Improved resolution of glutamate,glutamine and γ‐aminobutyric acid with optimized point‐resolved spectroscopy sequence timings for their simultaneous quantification at 9.4 T

Glutamine (Gln), glutamate (Glu) and γ‐aminobutyric acid (GABA) are relevant brain metabolites that can be measured with magnetic resonance spectroscopy (MRS). This work optimizes the point‐resolved spectroscopy (PRESS) sequence echo times, TE₁ and TE₂, for improved simultaneous quantification of the three metabolites at 9.4 T. Quantification was based on the proton resonances of Gln, Glu and GABA at ≈2.45, ≈2.35 and ≈2.28 ppm, respectively. Glu exhibits overlap with both Gln and GABA; in addition, the Gln peak is contaminated by signal from the strongly coupled protons of N‐acetylaspartate (NAA), which resonate at about 2.49 ppm. J‐coupling evolution of the protons was characterized numerically and verified experimentally. A {TE₁, TE₂} combination of {106 ms, 16 ms} minimized the NAA signal in the Gln spectral region, whilst retaining Gln, Glu and GABA peaks. The efficacy of the technique was verified on phantom solutions and on rat brain in vivo. LCModel was employed to analyze the in vivo spectra. The average T₂‐corrected Gln, Glu and GABA concentrations were found to be 3.39, 11.43 and 2.20 mM, respectively, assuming a total creatine concentration of 8.5 mM. LCModel Cramér–Rao lower bounds (CRLBs) for Gln, Glu and GABA were in the ranges 14–17%, 4–6% and 16–19%, respectively. The optimal TE resulted in concentrations for Gln and GABA that agreed more closely with literature concentrations compared with concentrations obtained from short‐TE spectra acquired with a {TE₁, TE₂} combination of {12 ms, 9 ms}. LCModel estimations were also evaluated with short‐TE PRESS and with the optimized long TE of {106 ms, 16 ms}, using phantom solutions of known metabolite concentrations. It was shown that concentrations estimated with LCModel can be inaccurate when combined with short‐TE PRESS, where there is peak overlap, even when low (<20%) CRLBs are reported.     

Covariance J‐resolved spectroscopy: Theory and application in vivo

Magnetic resonance spectroscopy (MRS) is a powerful tool capable of investigating the metabolic status of several tissues in vivo. In particular, single‐voxel‐based ¹H spectroscopy provides invaluable biochemical information from a volume of interest (VOI) and has therefore been used in a variety of studies. Unfortunately, typical one‐dimensional MRS data suffer from severe signal overlap and thus important metabolites are difficult to distinguish. One method that is used to disentangle overlapping resonances is the two‐dimensional J‐resolved spectroscopy (JPRESS) experiment. Due to the long acquisition duration of the JPRESS experiment, a limited number of points are acquired in the indirect dimension, leading to poor spectral resolution along this dimension. Poor spectral resolution is problematic because proper peak assignment may be hindered, which is why the zero‐filling method is often used to improve resolution as a post‐processing step. However, zero‐filling leads to spectral artifacts, which may affect visualization and quantitation of spectra. A novel method utilizing a covariance transformation, called covariance J‐resolved spectroscopy (CovJ), was developed in order to improve spectral resolution along the indirect dimension (F₁). Comparison of simulated data demonstrates that peak structures remain qualitatively similar between JPRESS and the novel method along the diagonal region (F₁ = 0 Hz), whereas differences arise in the cross‐peak (F₁≠0 Hz) regions. In addition, quantitative results of in vivo JPRESS data acquired on a 3T scanner show significant correlations (r²>0.86, p<0.001) when comparing the metabolite concentrations between the two methods. Finally, a quantitation algorithm, ‘COVariance Spectral Evaluation of ¹H Acquisitions using Representative prior knowledge’ (Cov‐SEHAR), was developed in order to quantify γ‐aminobutyric acid and glutamate from the CovJ spectra. These preliminary findings indicate that the CovJ method may be used to improve spectral resolution without hindering metabolite quantitation for J‐resolved spectra.     

