Publications
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(2024) Journal of Magnetic Resonance Imaging. Abstract
Background: Accurately fitting diffusion-time-dependent diffusion MRI (td-dMRI) models poses challenges due to complex and nonlinear formulas, signal noise, and limited clinical data acquisition. Purpose: Introduce a Bayesian methodology to refine microstructural fitting within the IMPULSED (Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion) model and optimize the prior distribution within the Bayesian framework. Study Type: Retrospective. Population: Involving 69 pediatric patients (median age 6 years, interquartile range [IQR] 39 years, 61% male) with 41 low-grade and 28 high-grade gliomas, of which 76.8% were identified within the brainstem or cerebellum. Field Strength/Sequence: 3 T, oscillating gradient spin-echo (OGSE) and pulsed gradient spin-echo (PGSE). Assessment: The Bayesian method's performance in fitting cell diameter ((Formula presented.)), intracellular volume fraction ((Formula presented.)), and extracellular diffusion coefficient ((Formula presented.)) was compared against the NLLS method, considering simulated and experimental data. The tumor region-of-interest (ROI) were manually delineated on the b0 images. The diagnostic performance in distinguishing high- and low-grade gliomas was assessed, and fitting accuracy was validated against H&E-stained pathology. Statistical Tests: T-test, receiver operating curve (ROC), area under the curve (AUC) and DeLong's test were conducted. Significance considered at P
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Simultaneous multi-transient linear-combination modeling of MRS data improves uncertainty estimation(2024) Magnetic Resonance in Medicine. Abstract
Purpose: The interest in applying and modeling dynamic MRS has recently grown. Two-dimensional modeling yields advantages for the precision of metabolite estimation in interrelated MRS data. However, it is unknown whether including all transients simultaneously in a 2D model without averaging (presuming a stable signal) performs similarly to one-dimensional (1D) modeling of the averaged spectrum. Therefore, we systematically investigated the accuracy, precision, and uncertainty estimation of both described model approaches. Methods: Monte Carlo simulations of synthetic MRS data were used to compare the accuracy and uncertainty estimation of simultaneous 2D multitransient linear-combination modeling (LCM) with 1D-LCM of the average. A total of 2,500 data sets per condition with different noise representations of a 64-transient MRS experiment at six signal-to-noise levels for two separate spin systems (scyllo-inositol and gamma-aminobutyric acid) were analyzed. Additional data sets with different levels of noise correlation were also analyzed. Modeling accuracy was assessed by determining the relative bias of the estimated amplitudes against the ground truth, and modeling precision was determined by SDs and Cramér-Rao lower bounds (CRLBs). Results: Amplitude estimates for 1D- and 2D-LCM agreed well and showed a similar level of bias compared with the ground truth. Estimated CRLBs agreed well between both models and with ground-truth CRLBs. For correlated noise, the estimated CRLBs increased with the correlation strength for the 1D-LCM but remained stable for the 2D-LCM. Conclusion: Our results indicate that the model performance of 2D multitransient LCM is similar to averaged 1D-LCM. This validation on a simplified scenario serves as a necessary basis for further applications of 2D modeling.
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(2024) Nature Communications. 15, 1, 906. Abstract
Consolidation of motor memories is vital to offline enhancement of new motor skills and involves short and longer-term offline processes following learning. While emerging evidence link glutamate and GABA dynamics in the primary motor cortex (M1) to online motor skill practice, its relationship with offline consolidation processes in humans is unclear. Using two-day repeated measures of behavioral and multimodal neuroimaging data before and following motor sequence learning, we show that short-term glutamatergic and GABAergic responses in M1 within minutes after learning were associated with longer-term learning-induced functional, structural, and behavioral modifications overnight. Furthermore, Glutamatergic and GABAergic modifications were differentially associated with different facets of motor memory consolidation. Our results point to unique and distinct roles of Glutamate and GABA in motor memory consolidation processes in the human brain across timescales and mechanistic levels, tying short-term changes on the neurochemical level to overnight changes in macroscale structure, function, and behavior.
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(2023) Proceedings of the National Academy of Sciences of the United States of America. 120, 52, e230398512. Abstract
Practicing motor skills stabilizes and strengthens motor memories by repeatedly reactivating and reconsolidating them. The conventional view, by which a repetitive practice is required for substantially improving skill performance, has been recently challenged by behavioral experiments, in which even brief reactivations of the motor memory have led to significant improvements in skill performance. However, the mechanisms which facilitate brief reactivation-induced skill improvements remain elusive. While initial memory consolidation has been repeatedly associated with increased neural excitation and disinhibition, reconsolidation has been shown to involve a poorly understood mixture of both excitatory and inhibitory alterations. Here, we followed a 3-d reactivationreconsolidation framework to examine whether the excitatory/inhibitory mechanisms which underlie brief reactivation and repetitive practice differ. Healthy volunteers practiced a motor sequence learning task using either brief reactivation or repetitive practice and were assessed using ultrahigh field (7T) magnetic resonance spectroscopy at the primary motor cortex (M1). We found that increased inhibition (GABA concentrations) and decreased excitation/inhibition (glutamate/GABA ratios) immediately following the brief reactivation were associated with overnight offline performance gains. These gains were on par with those exhibited following repetitive practice, where no correlations with inhibitory or excitatory changes were observed. Our findings suggest that brief reactivation and repetitive practice depend on fundamentally different neural mechanisms and that early inhibitionand not excitationis particularly important in supporting the learning gains exhibited by brief reactivation.
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(2023) Magnetic Resonance in Medicine. Abstract
Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on \u201cBest Practices & Tools for Diffusion MR Spectroscopy\u201d held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources.
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(2023) NMR in Biomedicine. e5046. Abstract
Temperature is a hallmark parameter influencing almost all magnetic resonance properties (e.g., T1, T2, proton density, and diffusion). In the preclinical setting, temperature has a large influence on animal physiology (e.g., respiration rate, heart rate, metabolism, and oxidative stress) and needs to be carefully regulated, especially when the animal is under anesthesia and thermoregulation is disrupted. We present an open-source heating and cooling system capable of regulating the temperature of the animal. The system was designed using Peltier modules capable of heating or cooling a circulating water bath with active temperature feedback. Feedback was obtained using a commercial thermistor, placed in the animal rectum, and a proportional-integral-derivative controller was used to modulate the temperature. Its operation was demonstrated in a phantom as well as in mouse and rat animal models, where the standard deviation of the temperature of the animal upon convergence was less than a 10th of a degree. An application where brain temperature of a mouse was modulated was demonstrated using an invasive optical probe and noninvasive magnetic resonance spectroscopic thermometry measurements.
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(2023) European Radiology. 33, p. 3744-3753 Abstract
Objectives: To investigate the clinical relevance of the relaxation times of lipids within breast cancer and normal fibroglandular tissue in vivo, using magnetic resonance spectroscopic fingerprinting (MRSF). Methods: Twelve patients with biopsy-confirmed breast cancer and 14 healthy controls were prospectively scanned at 3 T using a protocol consisting of diffusion tensor imaging (DTI), MRSF, and dynamic contrast-enhanced (DCE) MRI. Single-voxel MRSF data was recorded from the tumor (patients) identified using DTI or normal fibroglandular tissue (controls), in under 20 s. MRSF data was analyzed using in-house software. Linear mixed model analysis was used to compare the relaxation times of lipids in breast cancer VOIs vs. normal fibroglandular tissue. Results: Seven distinguished lipid metabolite peaks were identified and their relaxation times were recorded. Of them, several exhibited statistically significant changes between controls and patients, with strong significance (p −3) recorded for several of the lipid resonances at 1.3 ppm (T1 = 355 ± 17 ms vs. 389 ± 27 ms), 4.1 ppm (T1 = 255 ± 86 ms vs. 127 ± 33 ms), 5.22 ppm (T1 = 724 ± 81 ms vs. 516 ± 62 ms), and 5.31 ppm (T2 = 56 ± 5 ms vs. 44 ± 3.5 ms, respectively). Conclusions: The application of MRSF to breast cancer imaging is feasible and achievable in clinically relevant scan time. Further studies are required to verify and comprehend the underling biological mechanism behind the differences in lipid relaxation times in cancer and normal fibroglandular tissue. Key Points: The relaxation times of lipids in breast tissue are potential markers for quantitative characterization of the normal fibroglandular tissue and cancer. Lipid relaxation times can be acquired rapidly in a clinically relevant manner using a single-voxel technique, termed MRSF. Relaxation times of T1 at 1.3 ppm, 4.1 ppm, and 5.22 ppm, as well as of T2 at 5.31 ppm, were significantly different between measurements within breast cancer and the normal fibroglandular tissue.
