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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

Brain microstructural alterations possibly occur in the normal-appearing white matter (NAWM) and grey matter of small vessel disease (SVD) patients, and may contribute to cognitive impairment. The aim of this study was to explore cognitive related microstructural alterations in white matter and deep grey matter nuclei in SVD patients using magnetic resonance (MR) quantitative susceptibility mapping (QSM). 170 SVD patients, including 103 vascular mild cognitive impairment (VaMCI) and 67 no cognitive impairment (NCI), and 21 healthy control (HC) subjects were included, all underwent a whole-brain QSM scanning. Using a white matter and a deep grey matter atlas, subregion-based QSM analysis was conducted to identify and characterize microstructural alterations occurring within white matter and subcortical nuclei. Significantly different susceptibility values were revealed in NAWM and in several specific white matter tracts including anterior limb of internal capsule, corticospinal tract, medial lemniscus, middle frontal blade, superior corona radiata and tapetum among VaMCI, NCI and HC groups. However, no difference was found in white matter hyperintensities between VaMCI and NCI. A trend toward higher susceptibility in the caudate nucleus and globus pallidus of VaMCI patients compared to HC, indicating elevated iron deposition in these areas. Interestingly, some of these QSM parameters were closely correlated with both global and specific cognitive function scores, controlling age, gender and education level. Our study suggested that QSM may serve as a useful imaging tool for monitoring cognitive related microstructural alterations in brain. This is especially meaningful for white matter which previously lacks of attention.

Aim: The neuronal mechanism linking the association between maternal diabetes mellitus (DM) and risk of attention deficit hyperactivity disorder (ADHD) symptoms and working memory deficits in children was investigated. Methods: A total of 6291 children (52% boys) born beyond 28 weeks of gestation were included and underwent brain magnetic resonance imaging scans at 9–10 years. Subcortical brain volumes were estimated from the T1‐weighted images. ADHD symptoms were assessed using factorial analysis of the Child Behaviour Checklist completed by parents/caregivers. Working memory performance was assessed with the NIH Toolbox. Results: Compared to unexposed children, those exposed to DM (n = 422) had smaller (β = −0.15, p = 0.001) volumes of pooled deep grey matter (GM). Regional analysis revealed smaller volumes of the caudate nucleus, putamen, thalamus and cerebellum but not of hippocampus. They also had altered cortico‐striatal white matter projection tracts. DM was not associated with working memory deficits or inattention, but with increased hyperactivity/impulsivity and Sluggish Cognitive Tempo symptoms in boys. This hyperactivity/impulsivity symptom in boys was partially mediated by smaller deep GM volume. Conclusion: Exposure to DM during pregnancy leads to altered deep GM development during late childhood in their offspring. This contributed to an increased risk of hyperactivity/impulsivity symptoms in boys. [ABSTRACT FROM AUTHOR]

Apathy has been considered a common neuropsychiatric symptom and an important contributor to cognitive impairment in cerebral small vessel disease (SVD). However, the mechanism leading to apathy in SVD and the process whereby apathy promotes cognitive impairments remain largely unknown. We aimed to explore the relationship between apathy, cognition, and structural changes of deep grey matter (DGM) in SVD patients. Participants were screened for SVD, completed assessments of apathy cognition, underwent magnetic resonance imaging (MRI) scanning, and then stratified into apathy and non-apathy groups. We used region of interest (ROI)-based, voxel-based volume, and vertex-based shape analyses to compare DGM structures between study groups. Using linear regression analysis, we examined the association between apathy, structural changes, and cognition, followed by a mediation analysis of these factors. A total of sixty-four SVD participants were included, with thirty in the apathy group and thirty-four in the non-apathy group. Intergroup comparison showed significantly lower volumes in bilateral caudate, right putamen, and pallidum and smaller vertex-based shapes in the right caudate and pallidum in participants with apathy compared to those without apathy. Apathy was associated with the striatal atrophy (i.e., lower volumes and smaller shape) and independently contributed to cognitive impairments in SVD. However, the above structural differences did not mediate the association between apathy and cognitive impairments. These results highlight the important role of striatal atrophy in apathy in SVD and call for additional studies to explore the relationship between apathy, cognition, and DGM. • First study on deep grey matter structural changes in SVD-related apathy. • Combined volume and shape measurements to assess morphological abnormalities. • Underscore the role of striatal atrophy in SVD-related apathy. [ABSTRACT FROM AUTHOR]

