Are Cramér-Rao lower bounds an accurate estimate for standard deviations in in vivo magnetic resonance spectroscopy?

Due to inherent time constraints for in vivo experiments, it is infeasible to repeat multiple MRS scans to estimate standard deviations on the desired measured parameters. As such, the Cramér-Rao lower bounds (CRLBs) have become the routine method to approximate standard deviations for in vivo experiments. Cramér-Rao lower bounds, however, as the name suggests, are theoretically a lower bound on the standard deviation and it is not clear if and under what circumstances this approximation is valid. Realistic synthetic 3 T spectra were used to investigate the relationship between estimated CRLBs, true CRLBs and standard deviations. Here we demonstrate that, although the CRLBs are theoretically truly a lower bound on the standard deviation (not an equality) for the problem typically encountered in quantification, they are still an adequate approximation to standard deviation as long as the model perfectly characterizes the data. In the case when the macromolecule basis deviates from the measured macromolecules it was shown that the CRLBs can deviate from standard deviations by approximately 50% for N-acetylaspartic acid, creatine and glutamate and of the order of 100% or more for myo-inositol and γ-aminobutyric acid. In the case when the model perfectly reflects the data the CRLBs are within approximately 10% of standard deviations for all metabolites. The result of the CRLB being within 10% of standard deviations means that, for an accurate model, novel quantification methods such as machine learning or deep learning will not be able to obtain substantially more precise estimates for the desired parameters than traditional maximum-likelihood estimation.

FAMASITO: FASTMAP Shim Tool towards user-friendly single-step B0 homogenization.

Fast, automatic shimming by mapping along projections (FASTMAP) is an elegant analytical method developed to quantify three-dimensional first- and second-order spherical harmonic B0 shapes along six one-dimensional column projections. The straightforward application of this theoretical concept to B0 shimming, however, neglects crucial aspects of sequence implementation and shim hardware, commonly necessitating multistep iterative adjustments. We demonstrate a software package, referred to as FASTMAP Shim Tool (FAMASITO), which is composed of a FASTMAP pulse sequence, automated calibration and analysis routines, and a script for automatically performing experiments. With FAMASITO we demonstrate optimal single-step adjustment of first- and second-order terms (with potential <1% mean refinement of linear terms) in the prefrontal cortex of seven volunteers, one of the most difficult-to-shim areas in the adult human brain.

Magnetic resonance Spectrum simulator (MARSS), a novel software package for fast and computationally efficient basis set simulation.

The aim of this study was to develop a novel software platform for the simulation of magnetic resonance spin systems, capable of simulating a large number of spatial points (1283 ) for large in vivo spin systems (up to seven coupled spins) in a time frame of the order of a few minutes. The quantum mechanical density-matrix formalism is applied, a coherence pathway filter is utilized for handling unwanted coherence pathways, and the 1D projection method, which provides a substantial reduction in computation time for a large number of spatial points, is extended to include sequences of an arbitrary number of RF pulses. The novel software package, written in MATLAB, computes a basis set of 23 different metabolites (including the two anomers of glucose, seven coupled spins) with 1283 spatial points in 26 min for a three-pulse experiment on a personal desktop computer. The simulated spectra are experimentally verified with data from both phantom and in vivo MEGA-sLASER experiments. Recommendations are provided regarding the various assumptions made when computing a basis set for in vivo MRS with respect to the number of spatial points simulated and the consideration of relaxation.

Hippocampal single-voxel MR spectroscopy with a long echo time at 3 T using semi-LASER sequence.

The hippocampus is one of the most challenging brain regions for proton MR spectroscopy (MRS) applications. Moreover, quantification of J-coupled species such as myo-inositol (m-Ins) and glutamate + glutamine (Glx) is affected by the presence of macromolecular background. While long echo time (TE) MRS eliminates the macromolecules, it also decreases the m-Ins and Glx signal and, as a result, these metabolites are studied mainly with short TE. Here, we investigate the feasibility of reproducibly measuring their concentrations at a long TE of 120 ms, using a semi-adiabatic localization by adiabatic selective refocusing (sLASER) sequence, as this sequence was recently recommended as a standard for clinical MRS. Gradient offset-independent adiabatic refocusing pulses were implemented, and an optimal long TE for the detection of m-Ins and Glx was determined using the T2 relaxation times of macromolecules. Metabolite concentrations and their coefficients of variation (CVs) were obtained for a 3.4-mL voxel centered on the left hippocampus on 3-T MR systems at two different sites with three healthy subjects (aged 32.5 ± 10.2 years [mean ± standard deviation]) per site, with each subject scanned over two sessions, and with each session comprising three scans. Concentrations of m-Ins, choline, creatine, Glx and N-acetyl-aspartate were 5.4 ± 1.5, 1.7 ± 0.2, 5.8 ± 0.3, 11.6 ± 1.2 and 5.9 ± 0.4 mM (mean ± standard deviation), respectively. Their respective mean within-session CVs were 14.5% ± 5.9%, 6.5% ± 5.3%, 6.0% ± 3.4%, 10.6% ± 6.2% and 3.5% ± 1.4%, and their mean within-subject CVs were 17.8% ± 18.2%, 7.5% ± 6.3%, 7.4% ± 6.4%, 12.4% ± 5.3% and 4.8% ± 3.0%. The between-subject CVs were 25.0%, 12.3%, 5.3%, 10.7% and 6.4%, respectively. Hippocampal long-TE sLASER single voxel spectroscopy can provide macromolecule-independent assessment of all major metabolites including Glx and m-Ins.