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(2023) Magnetic Resonance in Medicine. Abstract
Purpose: Conventional sequences are static in nature, fixing measurement parameters in advance in anticipation of a wide range of expected tissue parameter values. We set out to design and benchmark a new, personalized approachtermed adaptive MRin which incoming subject data is used to update and fine-tune the pulse sequence parameters in real time. Methods: We implemented an adaptive, real-time multi-echo (MTE) experiment for estimating T2s. Our approach combined a Bayesian framework with model-based reconstruction. It maintained and continuously updated a prior distribution of the desired tissue parameters, including T2, which was used to guide the selection of sequence parameters in real time. Results: Computer simulations predicted accelerations between 1.7- and 3.3-fold for adaptive multi-echo sequences relative to static ones. These predictions were corroborated in phantom experiments. In healthy volunteers, our adaptive framework accelerated the measurement of T2 for n-acetyl-aspartate by a factor of 2.5. Conclusion: Adaptive pulse sequences that alter their excitations in real time could provide substantial reductions in acquisition times. Given the generality of our proposed framework, our results motivate further research into other adaptive model-based approaches to MRI and MRS.
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(2023) Magnetic Resonance in Medicine. 89, 2, p. 499-507 Abstract
Purpose: Many MRS paradigms produce 2D spectral-temporal datasets, including diffusion-weighted, functional, and hyperpolarized and enriched (carbon-13, deuterium) experiments. Conventionally, temporal parameterssuch as T2, T1, or diffusion constantsare assessed by first fitting each spectrum independently and subsequently fitting a temporal model (1D fitting). We investigated whether simultaneously fitting the entire dataset using a single spectral-temporal model (2D fitting) would improve the precision of the relevant temporal parameter. Methods: We derived a Cramer Rao lower bound for the temporal parameters for both 1D and 2D approaches for 2 experiments: a multi-echo experiment designed to estimate metabolite T2s, and a functional MRS experiment designed to estimate fractional change ((Formula presented.)) in metabolite concentrations. We investigated the dependence of the relative standard deviation (SD) of T2 in multi-echo and (Formula presented.) in functional MRS. Results: When peaks were spectrally distant, 2D fitting improved precision by approximately 20% relative to 1D fitting, regardless of the experiment and other parameter values. These gains increased exponentially as peaks drew closer. Dependence on temporal model parameters was weak to negligible. Conclusion: Our results strongly support a 2D approach to MRS fitting where applicable, and particularly in nuclei such as hydrogen and deuterium, which exhibit substantial spectral overlap.
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(2022) NeuroImage (Orlando, Fla.). 247, 118810. Abstract
The importance of the excitatory-inhibitory (E/I) balance in a wide range of cognitive and behavioral processes has prompted a commensurate interest in methods for reliably quantifying it. Proton Magnetic Resonance Spectroscopy (1H-MRS) remains the only method capable of safely and non-invasively measuring the concentrations of the brain's major excitatory (glutamate) and inhibitory (γ-aminobutyric-acid, GABA) neurotransmitters in-vivo. MRS relies on spectral Mescher-Garwood (MEGA) editing techniques at 3T to distinguish GABA from its overlapping resonances. However, with the increased spectral resolution at ultrahigh field strengths of 7T and above, non-edited spectroscopic techniques become potential viable alternatives to MEGA based approaches, and also address some of their shortcomings, such as signal loss, sensitivity to transmitter inhomogeneities and temporal resolution. We present a comprehensive comparison of both edited and non-edited strategies at 7T for simultaneously quantifying glutamate and GABA from the dorsal anterior cingulate cortex (dACC), and evaluate their reproducibility and relative bias. The combined root-mean-square test-retest reproducibility of Glu and GABA (CVE/I) was as low as 13.3% for unedited MRS at TE=80 ms using SemiLASER localization, while edited MRS at TE=80 ms yielded CVE/I=20% and 21% for asymmetric and symmetric MEGA editing, respectively. An unedited SemiLASER acquisition using a shorter echo time of TE=42 ms yielded CVE/I as low as 24.9%. Our results show that non-edited sequences at an echo time of 80 ms provide better reproducibility than either edited sequences at the same TE, or non-edited sequences at a shorter TE of 42 ms. This is supported by numerical simulations and is driven in part by a pseudo-singlet appearance of the GABA multiplets at TE=80 ms, and the excellent spectral resolution at 7T. Our results uphold a transition to non-edited MRS for monitoring the E/I balance at ultrahigh fields, and stress the importance of using a properly-optimized echo time.
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(2021) NMR in Biomedicine. 34, 6, e4507. Abstract
H-MRSI is commonly performed with gradient phase encoding, due to its simplicity and minimal radio frequency (RF) heating (specific absorption rate). Its two well-known main problems-(i) "voxel bleed" due to the intrinsic point-spread function, and (ii) chemical shift displacement error (CSDE) when slice-selective RF pulses are used, which worsens with increasing volume of interest (VOI) size-have long become accepted as unavoidable. Both problems can be mitigated with Hadamard multislice RF encoding. This is demonstrated and quantified with numerical simulations, in a multislice phantom and in five healthy young adult volunteers at 3 T, targeting a 2-cm thick temporal lobe VOI through the bilateral hippocampus. This frequently targeted region (e.g. in epilepsy and Alzheimer's disease) is subject to strong, 1-2 ppm.cm regional B0, susceptibility gradients that can dramatically reduce the signal-to-noise ratio (SNR) and water suppression effectiveness. The chemical shift imaging (CSI) sequence used a 3-ms Shinnar-Le Roux (SLR) 90° RF pulse, acquiring eight steps in the slice direction. The Hadamard sequence acquired two overlapping slices using the same SLR 90° pulses, under twofold stronger gradients that proportionally halved the CSDE. Both sequences used 2D 20 × 20 rosette spectroscopic imaging (RSI) for in-plane spatial localization and both used RF and gradient performance characteristics that are easily met by all modern MRI instruments. The results show that Hadamard spectroscopic imaging (HSI) suffered dramatically less signal bleed within the VOI compared with CSI (50%) in a phantom specifically designed to test these effects. The voxels' SNR per unit volume per unit time was also 40% higher for HSI. In a group of five healthy volunteers, we show that HSI with in-plane 2D-RSI facilitates fast, 3D multivoxel encoding at submilliliter spatial resolution, over the bilateral human hippocampus, in under 10 min, with negligible CSDE, spectral and spatial contamination and more than 6% improved SNR per unit time per unit volume.
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(2021) NMR in Biomedicine. 4492. Abstract
For the spectroscopic assessment of brain disorders that require large-volume coverage, the requirements of RF performance and field homogeneity are high. For epilepsy, this is also challenging given the inter-patient variation in location, severity and subtlety of anatomical identification and its tendency to involve the temporal region. We apply a targeted method to examine the utility of large-volume MR spectroscopic imaging (MRSI) in surgical epilepsy patients, implementing a two-step acquisition, comprised of a 3D acquisition to cover the fronto-parietal regions, and a contiguous parallel two-slice Hadamard-encoded acquisition to cover the temporal-occipital region, both with TR/TE = 2000/40 ms and matched acquisition times. With restricted (static, first/second-order) B0 shimming in their respective regions, the Cramér-Rao lower bounds for creatine from the temporal lobe two-slice Hadamard and frontal-parietal 3D acquisition are 8.1 ± 2.2% and 6.3 ± 1.9% respectively. The datasets are combined to provide a total 60 mm axial coverage over the frontal, parietal and superior temporal to middle temporal-occipital regions. We applied these acquisitions at a nominal 400 mm3 voxel resolution in n = 27 pre-surgical epilepsy patients and n = 20 controls. In controls, 86.6 ± 3.2% voxels with at least 50% tissue (white + gray matter, excluding CSF) survived spectral quality inclusion criteria. Since all patients were clinically followed for at least 1 year after surgery, seizure frequency outcome was available for all. The MRSI measurements of the total fractional metabolic dysfunction (characterized by the Cr/NAA metric) in FreeSurfer MRI gray matter segmented regions, in the patients compared with the controls, exhibited a significant Spearman correlation with post-surgical outcome. This finding suggests that a larger burden of metabolic dysfunction is seen in patients with poorer post-surgical seizure control.
