Dr Hongfu Sun

Purpose: To compare regional oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2) quantified from the microvascular quantitative susceptibility mapping (QSM) using a hypercapnic gas challenge with those measured by the dual-gas calibrated BOLD imaging (DGC-BOLD) in healthy subjects. Methods: Ten healthy subjects were scanned using a 3T MR system. The QSM data were acquired with a multi-echo gradient-echo sequence at baseline and hypercapnia. Cerebral blood flow data were acquired using the pseudo-continuous arterial spin labeling technique. Baseline OEF and CMRO2 were calculated using QSM and cerebral blood flow measurements. The DGC-BOLD data were also collected under a hypercapnic and a hyperoxic condition to yield baseline OEF and CMRO2. The QSM-OEF and CMRO2 maps were compared with DGC-BOLD OEF and CMRO2 maps using region of interest (vascular territories) analysis and Bland-Altman plots. Results: Hypercapnia is a robust stimulus for mapping OEF in combination with QSM. Average OEF in 16 vascular territory regions of interest across 10 subjects was 0.40 ± 0.04 by QSM-OEF and 0.38 ± 0.09 by DGC-BOLD. The average CMRO2 was 176 ± 35 and 167 ± 53 µmol O2/min/100g by QSM-OEF and DGC-BOLD, respectively. A Bland-Altman plot of regional OEF and CMRO2 in regions of interest revealed a statistically significant but small difference (OEF difference = 0.02, CMRO2 difference = 9 µmol O2/min/100g, p <.05) between the 2 methods for the 10 healthy subjects. Conclusion: Hypercapnic challenge¿assisted QSM-OEF is a feasible approach to quantify regional brain OEF and CMRO2. Compared with DGC-BOLD, hypercapnia QSM-OEF results in smaller intersubject variability and requires only 1 gas challenge.

Background: Quantitative susceptibility mapping (QSM) offers a means to track iron evolution in hemorrhage. However, standard QSM sequences have long acquisition times and are prone to motion artifact in hemorrhagic patients. Purpose: To minimize motion artifact and acquisition time by performing rapid QSM in intracerebral hemorrhage (ICH) using single-shot echo planar imaging (EPI). Study Type: Prospective method evaluation. Population/Subjects: Forty-five hemorrhages were analyzed from 35 MRI exams obtained between February 2016 and March 2019 from 27 patients (14 male / 13 female, age: 71 ± 12 years) with confirmed primary ICH. Field Strength/Sequence: 3T; susceptibility-weighted imaging (SWI) with 4.54-minute acquisition and 2D single-shot gradient EPI with 0.45-minute acquisition. Assessment: Susceptibility maps were constructed from both methods. Measurement of ICH area and mean magnetic susceptibility were made manually by three independent observers. Motion artifacts were quantified using the magnitude signal ratio of artifact-to-brain tissue to classify into three categories: mild or no artifact, moderate artifact, or severe artifact. The cutoff for each category was determined by four observers. Statistical Tests: Pearson's correlation coefficient and paired t-test using a = 0.05 were used to compare results. Inter- and intraclass correlation was used to assess observer variability. Results: Using 45 hemorrhages, the ICH regions measured on susceptibility maps obtained from EPI and SWI sequences had high correlation coefficients for area (R2 = 0.97) and mean magnetic susceptibility (R2 = 0.93) for all observers. The artifact-to-tissue ratio was significantly higher (P < 0.01) for SWI vs. EPI, and the standard deviation for the SWI method (SD = 0.05) was much larger than EPI (SD = 0.01). All observers' measurements showed high agreement. Data Conclusion: Single-shot EPI-QSM enabled rapid measurement of ICH area and mean magnetic susceptibility, with reduced motion as compared with more standard SWI. EPI-QSM requires minimal additional acquisition time and could be incorporated into iron tracking studies in ICH. Level of Evidence: 2. Technical Efficacy Stage: 1. J. Magn. Reson. Imaging 2020;51:712¿718.

