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.     

Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8‐depleted rhesus macaques: proton MRS imaging at 3 T

To test the hypotheses that global decreased neuro‐axonal integrity reflected by decreased N‐acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo‐inositol (mI), present in a CD8‐depleted rhesus macaque model of HIV‐associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 × 16 × 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre‐ and 4–6 weeks post‐simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm³ spatial resolution over ~35% of the brain) using linear regression. Pre‐ to post‐infection global WM NAA declined 8%: 6.6 ± 0.4 to 6.0 ± 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 ± 0.2 to 1.0 ± 0.1 mM (p < 0.003); global mI increased 11%: 5.7 ± 0.4 to 6.5 ± 0.5 mM (p < 0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response. Copyright © 2013 John Wiley & Sons, Ltd.     

The role of gray and white matter segmentation in quantitative proton MR spectroscopic imaging

Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's ¹H MR spectroscopy (¹H‐MRS) signal, reducing sensitivity to changes. While single‐voxel ¹H‐MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1‐mm³ resolution MRI into GM, WM and CSF masks that were co‐registered with the MRSI grid to yield their partial volumes in approximately every 1 cm³ spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i‐ metabolite's GM and WM concentrations C_i^GM, C_i^WM. With the voxels' GM and WM volumes as independent coefficients, the over‐determined system of equations was solved for the global averaged C_i^GM and C_i^WM. Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N‐acetylaspartate, creatine, choline and myo‐inositol C_i^GM concentrations of 8.5 ± 0.7, 6.9 ± 0.6, 1.2 ± 0.2, 5.3 ± 0.6mM, respectively, and C_i^WM concentrations of 7.7 ± 0.6, 4.9 ± 0.5, 1.4 ± 0.1 and 4.4 ± 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5–10% (more for ratios), which can often double the sample size required to establish statistical significance. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

Multi‐center reproducibility of neurochemical profiles in the human brain at 7 T

The purpose of this work was to harmonize data acquisition and post‐processing of single voxel proton MRS (¹H‐MRS) at 7 T, and to determine metabolite concentrations and the accuracy and reproducibility of metabolite levels in the adult human brain. This study was performed in compliance with local institutional human ethics committees. The same seven subjects were each examined twice using four different 7 T MR systems from two different vendors using an identical semi‐localization by adiabatic selective refocusing spectroscopy sequence. Neurochemical profiles were obtained from the posterior cingulate cortex (gray matter, GM) and the corona radiata (white matter, WM). Spectra were analyzed with LCModel, and sources of variation in concentrations (‘subject’, ‘institute’ and ‘random’) were identified with a variance component analysis. Concentrations of 10–11 metabolites, which were corrected for T₁, T₂, magnetization transfer effects and partial volume effects, were obtained with mean Cramér–Rao lower bounds below 20%. Data variances and mean concentrations in GM and WM were comparable for all institutions. The primary source of variance for glutamate, myo‐inositol, scyllo‐inositol, total creatine and total choline was between subjects. Variance sources for all other metabolites were associated with within‐subject and system noise, except for total N‐acetylaspartate, glutamine and glutathione, which were related to differences in signal‐to‐noise ratio and in shimming performance between vendors. After multi‐center harmonization of acquisition and post‐processing protocols, metabolite concentrations and the sizes and sources of their variations were established for neurochemical profiles in the healthy brain at 7 T, which can be used as guidance in future studies quantifying metabolite and neurotransmitter concentrations with ¹H‐MRS at ultra‐high magnetic field. Copyright © 2015 John Wiley & Sons, Ltd.     

Localized MRS reliability of in vivo glutamate at 3 T in shortened scan times: a feasibility study