Introduction: Quantitative Susceptibility Mapping (QSM) is generally acquired with full brain coverage, even though many QSM brain-iron studies focus on the deep grey matter (DGM) region only. Reducing the spatial coverage to the DGM vicinity can substantially shorten the scan time or enhance the spatial resolution without increasing scan time; however, this may lead to significant DGM susceptibility underestimation. Method: A recently proposed deep learning-based QSM method, namely xQSM, is investigated to assess the accuracy of dipole inversion on reduced brain coverages. The xQSM method is compared with two conventional dipole inversion methods using simulated and in vivo experiments from 4 healthy subjects at 3T. Pre-processed magnetic field maps are extended symmetrically from the centre of globus pallidus in the coronal plane to simulate QSM acquisitions of difference spatial coverages, ranging from 100% (∼32 mm) to 400% (∼128 mm) of the actual DGM physical size. Results: The proposed xQSM network led to the lowest DGM contrast loss in both simulated and in vivo subjects, with the smallest susceptibility variation range across all spatial coverages. For the digital brain phantom simulation, xQSM improved the DGM susceptibility underestimation more than 20% in small spatial coverages, as compared to conventional methods. For the in vivo acquisition, less than 5% DGM susceptibility error was achieved in 48 mm axial slabs using the xQSM network, while a minimum of 112 mm coverage was required for conventional methods. It is also shown that the background field removal process performed worse in reduced brain coverages, which further deteriorated the subsequent dipole inversion. Conclusion: The recently proposed deep learning-based xQSM method significantly improves the accuracy of DGM QSM from small spatial coverages as compared with conventional QSM algorithms, which can shorten DGM QSM acquisition time substantially.

• Whole brain QSM and atlas-based subregion analysis for 170 SVD patients. • QSM difference found in NAWM, some WM tracts, but not in WM hyperintense lesions. • QSM difference found in several deep GM subregion. • Correlation found for QSM and cognitive scores controlling age, sex and education. Brain microstructural alterations possibly occur in the normal-appearing white matter (NAWM) and grey matter of small vessel disease (SVD) patients, and may contribute to cognitive impairment. The aim of this study was to explore cognitive related microstructural alterations in white matter and deep grey matter nuclei in SVD patients using magnetic resonance (MR) quantitative susceptibility mapping (QSM). 170 SVD patients, including 103 vascular mild cognitive impairment (VaMCI) and 67 no cognitive impairment (NCI), and 21 healthy control (HC) subjects were included, all underwent a whole-brain QSM scanning. Using a white matter and a deep grey matter atlas, subregion-based QSM analysis was conducted to identify and characterize microstructural alterations occurring within white matter and subcortical nuclei. Significantly different susceptibility values were revealed in NAWM and in several specific white matter tracts including anterior limb of internal capsule, corticospinal tract, medial lemniscus, middle frontal blade, superior corona radiata and tapetum among VaMCI, NCI and HC groups. However, no difference was found in white matter hyperintensities between VaMCI and NCI. A trend toward higher susceptibility in the caudate nucleus and globus pallidus of VaMCI patients compared to HC, indicating elevated iron deposition in these areas. Interestingly, some of these QSM parameters were closely correlated with both global and specific cognitive function scores, controlling age, gender and education level. Our study suggested that QSM may serve as a useful imaging tool for monitoring cognitive related microstructural alterations in brain. This is especially meaningful for white matter which previously lacks of attention. [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.)