Background: Relapsing-Remitting MS (RRMS) Deep Grey Matter (DGM) 5 year changes were examined using MRI measures of volume, transverse relaxation rate (R2*) and quantitative magnetic susceptibility (QS). By applying Discriminative Analysis of Regional Evolution (DARE), R2* and QS changes from iron and non-iron sources were separated. Methods: 25 RRMS and 25 age-matched control subjects were studied at baseline and 5-year follow-up. Bulk DGM mean R2* and QS of the caudate nucleus, putamen, thalamus and globus pallidus were analyzed using mixed factorial analysis (a = 0.05) with sex as a covariate, while DARE employed non-parametric analysis to study regional changes. Regression/correlation analysis was performed with disease duration and MS Severity Score (MSSS). Results: No significant change in Extended Disability Status Score was found over 5 years (baseline = 2.4 ± 1.2; follow-up = 2.8 ± 1.3). Significant time effects were found for R2* in the caudate (Q = 0.000008; ¿2 = 0.36), putamen (Q = 0.0000007; ¿2 = 0.43), and globus pallidus (Q = 0.0000007; ¿2 = 0.43), while significant longitudinal effects were only found for QS in the putamen (Q = 0.002; ¿2 = 0.22). Significant bulk interaction was only found for thalamus volume (Q = 0.02; ¿2 = 0.20). Iron decrease was the only detected significant effect using DARE, and the highest significant DARE effect size was mean thalamus R2* iron decrease (Q = 0.002; ¿2 = 0.26). No significant correlations or regressions were demonstrated with clinical measures. Conclusions: Thalamic atrophy was the only bulk effect that demonstrated different rates of changes over 5 years compared to age-matched controls. DARE Iron decrease in regions of the caudate, putamen, and thalamus were prominent features in stable RRMS over 5 years.

Purpose: To follow the evolution of intracranial hemorrhage (ICH) by using quantitative susceptibility mapping (QSM). Materials and Methods: Thirty-six patients with ICH confirmed at CT were enrolled to follow ICH evolution on day 2, 7, and 30 after symptom onset between August 2013 and April 2017. QSM was reconstructed from MRI gradient-echo phase images acquired at 1.5 T or 3.0 T. ICH regions were manually drawn on two-dimensional sections of co-registered CT and MR images independently by two raters. The ICH areas and mean values were compared between CT and MRI by using Bland-Altman plots and Pearson correlation. QSM time evolution of ICH was assessed by using paired t tests and was compared with conventional T2-weighted fluid-attenuated inversion recovery, or T1-weighted or T2*-weighted magnitude intensities. Results: Significant reductions in ICH susceptibility were found between day 2 and day 7 (P , .001) and between day 7 and day 30 (P = .003), corresponding to different disease stages. The ICH areas measured at CT and QSM were linearly correlated (r2 = 0.98). The mean CT attenuation and mean susceptibility of ICH were linearly correlated (r2 = 0.29). Excellent intra- and interobserver reproducibility were found for QSM (intraclass correlation coefficient, 0.987 and 0.966, respectively). Conclusion: Longitudinal evolution of intracranial hemorrhage (ICH) by using quantitative susceptibility mapping (QSM) demonstrated susceptibility differences in different disease stages, which was not found at conventional MRI; therefore, QSM may assist in quantitatively following ICH iron content.

BACKGROUND AND PURPOSE: Noninvasive venous oxygenation quantification with MR imaging will improve the neurophysiologic investigation and the understanding of the pathophysiology in neurologic diseases. Available MR imaging methods are limited by sensitivity to flow and often require assumptions of the hematocrit level. In situ postmortem imaging enables evaluation of methods in a fully deoxygenated environment without flow artifacts, allowing direct calculation of hematocrit. This study compares 2 venous oxygenation quantification methods in in situ postmortem subjects. MATERIALS AND METHODS: Transverse relaxation (R2*) mapping and quantitative susceptibility mapping were performed on a whole-body 4.7T MR imaging system. Intravenous measurements in major draining intracranial veins were compared between the 2 methods in 3 postmortem subjects. The quantitative susceptibility mapping technique was also applied in 10 healthy control subjects and compared with reference venous oxygenation values. RESULTS: In 2 early postmortem subjects, R2* mapping and quantitative susceptibility mapping measurements within intracranial veins had a significant and strong correlation (R2 0.805, P .004 and R2 0.836, P .02). Higher R2* and susceptibility values were consistently demonstrated within gravitationally dependent venous segments during the early postmortem period. Hematocrit ranged from 0.102 to 0.580 in postmortem subjects, with R2* and susceptibility as large as 291 seconds1 and 1.75 ppm, respectively. CONCLUSIONS: Measurements of R2* and quantitative susceptibility mapping within large intracranial draining veins have a high correlation in early postmortem subjects. This study supports the use of quantitative susceptibility mapping for evaluation of in vivo venous oxygenation and postmortem hematocrit concentrations.

