In vivo detection of GABA in human brain using a localized double-quantum filter technique

A proton MR spectral editing technique employing a spatially localized, double-quantum filter (DQF) was used to measure γ-aminobutyric acid (GABA) in the human brain at 1.5 T. The double-quantum method provided robust, single-shot suppression of uncoupled resonances from choline, creatine, and NAA and allowed detection of the γCH₂ GABA (3.0 ppm) resonance with 30% efficiency. Spatial localization of the GABA measurement was achieved by incorporating PRESS localization within the double-quantum excitation and detection sequence. A calibration technique was developed to adjust the relative phases of the RF pulses to maximize the in vivo double-quantum detection efficiency for an arbitrary voxel location. The sequence efficiency, degree of suppression of uncoupled resonances, and characterization of the in vivo DQF technique was examined in phantom experiments and in a study of the occipital lobe of 10 normal subjects. The ratio of the 3.0-ppm GABA resonance to the 3.0-ppm creatine resonance was found to be 0.20 ± 0.05 (SD).     

In vivo GABA+ measurement at 1.5T using a PRESS-localized double quantum filter.

A point-resolved spectroscopy (PRESS)-localized double quantum filter was implemented on a 1.5T clinical scanner for the estimation of gamma-amino butyric acid (GABA) concentrations in vivo. Several calibrations were found to be necessary for consistent results to be obtained. The apparent filter yield was approximately 38%; filter strength was sufficient to reduce the singlet metabolite peaks in vivo to below the level of the noise. Metabolite-nulled experiments were performed, which confirmed that significant overlap occurred between macromolecule signals and the GABA resonance at 3.1 ppm. Although the multiplet arm at 2.9 ppm was confirmed to be relatively free of contamination with macromolecules, some contribution from these and from peptides is likely to remain; therefore, the term GABA+ is used. GABA+ concentrations were estimated relative to creatine (Cr) at the same echo time (TE) in a group of controls, studied on two occasions. The GABA+ concentration in 35-ml regions of interest (ROIs) in the occipital lobe was found to be 1.4 +/- 0.2 mM, with scan-rescan repeatability of 38%.     

Brain gamma-aminobutyric acid measurement by proton double-quantum filtering with selective J rewinding.

An optimized single-shot proton double-quantum (DQ) filter for the quantification of gamma-aminobutyric acid (GABA) levels in human brain is reported. It is demonstrated that creation of DQ coherences following dual-resonance-selective refocusing gives a theoretical editing efficiency of 50% for the detection of the GABA resonance at 3.01 ppm. The sequence times are optimized with both numerical and experimental analyses of the editing performance, giving an experimental editing efficiency of 42%. It is acknowledged that homocarnosine is partially coedited, leading to a 20% contribution to the edited signal; however, macromolecule contamination is negligible in vivo under these experimental conditions. The GABA concentration in human prefrontal cortex is estimated to be 0.8 +/- 0.1 micromol/g (mean +/- SD, n = 6), with reference to the internal standard creatine at 9 micromol/g.     

Measurement of GABA and contaminants in gray and white matter in human brain in vivo.

A preliminary study of discrimination between GABA and macromolecules (MMs) in human brain by proton double quantum filtering (DQF) at 3.0 T in vivo is presented. GABA-tuned and MM-tuned DQ filters were designed with dual-band 180 degrees radiofrequency (RF) pulses that were tuned for selective refocusing of GABA (3.0 and 1.9 ppm) and putative MM resonances (3.0 and 1.7 ppm), respectively. GABA and putative MM signals were extracted from a combined analysis of the filtered mixture signals and the calculated editing yields. Unexpectedly, the GABA and putative MM signals exhibited a similar doublet linewidth at the optimized TE = 82 ms. Furthermore, substantial MM-tuned DQF signal remained at TE = 148 ms, indicating the presence of a component other than MM. With water segmentation data, the GABA-tuned and MM-tuned DQF measures from the medial prefrontal and left frontal lobes were combined to give the concentrations of GABA and the additional component as 1.1 +/- 0.1 and 0.8 +/- 0.1 mM (mean +/- SD, N=3) for gray matter (GM) and 0.4 +/- 0.1 and 0.7+/-0.1 mM (N=3) for white matter (WM), respectively.     

In vivo prostate magnetic resonance spectroscopic imaging using two-dimensional J-resolved PRESS at 3 T.