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(2020) NeuroImage. 223, 117338. Abstract
Recent implications of glutamatergic signaling in a wide range of psychiatric disorders has highlighted the need to study the dynamics of glutamate (Glu) in the brain outside of steady state. A promising modality for doing so is functional Magnetic Resonance Spectroscopy (fMRS). Recent human studies at high magnetic fields (7T) have reported small but consistent changes in metabolite concentrations, in particular a 24% increase in Glu during visual and motor stimulation. While the origins of these changes remain the topic of ongoing research, the ability of fMRS to observe metabolites directly associated with neurotransmission and brain energetics could potentially aid our understanding of brain pathophysiology and the interpretation of functional imaging experiments. For this to happen, the current ultrahigh field results must be reproduced at lower, widely available clinical field strengths, in response to a wide variety of stimuli classes. Our goal herein was to investigate metabolite changes during a hand-clenching motor task at 3T, and to investigate the effect of the stimulation's temporal characteristics on the magnitude of the fMRS changes; specifically, we compared two block-designed functional activation paradigms, using short- and long-cycled clenching designs. Small but statistically significant increases in Glx=Glutamate+Glutamine (3.8%) and Glu (4.0%) concentrations were detected during the long-cycled design, while no statistically significant changes were observed during the short-cycled design. Activation during the long-cycled tasks was correlated to the frequency of clenching. We have also shown that using subject-level analysis in combination with a linear mixed model increases the observed effect size, and could help analyzing the weak MRS signals. Our results are in good agreement with the previous reports acquired at higher field systems, and support the viability of fMRS as a research tool at clinical field strengths, while also emphasizing the importance of the functional paradigm itself.
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(2020) NMR in Biomedicine. 33, 7, e4316. Abstract
B-0 field maps are used ubiquitously in neuroimaging, in disciplines ranging from magnetic resonance spectroscopy to temperature mapping and susceptibility-weighted imaging. Most B-0 maps are acquired using standard gradient-echo-based vendor-provided sequences, often comprised of two echoes spaced a few milliseconds apart. Herein, we analyze the optimal spacing of echo times, defined as those maximizing precision-minimizing the standard deviation-for a fixed total acquisition time. Field estimation is carried out using a weighted least squares estimator. The standard deviation is shown to be approximately inversely proportional to the total acquisition time, suggesting a law of diminishing returns, whereby substantial gains are obtained up to a certain point, with little improvement beyond that point. Validations are provided in a phantom and a group of volunteers. Multi-gradient echo sequences are readily available on all manufacturer platforms, making our recommendations straightforward to implement on any modern scanner.
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(2020) Magnetic Resonance in Medicine. 83, 1, p. 22-44 Abstract
Purpose: Unlike conventional MR spectroscopy (MRS), which only measures metabolite concentrations, multiparametric MRS also quantifies their longitudinal (T-1) and transverse (T-2) relaxation times, as well as the radiofrequency transmitter inhomogeneity (B1+). To test whether knowledge of these additional parameters can improve the clinical utility of brain MRS, we compare the conventional and multiparametric approaches in terms of expected classification accuracy in differentiating controls from patients with neurological disorders. Theory and Methods: A literature review was conducted to compile metabolic concentrations and relaxation times in a wide range of neuropathologies and regions of interest. Simulations were performed to construct receiver operating characteristic curves and compute the associated areas (area under the curve) to examine the sensitivity and specificity of MRS for detecting each pathology in each region. Classification accuracy was assessed using metabolite concentrations corrected using population-averages for T-1, T-2, and B1+ (conventional MRS); using metabolite concentrations corrected using per-subject values (multiparametric MRS); and using an optimal linear multiparametric estimator comprised of the metabolites' concentrations and relaxation constants (multiparametric MRS). Additional simulations were conducted to find the minimal intra-subject precision needed for each parameter. Results: Compared with conventional MRS, multiparametric approaches yielded area under the curve improvements for almost all neuropathologies and regions of interest. The median area under the curve increased by 0.14 over the entire dataset, and by 0.24 over the 10 instances with the largest individual increases. Conclusions: Multiparametric MRS can substantially improve the clinical utility of MRS in diagnosing and assessing brain pathology, motivating the design and use of novel multiparametric sequences.
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(2019) NMR in Biomedicine. e4196. Abstract
Clinical magnetic resonance spectroscopy (MRS) mainly concerns itself with the quantification of metabolite concentrations. Metabolite relaxation values, which reflect the microscopic state of specific cellular and sub-cellular environments, could potentially hold additional valuable information, but are rarely acquired within clinical scan times. By varying the flip angle, repetition time and echo time in a preset way (termed a schedule), and matching the resulting signals to a pre-generated dictionary - an approach dubbed magnetic resonance fingerprinting - it is possible to encode the spins' relaxation times into the acquired signal, simultaneously quantifying multiple tissue parameters for each metabolite. Herein, we optimized the schedule to minimize the averaged root mean square error (RMSE) across all estimated parameters: concentrations, longitudinal and transverse relaxation time, and transmitter inhomogeneity. The optimal schedules were validated in phantoms and, subsequently, in a cohort of healthy volunteers, in a 4.5 mL parietal white matter single voxel and an acquisition time under 5 minutes. The average intra-subject, inter-scan coefficients of variation (CVs) for metabolite concentrations, T-1 and T-2 relaxation times were found to be 3.4%, 4.6% and 4.7% in-vivo, respectively, averaged over all major singlets. Coupled metabolites were quantified using the short echo time schedule entries and spectral fitting, and reliable estimates of glutamate+glutamine, glutathione and myo-inositol were obtained.
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(2019) Journal of Magnetic Resonance Imaging. 50, 5, p. 1424-1432 Abstract
Background: 3D brain proton MR spectroscopic imaging (
1H MRSI) facilitates simultaneous metabolic profiling of multiple loci, at higher, sub-1 cm
3, spatial resolution than single-voxel
1H MRS with the ability to separate tissue-type partial volume contribution(s). Purpose: To determine if: 1) white matter (WM) damage in mild traumatic brain injury (mTBI) is homogeneously diffuse, or if specific regions are more affected; 2) partial-volume-corrected, structure-specific
1H MRSI voxel averaging is sensitive to regional WM metabolic abnormalities. Study Type: Retrospective cross-sectional cohort study. Population: Twenty-seven subjects: 15 symptomatic mTBI patients, 12 matched controls. Field Strength/Sequence: 3T using 3D
1H MRSI over a 360-cm
3 volume of interest (VOI) centered over the corpus callosum, partitioned into 480 voxels, each 0.75 cm
3. Assessment: N-acetyl-aspartate (NAA), creatine, choline, and myo-inositol concentrations estimated in predominantly WM regions: body, genu, and splenium of the corpus callosum, corona radiata, frontal, and occipital WM. Statistical Tests: Analysis of covariance (ANCOVA) to compare patients with controls in terms of regional concentrations. The effect sizes (Cohen's d) of the mean differences were compared across regions and with previously published global data obtained with linear regression of the WM over the entire VOI in the same dataset. Results: Despite patients' global VOI WM NAA being significantly lower than the controls', no regional differences were observed for any metabolite. Regional NAA comparisons, however, were all unidirectional (patients' NAA concentrations 1H MRSI detection threshold in small regions. Therefore, larger, ie, more sensitive, single-voxel
1H MRS, placed anywhere in WM regions, may be well suited for mTBI
1H MRS studies, given that these results are confirmed in other cohorts. Level of Evidence: 2. Technical Efficacy: Stage 3. J. Magn. Reson. Imaging 2019;50:14241432. -
(2019) Magnetic Resonance in Medicine. 82, 3, p. 867-876 Abstract
Purpose: To design and implement a multislice MRSI method for fast spectroscopic imaging, using a modified version of echo planar spectroscopic imaging (EPSI) that offers higher spectral width and/or shorter scan time.Methods: Echo planar spectroscopic imaging suffers from inconsistencies between readout lines acquired with gradients of opposite signs, which has typically been addressed by reconstructing the "positive" and "negative" data sets separately and averaging the two. Nevertheless, consistency between the readout lines of each phase encode can be achieved by interposing the EPSI readouts with alternating "blipped" phase-encode gradients. This method exchanges inconsistencies along the temporal dimension with inconsistencies along the phase-encode dimension, which are straightforward to correct, as is conventionally done in various EPI reconstruction schemes. Such consistent k-t-space EPSI doubles the spectral width in comparison to EPSI, or, in an alternative realization, yields the same spectral width as EPSI, but at half the acquisition time. In this work, multiband CAIPIRINHA (controlled aliasing in parallel imaging results in higher acceleration) slice selection was integrated with consistent k-t-space EPSI to further accelerate the measurement 2-fold.Results: The feasibility of a consistent k-t-space EPSI was demonstrated in both phantoms and in vivo brain imaging at 3 T, and four pulse scheme variants were evaluated. It was demonstrated to be useful in optimizing the spectral width and scan acceleration, both of which are limiting factors in vivo. Dual-band implementation was shown to shorten the duration of the scan 4-fold.Conclusion: The consistent k-t-space EPSI can be used to accelerate MRSI or, alternatively, double its spectral width. Adding dual-band CAIPIRINHA further accelerates the acquisition by a factor of 2.
