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PURPOSE To investigate the editing-pulse flip angle (FA) dependence of editing efficiency and ultimately to maximize the edited signal of commonly edited MR spectroscopy (MRS) signals, such as gamma-aminobutyric acid (GABA) and lactate. METHODS Density-matrix simulations were performed for a range of spin systems to find the editing-pulse FA for maximal editing efficiency. Simulations were confirmed by phantom experiments and in vivo measurements in 10 healthy participants using a 3T Philips scanner. Four MEGA-PRESS in vivo measurements targeting GABA+ and lactate were performed, comparing the conventional editing-pulse FA (FA = 180°) to the optimal one suggested by simulations (FA = 210°). RESULTS Simulations and phantom experiments show that edited GABA and lactate signals are maximal at FA = 210°. Compared to conventional editing (FA = 180°), in vivo signals from GABA+ and lactate signals increase on average by 8.5% and 9.3%, respectively. CONCLUSION Increasing the FA of editing-pulses in the MEGA-PRESS experiment from 180° to 210° increases the edited signals from GABA+ and lactate by about 9% in vivo.

Purpose To demonstrate J-difference editing of phosphorylethanolamine (PE) with chemical shifts at 3.22 (PE3.22 ) and 3.98 (PE3.98 ) ppm, and compare the merits of two editing strategies. Methods Density-matrix simulations of MEGA-PRESS (Mescher-Garwood PRESS) for PE were performed at TEs ranging from 80 to 200 ms in steps of 2 ms, applying 20-ms editing pulses (ON/OFF) at (1) 3.98/7.5 ppm to detect PE3.22 and (2) 3.22/7.5 ppm to detect PE3.98 . Phantom experiments were performed using a PE phantom to validate simulation results. Ten subjects were scanned using a Philips 3T MRI scanner at TEs of 90 ms and 110 ms to edit PE3.22 and PE3.98 . Osprey was used for data processing, modeling, and quantification. Results Simulations show substantial TE modulation of the intensity and shape of the edited signals due to coupling evolution. Simulated and phantom integrals suggest that TEs of 110 ms and 90 ms were optimal for the edited detection of PE3.22 and PE3.98 , respectively. Phantom results indicated strong agreement with the simulated spectra and integrals. In vivo quantification of the PE3.22 /total creatine and PE3.98 /total creatine concentration ratio yielded values of 0.26 ± 0.04 (between-subject coefficient of variation [CV]: 15.4%) and 0.18 ± 0.04 (CV: 22.8%), respectively, at TE = 90 ms, and 0.24 ± 0.02 (CV: 8.2%) and 0.23 ± 0.04 (CV: 18.0%), respectively, at TE = 110 ms. Conclusion Simulations and in vivo MEGA-PRESS of PE demonstrate that both PE3.22 and PE3.98 are potential candidates for editing, but PE3.22 at TE = 110 ms yields lower variation across TEs.

Background The dysfunctional activity of the medial prefrontal cortex has been associated with the appearance of the somatic symptom disorder, a key feature of the Parkinson's disease (PD) psychosis complex. Objectives The objectives of this study were to investigate whether the basal contents of inhibitory γ-aminobutyric acid and excitatory glutamate plus glutamine neurotransmitter levels are changed in the medial prefrontal cortex of patients with PD with somatic symptom disorder and whether this alteration represents a marker of susceptibility of PD to somatic symptom disorder, thus representing a signature of psychosis complex of PD. Methods Levels of the γ-aminobutyric acid and glutamate plus glutamine were investigated, at rest, with proton magnetic resonance spectroscopy. Total creatine was used as an internal reference. The study cohort included 23 patients with somatic symptom disorder plus PD, 19 patients with PD without somatic symptom disorder, 19 healthy control subjects, and 14 individuals with somatic symptom disorder who did not show other psychiatric or neurological disorders. Results We found that, compared with patients with PD without somatic symptom disorder or healthy control individuals, patients with somatic symptom disorder, with or without PD, show increased γ-aminobutyric acid/total creatine levels in the medial prefrontal cortex. The medial prefrontal cortex contents of glutamate plus glutamine/total creatine levels or γ-aminobutyric acid/glutamate plus glutamine were not different among groups. Conclusions Our findings highlight a crucial pathophysiologic role played by high γ-aminobutyric acid within the medial prefrontal cortex in the production of somatic symptom disorder. This phenomenon represents a signature of psychosis complex in patients with PD. © 2020 International Parkinson and Movement Disorder Society.