Glutamate is the prime excitatory neurotransmitter in the mammalian brain and has been implicated in a wide range of psychiatric conditions. To improve the applicability and clinical reach of magnetic resonance spectroscopy (MRS), research is needed to develop shortened, yet reliable, MRS scanning procedures for standard 1.5–3‐T clinical magnetic resonance imaging (MRI) systems, particularly with young or vulnerable populations unable to tolerate longer protocols. To this end, we evaluated the test–retest reliability of a shortened J ‐resolved MRS sequence in healthy adolescents (n  = 22) aged 12–14 years. Participants underwent a series of sequential 6‐min MRS scans, with the participants remaining in situ between successive scans. Glutamate and other metabolites were acquired from the rostral anterior cingulate cortex, as glutamatergic function in this region has been implicated in a number of psychiatric illnesses. Thirteen neurochemicals were quantified as ratios to total creatine, and reliability scores were expressed as the percentage difference between the two scans for each metabolite. Test–retest assessment of glutamate was reliable, as scores were less than 10% different (7.1 ± 4.2%), and glutamate values across scans were significantly correlated (Pearson r  = 0.680, p  < 10^?4). Several other neurochemicals demonstrated satisfactory reliability, including choline (Cho) (7.4 ± 5.6%), glutathione (GSH) (8.6 ± 4.1%), myo‐inositol (mI) (6.5 ± 7.1%) and N ‐acetylaspartate (NAA) (3.5 ± 3.6%), with test–retest correlations ranging from 0.747 to 0.953. A number of metabolites, however, did not demonstrate acceptable test–retest reliability using the current J ‐resolved MRS sequence, ranging from 13.8 ± 13.7% (aspartate, Asp) to 45.9 ± 38.3% (glycine, Gly). Collectively, test–retest analyses suggest that clinically viable quantitative data can be obtained on standard MRI systems for glutamate, as well as the other metabolites, during short scan times in a traditionally challenging brain region.     

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.     

Time‐efficient measurement of multi‐phase arterial spin labeling MR signal in white matter

White matter (WM) perfusion has great potential as a physiological biomarker in many neurological diseases. Although it has been demonstrated previously that arterial spin labeling magnetic resonance imaging (ASL‐MRI) enables the detection of the perfusion‐weighted signal in most voxels in WM, studies of cerebral blood flow (CBF) in WM by ASL‐MRI are relatively scarce because of its particular challenges, such as significantly lower perfusion and longer arterial transit times relative to gray matter (GM). Recently, ASL with a spectroscopic readout has been proposed to enhance the sensitivity for the measurement of WM perfusion. However, this approach suffers from long acquisition times, especially when acquiring multi‐phase ASL datasets to improve CBF quantification. Furthermore, the potential increase in the signal‐to‐noise ratio (SNR) by spectroscopic readout compared with echo planar imaging (EPI) readout has not been proven experimentally. In this study, we propose the use of time‐encoded pseudo‐continuous ASL (te‐pCASL) with single‐voxel point‐resolved spectroscopy (PRESS) readout to quantify WM cerebral perfusion in a more time‐efficient manner. Results are compared with te‐pCASL with a conventional EPI readout for both WM and GM perfusion measurements. Perfusion measurements by te‐pCASL PRESS and conventional EPI showed no significant difference for quantitative WM CBF values (Student's t‐test, p = 0.19) or temporal SNR (p = 0.33 and p = 0.81 for GM and WM, respectively), whereas GM CBF values (p = 0.016) were higher using PRESS than EPI readout. WM CBF values were found to be 18.2 ± 7.6 mL/100 g/min (PRESS) and 12.5 ± 5.5 mL/100 g/min (EPI), whereas GM CBF values were found to be 77.1 ± 11.2 mL/100 g/min (PRESS) and 53.6 ± 9.6 mL/100 g/min (EPI). This study demonstrates the feasibility of te‐pCASL PRESS for the quantification of WM perfusion changes in a highly time‐efficient manner, but it does not result in improved temporal SNR, as does traditional te‐pCASL EPI, which remains the preferred option because of its flexibility in use.     

Simultaneous voxel‐based magnetic susceptibility and morphometry analysis using magnetization‐prepared spoiled turbo multiple gradient echo