Measurement of regional variation of GABA in the human brain by optimized point‐resolved spectroscopy at 7 T in vivo

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

Improvement of resolution for brain coupled metabolites by optimized (1)H MRS at 7T

Resolution enhancement for glutamate (Glu), glutamine (Gln) and glutathione (GSH) in the human brain by TE‐optimized point‐resolved spectroscopy (PRESS) at 7 T is reported. Sub‐TE dependences of the multiplets of Glu, Gln, GSH, γ‐aminobutyric acid (GABA) and N‐acetylaspartate (NAA) at 2.2–2.6 ppm were investigated with density matrix simulations, incorporating three‐dimensional volume localization. The numerical simulations indicated that the C4‐proton multiplets can be completely separated with (TE₁, TE₂) = (37, 63) ms, as a result of a narrowing of the multiplets and suppression of the NAA 2.5 ppm signal. Phantom experiments reproduced the signal yield and lineshape from simulations within experimental errors. In vivo tests of optimized PRESS were conducted on the prefrontal cortex of six healthy volunteers. In spectral fitting by LCModel, Cramér–Rao lower bounds (CRLBs) of Glu, Gln and GSH were 2 ± 1, 5 ± 1 and 6 ± 2 (mean ± SD), respectively. To evaluate the performance of the optimized PRESS method under identical experimental conditions, stimulated‐echo spectra were acquired with (TE, TM) = (14, 37) and (74, 68) ms. The CRLB of Glu was similar between PRESS and short‐TE stimulated‐echo acquisition mode (STEAM), but the CRLBs of Gln and GSH were lower in PRESS than in both STEAM acquisitions. Copyright © 2010 John Wiley & Sons, Ltd.     

Quantification of glutamate and glutamine using constant‐time point‐resolved spectroscopy at 3 T

Separate quantification of glutamate (Glu) and glutamine (Gln) using conventional MRS on clinical scanners is challenging. In previous work, constant‐time point‐resolved spectroscopy (CT‐PRESS) was optimized at 3 T to detect Glu, but did not resolve Gln. To quantify Glu and Gln, a time‐domain basis set was constructed taking into account metabolite T₂ relaxation times and dephasing from B₀ inhomogeneity. Metabolite concentrations were estimated by fitting the basis one‐dimensional CT‐PRESS diagonal magnitude spectra to the measured spectrum. This method was first validated using seven custom‐built phantoms containing variable metabolite concentrations, and then applied to in vivo data acquired in rats exposed to vaporized ethanol and controls. Separate metabolite quantification revealed increased Gln after 16 weeks and increased Glu after 24 weeks of vaporized ethanol exposure in ethanol‐treated compared with control rats. Without separate quantification, the signal from the combined resonances of Glu and Gln (Glx) showed an increase at both 16 and 24 weeks in ethanol‐exposed rats, precluding the determination of the independent and differential contribution of each metabolite at each time. Copyright © 2012 John Wiley & Sons, Ltd.     

Accelerated echo planar J‐resolved spectroscopic imaging in prostate cancer: a pilot validation of non‐linear reconstruction using total variation and maximum entropy

The overlap of metabolites is a major limitation in one‐dimensional (1D) spectral‐based single‐voxel MRS and multivoxel‐based MRSI. By combining echo planar spectroscopic imaging (EPSI) with a two‐dimensional (2D) J‐resolved spectroscopic (JPRESS) sequence, 2D spectra can be recorded in multiple locations in a single slice of prostate using four‐dimensional (4D) echo planar J‐resolved spectroscopic imaging (EP‐JRESI). The goal of the present work was to validate two different non‐linear reconstruction methods independently using compressed sensing‐based 4D EP‐JRESI in prostate cancer (PCa): maximum entropy (MaxEnt) and total variation (TV). Twenty‐two patients with PCa with a mean age of 63.8 years (range, 46–79 years) were investigated in this study. A 4D non‐uniformly undersampled (NUS) EP‐JRESI sequence was implemented on a Siemens 3‐T MRI scanner. The NUS data were reconstructed using two non‐linear reconstruction methods, namely MaxEnt and TV. Using both TV and MaxEnt reconstruction methods, the following observations were made in cancerous compared with non‐cancerous locations: (i) higher mean (choline + creatine)/citrate metabolite ratios; (ii) increased levels of (choline + creatine)/spermine and (choline + creatine)/myo‐inositol; and (iii) decreased levels of (choline + creatine)/(glutamine + glutamate). We have shown that it is possible to accelerate the 4D EP‐JRESI sequence by four times and that the data can be reliably reconstructed using the TV and MaxEnt methods. The total acquisition duration was less than 13 min and we were able to detect and quantify several metabolites. Copyright © 2015 John Wiley & Sons, Ltd.     

