Accurate determination of brain metabolite concentrations using ERETIC as external reference

Magnetic Resonance Spectroscopy (MRS) can provide in vivo metabolite concentrations in standard concentration units if a reliable reference signal is available. For ¹H MRS in the human brain, typically the signal from the tissue water is used as the (internal) reference signal. However, a concentration determination based on the tissue water signal most often requires a reliable estimate of the water concentration present in the investigated tissue. Especially in clinically interesting cases, this estimation might be difficult. To avoid assumptions about the water in the investigated tissue, the Electric REference To access In vivo Concentrations (ERETIC) method has been proposed. In this approach, the metabolite signal is compared with a reference signal acquired in a phantom and potential coil‐loading differences are corrected using a synthetic reference signal. The aim of this study, conducted with a transceiver quadrature head coil, was to increase the accuracy of the ERETIC method by correcting the influence of spatial B₁ inhomogeneities and to simplify the quantification with ERETIC by incorporating an automatic phase correction for the ERETIC signal. Transmit field ( ) differences are minimized with a volume‐selective power optimization, whereas reception sensitivity changes are corrected using contrast‐minimized images of the brain and by adapting the voxel location in the phantom measurement closely to the position measured in vivo. By applying the proposed B₁ correction scheme, the mean metabolite concentrations determined with ERETIC in 21 healthy subjects at three different positions agree with concentrations derived with the tissue water signal as reference. In addition, brain water concentrations determined with ERETIC were in agreement with estimations derived using tissue segmentation and literature values for relative water densities. Based on the results, the ERETIC method presented here is a valid tool to derive in vivo metabolite concentration, with potential advantages compared with internal water referencing in diseased tissue.     

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.     

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.     

Reproducibility of whole‐brain temperature mapping and metabolite quantification using proton magnetic resonance spectroscopy

Assessing brain temperature can provide important information about disease processes (e.g., stroke, trauma) and therapeutic effects (e.g., cerebral hypothermia treatment). Whole‐brain magnetic resonance spectroscopic imaging (WB‐MRSI) is increasingly used to quantify brain metabolites across the entire brain. However, its feasibility and reliability for estimating brain temperature needs further validation. Therefore, the present study evaluates the reproducibility of WB‐MRSI for temperature mapping as well as metabolite quantification across the whole brain in healthy volunteers. Ten healthy adults were scanned on three occasions 1 week apart. Brain temperature, along with four commonly assessed brain metabolites—total N‐acetyl‐aspartate (tNAA), total creatine (tCr), total choline (tCho) and myo‐inositol (mI)—were measured from WB‐MRSI data. Reproducibility was evaluated using the coefficient of variation (CV). The measured mean (range) of the intra‐subject CVs was 0.9% (0.6%‐1.6%) for brain temperature mapping, and 4.7% (2.5%‐15.7%), 6.4% (2.4%‐18.9%) and 14.2% (4.4%‐52.6%) for tNAA, tCho and mI, respectively, with reference to tCr. Consistently larger variability was found when using H₂O as the reference for metabolite quantifications: 7.8% (3.3%‐17.8%), 7.8% (3.1%‐18.0%), 9.8% (3.7%‐31.0%) and 17.0% (5.9%‐54.0%) for tNAA, tCr, tCho and mI, respectively. Further, the larger the brain region (indicated by a greater number of voxels within that region), the better the reproducibility for both temperature and metabolite estimates. Our results demonstrate good reproducibility of whole‐brain temperature and metabolite measurements using the WB‐MRSI technique.     