The balance of excitation and inhibition in neural circuits is hypothesized to be increased in autism spectrum disorder, possibly mediated by altered signaling of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), yet empirical evidence in humans is inconsistent. We used edited magnetic resonance spectroscopy (MRS) to quantify signals associated with both GABA and the excitatory neurotransmitter glutamate in multiple regions of the sensory and sensorimotor cortex, including primary visual, auditory, and motor areas in adult individuals with autism and in neurotypical controls. Despite the strong a priori hypothesis of reduced GABA in autism spectrum disorder, we found no group differences in neurometabolite concentrations in any of the examined regions and no correlations of MRS measure with psychophysical visual sensitivity or autism symptomatology. We demonstrate high data quality that is comparable across groups, with a relatively large sample of well-characterized participants, and use Bayesian statistics to corroborate the lack of any group differences. We conclude that levels of GABA and Glx (glutamate, glutamine, and glutathione) in the sensory and sensorimotor cortex, as measured with MRS at 3T, are comparable in adults with autism and neurotypical individuals. Autism Res 2020, 13: 1111-1129. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: γ-Aminobutyric acid (GABA) and glutamate are the main inhibitory and excitatory neurotransmitters in the human brain, respectively, and their balanced interaction is necessary for neural function. Previous research suggests that the GABA and glutamate systems might be altered in autism. In this study, we used magnetic resonance spectroscopy to measure concentrations of these neurotransmitters in the sensory areas in the brains of young adults with autism. In contradiction to the common hypothesis of reduced GABA in autism, we demonstrate that concentrations of both GABA and glutamate, in all the brain regions examined, are comparable in individuals with autism and in neurotypical adults. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

J-difference-edited spectroscopy is a valuable approach for the in vivo detection of γ-aminobutyric-acid (GABA) with magnetic resonance spectroscopy (MRS). A recent expert consensus article recommends linear combination modeling (LCM) of edited MRS but does not give specific details regarding implementation. This study explores different modeling strategies to adapt LCM for GABA-edited MRS. Sixty-one medial parietal lobe GABA-edited MEGA-PRESS spectra from a recent 3-T multisite study were modeled using 102 different strategies combining six different approaches to account for co-edited macromolecules (MMs), three modeling ranges, three baseline knot spacings, and the use of basis sets with or without homocarnosine. The resulting GABA and GABA+ estimates (quantified relative to total creatine), the residuals at different ranges, standard deviations and coefficients of variation (CVs), and Akaike information criteria, were used to evaluate the models’ performance. Significantly different GABA+ and GABA estimates were found when a well-parameterized MM(3co) basis function was included in the model. The mean GABA estimates were significantly lower when modeling MM(3co), while the CVs were similar. A sparser spline knot spacing led to lower variation in the GABA and GABA+ estimates, and a narrower modeling range—only including the signals of interest—did not substantially improve or degrade modeling performance. Additionally, the results suggest that LCM can separate GABA and the underlying co-edited MM(3co). Incorporating homocarnosine into the modeling did not significantly improve variance in GABA+ estimates. In conclusion, GABA-edited MRS is most appropriately quantified by LCM with a well-parameterized co-edited MM(3co) basis function with a constraint to the non-overlapped MM(0.93), in combination with a sparse spline knot spacing (0.55 ppm) and a modeling range of 0.5–4 ppm.

