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While magnetic susceptibility is a major contributor to NMR resonance frequency variations in the human brain, a substantial contribution may come from the chemical exchange of protons between water and other molecules. Exchange-induced frequency shifts fe have been measured in tissue and protein solutions, but relatively lipid-rich white matter (WM) has a larger fe than gray matter, suggesting that lipids could contribute. Galactocerebrosides (GC) are a prime candidate as they are abundant in WM and susceptible to exchange. To investigate this, fe was measured in a model of WM lipid membranes in the form of multilamellar vesicles (MLVs), consisting of a 1:2 molar ratio of GC and phospholipids (POPC), and in MLVs with POPC only. Chemical shift imaging with 15% volume fraction of dioxane, an internal reference whose protons are assumed not to undergo chemical exchange, was used to remove susceptibility-induced frequency shifts in an attempt to measure fe in MLVs at several lipid concentrations. Initial analysis of these measurements indicated a necessity to correct for small unexpected variations in dioxane concentration due to its effect on the water frequency shift. To achieve this, the actual dioxane concentration was inferred from spectral analysis and its additional contribution to fe was removed through separate experiments which showed that the water-dioxane frequency shift depended linearly on the dioxane concentration at low concentrations with a proportionality constant of -0.021 ± 0.002 ppb/mM in agreement with published experiments. Contrary to expectations and uncorrected results, for GC + POPC vesicles, the dependence of the corrected fe on GC concentration was insignificant (0.023 ± 0.037 ppb/mM; r2 = 0.085, p > 0.57), whereas for the POPC-only vesicles a small but significant linear increase with POPC concentration was found: 0.044 ± 0.008 ppb/mM ( r2 = 0.877, p < 0.01). These findings suggest that the exchange-induced contribution of lipids to frequency contrast in WM may be small. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Objective: Reliable identification of the subthalamic nucleus (STN) and globus pallidus interna (GPi) is critical for deep brain stimulation (DBS) of these structures. The purpose of this study was to compare the visibility of the STN and GPi with various MRI techniques and to assess the suitability of each technique for direct stereotactic targeting.Methods: MR images were acquired from nine volunteers with T2- and proton density-weighted (PD-W) fast spin echo, susceptibility-weighted imaging (SWI), phase-sensitive inversion recovery and quantitative T1, T2 and T2* mapping sequences. Contrast-to-noise ratios (CNR) for the STN and GPi were calculated for all sequences. Targeting errors on SWI were evaluated on magnetic susceptibility maps. The sequences demonstrating the best conspicuity of DBS target structures (SWI and T2*) were then applied to ten patients with movement disorders, and the CNRs for these techniques were assessed.Results: SWI offers the highest CNR for the STN, but standard PD-W images provide the best CNR for the pallidum. Susceptibility maps indicated that the GPi margins may be shifted slightly on SWI, although no shifts were seen for the STN.Conclusion: SWI may improve the visibility of the STN on pre-operative MRI, potentially improving the accuracy of direct stereotactic targeting. [ABSTRACT FROM AUTHOR]

Background: Deep grey matter pathology is a key driver of disability worsening in people with multiple sclerosis. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique which quantifies local magnetic susceptibility from variations in phase produced by changes in the local magnetic field. In the deep grey matter, susceptibility has previously been validated against tissue iron concentration. However, it currently remains unknown whether susceptibility is abnormal in older progressive MS cohorts, and whether it correlates with disability., Objectives: To investigate differences in mean regional susceptibility in deep grey matter between people with secondary progressive multiple sclerosis (SPMS) and healthy controls; to examine in patients the relationships between deep grey matter susceptibility and clinical and imaging measures of disease severity., Methods: Baseline data from a subgroup of the MS-STAT2 trial (simvastatin vs. placebo in SPMS, NCT03387670) were included. The subgroup underwent clinical assessments and an advanced MRI protocol at 3T. A cohort of age-matched healthy controls underwent the same MRI protocol. Susceptibility maps were reconstructed using a robust QSM pipeline from multi-echo 3D gradient-echo sequence. Regions of interest (ROIs) in the thalamus, globus pallidus and putamen were segmented from 3D T1-weighted images, and lesions segmented from 3D fluid-attenuated inversion recovery images. Linear regression was used to compare susceptibility from ROIs between patients and controls, adjusting for age and sex. Where significant differences were found, we further examined the associations between ROI susceptibility and clinical and imaging measures of MS severity., Results: 149 SPMS (77% female; mean age: 53 yrs; median Expanded Disability Status Scale (EDSS): 6.0 [interquartile range 4.5-6.0]) and 33 controls (52% female, mean age: 57) were included.Thalamic susceptibility was significantly lower in SPMS compared to controls: mean (SD) 28.6 (12.8) parts per billion (ppb) in SPMS vs. 39.2 (12.7) ppb in controls; regression coefficient: -12.0 [95% confidence interval: -17.0 to -7.1], p < 0.001. In contrast, globus pallidus and putamen susceptibility were similar between both groups.In SPMS, a 10 ppb lower thalamic susceptibility was associated with a +0.13 [+0.01 to +0.24] point higher EDSS (p < 0.05), a -2.4 [-3.8 to -1.0] point lower symbol digit modality test (SDMT, p = 0.001), and a -2.4 [-3.7 to -1.1] point lower Sloan low contrast acuity, 2.5% (p < 0.01).Lower thalamic susceptibility was also strongly associated with a higher T2 lesion volume (T2LV, p < 0.001) and lower normalised whole brain, deep grey matter and thalamic volumes (all p < 0.001)., Conclusions: The reduced thalamic susceptibility found in SPMS compared to controls suggests that thalamic iron concentrations are lower at this advanced stage of the disease. The observed relationships between lower thalamic susceptibility and more severe physical, cognitive and visual disability suggests that reductions in thalamic iron may correlate with important mechanisms of clinical disease progression. Such mechanisms appear to intimately link reductions in thalamic iron with higher T2LV and the development of thalamic atrophy, encouraging further research into QSM-derived thalamic susceptibility as a biomarker of disease severity in SPMS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Purpose: The structural similarity index measure (SSIM) has become a popular quality metric to evaluate QSM in a way that is closer to human perception than RMS error (RMSE). However, SSIM may overpenalize errors in diamagnetic tissues and underpenalize them in paramagnetic tissues, resulting in biasing. In addition, extreme artifacts may compress the dynamic range, resulting in unrealistically high SSIM scores (hacking). To overcome biasing and