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.     

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.     

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.     

A comparison of 2‐hydroxyglutarate detection at 3 and 7 T with long‐TE semi‐LASER

Abnormally high levels of the ‘oncometabolite’ 2‐hydroxyglutarate (2‐HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2‐HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2‐HG detection. To combat this, several groups have proposed MRS methods at ultra‐high field (≥7 T) where theoretical increases in signal‐to‐noise ratio and spectral resolution could improve 2‐HG detection. Long echo time (long‐TE) semi‐localization by adiabatic selective refocusing (semi‐LASER) (TE = 110 ms) is a promising method for improved 2‐HG detection in vivo at either 3 or 7 T owing to the use of broad‐band adiabatic localization. Using previously published semi‐LASER methods at 3 and 7 T, this study directly compares the detectability of 2‐HG in phantoms and in vivo across nine patients. Cramér–Rao lower bounds (CRLBs) of 2‐HG fitting were found to be significantly lower at 7 T (6 ± 2%) relative to 3 T (15 ± 7%) (p = 0.0019), yet were larger at 7 T in an IDH wild‐type patient. Although no increase in SNR was detected at 7 T (77 ± 26) relative to 3 T (77 ± 30), the detection of 2‐HG was greatly enhanced through an improved spectral profile and increased resolution at 7 T. 7 T had a large effect on pairwise fitting correlations between γ‐aminobutyric acid (GABA) and 2‐HG (p = 0.004), and resulted in smaller coefficients. The increased sensitivity for 2‐HG detection using long‐TE acquisition at 7 T may allow for more rapid estimation of 2‐HG (within a few spectral averages) together with other associated metabolic markers in glioma.     

Detection of metabolite changes in response to a varying visual stimulation paradigm using short‐TE 1H MRS at 7 T

The two‐fold benefit of ¹H magnetic resonance spectroscopy (MRS) at high B₀ fields – enhanced sensitivity and increased spectral dispersion – has been used previously to study dynamic changes in metabolite concentrations in the human brain in response to visual stimulation. In these studies, a strong visual on/off stimulus was combined with MRS data acquisition in a voxel location in the occipital cortex determined by an initial functional magnetic resonance imaging experiment. However, 1) to exclude the possibility of systemic effects (heartbeat, blood flow, etc.), which tend to be different for on/off conditions, a modified stimulation condition not affecting the target voxel needs to be employed, and 2) to assess important neurotransmitters of low concentration, in particular γ‐aminobutyric acid (GABA), it may be advantageous to analyze steady‐state, rather than dynamic, conditions. Thus, the aim of this study was to use short‐TE ¹H MRS methodology at 7 T to detect differences in steady‐state metabolite levels in response to a varying stimulation paradigm in the human visual cortex. The two different stimulation conditions were termed voxel and control activation. Localized MR spectra were acquired using the SPECIAL (spin‐echo full‐intensity acquired localized) sequence. Data were analyzed using LCModel. Fifteen individual metabolites were reliably quantified. On comparison of steady‐state concentrations for voxel versus control activation, a decrease in GABA of 0.05 mmol/L (5%) and an increase in lactate of 0.04 mmol/L (7%) were found to be the only significant effects. The observed reduction in GABA can be interpreted as reduced neuronal inhibition during voxel activation, whereas the increase in lactate hints at an intensification of anaerobic glycolysis. Differences from previous studies, notably the absence of any changes in glutamate, are attributed to the modified experimental conditions. This study demonstrates that the use of advanced ¹H MRS methodology at 7 T allows the detection of subtle changes in metabolite concentrations involved in neuronal activation and inhibition.     