Across-vendor standardization of semi-LASER for single-voxel MRS at 3T.

The semi-adiabatic localization by adiabatic selective refocusing (sLASER) sequence provides single-shot full intensity signal with clean localization and minimal chemical shift displacement error and was recommended by the international MRS Consensus Group as the preferred localization sequence at high- and ultra-high fields. Across-vendor standardization of the sLASER sequence at 3 tesla has been challenging due to the B1 requirements of the adiabatic inversion pulses and maximum B1 limitations on some platforms. The aims of this study were to design a short-echo sLASER sequence that can be executed within a B1 limit of 15 µT by taking advantage of gradient-modulated RF pulses, to implement it on three major platforms and to evaluate the between-vendor reproducibility of its perfomance with phantoms and in vivo. In addition, voxel-based first and second order B0 shimming and voxel-based B1 adjustments of RF pulses were implemented on all platforms. Amongst the gradient-modulated pulses considered (GOIA, FOCI and BASSI), GOIA-WURST was identified as the optimal refocusing pulse that provides good voxel selection within a maximum B1 of 15 µT based on localization efficiency, contamination error and ripple artifacts of the inversion profile. An sLASER sequence (30 ms echo time) that incorporates VAPOR water suppression and 3D outer volume suppression was implemented with identical parameters (RF pulse type and duration, spoiler gradients and inter-pulse delays) on GE, Philips and Siemens and generated identical spectra on the GE 'Braino' phantom between vendors. High-quality spectra were consistently obtained in multiple regions (cerebellar white matter, hippocampus, pons, posterior cingulate cortex and putamen) in the human brain across vendors (5 subjects scanned per vendor per region; mean signal-to-noise ratio > 33; mean water linewidth between 6.5 Hz to 11.4 Hz). The harmonized sLASER protocol is expected to produce high reproducibility of MRS across sites thereby allowing large multi-site studies with clinical cohorts.

Simultaneous optimization of crusher and phase cycling schemes for magnetic resonance spectroscopy: an extension of dephasing optimization through coherence order pathway selection.

PURPOSE: To extend the dephasing optimization through coherence order pathway selection (DOTCOPS) algorithm, originally designed solely for gradient crusher schemes, to include tailored phase cycling schemes for arbitrary pulse sequences and arbitrary number of coupled spins. THEORY AND METHODS: The effects all possible nested and cogwheel phase cycling schemes have on the coherence order pathways for an arbitrary experiment are considered. The DOTCOPS algorithm uses a cost function to maximally eliminate unwanted coherence pathways, with schemes preferentially eliminating unwanted coherence pathways that are less affected by the crusher scheme. Efficacy was demonstrated experimentally in 2 separate MR spectroscopy (MRS) sequences: semi-localized adiabatic selective refocusing (sLASER) and MEscher-GArwood sLASER both with phantom and in vivo experiments. RESULTS: For all sequences investigated, cogwheel was found to theoretically outperform typical nested phase cycling schemes. The chosen cogwheel phase cycling schemes through DOTCOPS were found to outperform a typical 2-step phase cycling scheme in both phantom and in vivo experiments. Both crusher schemes and phase cycling schemes with 8, 16, or 32 steps are presented for 6 of the most common advanced MRS sequences. CONCLUSION: The DOTCOPS algorithm has been extended to provide optimal crusher and phase cycling schemes considered in tandem. DOTCOPS can be applied to any pulse sequence of interest for any number of coupled spins. DOTCOPS is now able to alleviate the long-standing issue of designing effective crusher and phase cycling schemes for complex MRS modern sequences and, as a result, is expected to improve the data quality of virtually all applications.