hacking, we propose XSIM: SSIM implemented in the native QSM range, and with internal parameters optimized for QSM., Methods: We used forward simulations from a COSMOS ground-truth brain susceptibility map included in the 2016 QSM Reconstruction Challenge to investigate the effect of QSM reconstruction errors on the SSIM, XSIM, and RMSE metrics. We also used these metrics to optimize QSM reconstructions of the in vivo challenge data set. We repeated this experiment with the QSM abdominal phantom. To validate the use of XSIM instead of SSIM for QSM quality assessment across a range of different reconstruction techniques/algorithms, we analyzed the reconstructions submitted to the 2019 QSM Reconstruction Challenge 2.0., Results: Our experiments confirmed the biasing and hacking effects on the SSIM metric applied to QSM. The XSIM metric was robust to those effects, penalizing the presence of streaking artifacts and reconstruction errors. Using XSIM to optimize QSM reconstruction regularization weights returned less overregularization than SSIM and RMSE., Conclusion: XSIM is recommended over traditional SSIM to evaluate QSM reconstructions against a known ground truth, as it avoids biasing and hacking effects and provides a larger dynamic range of scores., (© 2024 International Society for Magnetic Resonance in Medicine.)

Purpose: Data for QSM are typically acquired using multi-echo 3D gradient echo (GRE), but EPI can be used to accelerate QSM and provide shorter acquisition times. So far, EPI-QSM has been limited to single-echo acquisitions, which, for 3D GRE, are known to be less accurate than multi-echo sequences. Therefore, we compared single-echo and multi-echo EPI-QSM reconstructions across a range of parallel imaging and multiband acceleration factors., Methods: Using 2D single-shot EPI in the brain, we compared QSM from single-echo and multi-echo acquisitions across combined parallel-imaging and multiband acceleration factors ranging from 2 to 16, with volume pulse TRs from 21.7 to 3.2 s, respectively. For single-echo versus multi-echo reconstructions, we investigated the effect of acceleration factors on regional susceptibility values, temporal noise, and image quality. We introduce a novel masking method based on thresholding the magnitude of the local field gradients to improve brain masking in challenging regions., Results: At 1.6-mm isotropic resolution, high-quality QSM was achieved using multi-echo 2D EPI with a combined acceleration factor of 16 and a TR of 3.2 s, which enables functional applications. With these high acceleration factors, single-echo reconstructions are inaccurate and artefacted, rendering them unusable. Multi-echo acquisitions greatly improve QSM quality, particularly at higher acceleration factors, provide more consistent regional susceptibility values across acceleration factors, and decrease temporal noise compared with single-echo QSM reconstructions., Conclusion: Multi-echo acquisition is more robust for EPI-QSM across parallel imaging and multiband acceleration factors than single-echo acquisition. Multi-echo EPI can be used for highly accelerated acquisition while preserving QSM accuracy and quality relative to gold-standard 3D-GRE QSM., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Quantitative MRI (qMRI) has been shown to be clinically useful for numerous applications in the brain and body. The development of rapid, accurate, and reproducible qMRI techniques offers access to new multiparametric data, which can provide a comprehensive view of tissue pathology. This work introduces a multiparametric qMRI protocol along with full postprocessing pipelines, optimized for brain imaging at 3 Tesla and using state-of-the-art qMRI tools. The total scan time is under 50 minutes and includes eight pulse-sequences, which produce range of quantitative maps including T1, T2, and T2* relaxation times, magnetic susceptibility, water and macromolecular tissue fractions, mean diffusivity and fractional anisotropy, magnetization transfer ratio (MTR), and inhomogeneous MTR. Practical tips and limitations of using the protocol are also provided and discussed. Application of the protocol is presented on a cohort of 28 healthy volunteers and 12 brain regions-of-interest (ROIs). Quantitative values agreed with previously reported values. Statistical analysis revealed low variability of qMRI parameters across subjects, which, compared to intra-ROI variability, was x4.1 ± 0.9 times higher on average. Significant and positive linear relationship was found between right and left hemispheres' values for all parameters and ROIs with Pearson correlation coefficients of r>0.89 (P<0.001), and mean slope of 0.95 ± 0.04. Finally, scan-rescan stability demonstrated high reproducibility of the measured parameters across ROIs and volunteers, with close-to-zero mean difference and without correlation between the mean and difference values (across map types, mean P value was 0.48 ± 0.27). The entire quantitative data and postprocessing scripts described in the manuscript are publicly available under dedicated GitHub and Figshare repositories. The quantitative maps produced by the presented protocol can promote longitudinal and multi-center studies, and improve the biological interpretability of qMRI by integrating multiple metrics that can reveal information, which is not apparent when examined using only a single contrast mechanism., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Radunsky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This article provides recommendations for implementing QSM for clinical brain research. It is a consensus of the International Society of Magnetic Resonance in Medicine, Electro-Magnetic Tissue Properties Study Group. While QSM technical development continues to advance rapidly, the current QSM methods have been demonstrated to be repeatable and reproducible for generating quantitative tissue magnetic susceptibility maps in the brain. However, the many QSM approaches available have generated a need in the neuroimaging community for guidelines on implementation. This article outlines considerations and implementation recommendations for QSM data acquisition, processing, analysis, and publication. We recommend that data be acquired using a monopolar 3D multi-echo gradient echo (GRE) sequence and that phase images be saved and exported in Digital Imaging and Communications in Medicine (DICOM) format and unwrapped using an exact unwrapping approach. Multi-echo images should be combined before background field removal, and a brain mask created using a brain extraction tool with the incorporation of phase-quality-based masking. Background fields within the brain mask should be removed using a technique based on SHARP or PDF, and the optimization approach to dipole inversion should be employed with a sparsity-based regularization. Susceptibility values should be measured relative to a specified reference, including the common reference region of the whole brain as a region of interest in the analysis. The minimum acquisition and processing details required when reporting QSM results are also provided. These recommendations should facilitate clinical QSM research and promote harmonized data acquisition, analysis, and reporting., (© 2024 International Society for Magnetic Resonance in Medicine.)