Objective Defective cerebellar GABAergic inhibitory control may participate to the cognitive impairments seen in SZ. We tested the prediction of a model for the relationship between cerebellar GABA concentration and the associative/executive processes required by verbal fluency in patients with schizophrenia (SZ) and matched healthy controls (HC). Method Magnetic resonance spectroscopy of GABA was performed using a 3 Tesla scanner and verbal fluency assessed by the Controlled Word (WFT) and Semantic (SFT) Fluency tests. Cerebellar GABA measurements were obtained using the MEGA-PRESS acquisition sequence. Linear correlations between cerebellar GABA levels and the WFT, SFT score were performed to test differences between correlation coefficients of SZ and HC. Quantile regressions between GABA levels and the WFT score were performed. Results Higher cerebellar GABA concentration was associated in SZ with lower phonemic fluency and reduced number of switches among subcategories as opposed to what observed in HC (with higher cerebellar GABA associated with higher number of words and phonemic switches). GABA levels explained phonemic fluency in SZ performing above the group mean. Conclusion Studying cerebellar GABA provides a valid heuristic to explore the molecular mechanisms of SZ. This is crucial for developing pharmacological treatments to improve cognition and functional recovery in SZ.

Spectral editing in in vivo 1 H-MRS provides an effective means to measure low-concentration metabolite signals that cannot be reliably measured by conventional MRS techniques due to signal overlap, for example, γ-aminobutyric acid, glutathione and D-2-hydroxyglutarate. Spectral editing strategies utilize known J-coupling relationships within the metabolite of interest to discriminate their resonances from overlying signals. This consensus recommendation paper provides a brief overview of commonly used homonuclear editing techniques and considerations for data acquisition, processing and quantification. Also, we have listed the experts' recommendations for minimum requirements to achieve adequate spectral editing and reliable quantification. These include selecting the right editing sequence, dealing with frequency drift, handling unwanted coedited resonances, spectral fitting of edited spectra, setting up multicenter clinical trials and recommending sequence parameters to be reported in publications.

The aim of this work was to develop simultaneous edited MRS of γ-aminobutyric acid (GABA), glutathione (GSH), and ethanol (EtOH) using Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) at 3T. Density-matrix simulations of HERMES were carried out and compared with phantom experiments. In vivo experiments were performed in six healthy volunteers about 30 min after alcohol consumption. Simulations of HERMES showed GABA-, GSH-, and EtOH-edited spectra with low levels of crosstalk and excellent agreement with phantom spectra. In vivo experiments showed well edited GABA signals at 3.0 ppm, GSH at 2.95 ppm, and EtOH at 1.18 ppm in the respective Hadamard combination spectra. Measured integral ratios were 0.082 ± 0.012 for GABA/Cr, 0.037 ± 0.006 for GSH/Cr, and 0.305 ± 0.129 for EtOH/Cr. Simulated, phantom, and in vivo measurements of HERMES show excellent separation of GABA-, GSH-, and EtOH-edited signals with negligible levels of crosstalk. HERMES allows a threefold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-PRESS measurements.

There is growing evidence for dysfunctional glutamatergic excitation and/or gamma-aminobutyric acid (GABA)ergic inhibition in patients with multiple sclerosis (MS). Cognitive impairment may occur during the early stages of MS and hippocampal abnormalities have been suggested as biomarkers. However, researchers have not clearly determined whether changes in hippocampal GABA and glutamate (Glu) levels are associated with cognitive impairment and aberrant neural activity in patients with MS. We used magnetic resonance spectroscopy to measure GABA+ and Glu levels in the left hippocampal region of 29 patients with relapsing-remitting MS and 29 healthy controls (HCs). Resting-state functional connectivity (FC) with the hippocampus was also examined. Compared to HCs, patients exhibited significantly lower GABA+ and Glu levels, which were associated with verbal and visuospatial memory deficits, respectively. Patients also showed decreased FC strengths between the hippocampus and several cortical regions, which are located within the default mode network. Moreover, hippocampal GABA+ levels and Glu/GABA+ ratios correlated with the FC strengths in HCs but not in patients with MS. This study describes a novel method for investigating the complex relationships among excitatory/inhibitory neurotransmitters, brain connectivity and cognition in health and disease. Strategies that modulate Glu and GABA neurotransmission may represent new therapeutic treatments for patients with MS.