Background: Combined R2* and quantitative susceptibility (QS) has been previously used in cross-sectional multiple sclerosis (MS) studies to distinguish deep gray matter (DGM) iron accumulation and demyelination. Purpose: We propose and apply discriminative analysis of regional evolution (DARE) to define specific changes in MS and healthy DGM. Study Type: Longitudinal (baseline and 2-year follow-up) retrospective study. Subjects: Twenty-seven relapsing-remitting MS (RRMS), 17 progressive MS (PMS), and corresponding age-matched healthy subjects. Field Strength/Sequence: 4.7T 10-echo gradient-echo acquisition. Assessment: Automatically segmented caudate nucleus (CN), thalamus (TH), putamen (PU), globus pallidus, red nucleus (RN), substantia nigra, and dentate nucleus were retrospectively analyzed to quantify regional volumes, bulk mean R2*, and bulk mean QS. DARE utilized combined R2* and QS localized changes to compute spatial extent, mean intensity, and total changes of DGM iron and myelin/calcium over 2 years. Statistical Tests: We used mixed factorial analysis for bulk analysis, nonparametric tests for DARE (a = 0.05), and multiple regression analysis using backward elimination of DGM structures (a = 0.05, P = 0.1) to regress bulk and DARE measures with the follow-up Multiple Sclerosis Severity Score (MSSS). False detection rate correction was applied to all tests. Results: Bulk analysis only detected significant (Q = 0.05) interaction effects in RRMS CN QS (¿ = 0.45; Q = 0.004) and PU volume (¿ = 0.38; Q = 0.034). DARE demonstrated significant group differences in all RRMS structures, and in all PMS structures except the RN. The largest RRMS effect size was CN total R2* iron decrease (r = 0.74; Q = 0.00002), and TH mean QS myelin/calcium decrease for PMS (r = 0.70; Q = 0.002). DARE iron increase using total QS demonstrated the highest correlation with MSSS (r = 0.68; Q = 0.0005). Data Conclusion: DARE enabled discriminative assessment of specific DGM changes over 2 years, where iron and myelin/calcium changes were the primary drivers in RRMS and PMS compared to age-matched controls, respectively. Specific DARE measures of MS DGM correlated with follow-up MSSS, and may reflect complex disease pathology. Level of Evidence: 3. Technical Efficacy: Stage 1. J. Magn. Reson. Imaging 2018;48:652¿668.

A new dipole field inversion method for whole head quantitative susceptibility mapping (QSM) is proposed. Instead of performing background field removal and local field inversion sequentially, the proposed method performs dipole field inversion directly on the total field map in a single step. To aid this under-determined and ill-posed inversion process and obtain robust QSM images, Tikhonov regularization is implemented to seek the local susceptibility solution with the least-norm (LN) using the L-curve criterion. The proposed LN-QSM does not require brain edge erosion, thereby preserving the cerebral cortex in the final images. This should improve its applicability for QSM-based cortical grey matter measurement, functional imaging and venography of full brain. Furthermore, LN-QSM also enables susceptibility mapping of the entire head without the need for brain extraction, which makes QSM reconstruction more automated and less dependent on intermediate pre-processing methods and their associated parameters. It is shown that the proposed LN-QSM method reduced errors in a numerical phantom simulation, improved accuracy in a gadolinium phantom experiment, and suppressed artefacts in nine subjects, as compared to two-step and other single-step QSM methods. Measurements of deep grey matter and skull susceptibilities from LN-QSM are consistent with established reconstruction methods.