In vivo magnetic resonance spectroscopic imaging of the prostate using single-voxel and multivoxel two-dimensional (2D) J-resolved sequences is investigated at a main magnetic field strength of 3 T. Citrate, an important metabolite often used to aid the detection of prostate cancer in magnetic resonance spectroscopic exams, can be reliably detected along with the other metabolites using this method. We show simulations and measurements of the citrate metabolite using 2D J-resolved spectroscopy to characterize the spectral pattern. Furthermore, using spiral readout gradients, the single-voxel 2D J-resolved method is extended to provide the spatial distribution information as well all within a reasonable scan time (17 min). Phantom and in vivo data are presented to illustrate the multivoxel 2D J-resolved spiral chemical shift imaging sequence.     

Ultrafast 2D NMR spectroscopy using sinusoidal gradients: principles and ex vivo brain investigations.

A new methodology capable of delivering complete 2D NMR spectra within a single scan was recently introduced. The resulting potential gain in time resolution could open new opportunities for in vivo spectroscopy, provided that the technical demands of the methodology are satisfied by the corresponding hardware. Foremost among these demands are the relatively short switching times expected from the applied gradient-echo trains. These rapid transitions may be particularly difficult to accomplish on imaging systems. As a step toward solving this problem, we assessed the possibility of replacing the square-wave gradient train currently used during the course of the acquisition by a shaped sinusoidal gradient. Examples of the implementation of this protocol are given, and successful ultrafast acquisitions of 2D NMR spectra with suitable spectral widths on a microimaging probe (for both phantom solutions and ex vivo mouse brains) are demonstrated.     

In vivo GABA editing using a novel doubly selective multiple quantum filter.

A novel multiple quantum filtering method is proposed that uses a doubly selective pulse termed Delays Alternating with Nutations for Tailored Excitation (DANTE) for multiple quantum preparation. This method selectively prepares GABA-3 and GABA-4 into a multiple quantum state and suppresses all other resonances at 3.0 ppm in each single scan. Phantom tests demonstrated excellent GABA signal retention and complete suppression of overlapping metabolites. It is shown using numerical simulations that overlapping macromolecules are suppressed because the frequency of the first upfield 2pi rotation of the doubly selective DANTE pulse coincides with that of the macromolecules at 1.72 ppm. Excellent suppression of overlapping macromolecules was demonstrated in vivo. Using this method the concentration of GABA in the occipital lobe of healthy volunteers was measured to be 1.21 +/- 0.28 micromol/mL (mean +/-SD, N = 9).     

MRS定量测量急性缺氧缺血脑损伤猪脑代谢物研究

目的 评价外标准法MRS结合LCModel软件绝对定量测量急性缺氧缺血脑损伤猪脑N-乙酰天冬氨酸(NAA)、肌酸(Cr)和乳酸(Lac)浓度变化的价值.方法 8头7日龄健康猪麻醉后未作任何处理(正常组),麻醉清醒后1 d制成缺氧缺血性脑病(HIE)模型(HIE组),先后与内含已知浓度物质的外标准模型一起行1H-MRS检查,数据采集完毕后用LCModel软件定量分析测量NAA、Cr、Lac浓度,HIE前、后猪脑代谢物NAA、Cr、Lac间比较采用多元方差分析,并对2头HIE猪缺氧缺血0、2 h脑代谢物动态变化情况作初步观察.结果 l头猪因麻醉过深死亡而剔除,最后统计数据为7头.小猪急性缺氧缺血前脑NAA、Cr、Lac分别为(6.86±0.49)、(4.65±0.73)、0.00 mmol/kg,缺氧缺血后即刻脑NAA、Cr、Lac分别为(5.73±0.88)、(4.40±0.80)、(0.43±0.39)mmol/kg.急性缺氧缺血后即刻猪脑NAA浓度下降,差异有统计学意义(F=8.608,P=0.013);Cr浓度有所下降,但差异无统计学意义(F=0.379,P=0.550);Lac浓度升高,差异有统计学意义(F=8.600,P=0.013).初步观察脑代谢物动态变化见HIE后即刻出现Lac峰,2 h Lac峰下降.结论 外标准法MRS结合LCModel定量分析软件能方便准确地定量测量脑内代谢物,NAA与Lac浓度的改变均能敏感地反映急性缺氧缺血脑损伤早期改变,且以NAA浓度的改变稍敏感.     

Enhanced T2 contrast for MR histology of the mouse brain.