Levels of GABA, the main inhibitory neurotransmitter in the brain, can be regionally quantified using magnetic resonance spectroscopy (MRS). Although GABA is crucial for efficient neuronal functioning, little is known about age‐related differences in GABA levels and their relationship with age‐related changes in brain structure. Here, we investigated the effect of age on GABA levels within the left sensorimotor cortex and the occipital cortex in a sample of 85 young and 85 older adults using the MEGA‐PRESS sequence. Because the distribution of GABA varies across different brain tissues, various correction methods are available to account for this variation. Considering that these correction methods are highly dependent on the tissue composition of the voxel of interest, we examined differences in voxel composition between age groups and the impact of these various correction methods on the identification of age‐related differences in GABA levels. Results indicated that, within both voxels of interest, older (as compared to young adults) exhibited smaller gray matter fraction accompanied by larger fraction of cerebrospinal fluid. Whereas uncorrected GABA levels were significantly lower in older as compared to young adults, this age effect was absent when GABA levels were corrected for voxel composition. These results suggest that age‐related differences in GABA levels are at least partly driven by the age‐related gray matter loss. However, as alterations in GABA levels might be region‐specific, further research should clarify to what extent gray matter changes may account for age‐related differences in GABA levels within other brain regions.

Purpose To demonstrate simultaneous editing of the two most commonly edited and overlapping signals, γ-aminobutyric acid (GABA), and glutathione (GSH), with Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) using sLASER localization at 7T. Methods Density matrix simulations of HERMES at 7T were carried out and compared with phantom experiments. Additional phantom experiments were performed to characterize the echo time (TE) -dependent modulation of GABA- and GSH-edited HERMES spectra at TE of 80-160 ms. In vivo experiments were performed in 10 healthy volunteers, comparing HERMES (11 min) to sequentially acquired MEGA-sLASER detection of GABA and GSH (2 × 11 min). Results Simulations of HERMES show GABA- and GSH-edited spectra with negligible levels of crosstalk, and give modest agreement with phantom spectra. The TE series of GABA- and GSH-edited HERMES spectra modulate as a result of T2 relaxation and coupling evolution, with GABA showing a stronger TE-dependence. In vivo HERMES experiments show well-edited GABA and GSH signals. Measured concentrations are not statistically different between HERMES and MEGA-sLASER for GABA (1. 051 ± 0.254 i.u. and 1.053 ± 0.248 i.u; P > 0.985) or GSH (0.300 ± 0.091 i.u. and 0.302 ± 0.093 i.u; P > 0.940). Conclusion Simulated, phantom and in vivo measurements of HERMES show excellent segregation of GABA- and GSH-edited signals, and excellent agreement with separately acquired MEGA-sLASER data. HERMES allows two-fold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-sLASER measurements. Magn Reson Med 80:474-479, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Purpose Detection of endogenous metabolites using multiplexed editing substantially improves the efficiency of edited magnetic resonance spectroscopy. Multiplexed editing (i.e., performing more than one edited experiment in a single acquisition) requires a tailored, robust approach for correction of frequency and phase offsets. Here, a novel method for frequency and phase correction (FPC) based on spectral registration is presented and compared against previously presented approaches. Methods One simulated dataset and 40 γ-aminobutyric acid-/glutathione-edited HERMES datasets acquired in vivo at three imaging centers were used to test four FPC approaches: no correction; spectral registration; spectral registration with post hoc choline-creatine alignment; and multistep FPC. The performance of each routine for the simulated dataset was assessed by comparing the estimated frequency/phase offsets against the known values, whereas the performance for the in vivo data was assessed quantitatively by calculation of an alignment quality metric based on choline subtraction artifacts. Results The multistep FPC approach returned corrections that were closest to the true values for the simulated dataset. Alignment quality scores were on average worst for no correction, and best for multistep FPC in both the γ-aminobutyric acid- and glutathione-edited spectra in the in vivo data. Conclusions Multistep FPC results in improved correction of frequency/phase errors in multiplexed γ-aminobutyric acid-/glutathione-edited magnetic resonance spectroscopy experiments. The optimal FPC strategy is experiment-specific, and may even be dataset-specific. Magn Reson Med 80:21-28, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Background Parkinson's disease (PD) is divided into postural instability gait difficulty (PIGD) and tremor-dominant (TD) subtypes. Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of PD. Purpose To evaluate the differences of GABA levels between PD motor subtypes using MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS). Study Type: Cohort. SUBJECTS: PD patients were classified into PIGD (n = 13) and TD groups (n = 9); 16 age- and sex-matched healthy controls were also recruited. All subjects were right-handed. Sequence All subjects underwent an magnetic resonance spectroscopy scan including MEGA-PRESS at 3.0T. ASSESSMENT The detected GABA signal also contains signal from macromolecules (MM) and homocarnosine, so it is referred to as GABA+. GABA + levels and Creatine (Cr) levels were quantified in the left basal ganglia (BG) using Gannet 2.0 by Tao Gong. Statistical Tests Differences in GABA + levels between the three groups were analyzed using analysis of covariance. The relationship between GABA levels and a unified PD rating scale (UPDRS) was also analyzed. Results GABA + levels were significantly lower in left BG regions of PD patients compared with healthy controls (P < 0.001). In PD patients, the GABA concentration was lower in the TD group than the PIGD group (P = 0.019). Cr levels in PIGD and TD were lower than controls (P = 0.020; P = 0.002). A significant negative correlation was found in PIGD between GABA levels and UPDRS (r = −0.572, P = 0.041), while no correlation was found in TD (r = −0.339, P = 0.372). Data Conclusion Low BG GABA levels in PD patients, and differences between PIGD/TD patients, suggest that GABAergic dysfunction may play an important role in the pathogenesis of Parkinson's disease. Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