Quantification of GABA,glutamate and glutamine in a single measurement at 3 T using GABA‐edited MEGA‐PRESS

γ‐Aminobutyric acid (GABA) and glutamate (Glu), major neurotransmitters in the brain, are recycled through glutamine (Gln). All three metabolites can be measured by magnetic resonance spectroscopy in vivo, although GABA measurement at 3 T requires an extra editing acquisition, such as Mescher–Garwood point‐resolved spectroscopy (MEGA‐PRESS). In a GABA‐edited MEGA‐PRESS spectrum, Glu and Gln co‐edit with GABA, providing the possibility to measure all three in one acquisition. In this study, we investigated the reliability of the composite Glu + Gln (Glx) peak estimation and the possibility of Glu and Gln separation in GABA‐edited MEGA‐PRESS spectra. The data acquired in vivo were used to develop a quality assessment framework which identified MEGA‐PRESS spectra in which Glu and Gln could be estimated reliably. Phantoms containing Glu, Gln, GABA and N‐acetylaspartate (NAA) at different concentrations were scanned using GABA‐edited MEGA‐PRESS at 3 T. Fifty‐six sets of spectra in five brain regions were acquired from 36 healthy volunteers. Based on the Glu/Gln ratio, data were classified as either within or outside the physiological range. A peak‐by‐peak quality assessment was performed on all data to investigate whether quality metrics can discriminate between these two classes of spectra. The quality metrics were as follows: the GABA signal‐to‐noise ratio, the NAA linewidth and the Glx Cramer–Rao lower bound (CRLB). The Glu and Gln concentrations were estimated with precision across all phantoms with a linear relationship between the measured and true concentrations: R¹ = 0.95 for Glu and R¹ = 0.91 for Gln. A quality assessment framework was set based on the criteria necessary for a good GABA‐edited MEGA‐PRESS spectrum. Simultaneous criteria of NAA linewidth <8 Hz and Glx CRLB <16% were defined as optimum features for reliable Glu and Gln quantification. Glu and Gln can be reliably quantified from GABA‐edited MEGA‐PRESS acquisitions. However, this reliability should be controlled using the quality assessment methods suggested in this work.     

In vivo and ex vivo evidence for ketamine-induced hyperglutamatergic activity in the cerebral cortex of the rat: Potential relevance to schizophrenia

Subanesthetic doses of ketamine, a noncompetitive N‐methyl‐D ‐aspartate (NMDA) receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in patients with schizophrenia. In the present study, in vivo ¹H‐MRS and ex vivo ¹H high‐resolution magic angle spinning (HR‐MAS) spectroscopy was used to examine the brain metabolism of rats treated with subanesthetic doses of ketamine (30 mg/kg) for 6 days. A single voxel localization sequence (PRESS, TR/TE = 4000/20 ms and NEX = 512) was used to acquire the spectra in a 30‐µl voxel positioned in the cerebral cortex (including mainly PFC) of the rats (ketamine group: n = 12; saline group: n = 12) anesthetized with isoflurane. After the in vivo ¹H‐MRS acquisition, the animals were sacrificed and the cerebral cortex tissues were extracted (ketamine group: n = 7; saline group: n = 7) for ex vivo ¹H HR‐MAS spectroscopy (CPMG sequence, 2.0‐s presaturation delay, 2.0‐s acquisition time, 128 transients and 4‐ms inter‐pulse delay) using a 500‐MHz NMR spectrometer. All proton metabolites were quantified using the LCModel. For the in vivo spectra, there was a significant increase in glutamate concentration in the cerebral cortex of the ketamine group compared with the controls (p < 0.05). For the ex vivo HR‐MAS spectra, there was a significant increase in the glutamate/total creatine ratio, and a decrease in the glutamine/total creatine and glutamine/glutamate ratios in the cerebral cortex tissue of the ketamine group compared with the controls. The results of the present study demonstrated that administration of subanesthetic doses of ketamine in the rat may exert at least part of their effect in the cerebral cortex by activation of glutamatergic neurotransmission. Copyright © 2011 John Wiley & Sons, Ltd.     