Quantitative magnetic resonance spectroscopy at 3T based on the principle of reciprocity

Quantification of magnetic resonance spectroscopy signals using the phantom replacement method requires an adequate correction of differences between the acquisition of the reference signal in the phantom and the measurement in vivo. Applying the principle of reciprocity, sensitivity differences can be corrected at low field strength by measuring the RF transmitter gain needed to obtain a certain flip angle in the measured volume. However, at higher field strength the transmit sensitivity may vary from the reception sensitivity, which leads to wrongly estimated concentrations. To address this issue, a quantification approach based on the principle of reciprocity for use at 3T is proposed and validated thoroughly. In this approach, the RF transmitter gain is determined automatically using a volume‐selective power optimization and complemented with information from relative reception sensitivity maps derived from contrast‐minimized images to correct differences in transmission and reception sensitivity. In this way, a reliable measure of the local sensitivity was obtained. The proposed method is used to derive in vivo concentrations of brain metabolites and tissue water in two studies with different coil sets in a total of 40 healthy volunteers. Resulting molar concentrations are compared with results using internal water referencing (IWR) and Electric REference To access In vivo Concentrations (ERETIC). With the proposed method, changes in coil loading and regional sensitivity due to B₁ inhomogeneities are successfully corrected, as demonstrated in phantom and in vivo measurements. For the tissue water content, coefficients of variation between 2% and 3.5% were obtained (0.6–1.4% in a single subject). The coefficients of variation of the three major metabolites ranged from 3.4–14.5%. In general, the derived concentrations agree well with values estimated with IWR. Hence, the presented method is a valuable alternative for IWR, without the need for additional hardware such as ERETIC and with potential advantages in diseased tissue.     

Short-TE localised 1H MRS of the human brain at 3 T: quantification of the metabolite signals using two approaches to account for macromolecular signal contributions

The goal of this study was to validate metabolite quantification at short TE, with particular focus on how to best account for the macromolecular signal contribution. A robust, short-TE PRESS protocol is presented, which allows reliable quantification, in vivo, of metabolite signals at 3 T in human brain. Water suppression was adapted to the experimental conditions at 3 T. Metabolite signal from the parietal white matter was quantified in the time domain using QUEST (jMRUI). The increased macromolecular signal contribution at short TE was dealt with by two approaches, based on either metabolite nulling or initial signal truncation. A detailed comparison of the two approaches was made. The first used a metabolite-nulled signal, measured either individually or averaged over different subjects. The second used the total signal, metabolites and macromolecules, from a single scan. The two approaches gave similar quantification results in terms of metabolite concentrations, but differed in their precision and the number of metabolites quantified reliably. With an average metabolite-nulled baseline, a set of seven metabolites could be reliably quantified in parietal white matter under these experimental conditions: N-acetylaspartate, myo-inositol, glucose, glutamate, glutathione, creatine and choline. When initial signal truncation was used, glucose was removed from this set. The short TE (10-11 ms) facilitated quantification of glutamate. The reliable quantification of N-acetylaspartyl glutamate at 3 T proved very difficult.     

Anatomical and functional brain imaging using high-resolution echo-planar spectroscopic imaging at 1.5 Tesla

High-resolution echo-planar spectroscopic imaging (EPSI) of water resonance (i.e. without water suppression) is proposed for anatomic and functional imaging of the human brain at 1.5 T. Water spectra with a resolution of 2.6 Hz and a bandwidth of 333 Hz were obtained in small voxels (1.7 x 1.7 x 3 mm3) across a single slice. Although water spectra appeared Lorentzian in most of the voxels in the brain, non-Lorentzian broadening of the water resonance was observed in voxels containing blood vessels. In functional experiments with a motor task, robust activation in motor cortices was observed in high-resolution T2* maps generated from the EPSI data. Shift of the water resonance frequency occurred during neuronal activation in motor cortices. The activation areas appeared to be more localized after excluding the voxels in which the lineshape of the water resonance had elevated T2* and became more non-Lorentzian during the motor task. These preliminary results suggest that high-resolution EPSI is a promising tool to study susceptibility-related effects, such as BOLD contrast, for improved anatomical and functional imaging of the brain.     