This study aimed to develop and test a simultaneous acquisition and analysis pipeline for voxel‐based magnetic susceptibility and morphometry (VBMSM) on a single dataset using young volunteers, elderly healthy volunteers, and an Alzheimer's disease (AD) group. 3D T₁‐weighted and multi‐echo phase images for VBM and quantitative susceptibility mapping (QSM) were simultaneously acquired using a magnetization‐prepared spoiled turbo multiple gradient echo sequence with inversion pulse for QSM (MP‐QSM). The magnitude image was split into gray matter (GM) and white matter (WM) and was spatially normalized. The susceptibility map was reconstructed from the phase images. The segmented image and susceptibility map were compared with those obtained from conventional multiple spoiled gradient echo (mGRE) and MP‐spoiled gradient echo (MP‐GRE) in healthy volunteers to validate the availability of MP‐QSM by numerical measurements. To assess the feasibility of the VBMSM analysis pipeline, voxel‐based comparisons of susceptibility and morphometry in MP‐QSM were conducted in volunteers with a bimodal age distribution, and in elderly volunteers and the AD group, using spatially normalized GM and WM volume images and a susceptibility map. GM/WM contrasts in MP‐QSM, MP‐GRE, and mGRE were 0.14 ± 0.011, 0.17 ± 0.015, and 0.045 ± 0.010, respectively. Segmented GM and WM volumes in the MP‐QSM closely coincided with those in the MP‐GRE. Region of interest analyses indicated that the mean susceptibility values in MP‐QSM were completely in agreement with those in mGRE. In an evaluation of the aging effect, a significant increase and decrease in susceptibility and volume were found by VBMSM in deep GM and WM, respectively. Between the elderly volunteers and the AD group, the characteristic susceptibility and volume changes in GM and WM were observed. The proposed MP‐QSM sequence makes it possible to acquire acceptable‐quality images for simultaneous analysis and determine brain atrophy and susceptibility distribution without image registration by using voxel‐based analyses.     

Improved efficiency on editing MRS of lactate and γ‐aminobutyric acid by inclusion of frequency offset corrected inversion pulses at high fields

γ‐Aminobutyric acid (GABA) and lactate are metabolites which are present in the brain. These metabolites can be indicators of psychiatric disorders or tumor hypoxia, respectively. The measurement of these weakly coupled spin systems can be performed using MRS editing techniques; however, at high field strength, this can be challenging. This is due to the low available B₁⁺ field at high fields, which results in narrow‐bandwidth refocusing pulses and, consequently, in large chemical shift displacement artifacts. In addition, as a result of the increased chemical shift displacement artifacts and chemical shift dispersion, the efficiency of the MRS method is reduced, even when using adiabatic refocusing pulses. To overcome this limitation, frequency offset corrected inversion (FOCI) pulses have been suggested as a mean to substantially increase the bandwidth of adiabatic pulses. In this study, a Mescher–Garwood semi‐localization by adiabatic selection and refocusing (MEGA‐sLASER) editing sequence with refocusing FOCI pulses is presented for the measurement of GABA and lactate in the human brain. Metabolite detection efficiencies were improved by 20% and 75% for GABA and lactate, respectively, when compared with editing techniques that employ adiabatic radiofrequency refocusing pulses. The highly efficient MEGA‐sLASER sequence with refocusing FOCI pulses is an ideal and robust MRS editing technique for the measurement of weakly coupled metabolites at high field strengths. Copyright © 2013 John Wiley & Sons, Ltd.     

Quantification of γ‐aminobutyric acid (GABA) in 1H MRS volumes composed heterogeneously of grey and white matter

The quantification of γ‐aminobutyric acid (GABA) concentration using localised MRS suffers from partial volume effects related to differences in the intrinsic concentration of GABA in grey (GM) and white (WM) matter. These differences can be represented as a ratio between intrinsic GABA in GM and WM: r_M. Individual differences in GM tissue volume can therefore potentially drive apparent concentration differences. Here, a quantification method that corrects for these effects is formulated and empirically validated. Quantification using tissue water as an internal concentration reference has been described previously. Partial volume effects attributed to r_M can be accounted for by incorporating into this established method an additional multiplicative correction factor based on measured or literature values of r_M weighted by the proportion of GM and WM within tissue‐segmented MRS volumes. Simulations were performed to test the sensitivity of this correction using different assumptions of r_M taken from previous studies. The tissue correction method was then validated by applying it to an independent dataset of in vivo GABA measurements using an empirically measured value of r_M. It was shown that incorrect assumptions of r_M can lead to overcorrection and inflation of GABA concentration measurements quantified in volumes composed predominantly of WM. For the independent dataset, GABA concentration was linearly related to GM tissue volume when only the water signal was corrected for partial volume effects. Performing a full correction that additionally accounts for partial volume effects ascribed to r_M successfully removed this dependence. With an appropriate assumption of the ratio of intrinsic GABA concentration in GM and WM, GABA measurements can be corrected for partial volume effects, potentially leading to a reduction in between‐participant variance, increased power in statistical tests and better discriminability of true effects.     

Which pulse sequence is optimal for myo‐inositol detection at 3T?

