterogeneity of the statistical power to detect group differences, and show that there is an intrinsic spatial heterogeneity, with more 'central' structures having less variance within a population. Importantly, we also demonstrate a previously unreported feature of skeleton-based analysis methods, that is that the width of the skeleton depends on the relative orientation to the imaging matrix. Due to the way in which the inferential statistics are performed, this means that structures that are obliquely oriented to the imaging matrix are more likely to show significant differences than when aligned with the imaging matrix. This has profound implications for the interpretation of results obtained from such analysis, especially when there are no a priori hypotheses concerning the spatial location of any group differences. For a uniform (DC) offset between two groups, the skeleton projection-based approaches will be most likely to reveal a difference in centrally located white matter structures oriented obliquely to the imaging matrix., (Copyright © 2011 Elsevier B.V. All rights reserved.)

There is increasing interest in the J-PRESS technique, an in vivo implementation of two-dimensional J-spectroscopy combined with PRESS localization, for high-field spectroscopy studies of the human brain. The experiment is designed to resolve scalar couplings in the second, indirectly detected dimension, but will only do so if the slice-selective refocusing pulses in the PRESS sequence affect all coupled spins equally. At high magnet field strengths, due to limited RF pulse bandwidth, PRESS-based localization results in spatially dependent evolution of coupling. In some regions of the localized volume, coupling evolves during the PRESS echo time, while in other regions it may be partially or fully refocused. This study investigates the impact of this effect on the appearance of the J-PRESS spectrum for coupled spins, focusing on two commonly observed metabolites, lactate and N-acetyl aspartate, showing that such behavior results in additional peaks in the J-resolved spectrum (termed J-refocused peaks). It is also demonstrated that increasing the bandwidth of refocusing pulses significantly reduces the size of such signals., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: To evaluate the reproducibility of γ-amino-butyric acid (GABA) and glutamate concentrations derived using three different spectral fitting methods, and to investigate gender-related differences in neurotransmitter levels., Materials and Methods: Single voxel MEGA-edited PRESS MR spectra were acquired from a 30-mL voxel in the dorso-lateral prefrontal cortex in 14 adult volunteers (7 female) at 3 Tesla (3T). For each participant, four consecutive resting spectra were acquired within the same scanning session. Metabolite concentrations were derived using LCModel, jMRUI, and locally written peak fitting software. The within-session reproducibility for each analysis method was calculated as the average coefficient of variation (CV) of the GABA and Glx (glutamate+glutamine) concentrations. Gender differences in GABA and Glx were evaluated using a two-tailed unpaired t-test., Results: LCModel provided the best reproducibility for both GABA (CV 7%) and Glx (CV 6%). GABA, Glx, and glutamate concentrations were significantly higher in the male participants, (P = 0.02, P = 0.001, and P < 0.001, respectively)., Conclusion: GABA and glutamate can be quantified in vivo with high reproducibility (CV 6-7%) using frequency-domain spectral fitting methods like LCModel. However, the GABA and glutamate concentrations vary significantly between men and women, emphasizing the importance of gender-matching for studies investigating differences in neurotransmitter concentrations between mixed-cohort groups., (Copyright © 2011 Wiley-Liss, Inc.)

A spin echo-based MRSI sequence was developed to acquire edited spectra of γ-aminobutyric acid in an entire slice. Water and lipid signals were suppressed by a dual-band presaturation sequence, which included integrated outer volume suppression pulses for additional lipid suppression. Experiments in three normal volunteers were performed at 3 T using a 32-channel head coil. High signal-to-noise ratio spectra and metabolic images of γ-aminobutyric acid were acquired from nominal 4.5 cm3 voxels (estimated actual voxel size 7.0 cm3) in a scan time of 17 min. The sequence is also expected to co-edit homocarnosine and macromolecules, giving a composite γ-aminobutyric acid+ resonance. The γ-aminobutyric acid+ to water ratio was measured using a companion water MRSI scan and was found to correlate linearly with the % gray matter (GM) of each voxel (γ-aminobutyric acid+/water=(1.5×GM+3.2)×10(-5), R=0.27), with higher γ-aminobutyric acid+ levels in gray matter compared with white. In conclusion, high signal-to-noise ratio γ-aminobutyric acid-MRSI is possible at 3 T within clinically feasible scan times., (Copyright © 2010 Wiley-Liss, Inc.)