Proton MRS of early post-natal mouse brain modifications in vivo

NMR provides a non-invasive tool for the phenotypic characterisation of mouse models. The aim of the present study was to apply reliable in vivo MRS techniques for non-invasive investigations of brain development in normal and transgenic mice, by monitoring metabolite concentrations in different brain regions. The conditions of anaesthesia, immobilisation and respiratory monitoring were optimized to carry out in vivo MRS studies in young mice. All the experiments were performed in normal mice, at 9.4 T, applying a point-resolved spectroscopy (PRESS) sequence (TR = 2,000 ms; TE = 130 ms). We obtained reproducible in vivo (1)H NMR spectra of wild-type mouse brains as early as post-natal day 5, which allowed us to follow brain maturation variations from post-natal days 5 to 21. The survival rate of animals was between 66 and 90% at post-natal days 5 and 21, respectively. Developmental changes of metabolite concentrations were measured in three brain regions: the thalamus, a region rich in cell bodies, the olfactory bulb, rich in fibre tracts actively myelinated during brain maturation, and the cerebellum. The voxel size varied from 2 to 8 microL according to the size of the brain structure analysed. The absolute concentrations of the total creatine, taurine, total choline, N-acetylaspartate and of the glutamate/glutamine pool were determined from (1)H NMR spectra obtained in the different brain regions at post-natal day 5, 10, 15 and 21. Variations observed during brain development were in accordance with those previously reported in mice using ex vivo MRS studies, and also in rats and humans in vivo. Possibilities of longitudinal MRS analysis in maturing mice brains provide new perspectives to characterise better the tremendous number of transgenic mutant mice generated with the aim of decrypting the complexity of brain development and neurodegenerative diseases but also to follow the impact of environmental and therapeutic factors.     

Quantitative short echo-time 1H LASER-CSI in human brain at 4 T

A novel short echo-time (1)H chemical shift imaging (CSI) pulse sequence is presented that incorporates localization by adiabatic selective refocusing (LASER) for FOV-reduction, k-space weighted averaging and macromolecule subtraction, to obtain quantitative concentration measurements of N-acetyl-aspartate, glutamate, glucose, myo-inositol, creatine and choline using a nominal voxel size of 0.56 cm(3). A comparison of spectral quality and metabolite concentration measurements was made between LASER-CSI and LASER-single voxel spectroscopy (SVS) in a region of homogeneous parietal white matter (N = 8). No significant differences were found in linewidths, signal-to-noise ratios or the effectiveness of the macromolecule subtraction between SVS and CSI. Water suppression was 45% more effective in SVS than in CSI (p < 0.05). A linear regression of all paired metabolite measurements resulted in a slope = 1.01 +/- 0.03 (r(2) = 0.73). LASER-CSI concentration measurements of N-acetyl-aspartate, glutamate, glucose, myo-inositol, creatine and choline were in agreement (within standard deviations) with LASER-SVS measurements. LASER-CSI is, therefore, a viable and attractive option for future (1)H CSI investigations.     

Statistical evaluation of time-dependent metabolite concentrations: estimation of post-mortem intervals based on in situ 1H-MRS of the brain

Knowledge of the time interval from death (post-mortem interval, PMI) has an enormous legal, criminological and psychological impact. Aiming to find an objective method for the determination of PMIs in forensic medicine, 1H-MR spectroscopy (1H-MRS) was used in a sheep head model to follow changes in brain metabolite concentrations after death. Following the characterization of newly observed metabolites (Ith et al., Magn. Reson. Med. 2002; 5: 915-920), the full set of acquired spectra was analyzed statistically to provide a quantitative estimation of PMIs with their respective confidence limits. In a first step, analytical mathematical functions are proposed to describe the time courses of 10 metabolites in the decomposing brain up to 3 weeks post-mortem. Subsequently, the inverted functions are used to predict PMIs based on the measured metabolite concentrations. Individual PMIs calculated from five different metabolites are then pooled, being weighted by their inverse variances. The predicted PMIs from all individual examinations in the sheep model are compared with known true times. In addition, four human cases with forensically estimated PMIs are compared with predictions based on single in situ MRS measurements. Interpretation of the individual sheep examinations gave a good correlation up to 250 h post-mortem, demonstrating that the predicted PMIs are consistent with the data used to generate the model. Comparison of the estimated PMIs with the forensically determined PMIs in the four human cases shows an adequate correlation. Current PMI estimations based on forensic methods typically suffer from uncertainties in the order of days to weeks without mathematically defined confidence information. In turn, a single 1H-MRS measurement of brain tissue in situ results in PMIs with defined and favorable confidence intervals in the range of hours, thus offering a quantitative and objective method for the determination of PMIs.     