Optimized myo‐inositol (mI) detection is important for diagnosing and monitoring a multitude of pathological conditions of the brain. Simulations are presented in this work, performed to decide which pulse sequence has the most significant advantage in terms of improving repeatability and accuracy of mI measurements at 3T over the pulse sequence used typically in the clinic, a TE = 35 ms PRESS sequence. Five classes of pulse sequences, four previously suggested for optimized mI detection (a short TE PRESS, a Carr‐Purcell PRESS sequence, an optimized STEAM sequence, an optimized zero quantum filter), and one optimized for mI detection in this work (a single quantum filter) were compared to a standard, TE = 35 ms pulse sequence. While limiting the SNR of an acquisition to the equivalent SNR of a spectrum acquired in 5 min from an 8 cc voxel, it was found through simulations that the most repeatable mI measurements would be obtained with a Carr‐Purcell sequence. This sequence was implemented in a clinical scanner, and improved mI measurements were demonstrated in vivo. Copyright © 2008 John Wiley & Sons, Ltd.     

Medial frontal and dorsal cortical morphometric abnormalities are related to obsessive-compulsive disorder

Whole-brain voxel-based morphometry (VBM) studies provide support for orbitofrontal, medial frontal as well as for dorsal cortical volumetric alteration in obsessive-compulsive disorder (OCD). However, there is still a need to replicate a priori unpredicted findings and to elucidate white matter volumetric abnormalities and relationships between grey (GM) and white (WM) matter volume and clinical characteristics of OCD. We compared GM and WM volume in a group of 14 patients with OCD and 15 healthy controls using a 3 T MRI scanner and an optimized VBM protocol. Regression analysis was used to examine relationships between GM and WM volume and clinical variables. In OCD we have found total WM volume reduction and marked mediofrontal, right temporo-parieto-occipital, right precentral, left middle temporal, left cerebellar and bilateral pons and mesencephalon GM volume reduction in the voxel-based analysis (p ≤ 0.05, FDR corrected, extent threshold 100 voxels). Regression analysis indicated a positive relationship between left orbitofrontal GM volume and severity of obsessive-compulsive symptoms and a negative relationship between symptom severity and GM volume in supramarginal gyri. Earlier age of OCD onset and longer illness duration were associated with smaller left occipital GM and right parietal WM and with greater left medial frontal GM and left frontal WM (p ≤ 0.001, uncorrected, extent threshold 50 voxels). Our results confirm volumetric abnormalities in the medial frontal and dorsal cortical areas in OCD. The relationships between OCD and clinical variables provide further evidence that frontal, parietal and occipital structures play a role in the disorder.     

Magnetic resonance spectroscopy of the occipital cortex and the cerebellar vermis distinguishes individual cats affected with alpha‐mannosidosis from normal cats

A genetic deficiency of lysosomal alpha‐mannosidase causes the lysosomal storage disease alpha‐mannosidosis (AMD), in which oligosaccharide accumulation occurs in neurons and glia. The purpose of this study was to evaluate the role of magnetic resonance spectroscopy (MRS) in detecting the oligosaccharide accumulation in AMD. Five cats with AMD and eight age‐matched normal cats underwent in vivo MRS studies with a single voxel short echo time (20 ms) STEAM spectroscopy sequence on a 4.7T magnet. Two voxels were studied in each cat, from the cerebellar vermis and the occipital cortex. Metabolites of brain samples from these regions were extracted with perchloric acid and analyzed by high resolution NMR spectroscopy. A significantly elevated unresolved resonance signal between 3.4 and 4. ppm was observed in the cerebellar vermis and occipital cortex of all AMD cats, which was absent in normal cats. This resonance was shown to be from carbohydrate moieties by high resolution NMR of tissue extracts. Resonances from the Glc‐NAc group (1.8–2.2 ppm) along with anomeric proton signals (4.6–5.4 ppm) from undigested oligosaccharides were also observed in the extract spectra from AMD cats. This MRS spectral pattern may be a useful biomarker for AMD diagnosis as well as for assessing responses to therapy. Copyright © 2009 John Wiley & Sons, Ltd.     

Bi‐exponential 23Na T2* component analysis in the human brain

The purpose of this study was to measure the sodium transverse relaxation time T₂* in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T₂* values were fitted on a voxel‐by‐voxel basis using a bi‐exponential model. Data were also analysed using a continuous distribution fit with a region of interest‐based inverse Laplace transform. Average T₂* values were 3.4 ± 0.2 ms and 23.5 ± 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 ± 0.5 ms and 26.3 ± 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi‐exponential model. Continuous distribution fits yielded results of 3.1 ± 0.3 ms and 18.8 ± 3.2 ms in WM for the short and long components, respectively, and 2.9 ± 0.4 ms and 17.2 ± 2 ms in GM for the short and long components, respectively. ²³Na T₂* values of the brain for the short and long components for various anatomical locations using ultra‐short TEs are presented for the first time.     