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(2019) Magnetic Resonance in Medicine. 82, 1, p. 145-158 Abstract
Purpose: Multi-echo spin-echo (MESE) protocol is the most effective tool for mapping T-2 relaxation in vivo. Still, MESE extensive use of radiofrequency pulses causes magnetization transfer (MT)-related bias of the water signal, instigated by the presence of macromolecules (MMP). Here, we analyze the effects of MT on MESE signal, alongside their impact on quantitative T-2 measurements.Methods: Study used 3 models: in vitro urea phantom, ex vivo horse brain, and in vivo human brain. MT ratio (MTR) was measured between single-SE and MESE protocols under different scan settings including varying echo train lengths, number of slices, and inter-slice gap. MTR and T-2 values were extracted for each model and protocol.Results: MT interactions biased MESE signals, and in certain settings, the corresponding T-2 values. T-2 underestimation of up to 4.3% was found versus single-SE values in vitro and up to 13.8% ex vivo, correlating with the MMP content. T-2 bias originated from intra-slice saturation of the MMP, rather than from indirect saturation in multi-slice acquisitions. MT-related signal attenuation was caused by slice crosstalk and/or partial T-1 recovery, whereas smaller contribution was caused by MMP interactions. Inter-slice gap had a similar effect on in vivo MTR (21.2%), in comparison to increasing the number of slices (18.9%).Conclusions: MT influences MESE protocols either by uniformly attenuating the entire echo train or by cumulatively attenuating the signal along the train. Although both processes depend on scan settings and MMP content, only the latter will cause underestimation of T-2.
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(2019) NeuroImage (Orlando, Fla.). 184, p. 25-35 Abstract
The dorsal anterior cingulate cortex (dACC) is crucial for motivation, reward- and error-guided decision-making, yet its excitatory and inhibitory mechanisms remain poorly explored in humans. In particular, the balance between excitation and inhibition (E/I), demonstrated to play a role in animal studies, is difficult to measure in behaving humans. Here, we used functional magnetic-resonance-spectroscopy (1H-fMRS) to measure the brain's major inhibitory (GABA) and excitatory (Glutamate) neurotransmitters during reinforcement learning with three different conditions: high cognitive load (uncertainty); probabilistic discrimination learning; and a control null-condition. Participants learned to prefer the gain option in the discrimination phase and had no preference in the other conditions. We found increased GABA levels during the uncertainty condition, potentially reflecting recruitment of inhibitory systems during high cognitive load when trying to learn. Further, higher GABA levels during the null (baseline) condition correlated with improved discrimination learning. Finally, glutamate and GABA levels were correlated during high cognitive load. These results suggest that availability of dACC inhibitory resources enables successful learning. Our approach helps elucidate the potential contribution of the balance between excitation and inhibition to learning and motivation in behaving humans.GABA and Glutamate were measured in the dACC during learning.Learning included: cognitive-load, discrimination-learning and control conditions.Increased GABA levels were observed during high cognitive load.GABA levels during the control condition were correlated with better learning.Availability of dACC inhibitory resources enabled successful learning.
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(2018) NMR in Biomedicine. 31, 11, e4001. Abstract
Magnetic resonance fingerprinting has been proposed as a method for undersampling k-space while simultaneously yielding multiparametric tissue maps. In the context of single voxel spectroscopy, fingerprinting can provide a unified framework for parameter estimation. We demonstrate the utility of such a magnetic resonance spectroscopic fingerprinting (MRSF) framework for simultaneously quantifying metabolite concentrations, T-1 and T-2 relaxation times and transmit inhomogeneity for major singlets of N-acetylaspartate, creatine and choline. This is achieved by varying T-R, T-E and the flip angle of the first pulse in a PRESS sequence between successive excitations (i.e. successive T-R values). The need for multiparametric schemes such as MRSF for accurate medical diagnostics is demonstrated with the aid of realistic in vivo simulations; these show that certain schemes lead to substantial increases to the area under receiver operating characteristics of metabolite concentrations, when viewed as classifiers of pathologies. Numerical simulations and phantom and in vivo experiments using several different schedules of variable length demonstrate superior precision and accuracy for metabolite concentrations and longitudinal relaxation, and similar performance for the quantification of transverse relaxation.
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(2018) Medical Physics. 45, 9, p. 4066-4084 Abstract
Purpose: Magnetic resonance fingerprinting (MRF) is a relatively new approach that provides quantitative MRI measures using randomized acquisition. Extraction of physical quantitative tissue parameters is performed offline, without the need of patient presence, based on acquisition with varying parameters and a dictionary generated according to the Bloch equationsimulations. MRF uses hundreds of radio frequency (RF) excitation pulses for acquisition, and therefore, a high undersampling ratio in the sampling domain (k-space) is required for reasonable scanning time. This undersampling causes spatial artifacts that hamper the ability to accurately estimate the tissue's quantitative values. In this work, we introduce a new approach for quantitative MRI using MRF, called magnetic resonance fingerprinting with low rank (FLOR).Methods: We exploit the low-rank property of the concatenated temporal imaging contrasts, on top of the fact that the MRF signal is sparsely represented in the generated dictionary domain. We present an iterative recovery scheme that consists of a gradient step followed by a low-rank projection using the singular value decomposition.Results: Experimental results consist of retrospective sampling that allows comparison to a well defined reference, and prospective sampling that shows the performance of FLOR for a real-data sampling scenario. Both experiments demonstrate improved parameter accuracy compared to other compressed-sensing and low-rank based methods for MRF at 5% and 9% sampling ratios for the retrospective and prospective experiments, respectively.Conclusions: We have shown through retrospective and prospective experiments that by exploiting the low-rank nature of the MRF signal, FLOR recovers the MRF temporal undersampled images and provides more accurate parameter maps compared to previous iterative approaches.