In vivo T2 relaxation time measurement with echo‐time averaging

The accuracy of metabolite concentrations measured using in vivo proton (¹H) MRS is enhanced following correction for spin–spin (T₂) relaxation effects. In addition, metabolite proton T₂ relaxation times provide unique information regarding cellular environment and molecular mobility. Echo‐time (TE) averaging ¹H MRS involves the collection and averaging of multiple TE steps, which greatly simplifies resulting spectra due to the attenuation of spin‐coupled and macromolecule resonances. Given the simplified spectral appearance and inherent metabolite T₂ relaxation information, the aim of the present proof‐of‐concept study was to develop a novel data processing scheme to estimate metabolite T₂ relaxation times from TE‐averaged ¹H MRS data. Spectral simulations are used to validate the proposed TE‐averaging methods for estimating methyl proton T₂ relaxation times for N‐acetyl aspartate, total creatine, and choline‐containing compounds. The utility of the technique and its reproducibility are demonstrated using data obtained in vivo from the posterior‐occipital cortex of 10 healthy control subjects. Compared with standard methods, distinct advantages of this approach include built‐in macromolecule resonance attenuation, in vivo T₂ estimates closer to reported values when maximum TE ≈ T₂, and the potential for T₂ calculation of metabolite resonances otherwise inseparable in standard ¹H MRS spectra recorded in vivo. Copyright © 2014 John Wiley & Sons, Ltd.     

Brain γ‐aminobutyric acid (GABA) detection in vivo with the J‐editing 1H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement,macromolecule contamination and test–retest reliability

Abnormalities in brain γ‐aminobutyric acid (GABA) have been implicated in various neuropsychiatric and neurological disorders. However, in vivo GABA detection by ¹H MRS presents significant challenges arising from the low brain concentration, overlap by much stronger resonances and contamination by mobile macromolecule (MM) signals. This study addresses these impediments to reliable brain GABA detection with the J‐editing difference technique on a 3‐T MR system in healthy human subjects by: (i) assessing the sensitivity gains attainable with an eight‐channel phased‐array head coil; (ii) determining the magnitude and anatomic variation of the contamination of GABA by MM; and (iii) estimating the test–retest reliability of the measurement of GABA with this method. Sensitivity gains and test–retest reliability were examined in the dorsolateral prefrontal cortex (DLPFC), whereas MM levels were compared across three cortical regions: DLPFC, the medial prefrontal cortex (MPFC) and the occipital cortex (OCC). A three‐fold higher GABA detection sensitivity was attained with the eight‐channel head coil compared with the standard single‐channel head coil in DLPFC. Despite significant anatomical variation in GABA + MM and MM across the three brain regions (p < 0.05), the contribution of MM to GABA + MM was relatively stable across the three voxels, ranging from 41% to 49%, a non‐significant regional variation (p = 0.58). The test–retest reliability of GABA measurement, expressed as either the ratio to voxel tissue water (W) or to total creatine, was found to be very high for both the single‐channel coil and the eight‐channel phased‐array coil. For the eight‐channel coil, for example, Pearson's correlation coefficient of test vs. retest for GABA/W was 0.98 (R² = 0.96, p = 0.0007), the percentage coefficient of variation (CV) was 1.25% and the intraclass correlation coefficient (ICC) was 0.98. Similar reliability was also found for the co‐edited resonance of combined glutamate and glutamine (Glx) for both coils. Copyright © 2016 John Wiley & Sons, Ltd.     

A semi‐LASER,single‐voxel spectroscopic sequence with a minimal echo time of 20.1 ms in the human brain at 3 T

An optimized semi‐LASER sequence that is capable of acquiring artefact‐free data with an echo time (TE) of 20.1 ms on a standard clinical 3 T MR system was developed. Simulations were performed to determine the optimal TEs that minimize the expected Cramér‐Rao lower bound (CRLB) as proxy for quantification accuracy of metabolites. Optimized RF pulses, crusher gradients and phase cycling were used to achieve the shortest TE in a semi‐LASER sequence to date on a clinical system. Synthetic spectra were simulated using the density matrix formalism for TEs spanning from 20.1 to 220.1 ms. These simulations were used to calculate the expected CRLB for each of the 18 metabolites typically considered in ¹H MRS. High quality spectra were obtained in six healthy volunteers in the prefrontal cortex, which is known for spurious echoes due to its proximity to the paranasal sinuses, and in the parietal‐occipital cortex. Spectral transients were sufficient in quality to enable phase and frequency alignment prior to summation over all repetitions. Automated high‐quality water suppression was obtained for all voxels without manual adjustment. The shortest TE minimized the CRLB for all brain metabolites except glycine due to its overlap with myo‐inositol at this TE. It is also demonstrated that the CRLBs increase rapidly with TE for certain coupled metabolites.     