BACKGROUND AND PURPOSE: Deep gray matter iron accumulation is increasingly recognized in association with multiple sclerosis and can be measured in vivo with MR imaging. The cognitive implications of this pathology are not well-understood, especially vis-a-vis deep gray matter atrophy. Our aim was to investigate the relationships between cognition and deep gray matter iron in MS by using 2 MR imaging-based iron-susceptibility measures. MATERIALS AND METHODS: Forty patients with multiple sclerosis (relapsing-remitting, n = 16; progressive, n = 24) and 27 healthy controls were imaged at 4.7T by using the transverse relaxation rate and quantitative susceptibility mapping. The transverse relaxation rate and quantitative susceptibility mapping values and volumes (atrophy) of the caudate, putamen, globus pallidus, and thalamus were determined by multiatlas segmentation. Cognition was assessed with the Brief Repeatable Battery of Neuropsychological Tests. Relationships between cognition and deep gray matter iron were examined by hierarchic regressions. RESULTS: Compared with controls, patients showed reduced memory (P <.001) and processing speed (P =.02) and smaller putamen (P <.001), globus pallidus (P =.002), and thalamic volumes (P <.001). Quantitative susceptibility mapping values were increased in patients compared with controls in the putamen (P =.003) and globus pallidus (P =.003). In patients only, thalamus (P <.001) and putamen (P =.04) volumes were related to cognitive performance. After we controlled for volume effects, quantitative susceptibility mapping values in the globus pallidus (P =.03; trend for transverse relaxation rate, P =.10) were still related to cognition. CONCLUSIONS: Quantitative susceptibility mapping was more sensitive compared with the transverse relaxation rate in detecting deep gray matter iron accumulation in the current multiple sclerosis cohort. Atrophy and iron accumulation in deep gray matter both have negative but separable relationships to cognition in multiple sclerosis.

Standard functional MRI (fMRI), which includes resting-state or paradigm-driven designs, is widely used in studies of brain function, aging, and disease. These fMRI studies typically use two-dimensional gradient echo-planar imaging, which inherently contains phase data that enables quantitative susceptibility mapping (QSM). This work focuses on the dual value of QSM within fMRI studies, by providing both a localized analysis of functional changes in activated tissue, and iron-sensitive structural maps in deep grey matter (DGM). Using a visual paradigm fMRI study on healthy volunteers at clinical (1.5 T) and high field strength (4.7 T), we perform functional analysis of magnitude and QSM time series, and at the same time harness structural QSM of iron-rich DGM, including globus pallidus, putamen, caudate head, substantia nigra, and red nucleus. The effects of fMRI spatial resolution and time series variation on structural DGM QSM are investigated. Our results indicate that structural DGM QSM is feasible within existing fMRI studies, provided that the voxel dimensions are equal to or less than 3 mm, with higher resolutions preferred. The mean DGM QSM values were about 40 to 220 ppb, while the interquartile ranges of the DGM QSM time series varied from about 3 to 9 ppb, depending on structure and resolution. In contrast, the peak voxel functional QSM (fQSM) changes in activated visual cortex ranged from about -10 to -30 ppb, and functional clusters were consistently smaller on QSM than magnitude fMRI. Mean-level DGM QSM of the time series was successfully extracted in all cases, while fQSM results were more prone to residual background fields and showed less functional change compared with standard magnitude fMRI. Under the conditions prescribed, standard fMRI studies may be used for robust mean-level DGM QSM, enabling study of DGM iron accumulation, in addition to functional analysis. Copyright © 2016 John Wiley & Sons, Ltd.

Purpose: To create an automated framework for localized analysis of deep gray matter (DGM) iron accumulation and demyelination using sparse classification by combining quantitative susceptibility (QS) and transverse relaxation rate (R2*) maps, for evaluation of DGM in multiple sclerosis (MS) phenotypes relative to healthy controls. Materials and Methods: R2*/QS maps were computed using a 4.7T 10-echo gradient echo acquisition from 16 clinically isolated syndrome (CIS), 41 relapsing-remitting (RR), 40 secondary-progressive (SP), 13 primary-progressive (PP) MS patients, and 75 controls. Sparse classification for R2*/QS maps of segmented caudate nucleus (CN), putamen (PU), thalamus (TH), and globus pallidus (GP) structures produced localized maps of iron/myelin in MS patients relative to controls. Paired t-tests, with age as a covariate, were used to test for statistical significance (P = 0.05). Results: In addition to DGM structures found significantly different in patients compared to controls using whole region analysis, singular sparse analysis found significant results in RRMS PU R2* (P = 0.03), TH R2* (P = 0.04), CN QS (P = 0.04); in SPMS CN R2* (P = 0.04), GP R2* (P = 0.05); and in PPMS CN R2* (P = 0.04), TH QS (P = 0.04). All sparse regions were found to conform to an iron accumulation pattern of changes in R2*/QS, while none conformed to demyelination. Intersection of sparse R2*/QS regions also resulted in RRMS CN R2* becoming significant, while RRMS R2* TH and PPMS QS TH becoming insignificant. Common iron-associated volumes in MS patients and their effect size progressively increased with advanced phenotypes. Conclusion: A localized technique for identifying sparse regions indicative of iron or myelin in the DGM was developed. Progressive iron accumulation with advanced MS phenotypes was demonstrated, as indicated by iron-associated sparsity and effect size. Level of Evidence: 1. Technical Efficacy: Stage 1. J. Magn. Reson. Imaging 2017;46:1464¿1473.