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(2018) Magnetic Resonance in Medicine. 79, 5, p. 2481-2490 Abstract
Purpose: Application of phase rotation to the STRESS (=STEAM+PRESS) localization scheme, to shorten echo time, minimize J-coupling dephasing and estimate B
1+ inhomogeneity. STRESS (=STEAM + PRESS) simultaneously refocuses and acquires the double spin echo (SE
123) and stimulated echo (STE
-) pathways, combining PRESS-like signal with lower chemical shift displacement as in STEAM. Phase rotation effectively separates coherence pathways, allows reduction of spoiling gradients moments leading to reduction in echo time. Implementing it in STRESS allows one to individually phase-correct SE
123 and STE
- prior to combination. Moreover, B
1+ inhomogeneity can be assessed by comparing the measured ratio of resonance intensities of SE
123 and STE
- pathways to the simulated one. Methods: In vivo spectra were acquired from a single voxel placed in the sensory-motor cortex of 10 healthy volunteers, using phase rotation-STRESS/PRESS/STEAM sequences at 3 T scanner. The phases of each slice-selective pulse were incremented by Δϕ
1/2/3 = 22.5°/ - 45°/45°. Results: Phase rotation-STRESS showed quantification accuracy (% Cramer Rao lower bounds) and reproducibility (% coefficients of variation) comparable to PRESS and STEAM, in both phantoms and in vivo study. Minimal echo time achieved was 13 ms. Conclusion: Phase rotation complements STRESS by reducing echo time, allowing processing of each pathway individually prior to addition and providing B
1+ estimation in single voxel proton magnetic resonance spectroscopy. Magn Reson Med 79:24812490, 2018. -
(2017) Human Brain Mapping. 38, 8, p. 4047-4063 Abstract
Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI) in pre-lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1-hypointensity and T2-volume. Within 10 patients with relapsing-remitting course, there were 180 regions-of-interest consisting of up to seven semi-annual follow-ups of normal-appearing white matter (NAWM, n = 10), pre-lesional tissue giving rise to acute lesions which resolved (n = 3) or persisted (n = 3), and of moderately (n = 9) and severely hypointense (n = 6) chronic lesions. Compared with NAWM, pre-lesional tissue had higher Cr and Cho, while compared with lesions, pre-lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre- and post-formation, suggesting no long-term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1-hypointensity, with lesions larger than 1.5 cm(3) uniformly exhibiting very low (
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(2017) NMR in Biomedicine. 30, 7, e3710. Abstract
Metabolite levels measured using magnetic resonance spectroscopy (MRS) are often expressed as ratios rather than absolute concentrations. However, the inter-subject variability of the denominator metabolite can introduce uncertainty into a metabolite ratio. In a clinical setting, there are no guidelines on whether ratios or absolute quantification should be used for a more accurate classification of normal versus abnormal results based on their statistical properties. In a research setting, the choice of one over the other can have significant implications on sample size, which must be factored in at the study design stage. Herein, we derive the probability distribution function for the ratio of two normally distributed random variables, and present analytical expressions for the comparison of ratios with absolute quantification in terms of both sample size and area under the receiver operator characteristic curve. The two approaches are compared for typical metabolite values found in the literature, and their respective merits are illustrated using previously acquired clinical MRS data in two pathologies: mild traumatic brain injury and multiple sclerosis. Our analysis shows that the decision between ratios and absolute quantification is non-trivial: in some cases, ratios might offer a reduction in sample size, whereas, in others, absolute quantification might prove more desirable for individual (i.e. clinical) use. The decision is straightforward and exact guidelines are provided in the text, given that population means and standard deviations of numerator and denominator can be reliably estimated.
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(2016) American Journal of Neuroradiology. 37, 12, p. 2273-2279 Abstract
BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural abnormalities. We used(1)H-MR spectroscopy to test the hypothesis that these abnormalities are accompanied by NAA deficits, reflecting neuronal dysfunction, in patients compared with healthy controls. MATERIALS AND METHODS: Nineteen patients with schizophrenia (11 men; mean age, 40.6 +/- 10.1 years; mean disease duration, 19.5 +/- 10.5 years) and 11 matched healthy controls (5 men; mean age, 33.7 +/- 10.1 years) underwent MR imaging and multivoxel point-resolved spectroscopy (TE/TR, 35/1400 ms)H-1-MRS at 3T to obtain their hippocampal GM absolute NAA, Cr, Cho, and mins concentrations. Unequal variance t tests and ANCOVA were used to compare patients with controls. Bilateral volumes from manually outlined hippocampal masks were compared by using unequal variance t tests. RESULTS: Patients' average hippocampal GM Cr concentrations were 19% higher than that of controls, 8.7 +/- 2.2 versus 7.4 +/- 1.2 mmol/L (P.1). There was a positive correlation between mins and Cr in patients (r = 0.57, P=.05) but not in controls. The mean bilateral hippocampal volume was similar to 10% lower in patients: 7.5 +/- 0.9 versus 8.4 +/- 0.7 cm(3) (P
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(2016) 2016 38th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). p. 439-442 Abstract
Magnetic Resonance Fingerprinting (MRF) is a relatively new approach that provides quantitative MRI using randomized acquisition. Extraction of physical quantitative tissue values is preformed off-line, based on acquisition with varying parameters and a dictionary generated according to the Bloch equations. MRF uses hundreds of radio frequency (RF) excitation pulses for acquisition, and therefore high under-sampling ratio in the sampling domain (k-space) is required. This under-sampling causes spatial artifacts that hamper the ability to accurately estimate the quantitative tissue values. In this work, we introduce a new approach for quantitative MRI using MRF, called Low Rank MRF. We exploit the low rank property of the temporal domain, on top of the well-known sparsity of the MRF signal in the generated dictionary domain. We present an iterative scheme that consists of a gradient step followed by a low rank projection using the singular value decomposition. Experiments on real MRI data demonstrate superior results compared to conventional implementation of compressed sensing for MRF at 15% sampling ratio.
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(2016) Brain Imaging and Behavior. 10, 1, p. 115-123 Abstract
Working memory (Work-Mem), the capacity to hold and manipulate information, activates the anterior cingulate cortex (ACC), especially its caudal subregion. Impaired Work-Mem and structural and functional abnormalities of the ACC are reported in schizophrenia. This study aims to elucidate the pathogenesis of Work-Mem dysfunction in schizophrenia by comparing metabolite concentrations across ACC subregions. This retrospective study of 18 schizophrenia cases and 10 matched controls used proton magnetic resonance spectroscopic imaging (H-1-MRSI, TR/TE = 1800/35 ms, 0.5 cm(3) spatial resolution) to test whether the Work-Mem Index of the Wechsler Adult Intelligence Scale, third edition is associated with differences in the rostral to caudal ACC ratios of N-acetylaspartate (NAA) and creatine (Cr). Higher caudal: rostral ACC Cr (but not NAA) concentrations were associated with decreased Work-Mem Index in cases (r=-0.6, p=0.02), with a similar trend in controls (r=-0.56, p=0.10), although caudal: rostral ACC Cr correlated with NAA in cases and controls (r=0.67 and 0.62, p
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(2015) HIV Medicine. 16, 6, p. 381-387 Abstract
Objectives: As approximate to 40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging (H-1-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. Methods: The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T-2-weighted quantitative magnetic resonance imaging (MRI) and 16x16x4 multivoxel H-1-MRSI (echo time/repetition time=33/1440ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to H-1-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28cm(3) (approximate to 35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. Results: The mean (standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 +/- 0.9, 7.2 +/- 0.4 and 0.9 +/- 0.1mM, respectively; these concentrations increased 28% (p approximate to 0.06), 15% and 10% (both p
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(2015) Magnetic Resonance in Medicine. 73, 1, p. 31-43 Abstract
Purpose: To design a proton MR spectroscopy (H-1-MRS) localization sequence that combines the signal-to-noise-ratio (SNR) benefits of point resolved spectroscopy (PRESS) with the high pulse bandwidths, low chemical shift displacements (CSD), low specific absorption rates (SAR), short echo times (TE), and superior radiofrequency transmit field (B1+) immunity of stimulated echo acquisition mode (STEAM), by simultaneously refocusing and acquiring both the double-spin and stimulated echo coherence pathways from the volume of interest.Theory and Methods: We propose a family of H-1-MRS sequences comprising three orthogonal spatially selective pulses with flip angles 90 degreesResults: Phantom and in vivo brain experiments show that 83-100% of the PRESS SNR (metabolite-dependent) is achieved at under 75% of the SAR and 66% lower in-plane CSD.Conclusion: The advantages of STEAM can be augmented with the higher SNR of PRESS by combining the spin and stimulated echoes. Quantification, especially of J-coupled resonances and intermediate and long TEs, must be carefully considered. Magn Reson Med 73:31-43, 2015. (c) 2014 Wiley Periodicals, Inc.
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(2014) NMR in Biomedicine. 27, 11, p. 1275-1284 Abstract
Concentration of the neuronal marker, N-acetylaspartate (NAA), a quantitative metric for the health and density of neurons, is currently obtained by integration of the manually defined peak in whole-head proton (H-1)-MRS. Our goal was to develop a full spectral modeling approach for the automatic estimation of the whole-brain NAA concentration (WBNAA) and to compare the performance of this approach with a manual frequency-range peak integration approach previously employed. MRI and whole-head H-1-MRS from 18 healthy young adults were examined. Non-localized, whole-head H-1-MRS obtained at 3T yielded the NAA peak area through both manually defined frequency-range integration and the new, full spectral simulation. The NAA peak area was converted into an absolute amount with phantom replacement and normalized for brain volume (segmented from T-1-weighted MRI) to yield WBNAA. A paired-sample t test was used to compare the means of the WBNAA paradigms and a likelihood ratio test used to compare their coefficients of variation. While the between-subject WBNAA means were nearly identical (12.8 +/- 2.5mm for integration, 12.8 +/- 1.4mm for spectral modeling), the latter's standard deviation was significantly smaller (by similar to 50%, p=0.026). The within-subject variability was 11.7% (+/- 1.3mm) for integration versus 7.0% (+/- 0.8mm) for spectral modeling, i.e., a 40% improvement. The (quantifiable) quality of the modeling approach was high, as reflected by Cramer-Rao lower bounds below 0.1% and vanishingly small (experimental - fitted) residuals. Modeling of the whole-head H-1-MRS increases WBNAA quantification reliability by reducing its variability, its susceptibility to operator bias and baseline roll, and by providing quality-control feedback. Together, these enhance the usefulness of the technique for monitoring the diffuse progression and treatment response of neurological disorders. Copyright (c) 2014 John Wiley & Sons, Ltd.