Efficient γ-aminobutyric acid editing at 3T without macromolecule contamination: MEGA-SPECIAL

One of the most commonly used methods for in vivo MRS detection of γ‐aminobutyric acid (GABA) is the MEGA‐point‐resolved spectroscopy (MEGA‐PRESS) technique. However, accurate quantification of GABA using MEGA‐PRESS is complicated by spectral co‐editing of macromolecular resonances. In this article, a new pulse sequence is presented which enables GABA editing at 3T with the removal of macromolecule contamination. This sequence combines the conventional MEGA editing scheme with the SPECIAL localisation technique, and is therefore named MEGA‐SPECIAL. Simulations and phantom experiments indicate that this new approach provides improved GABA editing efficiency relative to MEGA‐PRESS, and in vivo results demonstrate effective removal of macromolecule contamination. In a study of the occipital lobe of five healthy volunteers, the macromolecule‐corrected GABA/creatine ratio was found to be 0.093 ± 0.007 (mean ± standard deviation), whereas prior to macromolecule correction, the ratio was found to be 0.173 ± 0.013. Copyright © 2011 John Wiley & Sons, Ltd.     

Measurement of glycine in healthy and tumorous brain by triple‐refocusing MRS at 3 T in vivo

Glycine (Gly) has been implicated in several neurological disorders, including malignant brain tumors. The precise measurement of Gly is challenging largely as a result of the spectral overlap with myo‐inositol (mI). We report a new triple‐refocusing sequence for the reliable co‐detection of Gly and mI at 3 T and for the evaluation of Gly in healthy and tumorous brain. The sequence parameters were optimized with density‐matrix simulations and phantom validation. With a total TE of 134 ms, the sequence gave complete suppression of the mI signal between 3.5 and 3.6 ppm and, consequently, well‐defined Gly (3.55 ppm) and mI (3.64 ppm) peaks. In vivo ¹H magnetic resonance spectroscopy (MRS) data were acquired from the gray matter (GM)‐dominant medial occipital and white matter (WM)‐dominant left parietal regions in six healthy subjects, and analyzed with LCModel using in‐house‐calculated basis spectra. Tissue segmentation was performed to obtain the GM and WM contents within the MRS voxels. Metabolites were quantified with reference to GM‐rich medial occipital total creatine at 8 mM. The Gly and mI concentrations were estimated to be 0.63 ± 0.05 and 8.6 ± 0.6 mM for the medial occipital and 0.34 ± 0.05 and 5.3 ± 0.8 mM for the left parietal regions, respectively. From linear regression of the metabolite estimates versus fractional GM content, the concentration ratios between pure GM and pure WM were estimated to be 2.6 and 2.1 for Gly and mI, respectively. Clinical application of the optimized sequence was performed in four subjects with brain tumor. The Gly levels in tumors were higher than those of healthy brain. Gly elevation was more extensive in a post‐contrast enhancing region than in a non‐enhancing region. The data indicate that the optimized triple‐refocusing sequence may provide reliable co‐detection of Gly and mI, and alterations of Gly in brain tumors can be precisely evaluated.     

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.     

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.     

An in vivo ultrahigh field 14.1 T 1H‐MRS study on 6‐OHDA and α‐synuclein‐based rat models of Parkinson's disease: GABA as an early disease marker