Background: Dementia is common in Parkinson's disease (PD), but there is wide variation in its timing. A critical gap in PD research is the lack of quantifiable markers of progression, and methods to identify early stages of dementia. Atrophy-based magnetic resonance imaging (MRI) has limited sensitivity in detecting or tracking changes relating to PD dementia, but quantitative susceptibility mapping (QSM), sensitive to brain tissue iron, shows potential for these purposes., Objective: The objective of the paper is to study, for the first time, the longitudinal relationship between cognition and QSM in PD in detail., Methods: We present a longitudinal study of clinical severity in PD using QSM, including 59 PD patients (without dementia at study onset), and 22 controls over 3 years., Results: In PD, increased baseline susceptibility in the right temporal cortex, nucleus basalis of Meynert, and putamen was associated with greater cognitive severity after 3 years; and increased baseline susceptibility in basal ganglia, substantia nigra, red nucleus, insular cortex, and dentate nucleus was associated with greater motor severity after 3 years. Increased follow-up susceptibility in these regions was associated with increased follow-up cognitive and motor severity, with further involvement of hippocampus relating to cognitive severity. However, there were no consistent increases in susceptibility over 3 years., Conclusions: Our study suggests that QSM may predict changes in cognitive severity many months prior to overt cognitive involvement in PD. However, we did not find robust longitudinal changes in QSM over the course of the study. Additional tissue metrics may be required together with QSM for it to monitor progression in clinical practice and therapeutic trials. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Temporal lobe epilepsy (TLE) is associated with widespread brain alterations. Using quantitative susceptibility mapping (QSM) alongside transverse relaxation rate ( R 2 * ), we investigated regional brain susceptibility changes in 36 patients with left-sided (LTLE) or right-sided TLE (RTLE) secondary to hippocampal sclerosis, and 27 healthy controls (HC). We compared three susceptibility calculation methods to ensure image quality. Correlations of susceptibility and R 2 * with age of epilepsy onset, frequency of focal-to-bilateral tonic-clonic seizures (FBTCS), and neuropsychological test scores were examined. Weak-harmonic QSM (WH-QSM) successfully reduced noise and removed residual background field artefacts. Significant susceptibility increases were identified in the left putamen in the RTLE group compared to the LTLE group, the right putamen and right thalamus in the RTLE group compared to HC, and a significant susceptibility decrease in the left hippocampus in LTLE versus HC. LTLE patients who underwent epilepsy surgery showed significantly lower left-versus-right hippocampal susceptibility. Significant R 2 * changes were found between TLE and HC groups in the amygdala, putamen, thalamus, and in the hippocampus. Specifically, decreased R 2 * was found in the left and right hippocampus in LTLE and RTLE, respectively, compared to HC. Susceptibility and R 2 * were significantly correlated with cognitive test scores in the hippocampus, globus pallidus, and thalamus. FBTCS frequency correlated positively with ipsilateral thalamic and contralateral putamen susceptibility and with R 2 * in bilateral globi pallidi. Age of onset was correlated with susceptibility in the hippocampus and putamen, and with R 2 * in the caudate. Susceptibility and R 2 * changes observed in TLE groups suggest selective loss of low-myelinated neurons alongside iron redistribution in the hippocampi, predominantly ipsilaterally, indicating QSM's sensitivity to local pathology. Increased susceptibility and R 2 * in the thalamus and putamen suggest increased iron content and reflect disease severity., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Prior studies have found an association between calcification and the epileptogenicity of tubers in tuberous sclerosis complex. Quantitative susceptibility mapping is a novel tool sensitive to magnetic susceptibility alterations due to tissue calcification. We assessed the utility of quantitative susceptibility mapping in identifying putative epileptogenic tubers in tuberous sclerosis complex using stereoelectroencephalography data as ground truth., Materials and Methods: We studied patients with tuberous sclerosis complex undergoing stereoelectroencephalography at a single center who had multiecho gradient-echo sequences available. Quantitative susceptibility mapping and R2* values were extracted for all tubers on the basis of manually drawn 3D ROIs using T1- and T2-FLAIR sequences. Characteristics of quantitative susceptibility mapping and R2* distributions from implanted tubers were compared using binary logistic generalized estimating equation models designed to identify ictal (involved in seizure onset) and interictal (persistent interictal epileptiform activity) tubers. These models were then applied to the unimplanted tubers to identify potential ictal and interictal tubers that were not sampled by stereoelectroencephalography., Results: A total of 146 tubers were identified in 10 patients, 76 of which were sampled using stereoelectroencephalography. Increased kurtosis of the tuber quantitative susceptibility mapping values was associated with epileptogenicity ( P  = .04 for the ictal group and P  = .005 for the interictal group) by the generalized estimating equation model. Both groups had poor sensitivity (35.0% and 44.1%, respectively) but high specificity (94.6% and 78.6%, respectively)., Conclusions: Our finding of increased kurtosis of quantitative susceptibility mapping values (heavy-tailed distribution) was highly specific, suggesting that it may be a useful biomarker to identify putative epileptogenic tubers in tuberous sclerosis complex. This finding motivates the investigation of underlying tuber mineralization and other properties driving kurtosis changes in quantitative susceptibility mapping values., (© 2023 by American Journal of Neuroradiology.)