Quantitative Susceptibility Mapping (QSM) is generally acquired with full brain coverage, even though many QSM brain-iron studies focus on the deep grey matter (DGM) region only. Reducing the spatial coverage to the DGM vicinity can substantially shorten the scan time or enhance the spatial resolution without increasing scan time; however, this may lead to significant DGM susceptibility underestimation. A recently proposed deep learning-based QSM method, namely xQSM, is investigated to assess the accuracy of dipole inversion on reduced brain coverages. The xQSM method is compared with two conventional dipole inversion methods using simulated and in vivo experiments from 4 healthy subjects at 3T. Pre-processed magnetic field maps are extended symmetrically from the centre of globus pallidus in the coronal plane to simulate QSM acquisitions of difference spatial coverages, ranging from 100% (∼32 mm) to 400% (∼128 mm) of the actual DGM physical size. The proposed xQSM network led to the lowest DGM contrast loss in both simulated and in vivo subjects, with the smallest susceptibility variation range across all spatial coverages. For the digital brain phantom simulation, xQSM improved the DGM susceptibility underestimation more than 20% in small spatial coverages, as compared to conventional methods. For the in vivo acquisition, less than 5% DGM susceptibility error was achieved in 48 mm axial slabs using the xQSM network, while a minimum of 112 mm coverage was required for conventional methods. It is also shown that the background field removal process performed worse in reduced brain coverages, which further deteriorated the subsequent dipole inversion. The recently proposed deep learning-based xQSM method significantly improves the accuracy of DGM QSM from small spatial coverages as compared with conventional QSM algorithms, which can shorten DGM QSM acquisition time substantially. [ABSTRACT FROM AUTHOR]

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results. [ABSTRACT FROM AUTHOR]

• NMOSD and MOGAD frequently occur with a relapsing course. • Recent studies have proposed the existence of subclinical pathological processes outside of acute episodes. • In MS, brain and spinal cord volumes has long been considered a valuable outcome measure. • The review examined the key studies on MRI measurements in adult patients with NMOSD and MOGAD. • We discuss differences with MS, current challenges and future perspectives. Neuromyelitis optica spectrum disorder (NMOSD) is a severe form of inflammation of the central nervous system (CNS) including acute myelitis, optic neuritis and brain syndrome. Currently, the classification of NMOSD relies on serologic testing, distinguishing between seropositive or seronegative anti-aquaporin-4 antibody (AQP4) status. However, the situation has recently grown more intricate with the identification of patients exhibiting the NMOSD phenotype and myelin oligodendrocyte glycoprotein antibodies (MOGAD). NMOSD is primarily recognized as a relapsing disorder; MOGAD can manifest with either a monophasic or relapsing course. Significant symptomatic inflammatory CNS injuries with stability in clinical findings outside the acute phase are reported in both diseases. Nevertheless, recent studies have proposed the existence of a subclinical pathological process, revealing longitudinal changes in brain and spinal cord atrophy. Within this context, we summarise key studies investigating brain and spinal cord measurements in adult NMOSD and MOGAD. We also explore their relationship with clinical aspects, highlight differences from multiple sclerosis (MS), and address future challenges. This exploration is crucial for determining the presence of chronic damage processes, enabling the customization of therapeutic interventions irrespective of the acute phase of the disease. [ABSTRACT FROM AUTHOR]

Background and rationale: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining. Methods: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor. Results: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values

Background: Deep grey matter (dGM) structures, particularly the thalamus, are clinically relevant in multiple sclerosis (MS). However, segmentation of dGM in MS is challenging; labeled MS-specific reference sets are needed for objective evaluation and training of new methods. Objectives: This study aimed to (i) create a standardized protocol for manual delineations of dGM; (ii) evaluate the reliability of the protocol with multiple raters; and (iii) evaluate the accuracy of a fast-semi-automated segmentation approach (FASTSURF). Methods: A standardized manual segmentation protocol for caudate nucleus, putamen, and thalamus was created, and applied by three raters on multi-center 3D T1-weighted MRI scans of 23 MS patients and 12 controls. Intra- and inter-rater agreement was assessed through intra-class correlation coefficient (ICC); spatial overlap through Jaccard Index (JI) and generalized conformity index (CIgen). From sparse delineations, FASTSURF reconstructed full segmentations; accuracy was assessed both volumetrically and spatially. Results: All structures showed excellent agreement on expert manual outlines: intra-rater JI > 0.83; inter-rater ICC ≥ 0.76 and CIgen ≥ 0.74. FASTSURF reproduced manual references excellently, with ICC ≥ 0.97 and JI ≥ 0.92. Conclusions: The manual dGM segmentation protocol showed excellent reproducibility within and between raters. Moreover, combined with FASTSURF a reliable reference set of dGM segmentations can be produced with lower workload.