PURPOSE To investigate frequency-offset effects in edited magnetic resonance spectroscopy (MRS) experiments arising from B0 eddy currents. MATERIALS AND METHODS Macromolecule-suppressed (MM-suppressed) γ-aminobutyric acid (GABA)-edited experiments were performed at 3T. Saturation-offset series of MEGA-PRESS experiments were performed in phantoms, in order to investigate different aspects of the relationship between the effective editing frequencies and eddy currents associated with gradient pulses in the sequence. Difference integrals were quantified for each series, and the offset dependence of the integrals was analyzed to quantify the difference in frequency (Δf) between the actual vs. nominal expected saturation frequency. RESULTS Saturation-offset N-acetyl-aspartate-phantom experiments show that Δf varied with voxel orientation, ranging from 10.4 Hz (unrotated) to 6.4 Hz (45° rotation about the caudal-cranial axis) and 0.4 Hz (45° rotation about left-right axis), indicating that gradient-related B0 eddy currents vary with crusher-gradient orientation. Fixing the crusher-gradient coordinate-frame substantially reduced the orientation dependence of Δf (to ∼2 Hz). Water-suppression crusher gradients also introduced a frequency offset, with Δf = 0.6 Hz ("excitation" water suppression), compared to 10.2 Hz (no water suppression). In vivo spectra showed a negative edited "GABA" signal, suggesting Δf on the order of 10 Hz; with fixed crusher-gradient coordinate-frame, the expected positive edited "GABA" signal was observed. CONCLUSION Eddy currents associated with pulsed field gradients may have a considerable impact on highly frequency-selective spectral-editing experiments, such as MM-suppressed GABA editing at 3T. Careful selection of crusher gradient orientation may ameliorate these effects. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:673-681.

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.

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.