J‐refocused 1H PRESS DEPT for localized 13C MR Spectroscopy

Proton point‐resolved spectroscopy (PRESS) localization has been combined with distortionless enhanced polarization transfer (DEPT) in multinuclear MRS to overcome the signal contamination problem in image‐selected in vivo spectroscopy (ISIS)‐combined DEPT, especially for lipid detection. However, homonuclear proton scalar couplings reduce the DEPT enhancement by modifying the spin coherence distribution under J modulation during proton PRESS localization. Herein, a J‐refocused proton PRESS‐localized DEPT sequence is presented to obtain simultaneously enhanced and localized signals from a large number of metabolites by in vivo ¹³C MRS. The suppression of J modulation during PRESS and the substantial recovery of signal enhancement by J‐refocused PRESS‐localized DEPT were demonstrated theoretically by product operator formalism, numerically by the spin density matrix simulations for different scalar coupling conditions, and experimentally with a glutamate phantom at various TEs, as well as a colza oil phantom. The application of the sequence for localized detection of saturated and unsaturated fatty acids in the calf bone marrow and skeletal muscle of healthy subjects yielded high signal enhancements simultaneously obtained for all components. Copyright © 2013 John Wiley & Sons, Ltd.     

Characterization of the response of taurine protons to PRESS at 9.4 T for Resolving choline and Determining taurine T2

Point‐resolved spectroscopy (PRESS), characterized by two TEs (TE₁ and TE₂), can be employed to perform animal magnetic resonance spectroscopy (MRS) studies at 9.4 T. Taurine (Tau) and choline (Cho) are relevant metabolites that can be measured by MRS. In this work, the response of the J‐coupled protons of Tau as a function of PRESS TE₁ and TE₂ was characterized at 9.4 T to achieve two objectives. The first was to determine two TE₁ and TE₂ combinations that could be used to obtain T₂‐corrected measures of Tau (3.42 ppm) that were minimally influenced by J coupling. The second was to exploit the Tau J coupling to find a timing combination that minimized the 3.25‐ppm Tau signal to enable the Cho (3.22 ppm) resonance to be resolved from the overlapping Tau signal. The response of Tau protons was investigated both numerically and experimentally. It was numerically determined that the timings {TE₁, TE₂} = {17 ms, 10 ms} and {TE₁, TE₂} = {80 ms, 70 ms} yielded similar 3.42‐ppm Tau resonance areas (5% difference), rendering them suitable for Tau T₂ determination. {TE₁, TE₂} = {25 ms, 50 ms} was found to yield minimal 3.25‐ppm Tau signal, reducing its interference with Cho. The efficacy of the timings was demonstrated on phantom solutions and in vivo in four Sprague Dawley rats. LCModel was employed to analyse the in vivo spectra and Tau T₂ values were estimated by fitting the Tau peak areas obtained with {TE₁, TE₂} = {17 ms, 10 ms} and {TE₁, TE₂} = {80 ms, 70 ms} to a monoexponentially decaying function. An average Tau T₂ of 106 ms (standard deviation, 12 ms) was obtained. LCModel analysis of rat spectra obtained with {TE₁, TE₂} = {25 ms, 50 ms} demonstrated negligible levels of Tau signal, compared with that obtained with short TE.     