The present study was carried out to investigate any possible linkage between cerebral grey matter volumetric, iron changes, white matter's lesions load and serum iron levels in a group of relapsing-remitting multiple sclerosis (RRMS) patients. Sixty-five RRMS patients along with thirty-four age-matched healthy controls (HCs) were recruited. Serum samples were isolated from blood samples which were collected in vacutainer plain tubes individually from both groups. Both groups were scanned at 1.5 T magnetic resonance imaging (MRI) using the following 3D sequences; T1-weighted gradient echo (MPRAGE), T2*-weighted gradient echo and T2-weighted fluid-attenuated inversion recovery (FLAIR). Significant differences were observed between the RRMS patients and HCs for cortical and deep grey matter (dGM) volumes where cortical and dGM volumes in RRMS patient were significantly smaller than those in HCs. While iron deposition in the cortex, putamen (PT) and globus pallidus (GP) of RRMS patients were significantly higher than those of HCs, iron levels in thalamus (TH) and serum were significantly lower in RRMS compared to those in HCs. Except for T2 lesion load, none of volumetric measures showed any association with patients' disability status. Cerebral grey matter's iron changes did not show any association with those of serum. Smaller cortical and subcortical grey matter volumes in RRMS patients compared to HCs were detected. None of the volumetric measures showed any association with patients' disability status. RRMS patients showed increased iron levels in the PT, GP and cortex and decreased levels in the TH and serum. [ABSTRACT FROM AUTHOR]

Background: Deep grey matter (DGM) atrophy in multiple sclerosis (MS) and its relation to cognitive and clinical decline requires accurate measurements. MS pathology may deteriorate the performance of automated segmentation methods. Accuracy of DGM segmentation methods is compared between MS and controls, and the relation of performance with lesions and atrophy is studied. Methods: On images of 21 MS subjects and 11 controls, three raters manually outlined caudate nucleus, putamen and thalamus; outlines were combined by majority voting. FSL-FIRST, FreeSurfer, Geodesic Information Flow and volBrain were evaluated. Performance was evaluated volumetrically (intra-class correlation coefficient (ICC)) and spatially (Dice similarity coefficient (DSC)). Spearman's correlations of DSC with global and local lesion volume, structure of interest volume (ROIV), and normalized brain volume (NBV) were assessed. Results: ICC with manual volumes was mostly good and spatial agreement was high. MS exhibited significantly lower DSC than controls for thalamus and putamen. For some combinations of structure and method, DSC correlated negatively with lesion volume or positively with NBV or ROIV. Lesion-filling did not substantially change segmentations. Conclusions: Automated methods have impaired performance in patients. Performance generally deteriorated with higher lesion volume and lower NBV and ROIV, suggesting that these may contribute to the impaired performance. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the role of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in detecting microstructural changes of normal-appearing deep grey matter (NDGM) in multiple sclerosis (MS). Patient and methods: We examined 40 patients with MS and 20 healthy volunteers using DTI to correlate average ADC and FA of the thalami, lentiform and caudate nuclei between the two groups. Receiver operating characteristic analysis was used to test the diagnostic performance of ADC and FA in detecting NDGM involvement in multiple sclerosis. Results: Between the two study groups, there was statistically significant difference of ADC of thalami, lentiform, caudate nuclei, and FA of the thalami (p