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(2014) Magnetic Resonance in Medicine. 72, 4, p. 923-933 Abstract
PurposeTo reduce the specific-absorption-rate (SAR) and chemical shift displacement (CSD) of three-dimensional (3D) Hadamard spectroscopic imaging (HSI) and maintain its point spread function (PSF) benefits.MethodsA 3D hybrid of 2D longitudinal, 1D transverse HSI (L-HSI, T-HSI) sequence is introduced and demonstrated in a phantom and the human brain at 3 Tesla (T). Instead of superimposing each of the selective Hadamard radiofrequency (RF) pulses with its N single-slice components, they are cascaded in time, allowing N-fold stronger gradients, reducing the CSD. A spatially refocusing 180 degrees RF pulse following the T-HSI encoding block provides variable, arbitrary echo time (TE) to eliminate undesirable short T-2 species' signals, e.g., lipids.ResultsThe sequence yields 10-15% better signal-to-noise ratio (SNR) and 8-16% less signal bleed than 3D chemical shift imaging of equal repetition time, spatial resolution and grid size. The 13 6, 22 +/- 7, 24 +/- 8, and 31 +/- 14 in vivo SNRs for myo-inositol, choline, creatine, and N-acetylaspartate were obtained in 21 min from 1 cm(3) voxels at TE approximate to 20 ms. Maximum CSD was 0.3 mm/ppm in each direction.ConclusionThe new hybrid HSI sequence offers a better localized PSF at reduced CSD and SAR at 3T. The short and variable TE permits acquisition of short T-2 and J-coupled metabolites with higher SNR. Magn Reson Med 72:923-933, 2014. (c) 2013 Wiley Periodicals, Inc.
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(2013) AIDS. 27, 16, p. 2519-2528 Abstract
Objective:As approximate to 40% of persons with HIV also suffer neurocognitive decline, we sought to assess metabolic dysfunction in the brains of simian immunodeficiency virus (SIV)-infected rhesus macaques, an advanced animal model, in structures involved in cognitive function. We test the hypothesis that SIV-infection produces proton-magnetic resonance spectroscopic imaging (H-1-MRSI)-observed decline in the neuronal marker, N-acetylaspartate (NAA), and elevations in the glial marker, myo-inositol (mI), and associated creatine (Cr) and choline (Cho) in these structures.Design:Pre- and 4-6 weeks post-SIV infection (with CD8(+) T-lymphocyte depletion) was monitored with T-2-weighted quantitative MRI and 16x16x4 multivoxel H-1-MRSI (TE/TR=33/1400ms) in the brains of five rhesus macaques.Methods:Exploiting the high-resolution H-1-MRSI grid, we obtained absolute, cerebrospinal fluid partial volume-corrected NAA, Cr, Cho and mI concentrations from centrum semiovale, caudate nucleus, putamen, thalamus and hippocampus regions.Results:Pre- to post-infection mean Cr increased in the thalamus: 7.20.4 to 8.0 +/- 0.8mmol/l (+11%, P
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(2013) Magnetic Resonance in Medicine. 70, 4, p. 895-904 Abstract
Purpose: To analyze the effect of B-0 field drift on multivoxel MR spectroscopic imaging and to propose an approach for its correction.Theory and Methods: It is shown, both theoretically and in a phantom, that for similar to 30 min acquisitions a linear B-0 drift (similar to 0.1 ppm/h) will cause localization errors that can reach several voxels (centimeters) in the slower varying phase encoding directions. An efficient and unbiased estimator is proposed for tracking the drift by interleaving short (similar to T-2*), nonlocalized acquisitions on the nonsuppressed water each pulse repetition time, as shown in 10 volunteers at 1.5 and 3 T.Results: The drift is shown to be predominantly linear in both the phantom and volunteers at both fields. The localization errors are observed and quantified in both phantom and volunteers. The unbiased estimator is shown to reliably track the instantaneous frequency in vivo despite only using a small portion of the FID.Conclusion: Contrary to single-voxel MR spectroscopy, where it leads to line broadening, field drift can lead to localization errors in the longer chemical shift imaging experiments. Fortunately, this drift can be obtained at a negligible cost to sequence timing, and corrected for in post processing.
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(2013) Journal of Neurotrauma. 30, 13, p. 1200-1204 Abstract
There are no established biomarkers for mild traumatic brain injury (mTBI), in part because post-concussive symptoms (PCS) are subjective and conventional imaging is typically unremarkable. To test whether diffuse axonal abnormalities quantified with three-dimensional (3D) proton magnetic resonance spectroscopic imaging (H-1-MRSI) correlated with patients' PCS, we retrospectively studied 26 mTBI patients (mean Glasgow Coma Scale [GCS] score of 14.7), 18- to 56-year-olds and 13 controls three to 55 days post-injury. All were scanned at 3 Tesla with T1- and T2-weighted MRI and 3D H-1-MRSI (480 voxels over 360 cm(3), similar to 30% of the brain). On scan day, patients completed a symptom questionnaire, and those who indicated at least one of the most common subacute mTBI symptoms (headache, dizziness, sleep disturbance, memory deficits, blurred vision) were grouped as PCS-positive. Global gray matter and white matter (GM/WM) absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) in PCS-positive and PCS-negative patients were compared to age-and gender-matched controls using two-way analysis of variance. The results showed that the PCS-negative group (n = 11) and controls (n = 8) did not differ in any GM or WM metabolite level. The PCS-positive patients (n = 15) had lower WM NAA than the controls (n = 12; 7.0 +/- 0.6 versus 7.9 +/- 0.5mM; p = 0.0007). Global WM NAA, therefore, showed sensitivity to the TBI sequelae associated with common PCS in patients with mostly normal neuroimaging, as well as GCS scores. This suggests a potential biomarker role in a patient population in which objective measures of injury and symptomatology are currently lacking.
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(2013) Magnetic Resonance in Medicine. 70, 1, p. 7-15 Abstract
A non-spin-echo multivoxel proton MR localization method based on three-dimensional transverse Hadamard spectroscopic imaging is introduced and demonstrated in a phantom and the human brain. Spatial encoding is achieved with three selective 90 degrees radiofrequency pulses along perpendicular axes: The first two create a longitudinal +/- MZ Hadamard order in the volume of interest. The third pulse spatially Hadamard-encodes the +/- MZs in the volume of interest in the third direction while bringing them to the transverse plane to be acquired immediately. The approaching-ideal point spread function of Hadamard encoding and very short acquisition delay yield signal-to-noise-ratios of 20 +/- 8, 23 +/- 9, and 31 +/- 10 for choline, creatine, and N-acetylaspartate in the human brain at 1.5 T from 1 cm3 voxels in 21 min. The advantages of transverse Hadamard spectroscopic imaging are that unlike gradient (Fourier) phase-encoding: (i) the volume of interest does not need to be smaller than the field of view to prevent aliasing; (ii) the number of partitions in each direction can be small, 8, 4, or even 2 at no cost in point spread function; (iii) the volume of interest does not have to be contiguous; and (iv) the voxel profile depends on the available B1 and pulse synthesis paradigm and can, therefore, at least theoretically, approach ideal 1 inside and 0 elsewhere. Magn Reson Med, 2013. (c) 2012 Wiley Periodicals, Inc.