A 3D Carr-Purcell-Meiboom-Gill (CPMG) sequence was implemented to obtain enhanced T(2) contrast in actively stained (perfusion with fixative and contrast agent) mouse brains at 9.4 T. Short interecho spacing was used to minimize diffusion and susceptibility losses. The sequence produced 16 3D volumes with an interecho spacing of 7 ms for isotropic 43-mu-resolution images of the mouse brains in a scan time of 4 hr. To enhance the signal-to-noise ratio (SNR) and contrast, the multiecho frequency domain image contrast (MEFIC) method was applied, resulting in a composite image with T(2)-weighted contrast. The high SNR and contrast thus achieved revealed aspects of mouse brain morphology, such as multiple cortical layers, groups of thalamic nuclei, layers of the inferior and superior colliculus, and molecular and granular layers of the cerebellum, with a high degree of definition and contrast that was not previously achieved in T(2)-weighted acquisitions at high fields.     

Measurement of GABA following GABA-transaminase inhibition by gabaculine: A 1H and 31P NMR spectroscopic study of rat brain in vivo

A selective ¹H NMR spin-echo editing method was used to detect the CCH, of GABA in rat brain in vivo before and after intravenous administration of the highly selective GABA transaminase inhibitor, gabaculine (3-amino-2,3-dihydrobenzoic acid-HCl; 100 mg/kg, intravenously). The effects of the inhibitor on high energy phosphates and pH, were determined by ³¹P NMR. GABA levels increased approximately linearly (r = 0.81 to 0.94; P < 0.0005) from 1.9 ± 0.4 μmol/g (pre-gabaculine; mean ± SD) to between 6 and 8 μmollg after 4 hr at rates of accumulation of 1.1 to 2.9 μmol/hr/g. ¹H NMR spectroscopic measurements of cerebral GABA and its rate of turnover offers a new approach in the study of GABA-mediated processes in vivo.     

Single-shot two-echo technique for simultaneous measurement of GABA and creatine in the human brain in vivo.

A single-shot, two-echo method for the simultaneous detection of multiple-quantum (MQ)-filtered gamma-aminobutyric acid (GABA) and creatine (Cr) was developed and demonstrated in the human brain in vivo at 3 Tesla. The simultaneously measured Cr singlet served as a navigator for the spectral phase of GABA and any frequency shift during measurements due to drift in the static magnetic field (B(0)) or subject movement, as well as an internal concentration reference. In addition, the use of a double-band frequency-selective MQ filter for C(3) and C(4) methylene protons of GABA provided a very robust measurement of GABA, with excellent suppression of overlapping metabolites such as Cr and glutathione (GSH) in each single scan. Contamination from overlapping macromolecules was also demonstrated to be negligible with this method. The GABA-to-Cr ratio was 0.09 +/- 0.03 (mean +/- SD, N = 17) and the estimated concentration of GABA in the frontoparietal region of the human brain in vivo was 0.66 +/- 0.19 micromol/g (mean +/- SD, N = 17) with the internal reference method, and 0.69 +/- 0.18 micromol/g (mean +/- SD, N = 17) with the external reference method. The observed pattern of GABA doublet was consistent among all subjects, with a frequency separation of approximately 13 Hz.     

Localized two-dimensional shift correlated MR spectroscopy of human brain.

A two-dimensional (2D) chemical shift correlated MR spectroscopic (COSY) sequence integrated into a new volume localization technique (90 degrees -180 degrees -90 degrees ) is proposed for whole-body MR spectroscopy (MRS). Using the product operator formalism, a theoretical calculation of the volume localization as well as the coherence transfer efficiencies in 2D MRS is presented. Phantom model solutions were used to test and optimize the efficiency of the proposed sequence. A combination of different MRI transmit/receive RF coils was used: a head MRI coil and a 3" surface coil receive combined with a body coil transmit. The J cross-peaks due to N-acetyl aspartate (NAA), glutamate/glutamine (Glx), myo-inositol (mI), creatine (Cr), choline (Ch), aspartate (Asp), gamma-aminobutyrate (GABA), taurine (Tau), glutathione (GSH), threonine (Thr), and macromolecules (MM) were identified. The cross-peak intensities excited by the proposed 2D sequence were asymmetric with respect to the diagonal peaks. Localized COSY (L-COSY) spectra of cerebral prefrontal and occipital gray/white matter regions in 15 healthy controls are presented. Magn Reson Med 46:58-67, 2001.     