Background: Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable., Objectives: Our goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure., Methods: We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)]., Results: Seven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = -0.93; p < 0.001)., Conclusions: We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.

Subliminal visual stimuli affect motor planning, but the size of such effects differs greatly between individuals. Here, we investigated whether such variation may be related to neurochemical differences between people. Cortical responsiveness is expected to be lower under the influence of more of the main inhibitory neurotransmitter, GABA. Thus, we hypothesized that, if an individual has more GABA in the supplementary motor area (SMA)--a region previously associated with automatic motor control--this would result in smaller subliminal effects. We measured the reversed masked prime--or negative compatibility--effect, and found that it correlated strongly with GABA concentration, measured with magnetic resonance spectroscopy. This occurred specifically in the SMA region, and not in other regions from which spectroscopy measurements were taken. We replicated these results in an independent cohort: more GABA in the SMA region is reliably associated with smaller effect size. These findings suggest that, across individuals, the responsiveness of subconscious motor mechanisms is related to GABA concentration in the SMA., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: To measure longitudinal (T(1)) and multi-echo transverse (T(2)) relaxation times of healthy breast tissue at 3 Tesla (T)., Materials and Methods: High-resolution relaxation time measurements were made in six healthy female subjects. Inversion recovery images were acquired at 10 inversion times between 100 ms and 4000 ms, and multiple spin echo images were acquired at 16 echo times between 10 ms and 160 ms., Results: Longitudinal relaxation times T(1) were measured as 423 ± 12 ms for adipose tissue and 1680 ± 180 ms for fibroglandular tissue. Multi-echo transverse relaxation times T(2) were measured as 154 ± 9 ms for adipose tissue and 71 ± 6 ms for fibroglandular tissue. Histograms of the voxel-wise relaxation times and quantitative relaxation time maps are also presented., Conclusion: T(1) and multi-echo T(2) relaxation times in normal human breast tissue are reported. These values are useful for pulse sequence design and optimization for 3T breast MRI. Compared with the literature, T(1) values are significantly longer at 3T, suggesting that longer repetition time and inversion time values should be used for similar image contrast.

Purpose: To demonstrate the application of Mescher-Garwood (MEGA) point-resolved spectroscopy sequence (PRESS) editing to the detection of lactate in the brain at 3T and to investigate changes in lactate concentration associated with inspiratory gas challenges., Materials and Methods: Edited lactate measurements were made in six healthy volunteers while the subjects breathed normoxic (21% O(2)), hypoxic (12% O(2)), and hyperoxic (40% O(2)) gas mixtures. Lactate concentration was quantified relative to the unsuppressed water signal from the same volume., Results: Lactate concentration was elevated in all subjects during hypoxia in a highly significant fashion (mean increase = 39%; P = 0.0003). There was no significant change seen in hyperoxia., Conclusion: MEGA-PRESS editing at 3T is sufficiently sensitive to detect lactate in the healthy brain with good signal-to-noise ratio (SNR), and can be used to investigate changes in cerebral metabolism arising during inspiratory gas challenges., (2010 Wiley-Liss, Inc.)

People vary markedly in the efficiency with which they can resolve competitive action decisions, even simple ones such as shifting gaze to one stimulus rather than another. We found that an individual's ability to rapidly resolve such competition is predicted by the concentration of GABA, the main inhibitory neurotransmitter, in a region of frontal cortex that is relevant for eye movements, but not in a control region (occipital cortex).