The detection of Parkinson's disease (PD) in its preclinical stages prior to outright neurodegeneration is essential to the development of neuroprotective therapies and could reduce the number of misdiagnosed patients. However, early diagnosis is currently hampered by lack of reliable biomarkers. ¹H magnetic resonance spectroscopy (MRS) offers a noninvasive measure of brain metabolite levels that allows the identification of such potential biomarkers. This study aimed at using MRS on an ultrahigh field 14.1 T magnet to explore the striatal metabolic changes occurring in two different rat models of the disease. Rats lesioned by the injection of 6‐hydroxydopamine (6‐OHDA) in the medial‐forebrain bundle were used to model a complete nigrostriatal lesion while a genetic model based on the nigral injection of an adeno‐associated viral (AAV) vector coding for the human α‐synuclein was used to model a progressive neurodegeneration and dopaminergic neuron dysfunction, thereby replicating conditions closer to early pathological stages of PD. MRS measurements in the striatum of the 6‐OHDA rats revealed significant decreases in glutamate and N‐acetyl‐aspartate levels and a significant increase in GABA level in the ipsilateral hemisphere compared with the contralateral one, while the αSyn overexpressing rats showed a significant increase in the GABA striatal level only. Therefore, we conclude that MRS measurements of striatal GABA levels could allow for the detection of early nigrostriatal defects prior to outright neurodegeneration and, as such, offers great potential as a sensitive biomarker of presymptomatic PD. Copyright © 2012 John Wiley & Sons, Ltd.     

A comparative study of short‐ and long‐TE 1H MRS at 3 T for in vivo detection of 2‐hydroxyglutarate in brain tumors

2‐Hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenase (IDH) 1 and 2. The ¹H resonances of the J‐coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here, we report a comparative study at 3 T of the utility of the point‐resolved spectroscopy sequence with a standard short TE (35 ms) and a long TE (97 ms), which had been theoretically designed for the detection of the 2HG 2.25‐ppm resonance. The performance of the methods is evaluated using data from phantoms, seven healthy volunteers and 22 subjects with IDH‐mutated gliomas. The results indicate that TE = 97 ms provides higher detectability of 2HG than TE = 35 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses. Copyright © 2013 John Wiley & Sons, Ltd.     

Spatial Hadamard encoding of J‐edited spectroscopy using slice‐selective editing pulses

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.     

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.     

Spectral fitting using basis set modified by measured B0 field distribution

This study sought to demonstrate and evaluate a novel spectral fitting method to improve quantification accuracy in the presence of large magnetic field distortion, especially with high fields. MRS experiments were performed using a point‐resolved spectroscopy (PRESS)‐type sequence at 7 T. A double‐echo gradient echo (GRE) sequence was used to acquire B₀ maps following MRS experiments. The basis set was modified based on the measured B₀ distribution within the MRS voxel. Quantification results were obtained after fitting the measured MRS data using the modified basis set. The proposed method was validated using numerical Monte Carlo simulations, phantom measurements, and comparison of occipital lobe MRS measurements under homogeneous and inhomogeneous magnetic field conditions. In vivo results acquired from voxels placed in thalamus and prefrontal cortex regions close to the frontal sinus agreed well with published values. Instead of noise‐amplifying complex division, the proposed method treats field variations as part of the signal model, thereby avoiding inherent statistical bias associated with regularization. Simulations and experiments showed that the proposed approach reliably quantified results in the presence of relatively large magnetic field distortion. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

Automated whole‐brain N‐acetylaspartate proton MRS quantification

Concentration of the neuronal marker, N‐acetylaspartate (NAA), a quantitative metric for the health and density of neurons, is currently obtained by integration of the manually defined peak in whole‐head proton (¹H)‐MRS. Our goal was to develop a full spectral modeling approach for the automatic estimation of the whole‐brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency‐range peak integration approach previously employed. MRI and whole‐head ¹H‐MRS from 18 healthy young adults were examined. Non‐localized, whole‐head ¹H‐MRS obtained at 3 T yielded the NAA peak area through both manually defined frequency‐range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T₁‐weighted MRI) to yield WBNAA. A paired‐sample t test was used to compare the means of the WBNAA paradigms and a likelihood ratio test used to compare their coefficients of variation. While the between‐subject WBNAA means were nearly identical (12.8 ± 2.5 mm for integration, 12.8 ± 1.4 mm for spectral modeling), the latter's standard deviation was significantly smaller (by ~50%, p = 0.026). The within‐subject variability was 11.7% (±1.3 mm ) for integration versus 7.0% (±0.8 mm ) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer–Rao lower bounds below 0.1% and vanishingly small (experimental ‐ fitted) residuals. Modeling of the whole‐head ¹H‐MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality‐control feedback. Together, these enhance the usefulness of the technique for monitoring the diffuse progression and treatment response of neurological disorders. Copyright © 2014 John Wiley & Sons, Ltd.     