Introduction: Reconstructing a bounded object from incomplete k-space data is a well posed problem, and it was recently shown that this incomplete spectrum approach can be used to reconstruct undersampled MRI images with similar quality to compressed sensing approaches. Here, we apply this incomplete spectrum approach to the field-to-source inverse problem encountered in quantitative magnetic susceptibility mapping (QSM). The field-to-source problem is an ill-posed problem because of conical regions in frequency space where the dipole kernel is zero or very small, which leads to the kernel's inverse being ill-defined. These "ill-posed" regions typically lead to streaking artifacts in QSM reconstructions. In contrast to compressed sensing, our approach relies on knowledge of the image-space support, more commonly referred to as the mask, of our object as well as the region in k-space with ill-defined values. In the QSM case, this mask is usually available, as it is required for most QSM background field removal and reconstruction methods., Methods: We tuned the incomplete spectrum method (mask and band-limit) for QSM on a simulated dataset from the most recent QSM challenge and validated the QSM reconstruction results on brain images acquired in five healthy volunteers, comparing incomplete spectrum QSM to current state-of-the art-methods: FANSI, nonlinear dipole inversion, and conventional thresholded k-space division., Results: Without additional regularization, incomplete spectrum QSM performs slightly better than direct QSM reconstruction methods such as thresholded k-space division (PSNR of 39.9 vs. 39.4 of TKD on a simulated dataset) and provides susceptibility values in key iron-rich regions similar or slightly lower than state-of-the-art algorithms, but did not improve the PSNR in comparison to FANSI or nonlinear dipole inversion. With added (ℓ1-wavelet based) regularization the new approach produces results similar to compressed sensing based reconstructions (at sufficiently high levels of regularization)., Discussion: Incomplete spectrum QSM provides a new approach to handle the "ill-posed" regions in the frequency-space data input to QSM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fuchs and Shmueli.)

Brain injury is a common complication of sickle cell anaemia (SCA). White matter (WM) and cortical and subcortical grey matter (GM), structures may have reduced volume in patients with SCA. This study focuses on whether silent cerebral infarction (SCI), vasculopathy or anaemia affects WM and regional GM volumes in children living in Africa. Children with SCA (n = 144; aged 5-20 years; 74 male) and sibling controls (n = 53; aged 5-17 years; 29 male) underwent magnetic resonance imaging. Effects of SCI (n = 37), vasculopathy (n = 15), and haemoglobin were assessed. Compared with controls, after adjusting for age, sex and intracranial volume, patients with SCA had smaller volumes for WM and cortical, subcortical and total GM, as well as bilateral cerebellar cortex, globus pallidus, amygdala and right thalamus. Left globus pallidus volume was further reduced in patients with vasculopathy. Putamen and hippocampus volumes were larger in patients with SCA without SCI or vasculopathy than in controls. Significant positive effects of haemoglobin on regional GM volumes were confined to the controls. Patients with SCA generally have reduced GM volumes compared with controls, although some subcortical regions may be spared. SCI and vasculopathy may affect the trajectory of change in subcortical GM and WM volume. Brain volume in non-SCA children may be vulnerable to contemporaneous anaemia., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: To compare different multi-echo combination methods for MRI QSM. Given the current lack of consensus, we aimed to elucidate how to optimally combine multi-echo gradient-recalled echo signal phase information, either before or after applying Laplacian-base methods (LBMs) for phase unwrapping or background field removal., Methods: Multi-echo gradient-recalled echo data were simulated in a numerical head phantom, and multi-echo gradient-recalled echo images were acquired at 3 Tesla in 10 healthy volunteers. To enable image-based estimation of gradient-recalled echo signal noise, 5 volunteers were scanned twice in the same session without repositioning. Five QSM processing pipelines were designed: 1 applied nonlinear phase fitting over TEs before LBMs; 2 applied LBMs to the TE-dependent phase and then combined multiple TEs via either TE-weighted or SNR-weighted averaging; and 2 calculated TE-dependent susceptibility maps via either multi-step or single-step QSM and then combined multiple TEs via magnitude-weighted averaging. Results from different pipelines were compared using visual inspection; summary statistics of susceptibility in deep gray matter, white matter, and venous regions; phase noise maps (error propagation theory); and, in the healthy volunteers, regional fixed bias analysis (Bland-Altman) and regional differences between the means (nonparametric tests)., Results: Nonlinearly fitting the multi-echo phase over TEs before applying LBMs provided the highest regional accuracy of χ $$ \chi $$ and the lowest phase noise propagation compared to averaging the LBM-processed TE-dependent phase. This result was especially pertinent in high-susceptibility venous regions., Conclusion: For multi-echo QSM, we recommend combining the signal phase by nonlinear fitting before applying LBMs., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Silent cerebral infarction (SCI) is the most commonly reported radiological abnormality in patients with sickle cell anemia (SCA) and is associated with future clinical stroke risk. To date, there have been few histological and quantitative MRI studies of SCI and multiple radiological definitions exist. As a result, the tissue characteristics and composition of SCI remain elusive. The objective of this work was therefore to investigate the composition of segmented SCI lesions using quantitative MRI for R 2 * and quantitative magnetic susceptibility mapping (QSM). 