Concentration and effective T2 relaxation times of macromolecules at 3T.

PURPOSE: We aimed to investigate the concentration and effective T2 relaxation time of macromolecules assessed with an ultra-short TE sLASER sequence in 2 brain regions, the occipital and frontal cortex, in both genders at 3T. METHODS: An optimized sLASER sequence was used in conjunction with a double-inversion preparation module to null the metabolites. Eight equally spaced TEs were chosen from 20.1 to 62.1 ms, and the macromolecules were modeled by 10 line broadened singlets. The amplitude of each of the macromolecule signals was extracted at each TE and fit to a monoexponential function to extract the respective effective T2 values. Absolute quantification of the macromolecule resonances was performed using water signal as a reference. A total of 10 young healthy adult subjects (5 females) were scanned, with spectra being obtained from both the frontal and occipital cortex. Differences in the effective T2 relaxation times and concentrations were investigated between both regions and genders. RESULTS: A wide disparity was observed between the effective T2 values of the individual resonances; however, no significant differences between gender or region for any of the measured macromolecule concentration or effective T2 values were found. CONCLUSION: The effective T2 relaxation times and concentration of 10 different macromolecule resonances were measured and found to be well represented by the monoexponential model. These results will be useful for absolute quantification of macromolecules in future studies, or in the generation of synthetic basis sets for optimization or machine learning.

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 1 H 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.

Elevated homocarnosine and GABA in subject on isoniazid as assessed through 1H MRS at 7T.

Typical magnetic resonance spectroscopy J-editing methods designed to quantify GABA suffer from contamination of both overlapping macromolecules and homocarnosine signal, introducing potential confounds. The aim of this study was to develop a novel method to assess accurately both the relative concentrations of homocarnosine as well as GABA free from overlapping creatine, homocarnosine and macromolecule signal. A novel method which utilized the combination of echo time STEAM and MEGA-sLASER magnetic resonance spectroscopy experiments at 7T were used to quantify the concentration of GABA and homocarnsoine independently, which are typically quantified in tandem. The metabolites GABA and homocarnosine were measured in brain of 6 healthy control subjects, and in a single subject medicated with isoniazid. It was found that (16.6±10.2)% of the supposed GABA signal in the brain originated from homocarnosine, and that isoniazid caused significantly elevated concentration of GABA and homocarnosine in a single subject compared to controls.

Theoretical description of modern 1 H in Vivo magnetic resonance spectroscopic pulse sequences.

This article reviews the most commonly used modern sequences designed to confront the two major challenges of in vivo magnetic resonance spectroscopy (MRS): spatial localization and metabolic specificity. The purpose of this review article is to provide a deeper and clearer understanding of the underlying mechanisms by which all modern MRS sequences operate. A descriptive explanation, consistent pulse sequence diagram, and theoretical concepts of the measured signal are given for five spatial localization sequences and three modules designed to increase metabolic specificity. Cross-sequence comparisons, including potential modifications for estimating quantitative measures like spin-lattice relaxation time T1 , spin-spin relaxation time T2 , and diffusion coefficients are briefly discussed. Level of Evidence: 5 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:1008-1029.

Dephasing optimization through coherence order pathway selection (DOTCOPS) for improved crusher schemes in MR spectroscopy.

PURPOSE: To develop an algorithm which can robustly eliminate all unwanted coherence pathways for an arbitrary magnetic resonance spectroscopy experiment through the adjustment of the relative amplitudes of crusher gradients, thereby reducing the effects of spurious echoes and mislocalization. THEORY AND METHODS: The effect of crushing gradients for all coherence pathways was modeled according to the associated physics, and a cost function was optimized which maximally crushes all unwanted coherence pathways, while unaffecting the desired coherence pathway(s). The efficacy of the method was tested versus literature schemes from 2 separate MR spectroscopy (MRS) sequences: sLASER and MEGA-sLASER with both phantom and in vivo experiments. RESULTS: Improved crushing power for 2 separate MRS sequences was demonstrated for 2 crushing schemes adopted from the literature in both phantom and in vivo data. CONCLUSION: A novel algorithm and associated software was developed based on rigorous treatment of all coherence pathways, which can be applied to any arbitrary magnetic resonance spectroscopic pulse sequence of interest and any arbitrary coupled spin system. This developed method solves a long-standing problem in in vivo MRS and is expected to critically improve the data quality of virtually all MRS applications.

Diffusion-weighted J-resolved spectroscopy.