Non‐invasive detection of glycine as a biomarker of malignancy in childhood brain tumours using in‐vivo 1H MRS at 1.5 Tesla confirmed by ex‐vivo high‐resolution magic‐angle spinning NMR

Management of brain tumours in children would benefit from improved non‐invasive diagnosis, characterisation and prognostic biomarkers. Metabolite profiles derived from in‐vivo MRS have been shown to provide such information. Studies indicate that using optimum a priori information on metabolite contents in the construction of linear combination (LC) models of MR spectra leads to improved metabolite profile estimation. Glycine (Gly) is usually neglected in such models due to strong overlap with myo‐inositol (mI) and a low concentration in normal brain. However, biological studies indicate that Gly is abundant in high‐grade brain tumours. This study aimed to investigate the quantitation of Gly in paediatric brain tumours using MRS analysed by LCModel?, and its potential as a non‐invasive biomarker of malignancy. Single‐voxel MRS was performed using PRESS (TR 1500 ms, TE 30 ms/135 ms) on a 1.5 T scanner. Forty‐seven cases (18 high grade (HG), 17 low grade (LG), 12 ungraded) were retrospectively selected if both short‐TE and long‐TE MRS (n = 33) or short‐TE MRS and high‐resolution magic‐angle spinning (HRMAS) of matched surgical samples (n = 15) were available. The inclusion of Gly in LCModel? analyses led to significantly reduced fit residues for both short‐TE and long‐TE MRS (p < 0.05). The Gly concentrations estimated from short‐TE MRS were significantly correlated with the long‐TE values (R = 0.91, p < 0.001). The Gly concentration estimated by LCModel? was significantly higher in HG versus LG tumours for both short‐TE (p < 1e‐6) and long‐TE (p = 0.003) MRS. This was consistent with the HRMAS results, which showed a significantly higher normalised Gly concentration in HG tumours (p < 0.05) and a significant correlation with the normalised Gly concentration measured from short‐TE in‐vivo MRS (p < 0.05). This study suggests that glycine can be reliably detected in paediatric brain tumours using in‐vivo MRS on standard clinical scanners and that it is a promising biomarker of tumour aggressiveness. Copyright © 2009 John Wiley & Sons, Ltd.     

The in vivo J‐difference editing MEGA‐PRESS technique for the detection of n‐3 fatty acids

In this study, we present a method for the detection of n‐3 fatty acid (n‐3 FA) signals using MRS in adipose tissue in vivo. This method (called oMEGA‐PRESS) is based on the selective detection of the CH₃ signal of n‐3 FA using the MEGA‐PRESS (MEshcher–GArwood Point‐RESolved Spectroscopy) J‐difference editing technique. We optimized the envelope shape and frequency of spectral editing pulses to minimize the spurious co‐editing and incomplete subtraction of the CH₃ signal of other FAs, which normally obscure the n‐3 FA CH₃ signal in MR spectra acquired using standard PRESS techniques. The post‐processing of the individual data scans with the phase and frequency correction before data subtraction and averaging was implemented to further improve the quality of in vivo spectra. The technique was optimized in vitro on lipid phantoms using various concentrations of n‐3 FA and examined in vivo at 3 T on 15 healthy volunteers. The proportion of n‐3 FA estimated by the oMEGA‐PRESS method in phantoms showed a highly significant linear correlation with the n‐3 FA content determined by gas chromatography. The signal attributed to n‐3 FA was observed in all subjects. Comparisons with the standard PRESS technique revealed an enhanced identification of the n‐3 FA signal using oMEGA‐PRESS. The presented method may be useful for the non‐invasive quantification of n‐3 FA in adipose tissue, and could aid in obtaining a better understanding of various aspects of n‐3 FA metabolism. Copyright © 2014 John Wiley & Sons, Ltd.     

Simultaneous detection of valine and lactate using MEGA‐PRESS editing in pyogenic brain abscess