211 SCI lesions were segmented from 32 participants with SCA and 6 controls. SCI were segmented according to two definitions (FLAIR+/-T1w-based threshold) using a semi-automated pipeline. Magnetic susceptibility (χ) and R 2 * maps were calculated from a multi-echo gradient echo sequence and mean SCI values were compared to an equivalent region of interest in normal appearing white matter (NAWM). SCI χ and R 2 * were investigated as a function of SCI definition, patient demographics, anatomical location, and cognition. Compared to NAWM, SCI were significantly less diamagnetic (χ = -0.0067 ppm vs. -0.0153 ppm, p < 0.001) and had significantly lower R 2 * (16.7 s -1 vs. 19.2 s -1 , p < 0.001). SCI definition had a significant effect on the mean SCI χ and R 2 * , with lesions becoming significantly less diamagnetic and having significantly lower R 2 * after the application of a more stringent T1w-based threshold. SCI-NAWM R 2 * decrease was significantly greater in patients with SCA compared with controls (-2.84 s -1 vs. -0.64 s -1 , p < 0.0001). No significant association was observed between mean SCI-NAWM χ or R2 * differences and subject age, lesion anatomical location, or cognition. The increased χ and decreased R 2 * in SCI relative to NAWM observed in both patients and controls is indicative of lower myelin or increased water content within the segmented lesions. The significant SCI-NAWM R 2 * differences observed between SCI in patients with SCA and controls suggests there may be differences in tissue composition relative to NAWM in SCI in the two populations. Quantitative MRI techniques such as QSM and R 2 * mapping can be used to enhance our understanding of the pathophysiology and composition of SCI in patients with SCA as well as controls., Competing Interests: FK was grant holder for GN2509, V4615, PB-PG-1112-29099, and R01HL079937 and has received honoraria from Global Blood Therapeutics, Bluebird Bio, Novartis, BIAL, Shire and Johnson and Johnson outside this work and not relevant to it. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Murdoch, Stotesbury, Kawadler, Saunders, Kirkham and Shmueli.)

In recent years, interest has grown in the potential for magnetic resonance imaging (MRI) measures of venous oxygen saturation (Y v ) to improve neurological risk prediction. T 2 -relaxation-under-spin-tagging (TRUST) is an MRI technique which has revealed changes in Y v in patients with sickle cell anemia (SCA). However, prior studies comparing Y v in patients with SCA relative to healthy controls have reported opposing results depending on whether the calibration model, developed to convert blood T 2 to Y v , is based on healthy human hemoglobin (HbA), bovine hemoglobin (HbBV) or sickle hemoglobin (HbS). MRI Quantitative Susceptibility Mapping (QSM) is an alternative technique that may hold promise for estimating Y v in SCA as blood magnetic susceptibility is linearly dependent upon Y v , and no significant difference has been found between the magnetic susceptibility of HbA and HbS. Therefore, the aim of this study was to compare estimates of Y v using QSM and TRUST with five published calibration models in healthy controls and patients with SCA. 17 patients with SCA and 13 healthy controls underwent MRI. Susceptibility maps were calculated from a multi-parametric mapping acquisition and Y v was calculated from the mean susceptibility in a region of interest in the superior sagittal sinus. TRUST estimates of T 2, within a similar but much smaller region, were converted to Y v using five different calibration models. Correlation and Bland-Altman analyses were performed to compare estimates of Y v between TRUST and QSM methods. For each method, t-tests were also used to explore group-wise differences between patients with SCA and healthy controls. In healthy controls, significant correlations were observed between QSM and TRUST measures of Y v, while in SCA, there were no such correlations. The magnitude and direction of group-wise differences in Y v varied with method. The TRUST-HbBV and QSM methods suggested decreased Y v in SCA relative to healthy controls, while the TRUST-HbS ( p < 0.01) and TRUST-HbA models suggested increased Y v in SCA as in previous studies. Further validation of all MRI measures of Y v , relative to ground truth measures such as O 15 PET and jugular vein catheterization, is required in SCA before QSM or TRUST methods can be considered for neurological risk prediction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Murdoch, Stotesbury, Hales, Kawadler, Kölbel, Clark, Kirkham and Shmueli.)

Purpose: Intra-arterial Digital Subtraction Angiography (DSA) is the gold standard technique for radiosurgery target delineation in brain Arterio-Venous Malformations (AVMs). This study aims to evaluate whether a combination of three Magnetic Resonance Angiography sequences (triple-MRA) could be used for delineation of brain AVMs for Gamma Knife Radiosurgery (GKR)., Methods: Fifteen patients undergoing DSA for GKR targeting of brain AVMs also underwent triple-MRA: 4D Arterial Spin Labelling based angiography (ASL-MRA), Contrast-Enhanced Time-Resolved MRA (CE-MRA) and High Definition post-contrast Time-Of-Flight angiography (HD-TOF). The arterial phase of the AVM nidus was delineated on triple-MRA by an interventional neuroradiologist and a consultant neurosurgeon (triple-MRA volume). Triple-MRA volumes were compared to AVM targets delineated by the clinical team for delivery of GKR using the current planning paradigm, i.e., stereotactic DSA and volumetric MRI (DSA volume). Difference in size, degree of inclusion (DI) and concordance index (CcI) between DSA and triple-MRA volumes are reported., Results: AVM target volumes delineated on triple-MRA were on average 9.8% smaller than DSA volumes (95%CI:5.6-13.9%; SD:7.14%; p  = .003). DI of DSA volume in triple-MRA volume was on average 73.5% (95%CI:71.2-76; range: 65-80%). The mean percentage of triple-MRA volume not included on DSA volume was 18% (95%CI:14.7-21.3; range: 7-30%)., Conclusion: The technical feasibility of using triple-MRA for visualisation and delineation of brain AVMs for GKR planning has been demonstrated. Tighter and more precise delineation of AVM target volumes could be achieved by using triple-MRA for radiosurgery targeting. However, further research is required to ascertain the impact this may have in obliteration rates and side effects.