Purpose Evaluate brain iron accumulation in alcohol use disorder (AUD) patients compared to controls using quantitative susceptibility mapping (QSM). Methods QSM was performed retrospectively by using phase images from resting state functional magnetic resonance imaging (fMRI). 20 male AUD patients and 15 matched healthy controls were examined. Susceptibility values were manually traced in deep grey matter regions including caudate nucleus, combined putamen and globus pallidus, combined substantia nigra and red nucleus, dentate nucleus, and a reference white matter region in the internal capsule. Average susceptibility values from each region were compared between the patients and controls. The relationship between age and susceptibility was also explored. Results The AUD group exhibited increased susceptibility in caudate nucleus (+8.5%, p=0.034), combined putamen and globus pallidus (+10.8%, p=0.006), and dentate nucleus (+14.9%, p=0.022). Susceptibility increased with age in two of the four measured regions - combined putamen and globus pallidus (p=0.013) and combined substantia nigra and red nucleus (p=0.041). AUD did not significantly modulate the rate of susceptibility increase with age in our data. Conclusion Retrospective QSM computed from standard fMRI datasets provides new opportunities for brain iron studies in psychiatry. Substantially elevated brain iron was found in AUD subjects in the basal ganglia and dentate nucleus. This was the first human AUD brain iron study and the first retrospective clinical fMRI QSM study.

Quantitative Susceptibility Mapping (QSM) is an emerging area of brain research with clear application to brain iron studies in deep gray matter. However, acquisition of standard whole brain QSM can be time-consuming. One means to reduce scan time is to use a focal acquisition restricted only to the regions of interest such as deep gray matter. However, the non-local dipole field necessary for QSM reconstruction extends far beyond the structure of interest. We demonstrate the practical implications of these non-local fields on the choice of brain volume for QSM. In an illustrative numerical simulation and then in human brain experiments, we examine the effect on QSM of volume reduction in each dimension. For the globus pallidus, as an example of iron-rich deep gray matter, we demonstrate that substantial errors can arise even when the field-of-view far exceeds the physical structural boundaries. Thus, QSM reconstruction requires a non-local field-of-view prescription to ensure minimal errors. An axial QSM acquisition, centered on the globus pallidus, should encompass at least 76 mm in the superior-inferior direction to conserve susceptibility values from the globus pallidus. This dimension exceeds the physical coronal extent of this structure by at least five-fold. As QSM sees wider use in the neuroscience community, its unique requirement for an extended field-of-view needs to be considered.

Purpose: To investigate gradient-echo phase errors caused by intracranial hemorrhage (ICH) of low signal magnitude, and propose methods to reduce artifacts from phase errors in quantitative susceptibility mapping (QSM) of ICH. Methods: Two QSM methods are proposed: (1) mask-inversion that masks the phase of low signal magnitude regions, and (2) ICH magnetic dipole field isolation followed by susceptibility superposition using multiple boundaries for background field removal. The reconstruction methods were tested in eight subjects with ICH using standard single-echo susceptibility-weighted imaging at 1.5 Tesla with 40 ms echo time. Different phase unwrapping algorithms were also compared. Results: Significant phase errors were evident inside ICHs with low signal magnitude. The mask-inversion method recovered susceptibility of ICH in numerical simulation and minimized phase error propagation in patients with ICH. The additional superposed dipole inversion process substantially suppressed and constrained streaking artifacts in all subjects. Using the proposed superposition method, ICH susceptibilities measured from long and short echo times were similar. Laplacian based phase unwrapping substantially underestimated the ICH dipole field as compared to a path-based method. Conclusion: The proposed methods of mask-inversion as well as ICH isolation and superposition can substantially reduce artifacts in QSM of ICH. Magn Reson Med 76:781¿791, 2016. © 2015 Wiley Periodicals, Inc.