Valine and lactate have been recognized as important metabolic markers to diagnose brain abscess by means of MRS. However, in vivo unambiguous detection and quantification is hampered by macromolecular contamination. In this work, MEGA‐PRESS difference editing of valine and lactate is proposed. The method is validated in vitro and applied for quantitative in vivo experiments in one healthy subject and two brain abscess patients. It is demonstrated that with this technique the overlapping lipid signal can be reduced by more than an order of magnitude and thus the robustness of valine and lactate detection in vivo can be enhanced. Quantification of the two abscess MEGA‐PRESS spectra yielded valine/lactate concentration ratios of 0.10 and 0.27. These ratios agreed with the concentration ratios determined from concomitantly acquired short‐T_E PRESS data and were in line with literature values. The quantification accuracy of lactate (as measured with Cramér‐Rao lower bounds in LCModel processing) was better for MEGA‐PRESS than for short‐T_E PRESS in all acquired in vivo datasets. The Cramér‐Rao lower bounds of valine were only better for MEGA‐PRESS in one of the two abscess cases, while in the other case coediting of isoleucine confounded the quantification in the MEGA‐PRESS analysis. MEGA‐PRESS and short‐T_E PRESS should be combined for unambiguous quantification of amino acids in abscess measurements. Simultaneous valine/lactate MEGA‐PRESS editing might benefit the distinction of brain abscesses from tumors, and further categorization of bacteria with reasonable sensitivity and specificity.     

Reproducibility and effect of tissue composition on cerebellar γ‐aminobutyric acid (GABA) MRS in an elderly population

MRS provides a valuable tool for the non‐invasive detection of brain γ‐aminobutyric acid (GABA) in vivo. GABAergic dysfunction has been observed in the aging cerebellum. The study of cerebellar GABA changes is of considerable interest in understanding certain age‐related motor disorders. However, little is known about the reproducibility of GABA MRS in an aged population. Therefore, this study aimed to explore the feasibility and reproducibility of GABA MRS in the aged cerebellum at 3.0 T and to examine the effect of differing tissue composition on GABA measurements. MRI and ¹H MRS examinations were performed on 10 healthy elderly volunteers (mean age, 75.2 ± 6.5 years) using a 3.0‐T Siemens Tim Trio scanner. Among them, five subjects were scanned twice to assess the short‐term reproducibility. The MEGA‐PRESS (Mescher–Garwood point‐resolved spectroscopy) J‐editing sequence was used for GABA detection in two volumes of interest (VOIs) in the left and right cerebellar dentate. MRS data processing and quantification were performed with LCModel 6.3‐0L using two separate basis sets, generated from density matrix simulations using published values for chemical shifts and J couplings. Raw metabolite levels from LCModel outputs were corrected for cerebrospinal fluid contamination and relaxation. GABA‐edited spectra yielded robust and stable GABA measurements with averaged intra‐individual coefficients of variation for corrected GABA+ between 4.0 ± 2.8% and 13.4 ± 6.3%, and inter‐individual coefficients of variation between 12.6% and 24.2%. In addition, there was a significant correlation between GABA+ obtained with the two LCModel basis sets. Overall, our results demonstrated the feasibility and reproducibility of cerebellar GABA‐edited MRS at 3.0 T in an elderly population. This information might be helpful for studies using this technique to study GABA changes in normal or diseased aging brain, e.g. for power calculations and the interpretation of longitudinal observations. Copyright © 2015 John Wiley & Sons, Ltd.     

In vivo magnetic resonance spectroscopy detection of combined glutamate‐glutamine in healthy upper cervical cord at 3 T

The possibility of quantifying the superimposed signal of glutamate and glutamine (Glx) and its components by ¹ H magnetic resonance spectroscopy (MRS) in the spinal cord is an exciting challenge with important clinical applications in neurological conditions. The spinal cord is a particularly difficult region of interest due to its small volume, magnetic field inhomogeneities and physiological motion. In this study, we investigated for the first time the feasibility of obtaining quantitative measurements of Glx in healthy cervical spinal cord by ¹ H MRS at 3 T. The aim of this study was to compare two commercially available MRS sequences by spectral simulations and in vivo. A short echo time (TE) point resolved spectroscopy (PRESS) with TE = 30 ms and a stimulated echo acquisition mode (STEAM) with TE = 11 ms and mixing time (TM) = 17 ms were compared for reliability of Glx fit. Data allowed us to determine sample size estimates for future clinical studies for the first time. Results showed that PRESS provided a reliable fit for Glx in all cases (Cramér Rao lower bounds < 20%) whereas no reliable Glx fits were achieved using STEAM. Neither protocol provided reliable Glu quantification. The power calculations showed that a minimum sample size of 17 subjects per group was needed to detect Glx changes of > 20% using the PRESS sequence. This study proposed a clinically feasible MRS method for Glx detection in the human cervical cord in vivo including sample sizes needed for conclusive clinical studies. Copyright © 2012 John Wiley & Sons, Ltd.     

