Publications

Background: Accurately fitting diffusion-time-dependent diffusion MRI (t_d-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

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.

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 T_R/T_E = 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.

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.

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.

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.

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 (

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

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

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.

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

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.

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?