Determination of metabolite concentrations in human brain tumour biopsy samples using HR-MAS and ERETIC measurements

Accurate determination of the concentration of the metabolites contained in intact human biopsies of 10 glioblastoma multiforme samples was achieved using one-dimensional (1)H high-resolution magic angle spinning (HR-MAS) NMR combined with ERETIC (electronic reference to in vivo concentrations) measurements. The amount of sample used ranged from 6.8 to 12.9 mg. Metabolite concentrations were measured in each sample using two methods: with DSS (2,2-dimethyl-2-silapentane-5-sulfonate sodium salt) as an internal reference and with ERETIC as an external electronically generated reference. The ERETIC signal was shown to be highly reproducible and did not affect the spectral quality. The concentrations calculated by the ERETIC method in model solutions were shown to be independent of the salt concentration in the range typically found in biological samples (0-250 mM). The ERETIC method proved to be straightforward to use in tissues and much more robust than the internal standard method. The concentrations calculated using the internal DSS concentration were systematically found to be higher than those determined using the ERETIC technique. These results indicate a possible interaction of the DSS molecules with the biopsy sample. Moreover, variations in the sample preparation process, with possible loss of DSS solution, may hamper the quantification process, as happens in one of the ten samples analysed. In this study, the ERETIC method was validated on model solutions and used in brain tumour tissues. Calculated metabolite concentrations obtained with the ERETIC procedure matched the values determined in the same type of tumours by in vivo, ex vivo and in vitro methodologies.     

Effect of paramagnetic manganese cations on (1)H MRS of the brain

Manganese cations (Mn(2+)) can be used as an intracellular contrast agent for structural, functional and neural pathway imaging applications. However, at high concentrations, Mn(2+) is neurotoxic and may influence the concentration of (1)H MR-detectable metabolites. Furthermore, the paramagnetic Mn(2+) cations may also influence the relaxation of the metabolites under investigation. Consequently, the purpose of this study was to investigate the effect of paramagnetic Mn(2+) cations on (1)H-MR spectra of the brain using in vivo and phantom models at 4.7 T. To investigate the direct paramagnetic effects of Mn(2+) cations on the relaxation of N-acetylaspartate (NAA), creatine and choline, T(1) relaxation times of metabolite solutions, with and without 5% albumin, and containing different Mn(2+) concentrations were determined. Relaxivity values with/without 5% albumin for NAA (4.8/28.1 s(-1) mM(-1)), creatine (2.8/2.8 s(-1) mM(-1)) and choline (1.8/1.1 s(-1) mM(-1)) showed NAA to be the most sensitive metabolite to the relaxation effects of the cations. Using an in vivo optic tract tracing imaging model, we obtained two adjacent regions of interest in the superior colliculi with different water T(1) values (Mn(2+)-enhanced = 1.01 s; unenhanced = 1.14 s) 24 h after intravitreal injection of 3 microL 50 mM MnCl(2). Using phantom and in vivo water relaxation time data, we estimated the in vivo Mn(2+) concentration to be 2-8 microM. The phantom data suggest that limited metabolite relaxation effects would be expected at this concentration. Consequently, this study indicates that, in this model, the presence of Mn(2+) cations does not significantly affect (1)H-MR spectra despite possible toxic and paramagnetic effects.     

Diffusion‐weighted MRS of acetate in the rat brain

Acetate has been proposed as an astrocyte‐specific energy substrate for metabolic studies in the brain. The determination of the relative contribution of the intracellular and extracellular compartments to the acetate signal using diffusion‐weighted magnetic resonance spectroscopy can provide an insight into the cellular environment and distribution volume of acetate in the brain. In the present study, localized ¹H nuclear magnetic resonance (NMR) spectroscopy employing a diffusion‐weighted stimulated echo acquisition mode (STEAM) sequence at an ultra‐high magnetic field (14.1 T) was used to investigate the diffusivity characteristics of acetate and N‐acetylaspartate (NAA) in the rat brain in vivo during prolonged acetate infusion. The persistence of the acetate resonance in ¹H spectra acquired at very large diffusion weighting indicated restricted diffusion of acetate and was attributed to intracellular spaces. However, the significantly greater diffusion of acetate relative to NAA suggests that a substantial fraction of acetate is located in the extracellular space of the brain. Assuming an even distribution for acetate in intracellular and extracellular spaces, the diffusion properties of acetate yielded a smaller volume of distribution for acetate relative to water and glucose in the rat brain.     