Global brain metabolic quantification with whole‐head proton MRS at 3 T

Total N‐acetyl‐aspartate + N‐acetyl‐aspartate–glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS (¹H–MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%–65% of the brain. Here we wish to demonstrate that non‐localized, whole‐head (WH) ¹H–MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T₁‐weighted MRI for tissue segmentation, non‐localizing, approximately 3 min WH ¹H–MRS (T_E/T_R/T_I = 5/10 1 /940 ms) and 30 min ¹H–MR spectroscopic imaging (MRSI) (T_E/T_R = 35/2100 ms) in a 360 cm³ volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The mean NAA/Cr and NAA/Cho ratios in the WH were only slightly higher than the “brain‐only” VOI: 1.5 versus 1.4 (7%) and 6.6 versus 5.9 (11%); Cho/Cr were not different. The brain/WH volume ratio was 0.31 ± 0.03 (brain ≈ 30% of WH volume). Air‐tissue susceptibility‐driven local magnetic field changes going from the brain outwards showed sharp gradients of more than 100 Hz/cm (1 ppm/cm), explaining the skull's Cr and Cho signal losses through resonance shifts, line broadening and destructive interference. The similarity of non‐localized WH and localized VOI NAA, Cr and Cho concentrations and their ratios suggests that their signals originate predominantly from the brain. Therefore, the fast, comprehensive WH‐¹H‐MRS method may facilitate quantification of these metabolites, which are common surrogate markers in neurological disorders.     

Validating a robust double‐quantum‐filtered 1H MRS lactate measurement method in high‐grade brain tumours

¹H MRS measurements of lactate are often confounded by overlapping lipid signals. Double‐quantum (DQ) filtering eliminates lipid signals and permits single‐shot measurements, which avoid subtraction artefacts in moving tissues. This study evaluated a single‐voxel‐localized DQ filtering method qualitatively and quantitatively for measuring lactate concentrations in the presence of lipid, using high‐grade brain tumours in which the results could be compared with standard acquisition as a reference. Paired standard acquisition and DQ‐filtered ¹H MR spectra were acquired at 3T from patients receiving treatment for glioblastoma, using fLASER (localization by adiabatic selective refocusing using frequency offset corrected inversion pulses) single‐voxel localization. Data were acquired from 2 × 2 × 2 cm³ voxels, with a repetition time of 1 s and 128 averages (standard acquisition) or 256 averages (DQ‐filtered acquisition), requiring 2.15 and 4.3 min respectively. Of 37 evaluated data pairs, 20 cases (54%) had measureable lactate (fitted Cramér–Rao lower bounds ≤ 20%) in either the DQ‐filtered or the standard acquisition spectra. The measured DQ‐filtered lactate signal was consistently downfield of lipid (1.33 ± 0.03 ppm vs 1.22 ± 0.08 ppm; p = 0.002), showing that it was not caused by lipid breakthrough, and that it matched the lactate signal seen in standard measurements (1.36 ± 0.02 ppm). In the absence of lipid, similar lactate concentrations were measured by the two methods (mean ratio DQ filtered/standard acquisition = 1.10 ± 0.21). In 7/20 cases with measurable lactate, signal was not measureable in the standard acquisition owing to lipid overlap but was quantified in the DQ‐filtered acquisition. Conversely, lactate was undetected in seven DQ‐filtered acquisitions but visible using the standard acquisition. In conclusion, the DQ filtering method has proven robust in eliminating lipid and permits uncontaminated measurement of lactate. This is important validation prior to use in tissues outside the brain, which contain large amounts of lipid and which are often susceptible to motion.     