PURPOSE: To develop a novel diffusion-weighted magnetic resonance spectroscopy (DW-MRS) technique in conjunction with J-resolved spatially localized spectroscopy (JPRESS) to measure the apparent diffusion coefficients (ADCs) of brain metabolites beyond N-acetylaspartic acid (NAA), creatine (Cr), and choline (Cho) at 3T. This technique will be useful to probe tissue microstructures in vivo, as the various metabolites have different physiological characteristics. METHODS: Two JPRESS spectra were collected (high b-value and low b-value), and the ADCs of 16 different metabolites were estimated. Two analysis pipelines were developed: 1) a 2D pipeline that uses ProFit software to extract ADCs from metabolites not typically accessible at 3T and 2) a 1D pipeline that uses TARQUIN software to extract the metabolite concentrations from each line in the 2D dataset, allowing for scaling as well as validation. RESULTS: The ADCs of 16 different metabolites were estimated from within six subjects in parietal white matter. There was excellent agreement between the results obtained from the 1D and 2D pipelines for NAA, Cr, and Cho. CONCLUSION: The proposed technique provided consistent estimates for the ADCs of NAA, Cr, Cho, glutamate + glutamine, and myo-inositol in all subjects and additionally glutathione and scyllo-inositol in all but one subject. Magn Reson Med 78:1235-1245, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

A rapid inversion technique for the measurement of longitudinal relaxation times of brain metabolites: application to lactate in high-grade gliomas at 3 T.

The aim of this study was to develop a time-efficient inversion technique to measure the T1 relaxation time of the methyl group of lactate (Lac) in the presence of contaminating lipids and to measure T1 at 3 T in a cohort of primary high-grade gliomas. Three numerically optimized inversion times (TIs) were chosen to minimize the expected error in T1 estimates for a given input total scan duration (set to be 30 min). A two-cycle spectral editing scheme was used to suppress contaminating lipids. The T1 values were then estimated from least-squares fitting of signal measurements versus TI. Lac T1 was estimated as 2000 ± 280 ms. After correcting for T1 (and T2 from literature values), the mean absolute Lac concentration was estimated as 4.3 ± 2.6 mm. The technique developed agrees with the results obtained by standard inversion recovery and can be used to provide rapid T1 estimates of other spectral components as required. Lac T1 exhibits similar variations to other major metabolites observable by MRS in high-grade gliomas. The T1 estimate provided here will be useful for future MRS studies wishing to report relaxation-corrected estimates of Lac concentration as an objective tumor biomarker. Copyright © 2016 John Wiley & Sons, Ltd.

Simultaneous detection of metabolite concentration changes, water BOLD signal and pH changes during visual stimulation in the human brain at 9.4T.

This study presents a method to directly link metabolite concentration changes and BOLD response in the human brain during visual stimulation by measuring the water and metabolite signals simultaneously. Therefore, the metabolite-cycling (MC) non-water suppressed semiLASER localization technique was optimized for functional 1H MRS in the human brain at 9.4 T. Data of 13 volunteers were acquired during a 26:40 min visual stimulation block-design paradigm. Activation-induced BOLD signal was observed in the MC water signal as well as in the NAA-CH3 and tCr-CH3 singlets. During stimulation, glutamate concentration increased 2.3 ± 2.0% to a new steady-state, while a continuous increase over the whole stimulation period could be observed in lactate with a mean increase of 35.6 ± 23.1%. These increases of Lac and Glu during brain activation confirm previous findings reported in literature. A positive correlation of the MC water BOLD signal with glutamate and lactate concentration changes was found. In addition, a pH decrease calculated from a change in the ratio of PCr to Cr was observed during brain activation, particularly at the onset of the stimulation.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin ßE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

INSPECTOR: free software for magnetic resonance spectroscopy data inspection, processing, simulation and analysis.

In vivo magnetic resonance spectroscopy (MRS) is a powerful tool for biomedical research and clinical diagnostics, allowing for non-invasive measurement and analysis of small molecules from living tissues. However, currently available MRS processing and analytical software tools are limited in their potential for in-depth quality management, access to details of the processing stream, and user friendliness. Moreover, available MRS software focuses on selected aspects of MRS such as simulation, signal processing or analysis, necessitating the use of multiple packages and interfacing among them for biomedical applications. The freeware INSPECTOR comprises enhanced MRS data processing, simulation and analytical capabilities in a one-stop-shop solution for a wide range of biomedical research and diagnostic applications. Extensive data handling, quality management and visualization options are built in, enabling the assessment of every step of the processing chain with maximum transparency. The parameters of the processing can be flexibly chosen and tailored for the specific research problem, and extended confidence information is provided with the analysis. The INSPECTOR software stands out in its user-friendly workflow and potential for automation. In addition to convenience, the functionalities of INSPECTOR ensure rigorous and consistent data processing throughout multi-experiment and multi-center studies.