Background: Abnormal responses to tactile stimuli are a common feature of autism spectrum disorder (ASD). Several lines of evidence suggest that GABAergic function, which has a crucial role in tactile processing, is altered in ASD. In this study, we determine whether in vivo GABA levels are altered in children with ASD, and whether alterations in GABA levels are associated with abnormal tactile function in these children. Methods: GABA-edited magnetic resonance spectroscopy was acquired in 37 children with Autism and 35 typically developing children (TDC) from voxels over primary sensorimotor and occipital cortices. Children performed tactile tasks previously shown to be altered in ASD, linked to inhibitory mechanisms. Detection threshold was measured with- and without the presence of a slowly increasing sub-threshold stimulus. Amplitude discrimination was measured with- and without the presence of an adapting stimulus, and frequency discrimination was measured. Results: Sensorimotor GABA levels were significantly reduced in children with autism compared to healthy controls. Occipital GABA levels were normal. Sensorimotor GABA levels correlated with dynamic detection threshold as well as with the effect of sub-threshold stimulation. Sensorimotor GABA levels also correlated with amplitude discrimination after adaptation (an effect absent in autism) and frequency discrimination in controls, but not in children with autism. Conclusions: GABA levels correlate with behavioral measures of inhibition. Children with autism have reduced GABA, associated with abnormalities in tactile performance. We show here that altered in vivo GABA levels might predict abnormal tactile information processing in ASD and that the GABA system may be a future target for therapies. Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

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

Purpose To investigate the effects of B0 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 B0 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 B0 stabilization, such as that provided by IWR. J. Magn. Reson. Imaging 2016;44:1474–1482.

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 T2 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 T2 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.

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 0.5 for all regions). Corrected GABA values differ significantly based on the segmentation procedure used (P

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 “GABAþ”. 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 GABAþ 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 GABAþ and MM-suppressed GABA measures was then determined. Results: Across all data, a significant correlation between GABAþ and MM-suppressed GABA was found (r ¼0.48; P ¼0.02). Regionally, the sensorimotor voxel showed a trend toward a correlation of r ¼0.53, P ¼0.07 and the occipital voxel did not show a correlation, r ¼0.058, P ¼0.9. Conclusion: GABAþ 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 GABAþ and MM-suppressed GABA. Magn Reson Med 000:000–000, 2014. V C 2014 Wiley Periodicals, Inc.

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. Magn Reson Med 74:607–613, 2015. © 2014 Wiley Periodicals, Inc.

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 (1H-MRS). Materials and Methods Fifteen AD patients and fifteen age- and gender-matched healthy controls underwent 1H-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. J. Magn. Reson. Imaging 2015;41:1326–1331. © 2014 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 1H-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 1H-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.

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.

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.

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. J. Magn. Reson. Imaging 2013;38:460–467. © 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.

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. Magn Reson Med 70:1183–1191, 2013. © 2012 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

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.

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.

Objective Recent scientific findings have reinvigorated interest in examining the role of gamma-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 pressurepain 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 pressurepain 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. (Less)