Hadamard editing of glutathione and macromolecule‐suppressed GABA

The primary inhibitory neurotransmitter γ‐aminobutyric acid (GABA) and the major antioxidant glutathione (GSH) are compounds of high importance for the function and integrity of the human brain. In this study, a method for simultaneous J‐difference spectral‐edited magnetic resonance spectroscopy (MRS) of GSH and GABA with suppression of macromolecular (MM) signals at 3 T is proposed. MM‐suppressed Hadamard encoding and reconstruction of MEGA (Mescher–Garwood)‐edited spectroscopy (HERMES) consists of four sub‐experiments (TE = 80 ms), with 20‐ms editing pulses applied at: (A) 4.56 and 1.9 ppm; (B) 4.56 and 1.5 ppm; (C) 1.9 ppm; and (D) 1.5 ppm. One Hadamard combination (A + B – C – D) yields GSH‐edited spectra, and another (A – B + C – D) yields GABA‐edited spectra, with symmetric suppression of the co‐edited MM signal. MM‐suppressed HERMES, conventional HERMES and separate Mescher–Garwood point‐resolved spectroscopy (MEGA‐PRESS) data were successfully acquired from a (33 mm)³ voxel in the parietal lobe in 10 healthy subjects. GSH‐ and GABA‐edited MM‐suppressed HERMES spectra were in close agreement with the respective MEGA‐PRESS spectra. Mean GABA (and GSH) estimates were 1.10 ± 0.15 i.u. (0.59 ± 0.12 i.u.) for MM‐suppressed HERMES, and 1.13 ± 0.09 i.u. (0.66 ± 0.09 i.u.) for MEGA‐PRESS. Mean GABA (and GSH) differences between MM‐suppressed HERMES and MEGA‐PRESS were –0.03 ± 0.11 i.u. (–0.07 ± 0.11 i.u.). The mean signal‐to‐noise ratio (SNR) improvement of MM‐suppressed HERMES over MEGA‐PRESS was 1.45 ± 0.25 for GABA and 1.32 ± 0.24 for GSH. These results indicate that symmetric suppression of the MM signal can be accommodated into the Hadamard editing framework. Compared with sequential single‐metabolite MEGA‐PRESS experiments, MM‐suppressed HERMES allows for simultaneous edited measurements of GSH and GABA without MM contamination in only half the scan time, and SNR is maintained.     

T2 measurement of J-coupled metabolites in the human brain at 3T

Proton T₂ relaxation times of metabolites in the human brain were measured using point resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~ 2.35 ppm. In vivo data were obtained from medial and left occipital cortices of five healthy volunteers. The cortices contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume‐localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T₂ (T₂^?). T₂^? was estimated to be similar between the brain regions for creatine, choline, glutamate and myo‐inositol, but significantly different for N‐acetylaspartate singlet and multiplet. T₂^?s of glutamate and myo‐inositol were measured as 181 ± 16 and 197 ± 14 ms (mean ± SD, N = 5) for medial occipital cortices, and 180 ± 12 and 196 ± 17 ms for left occipital cortices, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Difference spectroscopy using PRESS asymmetry: application to glutamate,glutamine, and myo‐inositol

A simple, clinically viable technique utilizing PRESS and strong coupling properties is presented for discrimination of coupled brain metabolites. The method relies on signal variation due to alteration of inter‐echo timings (PRESS asymmetry) while maintaining a constant total echo time. Spin response of singlets and weakly coupled spins is unchanged due to PRESS asymmetry, allowing difference spectroscopy to detect unobstructed strongly coupled resonances. No changes to the standard PRESS sequence are required except variation of inter‐echo timings. The procedure is illustrated for the separate detection of glutamate from glutamine and the detection of myo‐inositol in simulation, phantom, and in vivo experiments at 4.7 T. The subtraction yields calculated from the simulation were 53% for glutamate and 75% for myo‐inositol, and a resultant contribution of 96% glutamate to the total glutamate/glutamine multiplet in the 2.04–2.14 ppm range. To extend the treatment to other field strengths and metabolites, an analytical approximation based on a strongly coupled AB system was used to model individual spin groups. Subtraction spectroscopy yields for different combinations of coupling parameters were calculated for the detection of various strongly coupled metabolites at common clinical field strengths. The approximation also predicts adequate glutamate/glutamine discrimination at 3.0 T using the difference spectroscopy method. Copyright © 2009 John Wiley & Sons, Ltd.     