Purpose: To characterize microstructural contributions to the magnetic susceptibility of carotid arteries., Method: Arterial vessels were scanned using high-resolution quantitative susceptibility mapping (QSM) at 7 Tesla. Models of vessel degradation were generated using ex vivo porcine carotid arteries that were subjected to several different enzymatic digestion treatments that selectively removed microstructural components (smooth muscle cells, collagen, and elastin). Magnetic susceptibilities measured in these tissue models were compared to those in untreated (native) porcine arteries. Magnetic susceptibility measured in native porcine carotid arteries was further compared to the susceptibility of cadaveric human carotid arteries to investigate their similarity., Results: The magnetic susceptibility of native porcine vessels was diamagnetic (χ native = -0.1820 ppm), with higher susceptibilities in all models of vessel degradation (χ elastin-degraded = -0.0163 ppm; χ collagen-degraded = -0.1158 ppm; χ decellularized = -0.1379 ppm; χ fixed native = -0.2199 ppm). Magnetic susceptibility was significantly higher in collagen-degraded compared to native porcine vessels (Tukey-Kramer, P < .01) and between elastin-degraded and all other models (including native, Tukey-Kramer, P < .001). The susceptibility of fixed healthy human arterial tissue was diamagnetic, and no significant difference was found between fixed human and fixed porcine arterial tissue susceptibilities (analysis of variance, P > .05)., Conclusions: Magnetic susceptibility measured using QSM is sensitive to the microstructural composition of arterial vessels-most notably to collagen. The similarity of human and porcine arterial tissue susceptibility values provides a solid basis for translational studies. Because vessel microstructure becomes disrupted during the onset and progression of carotid atherosclerosis, QSM has the potential to provide a sensitive and specific marker of vessel disease., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Quantitative susceptibility mapping (QSM) is a promising non-invasive method for obtaining information relating to oxygen metabolism. However, the optimal acquisition sequence and QSM reconstruction method for reliable venous susceptibility measurements are unknown. Full flow compensation is generally recommended to correct for the influence of venous blood flow, although the effect of flow compensation on the accuracy of venous susceptibility values has not been systematically evaluated. In this study, we investigated the effect of different acquisition sequences, including different flow compensation schemes, and different QSM reconstruction methods on venous susceptibilities. Ten healthy subjects were scanned with five or six distinct QSM sequence designs using monopolar readout gradients and different flow compensation schemes. All data sets were processed using six different QSM pipelines and venous blood susceptibility was evaluated in whole-brain segmentations of the venous vasculature and single veins. The quality of vein segmentations and the accuracy of venous susceptibility values were analyzed and compared between all combinations of sequences and reconstruction methods. The influence of the QSM reconstruction method on average venous susceptibility values was found to be 2.7-11.6 times greater than the influence of the acquisition sequence, including flow compensation. The majority of the investigated QSM reconstruction methods tended to underestimate venous susceptibility values in the vein segmentations that were obtained. In summary, we found that multi-echo gradient-echo acquisition sequences without full flow compensation yielded venous susceptibility values comparable to sequences with full flow compensation. However, the QSM reconstruction method had a great influence on susceptibility values and thus needs to be selected carefully for accurate venous QSM., Competing Interests: Declaration of Competing Interest Emma Biondetti received grant funding from Biogen Inc. and France Parkinson unrelated to the scope of this study., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Malformations of cortical development (MCD), including focal cortical dysplasia (FCD), are the most common cause of drug-resistant focal epilepsy in children. Histopathological lesion characterisation demonstrates abnormal cell types and lamination, alterations in myelin (typically co-localised with iron), and sometimes calcification. Quantitative susceptibility mapping (QSM) is an emerging MRI technique that measures tissue magnetic susceptibility (χ) reflecting it's mineral composition. We used QSM to investigate abnormal tissue composition in a group of children with focal epilepsy with comparison to effective transverse relaxation rate (R2*) and Synchrotron radiation X-ray fluorescence (SRXRF) elemental maps. Our primary hypothesis was that reductions in χ would be found in FCD lesions, resulting from alterations in their iron and calcium content. We also evaluated deep grey matter nuclei for changes in χ with age., Methods: QSM and R2* maps were calculated for 40 paediatric patients with suspected MCD (18 histologically confirmed) and 17 age-matched controls. Patients' sub-groups were defined based on concordant electro-clinical or histopathology data. Quantitative investigation of QSM and R2* was performed within lesions, using a surface-based approach with comparison to homologous regions, and within deep brain regions using a voxel-based approach with regional values modelled with age and epilepsy as covariates. Synchrotron radiation X-ray fluorescence (SRXRF) was performed on brain tissue resected from 4 patients to map changes in iron, calcium and zinc and relate them to MRI parameters., Results: Compared to fluid-attenuated inversion recovery (FLAIR) or T1-weighted imaging, QSM improved lesion conspicuity in 5% of patients. In patients with well-localised lesions, quantitative profiling demonstrated decreased χ, but not R2*, across cortical depth with respect to the homologous regions. Contra-lateral homologous regions additionally exhibited increased χ at 2-3 mm cortical depth that was absent in lesions. The iron decrease measured by the SRXRF in FCDIIb lesions was in agreement with myelin reduction observed by Luxol Fast Blue histochemical staining. SRXRF analysis in two FCDIIb tissue samples showed increased zinc and calcium in one patient, and decreased iron in the brain region exhibiting low χ and high R2* in both patients. QSM revealed expected age-related changes in the striatum nuclei, substantia nigra, sub-thalamic and red nucleus., Conclusion: QSM non-invasively revealed cortical/sub-cortical tissue alterations in MCD lesions and in particular that χ changes in FCDIIb lesions were consistent with reduced iron, co-localised with low myelin and increased calcium and zinc content. These findings suggest that measurements of cortical χ could be used to characterise tissue properties non-invasively