Neurometabolic and structural alterations in rat brain due to acute hypobaric hypoxia: in vivo 1H MRS at 7 T

In response to hypobaric hypoxia (HH), which occurs at high altitude, the brain undergoes deleterious changes at the structural and metabolite level. In vivo T₂ weighted imaging (T2WI) and ¹H‐MRS was performed to understand the structural and metabolic changes in the hippocampus region of rat brain. Data were acquired pre‐exposure (baseline controls), immediately after exposure and subsequently at the first, fourth, seventh and 14th days post exposure at normoxia. T₂ weighted images of rat brain showed hyperintensity in the CA2/CA3 region of the hippocampus 7 d after acute HH, which persisted till 14 d, probably indicating structural changes in the hippocampus. ¹H‐MRS results showed no change in metabolite level immediately after acute HH exposure, but on the first day of normoxia the myo‐inositol level was significantly decreased, possibly due to altered astrocyte metabolism. Metabolic alterations showing an increase in choline and decrease in glutamate on the fourth day of normoxia may be seen as a process of demyelination and loss of glutamate pool respectively. On the seventh and 14th days of normoxia, decreases in N‐acetylaspartate, creatine and glutamine + glutamate were observed, which might be due to decreased viability of glutamatergic neurons. In vivo ¹H‐MRS demonstrated early neurometabolic changes prior to probable structural changes post acute HH exposure. The extension of these studies will help in early risk assessment, developing intervention and strategies for combating HH related changes. Copyright © 2014 John Wiley & Sons, Ltd.     

Correlation between the temperature dependence of intrinsic MR parameters and thermal dose measured by a rapid chemical shift imaging technique

In order to investigate simultaneous MR temperature imaging and direct validation of tissue damage during thermal therapy, temperature‐dependent signal changes in proton resonance frequency (PRF) shifts, R₂* values, and T1‐weighted amplitudes are measured from one technique in ex vivo tissue. Using a multigradient echo acquisition and the Stieglitz‐McBride algorithm, the temperature sensitivity coefficients of these parameters are measured in each tissue at high spatiotemporal resolutions (1.6x1.6x4mm3, ≤ 5sec) at the range of 25‐61 °C. Non‐linear changes in MR parameters are examined and correlated with an Arrhenius rate dose model of thermal damage. Using logistic regression, the probability of changes in these parameters is calculated as a function of thermal dose to determine if changes correspond to thermal damage. Temperature sensitivity of R₂* and, in some cases, T1‐weighted amplitudes are statistically different before and after thermal damage occurred. Significant changes in the slopes of R₂* as a function of temperature are observed. Logistic regression analysis shows that these changes could be accurately predicted using the Arrhenius rate dose model (Ω = 1.01 ± 0.03), thereby showing that the changes in R₂* could be direct markers of protein denaturation. Overall, by using a chemical shift imaging technique with simultaneous temperature estimation, R₂* mapping and T1‐W imaging, it is shown that changes in the sensitivity of R₂* and, to a lesser degree, T1‐W amplitudes are measured in ex vivo tissue when thermal damage is expected to occur. These changes could possibly be used for direct validation of thermal damage in contrast to model‐based predictions. Copyright © 2011 John Wiley & Sons, Ltd.     