Neuronal orientation selectivity has been shown in animal models to require corticocortical network cooperation and to be dependent on the presence of GABAergic inhibition. However, it is not known whether variability in these fundamental neurophysiological parameters leads to variability in behavioral performance. Here, using a combination of magnetic resonance spectroscopy, magnetoencephalography, and visual psychophysics, we show that individual performance on a visual orientation discrimination task is correlated with both the resting concentration of GABA and the frequency of stimulus-induced gamma oscillations in human visual cortex. Behaviorally, a strong oblique effect was found, with the mean angular threshold for oblique discrimination being five times higher than that for vertically oriented stimuli. Similarly, we found an oblique effect for the dependency of performance on neurophysiological parameters. Orientation detection thresholds were significantly negatively correlated with visual cortex GABA concentration for obliquely oriented patterns (r = -0.65, p < 0.015) but did not reach significance for vertically oriented stimuli (r = -0.39, p = 0.2). Similarly, thresholds for obliquely oriented stimuli were negatively correlated with gamma oscillation frequency (r = -0.65, p < 0.017), but thresholds for vertical orientations were not (r = -0.02, p = 0.9). Gamma oscillation frequency was positively correlated with GABA concentration in primary visual cortex (r = 0.67, p < 0.013). These results confirm the importance of GABAergic inhibition in orientation selectivity and demonstrate, for the first time, that interindividual performance on a simple visual task is linked to neurotransmitter concentration. The results also suggest a key role for GABAergic gamma oscillations in visual discrimination tasks.

Functional imaging of the human brain is an increasingly important technique for clinical and cognitive neuroscience research, with functional MRI (fMRI) of the blood oxygen level-dependent (BOLD) response and electroencephalography or magnetoencephalography (MEG) recordings of neural oscillations being 2 of the most popular approaches. However, the neural and physiological mechanisms that generate these responses are only partially understood and sources of interparticipant variability in these measures are rarely investigated. Here, we test the hypothesis that the properties of these neuroimaging metrics are related to individual levels of cortical inhibition by combining magnetic resonance spectroscopy to quantify resting GABA concentration in the visual cortex, MEG to measure stimulus-induced visual gamma oscillations and fMRI to measure the BOLD response to a simple visual grating stimulus. Our results demonstrate that across individuals gamma oscillation frequency is positively correlated with resting GABA concentration in visual cortex (R = 0.68; P < 0.02), BOLD magnitude is inversely correlated with resting GABA (R = -0.64; P < 0.05) and that gamma oscillation frequency is strongly inversely correlated with the magnitude of the BOLD response (R = -0.88; P < 0.001). Our results are therefore supportive of recent theories suggesting that these functional neuroimaging metrics are dependent on the excitation/inhibition balance in an individual's cortex and have important implications for the interpretation of functional imaging results, particularly when making between-group comparisons in clinical research.

T(1) and T(2) were measured for white matter (WM) and gray matter (GM) in the human cervical spinal cord at 3T. T(1) values were calculated using an inversion-recovery (IR) and B(1)-corrected double flip angle gradient echo (GRE) and show significant differences (p = 0.002) between WM (IR = 876 +/- 27 ms, GRE = 838 +/- 54 ms) and GM (IR = 973 +/- 33 ms, GRE = 994 +/- 54 ms). IR showed significant difference between lateral and dorsal column WM (863 +/- 23 ms and 899 +/- 18 ms, respectively, p = 0.01) but GRE did not (p = 0.40). There was no significant difference (p = 0.31) in T(2) between WM (73 +/- 6 ms) and GM (76 +/- 3 ms) or between lateral and dorsal columns (lateral: 73 +/- 6 ms, dorsal: 72 +/- 7 ms, p = 0.59). WM relaxation times were similar to brain structures with very dense fiber packing (e.g., corpus callosum), while GM values resembled deep GM in brain. Optimized sequence parameters for maximal contrast between WM and GM, and between WM and cerebrospinal fluid (CSF) were derived. Since the spinal cord has rostral-caudal symmetry, we expect these findings to be applicable to the whole cord., ((c) 2008 Wiley-Liss, Inc.)

The MEGA-PRESS-IVS method has been developed, which combines MEGA (a frequency-selective editing technique) editing with the point-resolved spectroscopy sequence (PRESS) and inner volume saturation (IVS) localization, reducing the deleterious effects of spatial variation in coupling evolution. The IVS method has been previously described for improved efficiency of lactate detection. The current study demonstrates that the combination of MEGA-PRESS with IVS results in increased sensitivity for edited single-voxel measurements of glutamate and gamma-aminobutyric acid (GABA). A four-compartment model of coupling evolution is investigated through simple product operators and full spin-system simulations and the predicted pattern of signal evolution is demonstrated through MEGA-PRESS-MRSI. MEGA-PRESS-IVS is then compared to MEGA-PRESS in a phantom and an average signal increase of 24% is demonstrated in five healthy volunteers., ((c) 2007 Wiley-Liss, Inc.)