in epilepsy lesions., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson's disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson's disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15 745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson's disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson's disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson's disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson's disease, particularly the processes involving iron accumulation., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: To develop a rapid and accurate MRI phase-unwrapping technique for challenging phase topographies encountered at high magnetic fields, around metal implants, or postoperative cavities, which is sufficiently fast to be applied to large-group studies including Quantitative Susceptibility Mapping and functional MRI (with phase-based distortion correction)., Methods: The proposed path-following phase-unwrapping algorithm, ROMEO, estimates the coherence of the signal both in space-using MRI magnitude and phase information-and over time, assuming approximately linear temporal phase evolution. This information is combined to form a quality map that guides the unwrapping along a 3D path through the object using a computationally efficient minimum spanning tree algorithm. ROMEO was tested against the two most commonly used exact phase-unwrapping methods, PRELUDE and BEST PATH, in simulated topographies and at several field strengths: in 3T and 7T in vivo human head images and 9.4T ex vivo rat head images., Results: ROMEO was more reliable than PRELUDE and BEST PATH, yielding unwrapping results with excellent temporal stability for multi-echo or multi-time-point data. It does not require image masking and delivers results within seconds, even in large, highly wrapped multi-echo data sets (eg, 9 seconds for a 7T head data set with 31 echoes and a 208 × 208 × 96 matrix size)., Conclusion: Overall, ROMEO was both faster and more accurate than PRELUDE and BEST PATH, delivering exact results within seconds, which is well below typical image acquisition times, enabling potential on-console application., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

The primary lesion arising from the initial insult after traumatic brain injury (TBI) triggers a cascade of secondary tissue damage, which may also progress to connected brain areas in the chronic phase. The aim of this study was, therefore, to investigate variations in the susceptibility distribution related to these secondary tissue changes in a rat model after severe lateral fluid percussion injury. We compared quantitative susceptibility mapping (QSM) and R 2 * measurements with histological analyses in white and grey matter areas outside the primary lesion but connected to the lesion site. We demonstrate that susceptibility variations in white and grey matter areas could be attributed to reduction in myelin, accumulation of iron and calcium, and gliosis. QSM showed quantitative changes attributed to secondary damage in areas located rostral to the lesion site that appeared normal in R 2 * maps. However, combination of QSM and R 2 * was informative in disentangling the underlying tissue changes such as iron accumulation, demyelination, or calcifications. Therefore, combining QSM with R 2 * measurement can provide a more detailed assessment of tissue changes and may pave the way for improved diagnosis of TBI, and several other complex neurodegenerative diseases., (© 2020 John Wiley & Sons, Ltd.)

Purpose: Quantitative Susceptibility Mapping (QSM) is an emerging technique sensitive to disease-related changes including oxygenation. It is extensively used in brain studies and has increasing clinical applications outside the brain. Here we present the first MRI acquisition protocol and QSM pipeline optimized for the head-and-neck region together with a repeatability analysis performed in healthy volunteers., Methods: We investigated both the intrasession and the intersession repeatability of the optimized method in 10 subjects. We also implemented two, Tikhonov-regularisation-based susceptibility calculation techniques that were found to have higher contrast-to-noise than existing methods in the head-and-neck region. Repeatability was evaluated by calculating the distributions of susceptibility differences between repeated scans and the corresponding minimum detectable effect sizes (MDEs)., Results: Deep brain regions had higher QSM repeatability than neck regions. As expected, intrasession repeatability was generally better than intersession repeatability. Susceptibility maps calculated using projection onto dipole fields for background field removal were more repeatable than using the Laplacian boundary value method in the head-and-neck region. Small (short-axis diameter <5 mm) lymph nodes had the lowest repeatability (MDE = 0.27 ppm) as imperfect segmentation included some of the surrounding paramagnetic fatty fascia, highlighting the importance of accurate region delineation. MDEs in the larger lymph nodes (0.16 ppm), submandibular glands (0.10 ppm), and especially the parotid glands (0.06 ppm) were much lower, comparable to those of the brain regions., Conclusions: The high repeatability of the acquisition and pipeline optimized for QSM will facilitate clinical studies in the head-and-neck region., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Multi-echo gradient-recalled echo acquisitions for QSM enable optimizing the SNR for several tissue types through multi-echo (TE) combination or investigating temporal variations in the susceptibility (potentially reflecting tissue microstructure) by calculating one QSM image at each TE (TE-dependent QSM). In contrast with multi-echo QSM, applying Laplacian-based methods (LBMs) for phase unwrapping and background field removal to single TEs could introduce nonlinear temporal variations (independent of tissue microstructure) into the measured susceptibility. Here, we aimed to compare the effect of LBMs on the QSM susceptibilities in TE-dependent versus multi-echo QSM., Methods: TE-dependent recalled echo data simulated in a numerical head phantom and gradient-recalled echo images acquired at 3 T in 10 healthy volunteers. Several QSM pipelines were tested, including four distinct LBMs: sophisticated harmonic artifact reduction for phase data (SHARP), variable-radius sophisticated harmonic artifact reduction for phase data (V-SHARP), Laplacian boundary value background field removal (LBV), and one-step total generalized variation (TGV). Results from distinct pipelines were compared using visual inspection, summary statistics of susceptibility in deep gray matter/white matter/venous regions of interest, and, in the healthy volunteers, regional susceptibility bias analysis and nonparametric tests., Results: Multi-echo versus TE-dependent QSM had higher regional accuracy, especially in high-susceptibility regions and at shorter TEs. Everywhere except in the veins, a