Optimization of blood oxygenation level-dependent sensitivity in magnetic resonance imaging using intermolecular double-quantum coherence

PURPOSE: To optimize timing parameters in an intermolecular double-quantum coherence (iDQC) imaging pulse sequence for overall image signal-to-noise ratio (SNR) and blood oxygenation level-dependent (BOLD) sensitivity for brain functional imaging. MATERIAL AND METHODS: Fresh human blood was measured under different oxygenation conditions, and human brain functional magnetic resonance (fMR) images in three normal volunteers were obtained, using iDQC techniques at 1.5 T. The dependence of SNR and BOLD sensitivity was measured as a function of time delays after the iDQC evolution period. RESULTS: A time delay after the iDQC evolution period tau can be adjusted either to refocus the dephasing accumulated during tau, thus increasing SNR, with full rephasing occurring at delay = +/-2tau (for iDQC order n = +/-2), or to enhance BOLD effects with consequent reduced image SNR at delay = 0. CONCLUSION: Image SNR and BOLD sensitivity often impose different requirements for iDQC image sequence design and timing parameter selections. It is therefore important to select properly relevant parameters for different applications.     

Spatial effects in the detection of gamma-aminobutyric acid: improved sensitivity at high fields using inner volume saturation.

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.     

In vivo spatially localized high resolution 1H MRS via intermolecular single‐quantum coherence of rat brain at 7 T

Purpose:

To compare the conventional localized point‐resolved spectroscopy (PRESS) with localized 2D intermolecular single‐quantum coherence (iSQC) magnetic resonance spectroscopy (MRS) and obtain in vivo MRS spectrum of rat brain using the latter technique.

Materials and Methods:

A brain phantom, an intact pig brain tissue, and mature Sprague–Dawley rat were studied by PRESS, Nano magic‐angle spinning spectroscopy, and iSQC MRS.

Results:

Using PRESS, high‐resolution MRS can be obtained from the brain phantom and pig brain tissue with a small voxel in a relatively homogeneous field. When a large voxel is selected, the field homogeneity is distinctly reduced. No useful information is obtained from the PRESS spectra. However, using the iSQC MRS, high‐resolution spectra can be obtained from the two samples with a relatively large voxel. In the same way, an iSQC MRS spectrum can be obtained from a relatively large voxel of in vivo rat brain with a comparable resolution to the PRESS spectrum with a small voxel.

Conclusion:

Compared to PRESS, the iSQC MRS may be more feasible and promising for detection of strongly structured tissues with relatively large voxels. J. Magn. Reson. Imaging 2013;37:359–364. © 2012 Wiley Periodicals, Inc.     

Observation and identification of metabolites emerging during postmortem decomposition of brain tissue by means of in situ 1H-magnetic resonance spectroscopy.

Postmortem decomposition of brain tissue was investigated by (1)H-magnetic resonance spectroscopy (MRS) in a sheep head model and selected human cases. Aiming at the eventual estimation of postmortem intervals in forensic medicine, this study focuses on the characterization and identification of newly observed metabolites. In situ single-voxel (1)H-MRS at 1.5 T was complemented by multidimensional homo- and heteronuclear high-resolution NMR spectroscopy of an extract of sheep brain tissue. The inclusion of spectra of model solutions in the program LC Model confirmed the assignments in situ. The first postmortem phase was characterized mainly by changes in the concentrations of metabolites usually observed in vivo and by the appearance of previously reported decay products. About 3 days postmortem, new metabolites, including free trimethylammonium, propionate, butyrate, and iso-butyrate, started to appear in situ. Since the observed metabolites and the time course is comparable in sheep and human brain tissue, the model system seems to be appropriate.     

In vivo measurement of regional brain metabolic response to hyperventilation using magnetic resonance: Proton echo planar spectroscopic imaging (PEPSI)

A new rapid spectroscopic imaging technique with improved sensitivity and lipid suppression, referred to as Proton Echo Planar Spectroscopic Imaging (PEPSI), has been developed to measure the 2-dimensional distribution of brain lactate increases during hyperventilation on a conventional clincal scanner equipped with a head surface coil phased array. PEPSI images (nominal voxel size: 1.125 cm³) in five healthy subjects from an axial section approximately 20 mm inferior to the intercommissural line were obtained during an 8.5-min baseline period of normocapnia and during the final 8.5 min of a 10-min period of capnometry-controlled hyperventilation (end-tidal PCO₂ of 20 mmHg). The lactate/N-acetyl aspartate signal increased significantly from baseline during hyperventilation for the insular cortex, temporal cortex, and occipital regions of both the right and left hemispheres, but not in the basal ganglia. Regional or hemispheric right-to-left differences were not found. The study extends previous work using single-voxel MR spectroscopy to dynamically study hyperventilation effects on brain metabolism.