Volumetric Neuroimaging of the Atlantic White‐Sided Dolphin (Lagenorhynchus acutus) Brain from in situ Magnetic Resonance Images

The structure and development of the brain are extremely difficult to study in free‐ranging marine mammals. Here, we report measurements of total white matter (WM), total gray matter (GM), cerebellum (WM and GM), hippocampus, and corpus callosum made from magnetic resonance (MR) images of fresh, postmortem brains of the Atlantic white‐sided dolphin (Lagenorhynchus acutus) imaged in situ (i.e., the brain intact within the skull, with the head still attached to the body). WM:GM volume ratios of the entire brain increased from fetus to adult, illustrating the increase in myelination during ontogeny. The cerebellum (WM and GM combined) of subadult and adult dolphins ranged from 13.8 to 15.0% of total brain size, much larger than that of primates. The corpus callosum mid‐sagittal area to brain mass ratios (CCA/BM) ranged from 0.088 to 0.137, smaller than in most mammals. Dolphin hippocampal volumes were smaller than those of carnivores, ungulates, and humans, consistent with previous qualitative results assessed from histological studies of the bottlenose dolphin brain. These quantitative measurements of white matter, gray matter, corpus callosum, and hippocampus are the first to be determined from MR images for any cetacean species. We establish here an approach for accurately determining the size of brain structures from in situ MR images of stranded, dead dolphins. This approach can be used not only for comparative and developmental studies of marine mammal brains but also for investigation of the potential impacts of natural and anthropogenic chemicals on neurodevelopment and neuroanatomy in exposed marine mammal populations. Anat Rec, 291:263–282, 2008. © 2008 Wiley‐Liss, Inc.     

Errors in 1H‐MRS estimates of brain metabolite concentrations caused by failing to take into account tissue‐specific signal relaxation

Accurate measurement of brain metabolite concentrations with proton magnetic resonance spectroscopy (¹H‐MRS) can be problematic because of large voxels with mixed tissue composition, requiring adjustment for differing relaxation rates in each tissue if absolute concentration estimates are desired. Adjusting for tissue‐specific metabolite signal relaxation, however, also requires a knowledge of the relative concentrations of the metabolite in gray (GM) and white (WM) matter, which are not known a priori. Expressions for the estimation of the molality and molarity of brain metabolites with ¹H‐MRS are extended to account for tissue‐specific relaxation of the metabolite signals and examined under different assumptions with simulated and real data. Although the modified equations have two unknowns, and hence are unsolvable explicitly, they are nonetheless useful for the estimation of the effect of tissue‐specific metabolite relaxation rates on concentration estimates under a range of assumptions and experimental parameters using simulated and real data. In simulated data using reported GM and WM T₁ and T₂ times for N‐acetylaspartate (NAA) at 3 T and a hypothetical GM/WM NAA ratio, errors of 6.5–7.8% in concentrations resulted when TR = 1.5 s and TE = 0.144 s, but were reduced to less than 0.5% when TR = 6 s and TE = 0.006 s. In real data obtained at TR/TE = 1.5 s/0.04 s, the difference in the results (4%) was similar to that obtained with simulated data when assuming tissue‐specific relaxation times rather than GM–WM‐averaged times. Using the expressions introduced in this article, these results can be extrapolated to any metabolite or set of assumptions regarding tissue‐specific relaxation. Furthermore, although serving to bound the problem, this work underscores the challenge of correcting for relaxation effects, given that relaxation times are generally not known and impractical to measure in most studies. To minimize such effects, the data should be acquired with pulse sequence parameters that minimize the effect of signal relaxation.     

Effects of normal aging and SCN1A risk‐gene expression on brain metabolites: evidence for an association between SCN1A and myo‐inositol

Previously reported MRS findings in the aging brain include lower N‐acetylaspartate (NAA) and higher myo‐inositol (mI), total creatine (Cr) and choline‐containing compound (Cho) concentrations. Alterations in the sodium channel voltage gated type I, alpha subunit SCN1A variant rs10930201 have been reported to be associated with several neurological disorders with cognitive deficits. MRS studies in SCN1A‐related diseases have reported striking differences in the mI concentrations between patients and controls. In a study on ‘healthy aging’, we investigated metabolite spectra in a sample of 83 healthy volunteers and determined their age dependence. We also investigated a potential link between SCN1A and mI. We observed a significantly negative association of NAA (p = 0.004) and significantly positive associations of mI (p ≤ 0.001), Cr (p ≤ 0.001) and Cho (p = 0.034) with age in frontal white matter. The linear association of Cho ends at the age of about 50 years and is followed by an inverted ‘U’‐shaped curve. Further, mI was higher in C allele carriers of the SCN1A variant rs10930201. Our results corroborated the age‐related changes in metabolite concentrations, and found evidence for a link between SCN1A and frontal white matter mI in healthy subjects. Copyright © 2013 John Wiley & Sons, Ltd.