processing pipeline incorporating TGV provided the most temporally stable TE-dependent QSM results with an accuracy similar to multi-echo QSM., Conclusions: For TE-dependent QSM, carefully choosing LBMs can minimize the introduction of LBM-related nonlinear temporal susceptibility variations., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Positron emission tomography/magnetic resonance imaging (PET/MRI) potentially offers several advantages over positron emission tomography/computed tomography (PET/CT), for example, no CT radiation dose and soft tissue images from MR acquired at the same time as the PET. However, obtaining accurate linear attenuation correction (LAC) factors for the lung remains difficult in PET/MRI. LACs depend on electron density and in the lung, these vary significantly both within an individual and from person to person. Current commercial practice is to use a single-valued population-based lung LAC, and better estimation is needed to improve quantification. Given the under-appreciation of lung attenuation estimation as an issue, the inaccuracy of PET quantification due to the use of single-valued lung LACs, the unique challenges of lung estimation, and the emerging status of PET/MRI scanners in lung disease, a review is timely. This paper highlights past and present methods, categorizing them into segmentation, atlas/mapping, and emission-based schemes. Potential strategies for future developments are also presented., (© 2019 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Brain arteriovenous malformations (AVMs) are congenital vascular anomalies characterized by arteriovenous shunting through a network of coiled and tortuous vessels. Because of this anatomy, the venous drainage of an AVM is hypothesized to contain more oxygenated, arterialized blood than healthy veins. By exploiting the paramagnetic properties of deoxygenated hemoglobin in venous blood using magnetic resonance imaging (MRI) quantitative susceptibility mapping (QSM), we aimed to explore venous density and oxygen saturation (SvO 2 ) in patients with a brain AVM. We considered three groups of subjects: patients with a brain AVM before treatment using gamma knife radiosurgery (GKR); patients three or more years post-GKR treatment; and healthy volunteers. First, we investigated the appearance of AVMs on QSM images. Then, we investigated whether QSM could detect increased SvO 2 in the veins draining the malformations. In patients before GKR, venous density, but not SvO 2 , was significantly larger in the hemisphere containing the AVM compared to the contralateral hemisphere (p = 0.03). Such asymmetry was not observed in patients after GKR or in healthy volunteers. Moreover, in all patients before GKR, the vein immediately draining the AVM nidus had a higher SvO 2 than healthy veins. Therefore, QSM can be used to detect SvO 2 alterations in brain AVMs. However, since factors such as flow-induced signal dephasing or the presence of hemosiderin deposits also strongly affect QSM image contrast, AVM vein segmentation must be performed based on alternative MRI acquisitions, e.g., time of flight magnetic resonance angiography or T 1 -weighted images. This is the first study to show, non-invasively, that AVM draining veins have a significantly larger SvO 2 than healthy veins, which is a finding congruent with arteriovenous shunting., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recent magnetic resonance imaging (MRI) techniques, such as quantitative magnetic susceptibility mapping, employ the signal phase to reveal disease-related changes in tissue composition, including iron or calcium content. The MRI phase is also routinely used in functional and diffusion MRI for distortion correction. However, phase images are wrapped into a range of 2π radians. Phase region expanding labeller for unwrapping discrete estimates (PRELUDE) is the gold standard method for robust, spatial, 3-D, MRI phase unwrapping. Unfortunately, PRELUDE's computation time can reach 15 min for a severely wrapped brain image and nearly 10 h to unwrap a full head-and-neck image on a standard PC. In this paper, we develop a Speedy rEgion-Growing algorithm for Unwrapping Estimated phase (SEGUE) based on similar principles to PRELUDE, implemented with additional methods for acceleration. We compared PRELUDE and SEGUE in numerical phantoms, and using in vivo images of the brain, head and neck, and pelvis acquired in 4-5 healthy volunteers and at 4-6 echo times. To overcome chemical-shift-induced errors within the head and neck, and pelvic images, we also investigated applying both techniques within fat and water masks separately. SEGUE provided almost identical unwrapped phase maps to the gold standard PRELUDE. SEGUE was (1.5 to 70 times) faster than PRELUDE, especially in severely wrapped images at later echoes and in the head and neck, and pelvic images. Applying these techniques within fat and water masks separately removed chemical-shift-induced errors successfully. SEGUE's MATLAB implementation is available for download. SEGUE is a general unwrapping algorithm not specific to MRI, and therefore could be used in images acquired with other modalities.

Purpose: To evaluate the relationship between bone mineral density (BMD) and magnetic susceptibility, and between proton density fat fraction and susceptibility, in inflamed trabecular bone., Methods: Two different phantoms modeling the fat fraction (FF) and BMD values of healthy bone marrow and disease states were scanned using a multiecho gradient echo acquisition at 3T. After correction for fat-water chemical shift, susceptibility mapping was performed, and susceptibility measurements were compared with BMD and FF values using linear regression. Patients with spondyloarthritis were scanned using the same protocol, and susceptibility values were calculated in areas of inflamed bone (edema) and fat metaplasia, both before and after accounting for the contribution of fat to the total susceptibility., Results: Susceptibility values in the phantoms were accurately described by a 2D linear function, with a negative correlation between BMD and susceptibility and a positive correlation between FF and susceptibility (adjusted R 2 = 0.77; P = 3·10 -5 ). In patients, significant differences in susceptibility were observed between fat metaplasia and normal marrow, but these differences were eliminated by removing the fat contribution to the total susceptibility., Conclusions: BMD and proton density fat fraction both influence the total susceptibility of bone marrow and failure to account for the fat contribution could lead to errors in BMD quantification. We propose a method for removing the fat contribution from the total susceptibility, based on the observed linear relationship between susceptibility and FF. In inflamed bone, the overall increase in susceptibility in areas of fat metaplasia is at least partly due to increased fat content., (© 2019 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)