UTE-SPECIAL for3D localization at an echo time of 4 ms on a clinical 3 T scanner.

Reducing the echo time of magnetic resonance spectroscopy experiments is appealing because it increases the available signal and reduces J-evolution of coupled metabolites. In this manuscript a novel sequence, referred to as Ultrashort echo TimE, SPin ECho, full Intensity Acquired Localized (UTE-SPECIAL), is described which is able to achieve ultrashort echo times (4 ms) on a standard clinical 3 T MR system while recovering the entirety of the available magnetization. UTE-SPECIAL obtains full 3D spatial localization through a 2D adiabatic inversion pulse which is cycled "on" and "off" every other repetition, in combination with a slice-selective excitation pulse. In addition to an ultrashort echo time, UTE-SPECIAL has negligible chemical shift displacement artefact and, because it uses no slice-selective refocusing pulse, has no signal cancellation at the borders for J-coupled metabolites. Spectra with an ultrashort echo time of 4 ms are demonstrated in vivo at 3 T, as well as J-resolved spectra obtained in a phantom and a healthy volunteer.

Quantifying the Metabolic Signature of Multiple Sclerosis by in vivo Proton Magnetic Resonance Spectroscopy: Current Challenges and Future Outlook in the Translation From Proton Signal to Diagnostic Biomarker.

Proton magnetic resonance spectroscopy (1H-MRS) offers a growing variety of methods for querying potential diagnostic biomarkers of multiple sclerosis in living central nervous system tissue. For the past three decades, 1H-MRS has enabled the acquisition of a rich dataset suggestive of numerous metabolic alterations in lesions, normal-appearing white matter, gray matter, and spinal cord of individuals with multiple sclerosis, but this body of information is not free of seeming internal contradiction. The use of 1H-MRS signals as diagnostic biomarkers depends on reproducible and generalizable sensitivity and specificity to disease state that can be confounded by a multitude of influences, including experiment group classification and demographics; acquisition sequence; spectral quality and quantifiability; the contribution of macromolecules and lipids to the spectroscopic baseline; spectral quantification pipeline; voxel tissue and lesion composition; T 1 and T 2 relaxation; B1 field characteristics; and other features of study design, spectral acquisition and processing, and metabolite quantification about which the experimenter may possess imperfect or incomplete information. The direct comparison of 1H-MRS data from individuals with and without multiple sclerosis poses a special challenge in this regard, as several lines of evidence suggest that experimental cohorts may differ significantly in some of these parameters. We review the existing findings of in vivo 1H-MRS on central nervous system metabolic abnormalities in multiple sclerosis and its subtypes within the context of study design, spectral acquisition and processing, and metabolite quantification and offer an outlook on technical considerations, including the growing use of machine learning, by future investigations into diagnostic biomarkers of multiple sclerosis measurable by 1H-MRS.

Synchrotron-based coherent scatter x-ray projection imaging using an array of monoenergetic pencil beams.

Traditional projection x-ray imaging utilizes only the information from the primary photons. Low-angle coherent scatter images can be acquired simultaneous to the primary images and provide additional information. In medical applications scatter imaging can improve x-ray contrast or reduce dose using information that is currently discarded in radiological images to augment the transmitted radiation information. Other applications include non-destructive testing and security. A system at the Canadian Light Source synchrotron was configured which utilizes multiple pencil beams (up to five) to create both primary and coherent scatter projection images, simultaneously. The sample was scanned through the beams using an automated step-and-shoot setup. Pixels were acquired in a hexagonal lattice to maximize packing efficiency. The typical pitch was between 1.0 and 1.6 mm. A Maximum Likelihood-Expectation Maximization-based iterative method was used to disentangle the overlapping information from the flat panel digital x-ray detector. The pixel value of the coherent scatter image was generated by integrating the radial profile (scatter intensity versus scattering angle) over an angular range. Different angular ranges maximize the contrast between different materials of interest. A five-beam primary and scatter image set (which had a pixel beam time of 990 ms and total scan time of 56 min) of a porcine phantom is included. For comparison a single-beam coherent scatter image of the same phantom is included. The muscle-fat contrast was 0.10 ± 0.01 and 1.16 ± 0.03 for the five-beam primary and scatter images, respectively. The air kerma was measured free in air using aluminum oxide optically stimulated luminescent dosimeters. The total area-averaged air kerma for the scan was measured to be 7.2 ± 0.4 cGy although due to difficulties in small-beam dosimetry this number could be inaccurate.