γ-aminobutyric acid measurement in the human brain at 7 T: Short echo-time or Mescher–Garwood editing

The purposes of the current study were to introduce a Mescher–Garwood (MEGA) semi-adiabatic spin-echo full-intensity localization (MEGA-sSPECIAL) sequence with macromolecule (MM) subtraction and to compare the test–retest reproducibility of γ-aminobutyric acid (GABA) measurements at 7 T using the sSPECIAL and MEGA-sSPECIAL sequences. The MEGA-sSPECIAL editing scheme using asymmetric adiabatic and highly selective Gaussian pulses was used to compare its GABA measurement reproducibility with that of short echo-time (TE) sSPECIAL. Proton magnetic resonance spectra were acquired in the motor cortex (M1) and medial prefrontal cortex (mPFC) using the sSPECIAL (TR/TE = 4000/16 ms) and MEGA-sSPECIAL sequences (TR/TE = 4000/80 ms). The metabolites were quantified using LCModel with unsuppressed water spectra. The concentrations are reported in institutional units. The test–retest reproducibility was evaluated by scanning each subject twice. Between-session reproducibility was assessed using coefficients of variation (CVs), Pearson's r correlation coefficients, and intraclass correlation coefficients (ICCs). Intersequence agreement was evaluated using Pearson's r correlation coefficients and Bland–Altman plots. Regarding GABA measurements by sSPECIAL, the GABA concentrations were 0.92 ± 0.31 (IU) in the M1 and 1.56 ± 0.49 (IU) in the mPFC. This demonstrated strong between-session correlation across both regions (r = 0.81, p < 0.01; ICC = 0.82). The CVs between the two scans were 21.8% in the M1 and 10.2% in the mPFC. On the other hand, the GABA measurements by MEGA-sSPECIAL were 0.52 ± 0.04 (IU) in the M1 and 1.04 ± 0.24 (IU) in the mPFC. MEGA-sSPECIAL demonstrated strong between-session correlation across the two regions (r = 0.98, p < 0.001; ICC = 0.98) and lower CVs than sSPECIAL, providing 4.1% in the M1 and 5.8% in the mPFC. The MEGA-editing method showed better reproducibility of GABA measurements in both brain regions compared with the short-TE sSPECIAL method. Thus it is a more sensitive method with which to detect small changes in areas with low GABA concentrations. In GABA-rich brain regions, GABA measurements can be achieved reproducibly using both methods.     

Improved detection of lactate and β‐hydroxybutyrate using MEGA‐sLASER at 3 T

Lactate and β‐hydroxybutyrate are important MRS‐visible biomarkers for the energy metabolism of the human brain. A major obstacle for their unambiguous detection and quantification in vivo is their inherently low concentration and spectral overlap with resonances from lipids and macromolecules. In this work, we demonstrate the improved detectability of lactate and β‐hydroxybutyrate with MEGA‐sLASER compared to MEGA‐PRESS at the clinical field strength of 3 T. The method is validated by numerical simulations, in vitro measurements and in vivo experiments on healthy subjects. It is demonstrated that MEGA‐sLASER offers an SNR increase of approximately 70% for lactate and β‐hydroxybutyrate detection compared to MEGA‐PRESS in various brain regions. This increased SNR translates into reduced Cramér‐Rao lower bounds for quantification and enables a more robust detection of subtle changes in the (brain) energy metabolism. The sensitivity of the method for detection of β‐hydroxybutyrate concentration changes is demonstrated through measurements before and during a ketogenic diet while the sensitivity for detection of lactate concentration changes is shown by measurements before and after an intensive anaerobic exercise.