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(2013) Epilepsy and Behavior. 27, 2, p. 319-325 Abstract
Since approximately 5-10% of the similar to 50,000 tuberous sclerosis complex (TSC) patients in the US are "MRI-negative," our goal was to test the hypothesis that they nevertheless exhibit metabolic abnormalities. To test this, we used proton MR spectroscopy to obtain and compare gray and white matter (GM and WM) levels of the neuronal marker, N-acetylaspartate (NAA), the glial marker, myo-inositol (mI), and its associated creatine (Cr), and choline (Cho) between two " MRI-negative" female TSC patients (ages 5 and 43 years) and their matched controls. The NAA, Cr, Cho and mI concentrations, 9.8, 6.3, 1.4, and 5.7 mM, in the pediatric control were similar to those of the patients, whereas the adult patient revealed a 17% WM NAA decrease and 16% WM Cho increase from their published means for healthy adults - both outside their respective 90% prediction intervals. These findings suggest that longer disease duration and/or TSC2 gene mutation may cause axonal dysfunction and demyelination. (C) 2013 Elsevier Inc. All rights reserved.
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(2013) NMR in Biomedicine. 26, 4, p. 480-488 Abstract
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 16x16x4 multivoxel proton MRS imaging (TE/TR=33/1400ms) in five macaques pre- and 46weeks 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 0.125cm3 spatial resolution over similar to 35% of the brain) using linear regression. Pre- to post-infection global WM NAA declined 8%: 6.6 +/- 0.4 to 6.0 +/- 0.5mM (p=0.05); GM Cho declined 20%: 1.3 +/- 0.2 to 1.0 +/- 0.1mM (p
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(2013) Magnetic Resonance in Medicine. 69, 4, p. 903-911 Abstract
We propose and demonstrate a full 3D longitudinal Hadamard spectroscopic imaging scheme for obtaining chemical shift maps, using adiabatic inversion pulses to encode the spins' positions. The approach offers several advantages over conventional Fourier-based encoding methods, including a localized point spread function; no aliasing, allowing for volumes of interest smaller than the object being imaged; an option for acquiring noncontiguous voxels; and inherent outer volume rejection. The latter allows for doing away with conventional outer volume suppression schemes, such as point resolved spectroscopy (PRESS) and stimulated echo acquisition mode (STEAM), and acquiring non-spin-echo spectra with short acquisition delay times, limited only by the excitation pulse's duration. This, in turn, minimizes T-2 decay, maximizes the signalto-noise ratio, and reduces J-coupling induced signal decay. Results are presented for both a phantom and an in vivo healthy volunteer at 3 T. Magn Reson Med 69:903-911, 2013. (C) 2012 Wiley Periodicals, Inc.
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(2013) Neurology. 80, 1, p. 39-46 Abstract
Objective: To characterize and follow the diffuse gray and white matter (GM/WM) metabolic abnormalities in early relapsing-remitting multiple sclerosis using proton magnetic resonance spectroscopic imaging (H-1-MRSI).Methods: Eighteen recently diagnosed, mildly disabled patients (mean baseline time from diagnosis 32 months, mean Expanded Disability Status Scale [EDSS] score 1.3), all on immunomodulatory medication, were scanned semiannually for 3 years with T1-weighted and T2-weighted MRI and 3D 1H-MRSI at 3 T. Ten sex- and age-matched controls were followed annually. Global absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI) were obtained for all GM and WM in the 360 cm(3) H-1-MRSI volume of interest.Results: Patients' average WM Cr, Cho, and mI concentrations (over all time points), 5.3 +/- 0.4, 1.6 +/- 0.1, and 5.1 +/- 0.7 mM, were 8%, 12%, and 11% higher than controls' (pConclusions: Diffuse WM glial abnormalities were larger in magnitude than the axonal abnormalities and increased over time independently of conventional clinical or imaging metrics and despite immunomodulatory treatment. In contrast, the axonal abnormalities showed partial recovery, suggesting that patients' lower WM NAA levels represented a dysfunction, which may abate with treatment. Absence of detectable diffuse changes in GM suggests that injury there is minimal, focal, or heterogeneous between cortex and deep GM nuclei. Neurology (R) 2013; 80: 39-46
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(2013) Journal of Neurology. 260, 1, p. 242-252 Abstract
Since mild traumatic brain injury (mTBI) often leads to neurological symptoms even without clinical MRI findings, our goal was to test whether diffuse axonal injury is quantifiable with multivoxel proton MR spectroscopic imaging (H-1-MRSI). T1- and T2-weighted MRI images and three-dimensional H-1-MRSI (480 voxels over 360 cm(3), about 30 % of the brain) were acquired at 3 T from 26 mTBI patients (mean Glasgow Coma Scale score 14.7, 18-56 years old, 3-55 days after injury) and 13 healthy matched contemporaries as controls. The N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) concentrations and gray-matter/white-matter (GM/WM) and cerebrospinal fluid fractions were obtained in each voxel. Global GM and WM absolute metabolic concentrations were estimated using linear regression, and patients were compared with controls using two-way analysis of variance. In patients, mean NAA, Cr, Cho and mI concentrations in GM (8.4 +/- A 0.7, 6.9 +/- A 0.6, 1.3 +/- A 0.2, 5.5 +/- A 0.6 mM) and Cr, Cho and mI in WM (4.8 +/- A 0.5, 1.4 +/- A 0.2, 4.6 +/- A 0.7 mM) were not different from the values in controls. The NAA concentrations in WM, however, were significantly lower in patients than in controls (7.2 +/- A 0.8 vs. 7.7 +/- A 0.6 mM, p = 0.0125). The Cho and Cr levels in WM of patients were positively correlated with time since mTBI. This H-1-MRSI approach allowed us to ascertain that early mTBI sequelae are (1) diffuse (not merely local), (2) neuronal (not glial), and (3) in the global WM (not GM). These findings support the hypothesis that, similar to more severe head trauma, mTBI also results in diffuse axonal injury, but that dysfunction rather than cell death dominates shortly after injury.
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(2012) NMR in Biomedicine. 25, 12, p. 1392-1400 Abstract
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 CiGM, CiWM. With the voxels' GM and WM volumes as independent coefficients, the over-determined system of equations was solved for the global averaged CiGM and CiWM. 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 CiGM concentrations of 8.5?+/-?0.7, 6.9?+/-?0.6, 1.2?+/-?0.2, 5.3?+/-?0.6mM, respectively, and CiWM 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 510% (more for ratios), which can often double the sample size required to establish statistical significance. Copyright (c) 2012 John Wiley & Sons, Ltd.
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(2011) Radiology. 261, 2, p. 542-550 Abstract
Purpose: To test the hypothesis that anterior cingulate cortex (ACC) subregions in patients with schizophrenia are metabolically different from those in healthy control subjects.Materials and Methods: This institutional review board-approved study was HIPAA compliant, and all participants provided written informed consent. Twenty-two patients with schizophrenia (13 male, nine female; 39.4 years +/- 10.6 [standard deviation]) and 11 age-and sex-matched control subjects (seven male, four female; 35.5 years +/- 10.7) underwent magnetic resonance (MR) imaging and three-dimensional 3-T voxel proton MR spectroscopy to measure absolute rostral and caudal ACC N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) concentrations. Exact Mann-Whitney test was used to compare patient data with control data, paired-sample Wilcoxon signed rank test was used to compare subregions within groups, and receiver operating characteristic curve analysis was used to assess sensitivity and specificity in diagnosis of schizophrenia.Results: There were no significant metabolic differences between patients and control subjects or between ACC subregions in control subjects. In patients, rostral ACC NAA and Cr concentrations were significantly lower than those in caudal ACC (6.2 mM +/- 1.3 vs 7.1 mM +/- 1.3, P
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(2010) Progress in Nuclear Magnetic Resonance Spectroscopy. 57, 3, p. 241-292 Abstract
Spatial encoding, as encompassing the monitoring of spin evolutions on the basis of selective frequency-swept pulses and of magnetic field gradients, provides a new way for measuring NMR spectra or MRI images. In contrast to time-domain schemes or to continuous-wave approaches, these new RF/gradient combinations can act together to create interaction-dependent spatial patterns of spin magnetizations or coherences extending throughout a sample. These patterns can then be read-out with the aid of a second set of gradients while digitizing the data, to endow NMR/MRI acquisitions with hitherto unavailable capabilities. The present Review described various facets of these new approaches to monitor NMR spectra and MRI images. We began with a thorough introduction on how to visualize the effects of swept RF pulses - be them of an excitation or refocusing nature - applied in the presence of linear field gradients. It was then discussed how, in a spectroscopic setting, the idea of spatial encoding can be exploited to compress an nD spectroscopic NMR experiment into a single-scan. Numerous acquisition schemes capable of retrieving this kind of results for a variety of 2D experiments were presented, and their relative merits and limitations were surveyed. Similar ideas were shown to have applications in other spectroscopic aradigms involving multi-scan experiments, such as Hadamard spectroscopy. It was once again shown that by partitioning the sample and exciting different patterns for each site, one could produce a single-scan, sub-second version of a complex experiment. Similar versions of multi-scan phase cycling have also been demonstrated [71]. The final part extended these spatially-selective encoding concepts in what we believe are novel imaging sequences, though related to decades-old developments in this field. By suitable excitation protocols, the spins in the sample can, in these MRI settings, be made to interfere destructively - except within a particular voxel which can be chosen at will. This voxel can be shifted along a predefined trajectory, set by shaping the acquisition gradients, yielding a signal proportional to the spin density along that path. Therefore, spatially encoded imaging differs from conventional Fourier imaging by acquiring images in real rather than in k-space. The point-by-point nature of the ensuing approach can then address a number of challenging measurements, including the single-scan acquisition of images arising from different chemical sites, or in the presence of field inhomogeneities. Overall, it is hoped that as the technical details underlying these new methods become clearer and as their user-base expands, further improvements will materialize and new, unforeseen applications of spatial-encoding will emerge - both in the spectroscopy and imaging realms. (Figure presented).