PRESS timings for resolving 13C4‐glutamate 1H signal at 9.4 T: Demonstration in rat with uniformly labelled 13C‐glucose

MRS of ¹³C₄‐labelled glutamate (¹³C₄‐Glu) during an infusion of a carbon‐13 (¹³C)‐labelled substrate, such as uniformly labelled glucose ([U‐¹³C₆]‐Glc), provides a measure of Glc metabolism. The presented work provides a single‐shot indirect ¹³C detection technique to quantify the approximately 2.51 ppm ¹³C₄‐Glu satellite proton (¹H) peak at 9.4 T. The methodology is an optimized point‐resolved spectroscopy (PRESS) sequence that minimizes signal contamination from the strongly coupled protons of N‐acetylaspartate (NAA), which resonate at approximately 2.49 ppm. J‐coupling evolution of protons was characterized numerically and verified experimentally. A (TE₁, TE₂) combination of (20 ms, 106 ms) was found to be suitable for minimizing NAA signal in the 2.51 ppm ¹H ¹³C₄‐Glu spectral region, while retaining the ¹³C₄‐Glu ¹H satellite peak. The efficacy of the technique was verified on phantom solutions and on two rat brains in vivo during an infusion of [U‐¹³C₆]‐Glc. LCModel was employed for analysis of the in vivo spectra to quantify the 2.51 ppm ¹H ¹³C₄‐Glu signal to obtain Glu C4 fractional enrichment time courses during the infusions. Cramér‐Rao lower bounds of about 8% were obtained for the 2.51 ppm ¹³C₄‐Glu ¹H satellite peak with the optimal TE combination.     

Effect of J coupling on 1.3‐ppm lipid methylene signal acquired with localised proton MRS at 3 T

The purpose of this work was to investigate the effect of J‐coupling interactions on the quantification and T₂ determination of 1.3‐ppm lipid methylene protons at 3 T. The response of the 1.3‐ppm protons of hexanoic, heptanoic, octanoic, linoleic and oleic acid was measured as a function of point‐resolved spectroscopy (PRESS) and stimulated echo acquisition mode (STEAM) TE. In addition, a narrow‐bandwidth refocusing PRESS sequence designed to rewind J‐coupling evolution of the 1.3‐ppm protons was applied to the five fatty acids, to corn oil and to tibial bone marrow of six healthy volunteers. Peak areas were plotted as a function of TE, and data were fitted to monoexponentially decaying functions to determine M_o (the extrapolated area for TE = 0 ms) and T₂ values. In phantoms, rewinding J‐coupling evolution resulted in 198%, 64%, 44%, 20% and 15% higher T₂ values for heptanoic, octanoic, linoleic and oleic acid, and corn oil, respectively, compared with those obtained with standard PRESS. The narrow‐bandwidth PRESS sequence also resulted in significant changes in M_o, namely ?77%, ?22%, 28%, 23% and 28% for heptanoic, octanoic, linoleic and oleic acid, and corn oil, respectively. T₂ values obtained with STEAM were closer to the values measured with narrow‐bandwidth PRESS. On average, in tibial bone marrow (six volunteers) rewinding J‐coupling evolution resulted in 21% ± 3% and 9 % ± 1% higher M_o and T₂ values, respectively. This work demonstrates that the consequence of neglecting to consider scalar coupling effects on the quantification of 1.3‐ppm lipid methylene protons and their T₂ values is not negligible. The linoleic and oleic acid T₂ results indicate that T₂ measures of lipids with standard MRS techniques are dependent on lipid composition. Copyright © 2015 John Wiley & Sons, Ltd.