Sequential proton MRS study of brain metabolite changes monitored during a complete pathological cycle of demyelination and remyelination in a lysophosphatidyl choline (LPC)-induced experimental demyelinating lesion model

Metabolite changes in rat brain internal capsule (ic) area were monitored using volume localized in vivo proton MR spectroscopy (MRS) in a lysophosphatidyl choline (LPC)-induced experimental demyelinating lesion model of multiple sclerosis (MS), during the early phase (pre-acute) as well as during the complete pathological cycle of de- and re-myelination processes. The N-acetyl aspartate (NAA) peak showed reduction during the early phase of the lesion progression (demyelination) until day 10 and increased thereafter during remyelination. However, choline (Cho) and lipid resonances showed increased signal intensity during the early phase and decreased during remyelination. A progressive reduction of the NAA/Cr metabolite ratio in lesioned rats was observed during demyelination (up to day 10) compared with before lesion (control), and the value increased thereafter during remyelination (from day 15). During this period, however, the Cho/Cr ratio was a higher until day 10 and subsequently declined and was close to that calculated before lesion creation. The changes in NAA/Cr and Cho/Cr metabolite ratios correspond to changes in the individual metabolite peaks such as NAA and Cho. The increase in the intensity of the choline resonance during the early phase is indicative of the onset of an inflammatory demyelination process, and its rapid decrease thereafter is due to reduction in the inflammatory process associated with remyelination. Similarly, the increase in the intensity of lipids during the pre-acute stage of the lesion is attributed to active demyelination, which significantly decreased during remyelination. These MR results correlate well with the histology data obtained.     

Automated tissue segmentation and blind recovery of (1)H MRS imaging spectral patterns of normal and diseased human brain

Constrained non-negative matrix factorization (cNMF) with iterative data selection is described and demonstrated as a data analysis method for fast and automatic recovery of biochemically meaningful and diagnostically specific spectral patterns of the human brain from (1)H MRS imaging ((1)H MRSI) data. To achieve this goal, cNMF decomposes in vivo multidimensional (1)H MRSI data into two non-negative matrices representing (a) the underlying tissue-specific spectral patterns and (b) the spatial distribution of the corresponding metabolite concentrations. Central to the proposed approach is automatic iterative data selection which uses prior knowledge about the spatial distribution of the spectra to remove voxels that are due to artifacts and undesired metabolites/tissues such as the strong lipid and water components. The automatic recovery of diagnostic spectral patterns is demonstrated for long-TE (1)H MRSI data on normal human brain, multiple sclerosis, and serial brain tumor. The results show the ability of cNMF with iterative data selection to automatically and simultaneously recover tissue-specific spectral patterns and achieve segmentation of normal and diseased human brain tissue, concomitant with simplification of information content. These features of cNMF, which permit rapid recovery, reduction and interpretation of the complex diagnostic information content of large multi-dimensional spectroscopic imaging data sets, have the potential to enhance the clinical utility of in vivo(1)H MRSI.     

Whole-brain high-resolution metabolite mapping with 3D compressed-sensing SENSE low-rank 1H FID-MRSI

There is a growing interest in the neuroscience community to map the distribution of brain metabolites in vivo. Magnetic resonance spectroscopic imaging (MRSI) is often limited by either a poor spatial resolution and/or a long acquisition time, which severely restricts its applications for clinical and research purposes. Building on a recently developed technique of acquisition-reconstruction for 2D MRSI, we combined a fast Cartesian ¹H-FID-MRSI acquisition sequence, compressed-sensing acceleration, and low-rank total-generalized-variation constrained reconstruction to produce 3D high-resolution whole-brain MRSI with a significant acquisition time reduction. We first evaluated the acceleration performance using retrospective undersampling of a fully sampled dataset. Second, a 20 min accelerated MRSI acquisition was performed on three healthy volunteers, resulting in metabolite maps with 5 mm isotropic resolution. The metabolite maps exhibited the detailed neurochemical composition of all brain regions and revealed parts of the underlying brain anatomy. The latter assessment used previous reported knowledge and a atlas-based analysis to show consistency of the concentration contrasts and ratio across all brain regions. These results acquired on a clinical 3 T MRI scanner successfully combined 3D ¹H-FID-MRSI with a constrained reconstruction to produce detailed mapping of metabolite concentrations at high resolution over the whole brain, with an acquisition time suitable for clinical or research settings.