Proton Magnetic Resonance spectroscopy (1H-MRS) is a useful technique to probe in vivo biochemical status noninvasively, which has been widely applied to study the brain in both clinical and neuroscience settings. If tissue water content is known, metabolite concentrations are often calculated from the relative intensities of metabolite and water signals (1), making appropriate corrections for longitudinal and transverse relaxation (characterized by the time constants T1 and T2, respectively). Thus, the measurement of metabolite relaxation parameters is an important prerequisite for absolute quantification of in vivo MR spectra. In vivo transverse relaxation times (T2) are usually measured by making localized single-voxel measurements at a range of echo times (TE). For singlet resonances, such as N-acetyl aspartate (NAA), creatine (Cr) and choline (Cho), the TE-dependent decay in signal intensity can generally be modeled by a single exponential with time constant T2; metabolite T2s have been measured in this way at a range of field strengths (2–7). The TE-dependence of coupled spin systems is more complicated, because their signals are modulated by both T2 relaxation and scalar coupling evolution. The in vivo T2 of the coupled metabolite glutamate has been measured by modeling the TE dependence of the Glutamate signal (8). However, for many coupled metabolites (such as γ-aminobutyric acid [GABA] (9), glutathione (10), ascorbate (11), and NAAG (12)), low signal amplitude and signal overlap hamper their detection in vivo using conventional MRS methods, and it is usual to use spectral editing methods to detect them reliably. To the best of our knowledge, no method has been published to date that is able to measure the in vivo T2 of metabolites detected using spectral editing techniques. There has been considerable recent interest in MRS measurements of the inhibitory neurotransmitter, GABA, investigating the role of GABA in disease, and the relationships between GABA and functional imaging (13–15) and behavior (16–19). However, although spectral editing methods have been extensively applied to investigate the individual and group differences in GABA levels, they have not been truly quantitative, as human in vivo relaxation parameters for GABA have not been previously measured. Relative measurements of this kind, often quantified in institutional units (i.u.), hamper inferences from separately published studies, both within and between centers. The most common method applied in these studies is J-difference editing (9), often implemented through the MEGA-PRESS technique (20), detecting GABA signals at an intermediate TE (~70 ms). Because this TE is of similar length to typical metabolite T2s (and therefore the anticipated T2 of GABA), measuring the in vivo T2 of GABA is an important step in making these measurements quantitative. It is also known that the “GABA” signal detected at 3.0 ppm using standard J-difference techniques at 3 Tesla (T) contains an appreciable contribution from macromolecules (MM) which has a coupling partner at 1.7 ppm (20). The presence of this MM resonance needs to be accounted for, both for the determination of GABA T2 and for the estimation of “pure” GABA concentrations. In this study, we present a framework for the determination of the in vivo T2 of edited metabolites, that is entirely experimental and does not rely upon simulation, and demonstrate the method to measure the in vivo T2 of GABA at 3T.

It has previously been demonstrated that there is a negative correlation between the ampli- tude of the BOLD response and resting c 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 ¼ 15, aged 20-28 years). The results demonstrate that GABA concentration is negatively correlated with BOLD response amplitude (r ¼� 0.64, P < 0.02) and posi- tively correlated with HRF width (r ¼ 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 cer- ebral 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 character- istics may also make a significant contribution. Our results reinforce the view that variability in endog- enous 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. Hum Brain Mapp 00:000-000, 2011. V C 2011 Wiley-Liss, Inc.

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.

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.

Purpose:To establish the diurnal stability of edited magnetic resonance spectroscopy measurements of gamma-aminobutyric acid (GABA) in visual and sensorimotor regions of the brain. Materials and Methods:GABA measurements were made in two regions of the brain (an occipital, “visual” region and a “sensorimotor” region centered on the precentral gyrus) using the MEGA-PRESS editing method, scanning eight healthy adults at five timepoints during a single day. GABA concentration was quantified from the ratio of the GABA integral to the unsuppressed water signal. Results:No significant effect of time on GABA concentration was seen (P = 0.35). GABA was shown to be significantly more concentrated in visual regions than in sensorimotor regions (1.10 i.u. and 1.03 i.u., respectively; P = 0.050). Coefficients of variability (CVs) across all subjects of 9.1% and 12% (visual and sensorimotor) were significantly higher than mean within-subjects CVs of 6.5% and 8.8. Conclusion:This study demonstrates the excellent reproducibility of MEGA-PRESS detection of GABA, demonstrating that the method is sufficiently sensitive to detect inter-subject variability, and suggests that (within the sensitivity limits of current measurements) time of day can be ignored in the design of MRS studies of visual and sensorimotor regions.

T1 and T2 were measured for white matter (WM) and gray matter (GM) in the human cervical spinal cord at 3T. T1 values were calculated using an inversion-recovery (IR) and B1-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 T2 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. Magn Reson Med 60:213–219, 2008. © 2008 Wiley-Liss, Inc.

