Faculty Bibliography

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.

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, T₁ and T₂ 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.

PURPOSE/OBJECTIVE: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 off-line, without the need of patient presence, based on acquisition with varying parameters and a dictionary generated according to the Bloch equation simulations. 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 lowrank 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.

PURPOSE/OBJECTIVE: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 Δϕ1/2/3=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/CONCLUSIONS:estimation in single voxel proton magnetic resonance spectroscopy. Magn Reson Med 79:2481-2490, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

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 cm3 uniformly exhibiting very low (<4.5 millimolar) NAA concentrations. A positive correlation between longitudinal changes in Cho and in lesion volume in moderately hypointense lesions implied that lesion size is mediated by chronic inflammation. These and other results are integrated in a discussion on the steady-state metabolism of lesion evolution in multiple sclerosis, viewed in the context of conventional MRI measures. Hum Brain Mapp, 2017. (c) 2017 Wiley Periodicals, Inc.

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.

BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural abnormalities. We used 1H-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) 1H-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 < .05); showing no differences, concentrations in NAA were 8.8 +/- 1.6 versus 8.7 +/- 1.2 mmol/L; in Cho, 2.3 +/- 0.7 versus 2.1 +/- 0.3 mmol/L; and in mIns, 6.1 +/- 1.5 versus 5.2 +/- 0.9 (all 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 approximately 10% lower in patients: 7.5 +/- 0.9 versus 8.4 +/- 0.7 cm3 (P < .05). CONCLUSIONS: These findings suggest that the hippocampal volume deficit in schizophrenia is not due to net loss of neurons, in agreement with histopathology studies but not with prior 1H-MR spectroscopy reports. Elevated Cr is consistent with hippocampal hypermetabolism, and its correlation with mIns may also suggest an inflammatory process affecting some cases; these findings may suggest treatment targets and markers to monitor them.

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.

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 (1H-MRSI, TR/TE = 1800/35 ms, 0.5 cm3 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 < 0.05 for both). NAA and Cr ratios did not correlate with myo-inositol, excluding gliosis as the underlying process. Subjects' sex and age had no effects on these relationships. The findings suggest that rostral ACC energy hypo-metabolism, possibly arising from neurodevelopmental processes, is associated with working memory impairment in schizophrenia. Changes in the rostral (not the expected caudal) subregion underscore the interconnections between the ACC subregions and may offer laboratory markers for treatment trials, etiology studies, and perhaps even enhanced identification of prodromal "at risk" subjects.

OBJECTIVES: As approximately 40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-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 T2 -weighted quantitative magnetic resonance imaging (MRI) and 16x16x4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-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, 28 cm(3) ( approximately 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 +/- 0.1 mM, respectively; these concentrations increased 28% (p approximately 0.06), 15% and 10% (both p < 0.05), respectively, post-infection. The mean concentration of neuronal marker NAA remained unchanged (7.0 +/- 0.6 mM pre-infection vs. 7.3 +/- 0.8 mM post-infection; p approximately 0.37). The mean cortex volume was also unchanged (8.1 +/- 1.1 cm(3) pre-infection vs. 8.3 +/- 0.5 cm(3) post-infection; p approximately 0.76). CONCLUSIONS: These results support the hypothesis that early cortical glial activation occurs after SIV infection prior to the onset of neurodegeneration. This suggests HIV therapeutic interventions should potentially target early glial activation in the cerebral cortex.