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(2009) Magnetic Resonance in Chemistry. 47, 5, p. 415-422 Abstract
Single-scan 2D NMR relies on a spatial axis for encoding the indirect-domain internal spin interactions. Various strategies have been demonstrated for fulfilling the needs underlying this procedure. All such schemes use gradient-echoed sequences that leave at their conclusion solely the effects of the internal interactions along the indirect domain; they also include a real-time scheme that though simple, yields in general mixed-phase line shapes. The present paper introduces two new proposals geared up for easing the spatial encoding underlying single-scan 2D NMR methodologies. One of these is capable of delivering dispersive-free peaks along the indirect domain, and thereby purely-absorptive 2D line shapes, in amplitude- encoded experiments. The other demonstrates for the first time, the possibility to obtain single-scan 2D spectra without echoing the effects of the encoding gradient-simply by applying a single-pulse frequency sweep to encode the interactions. Both of these modes are compatible with homo- and heteronuclear correlations, and exhibit a number of complementary features vis-à-vis encoding alternatives that have so far been presented. The overall principles underlying these new spatially encoding protocols are derived, and their performance demonstrated with single-scan 2D NMR TOCSY and HSQC experiments on model compounds.
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(2009) ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. 48, 15, p. 2732-2736 Abstract
Scan and deliver: By combining imaging-based spectral/spatial 2D radiofrequency manipulations (see scheme, left) with Hadamard-weighting principles, 2D NMR spectra can be retrieved within a single scan (right). This approach can give homo- or heteronuclear correlations with an enhanced sensitivity over conventional ultrafast 2D NMR spectroscopy.
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(2007) JOURNAL OF MAGNETIC RESONANCE. 189, 1, p. 46-58 Abstract
We have recently proposed a protocol for retrieving multidimensional magnetic resonance images within a single scan, based on a spatial encoding of the spin interactions. This methodology relies on progressively dephasing spin coherences throughout a sample; for instance, by sweeping a radiofrequency pulse in the presence of a magnetic field gradient. When spins are suitably refocused by a second (acquisition) field gradient, this yields a time-domain signal reflecting in its magnitude the spatial distribution of spins throughout the sample. It is hereby shown that whereas the absolute value of the resulting signals conveys such imaging information, the hitherto unutilized phase modulation of the signal encodes the chemical shift offsets of the present speciae. Spectroscopically-resolved multidimensional images can thereby be retrieved in this fashion at no additional expense in either experimental complexity, sensitivity or acquisition time-simply by performing an additional analysis of the collected data. The resulting approach to single-scan spectroscopic imaging can also incorporate "RF shimming" compensating abilities, capable of providing high-resolution spectral and high-definition imaging data even under the presence of substantial magnetic field inhomogeneities. The principles of these methodologies as applied to spectroscopic imaging are briefly reviewed and compared against the background of traditional Fourier-based single-scan spectroscopic imaging protocols. Demonstrations of these new multidimensional spectroscopic MRI experiments on simple phantoms are also given.
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(2006) JOURNAL OF MAGNETIC RESONANCE. 182, 2, p. 179-194 Abstract
We have recently proposed a protocol for retrieving multidimensional magnetic resonance spectra and images within a single scan, based on a spatial encoding of the spin interactions. The spatial selectivity of this encoding process also opens up new possibilities for compensating magnetic field inhomogeneities; not by demanding extreme uniformities from the B0 fields, but by compensating for their effects at an excitation and/or refocusing level. This potential is hereby discussed and demonstrated in connection with the single-scan acquisition of high-definition multidimensional images. It is shown that in combination with time-dependent gradient and radiofrequency manipulations, the new compensation approach can be used to counteract substantial field inhomogenities at either global or local levels over relatively long periods of time. The new compensation scheme could find uses in areas where heterogeneities in magnetic fields present serious obstacles, including rapid studies in regions near tissue/air interfaces. The principles of the B0 compensation method are reviewed for one- and higher-dimensional cases, and experimentally demonstrated on a series of 1D and 2D single-scan MRI experiments on simple phantoms.
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Translational entanglement and teleportation of matter wavepackets by collisions and half-collisions(2005) International Journal of Modern Physics B. 19, 26, p. 3897-3921 Abstract
To date, the translationally-entangled state originally proposed by Einstein, Podolsky and Rosen (EPR) in 1935 has not been experimentally realized for massive particles. Opatrný and Kurizki [Phys. Rev. Lett. 86, 3180 (2000)] have suggested the creation of a position- and momentum-correlated, i.e., translationally-entangled, pair of particles approximating the EPR state by dissociation of cold diatomic molecules, and further manipulation of the EPR pair effecting matter-wave teleportation. Here we aim at setting the principles of and quantifying translational entanglement by collisions and half-collisions. In collisions, the resonance width s and the initial phase-space distributions are shown to determine the degree of post-collisional momentum entanglement. Half-collisions (dissociation) are shown to yield different types of approximate EPR states. We analyse a feasible realization of translational EPR entanglement and teleportation via cold-molecule Raman dissociation and subsequent collisions, resolving both practical and conceptual difficulties it has faced so far: How to avoid entanglement loss due to the wavepacket spreading of the dissociation fragments? How to measure both position and momentum correlations of the dissociation fragments with sufficient accuracy to verify their EPR correlations? How to reliably perform two-particle (Bell) position and momentum measurements on one of the fragments and the wavepacket to be teleported?
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(2005) JOURNAL OF MAGNETIC RESONANCE. 176, 1, p. 107-114 Abstract
Ultrafast 2D NMR replaces the time-domain parametrization usually employed to monitor the indirect-domain spin evolution, with an equivalent encoding along a spatial geometry. When coupled to a gradient-assisted decoding during the acquisition, this enables the collection of complete 2D spectra within a single transient. We have presented elsewhere two strategies for carrying out the spatial encoding underlying ultrafast NMR: a discrete excitation protocol capable of imparting a phase-modulated encoding of the interactions, and a continuous protocol yielding amplitude-modulated signals. The former is general but has associated with it a number of practical complications; the latter is easier to implement but unsuitable for certain 2D NMR acquisitions. The present communication discusses a new protocol that incorporates attractive attributes from both alternatives, imparting a continuous spatial encoding of the interactions yet yielding a phase modulation of the signal. This in turn enables a number of basic experiments that have shown particularly useful in the context of in vivo 2D NMR, including 2D J-resolved and 2D H,H-COSY spectroscopies. It also provides a route to achieving sensitivity-enhanced acquisitions for other homonuclear correlation experiments, such as ultrafast 2D TOCSY. The main features underlying this new spatial encoding protocol are derived, and its potential demonstrated with a series of phase-modulated homonuclear single-scan 2D NMR examples.
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(2005) Physical review letters. 94, 16, 160503. Abstract
We study collisions mediated by finite-range potentials as a tool for generating translational entanglement between unbound particles or multipartite systems. The general analysis is applied to one-dimensional scattering, where resonances and the initial phase-space distribution are shown to determine the degree of postcollisional entanglement.