Vascular space occupancy (VASO)-dependent functional MRI (fMRI) is a blood-nulling technique capable of generating microvascular cerebral blood volume (CBV)-weighted images. It is shown that at high magnetic field (3.0T) and high spatial resolution (1.89 × 1.89 × 3 mm3), the VASO signal changes are too large (6–7%) to originate from CBV effects alone. Additional contributions are investigated theoretically and experimentally as a function of MRI parameters (TR and TE), as well as the signal-to-noise ratio, (SNR) and spatial resolution. First, it is found that an arterial spin labeling (ASL) contribution causes large negative VASO signal changes at short TR. Second, even at high fMRI spatial resolution, CSF volume contributions (7–13%) cause VASO signal changes to become more negative, most noticeably at long TR and TE. Third, white matter (WM) effects reduce signal changes at lower spatial resolution. The VASO technique has been tested using different stimulus paradigms and field strengths (1–3), giving results consistent with comparable tasks investigated using BOLD and cerebral blood flow (CBF)-based techniques. Finally, simulations show that a mixture of fresh and steady-state blood may significantly alter signal changes at short TR (≤3 s), permitting larger VASO signal changes than expected under pure steady-state conditions. Thus, many competing effects contribute to VASO contrast and care should be taken during interpretation. Magn Reson Med, 2006. © 2006 Wiley-Liss, Inc.

Two spectral editing techniques for the simultaneous detection of glutathione (GSH) and lactate (Lac) in the human brain at 3 T are described and evaluated. These methods, ‘sMEGA’ (sinc-MEscher and GArwood) and ‘DEW’ (Double Editing With), were optimized to detect GSH and Lac simultaneously at 3 T using density-matrix simulations and validation in phantoms. Simulations to test for co-edited metabolites within the detected GSH region of the spectrum were also performed. In vivo data were acquired in the midline parietal region of seven subjects using both methods, and compared with conventional MEGA-PRESS (MEscher and GArwood-Point RESolved Spectroscopy) acquisitions of GSH and Lac. Simulations and phantom experiments showed that sMEGA and DEW had a high editing efficiency for both GSH and Lac. In the phantom, the editing efficiency of GSH was >88% relative to a conventional GSH MEGA-PRESS acquisition, whereas, for Lac, the editing efficiency was >95% relative to a conventional Lac MEGA-PRESS acquisition. Simulations also showed that the editing efficiency of both methods was comparable with separate MEGA-PRESS acquisitions of the same metabolites. In addition, simulations and in vivo spectra showed that, at a TE of 140 ms, there was a partial overlap between creatine (Cr) and GSH peaks, and that N-acetyl aspartate/N-acetyl aspartyl glutamate (NAA/NAAG) were sufficiently resolved from GSH. In vivo measurements showed that both sMEGA and DEW edited GSH and Lac reliably with the same editing efficiency as conventional MEGA-PRESS acquisitions of the same metabolites, with measured GSH integrals of 2.23 ± 0.51, 2.31 ± 0.38, 2.38 ± 0.53 and measured Lac integrals of 1.72 ± 0.67, 1.55 ± 0.35 and 1.53 ± 0.54 for MEGA-PRESS, DEW and sMEGA, respectively. Simultaneous detection of GSH and Lac using sMEGA and DEW is possible at 3 T with high editing efficiency.

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.

This paper describes a number of improvements to a method, developed in this laboratory and described in J. Magn. Reson. 85 (1989) 111–113, which makes it possible to determine values of long-range 13C–1H coupling constants from heteronuclear multiple bond correlation (HMBC) spectra. First, it is shown how pulsed-field gradients can be introduced into the HMBC experiment without perturbing the form of the cross-peak multiplets; a one-dimensional version of the experiment is also described which permits the rapid measurement of a small number of couplings. Second, the experiment is modified so that one-bond and long-range cross-peaks can be separated, and so that the one-bond cross-peaks have more reliable intensities. Finally, it is shown how these one-bond cross-peaks can be used to advantage in the fitting procedure.