Purpose To evaluate the role of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in detecting microstructural changes of normal-appearing deep grey matter (NDGM) in multiple sclerosis (MS). Patient and methods We examined 40 patients with MS and 20 healthy volunteers using DTI to correlate average ADC and FA of the thalami, lentiform and caudate nuclei between the two groups. Receiver operating characteristic analysis was used to test the diagnostic performance of ADC and FA in detecting NDGM involvement in multiple sclerosis. Results Between the two study groups, there was statistically significant difference of ADC of thalami, lentiform, caudate nuclei, and FA of the thalami (p < .05). No statistically significant difference of FA of lentiform (p = .2) and caudate (p = .06) nuclei. For detection of microstructural changes of NDGM, ADC cut off values were 0.762 × 10 −3  mm 2 /s for thalamus (90% sensitivity and 66% specificity), 0.529 × 10 −3  mm 2 /s for lentiform (86% sensitivity and 60% specificity) and 0.784 × 10 −3  mm 2 /s for caudate nuclei (83% sensitivity and 67% specificity). Conclusion ADC has better diagnostic performance and is more accurate than FA as a measure to detect microstructural changes of NDGM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To investigate brain functional connectivity (FC) alterations in patients with clinically isolated syndromes (CIS) presenting without conventional brain MRI lesions, and to identify the FC differences between the CIS patients who converted to multiple sclerosis (MS) and those not converted during a 5-year follow-up.Methods: We recruited 20 CIS patients without conventional brain lesions, 28 patients with MS and 28 healthy controls (HC). Normalized voxel-based functional connectivity strength (nFCS) was determined using resting-state fMRI (R-fMRI) and compared among groups. Furthermore, 5-years clinical follow-up of the CIS patients was performed to examine the differences in nFCS between converters and non-converters.Results: Compared to HC, CIS patients showed significantly decreased nFCS in the visual areas and increased nFCS in several brain regions predominately in the temporal lobes. MS patients revealed more widespread higher nFCS especially in deep grey matter (DGM), compared to CIS and HC. In the four CIS patients converting to MS, significantly higher nFCS was found in right anterior cingulate gyrus (ACC) and fusiform gyrus (FG), compared to non-converted patients.Conclusion: We demonstrated both functional impairment and compensation in CIS by R-fMRI. nFCS alteration in ACC and FG seems to occur in CIS patients at risk of developing MS.Key Points: • Both functional impairment and compensation occur in CIS without conventional brain lesions. • MS patients revealed more widespread higher nFCS especially in deep grey matter. • nFCS alteration may help stratifying CIS at risk of developing MS. [ABSTRACT FROM AUTHOR]

Although deep grey matter (GM) involvement in multiple sclerosis (MS) is well documented, in-vivo multi-parameter magnetic resonance imaging (MRI) studies and association with detailed cognitive measures are limited. We investigated volumetric, diffusion and perfusion metrics in thalamus, hippocampus, putamen, caudate nucleus and globus pallidum, and neuropsychological measures, spanning 4 cognitive domains, in 60 relapsing-remitting MS patients (RRMS) (mean disease duration of 5.1 years, median EDSS of 1.5) and 30 healthy controls. There was significantly reduced volume of thalamus, hippocampus and putamen in the RRMS patients, but no diffusion or perfusion changes in these structures. Decreased volume in these deep GM volumes in RRMS patients was associated with a modest reduction in cognitive performance, particularly information processing speed, consistent with a subtle disruption of distributed networks, that subserve cognition, in these patients. Future longitudinal studies are needed to elucidate the influence of deep GM changes on the evolution of cognitive deficits in MS. [ABSTRACT FROM AUTHOR]

The article presents a study, which aims to identify independent determinants of iron accumulation in multiple sclerosis (MS) patients. The study performs R2* mapping on 3 Tesla (T) magnetic resonance imaging (MRI) systems using 97 MS patients and 81 controls. Result shows that reduction of cortical volume was not related on iron accumulation in deep grey matter (GM). Moreover, duration and severity of the disease was identified to be strongly related to iron accumulation in deep GM.

Abstract: Objective: Abnormal iron accumulation in MS has been known for decades, however it remains to be established whether iron reflects a cause or epiphenomenon of pathology. The objective of the present study is to determine if iron is increased in the brains of patients with clinically isolated syndromes (CIS) suggestive of early MS. Methods: Twenty-two patients with a CIS and 16 age- and sex-matched controls underwent 3T MRI studies. Differences in R2*, a metric of iron concentration, were assessed for all voxels throughout the brain. Similar clusters of significant differences were grouped, wherein mean R2* was regressed against a number of parameters, including extended disability status scale (EDSS), age, disease duration, and internal jugular vein (IJV) cross-sectional area (CSA), as measured from magnetic resonance time-of-flight venograms. Results: Patients had significantly increased R2* in globus pallidus, thalamus, right pulvinar, and cortical areas. Thalamic R2* correlated positively with EDSS. Decreased white matter R2* was detected at various positions in the patient group average. No correlations were found between any changes in R2* and IJV CSA. Interpretation: Iron is increased in CIS in deep gray matter, suggesting this iron accumulation, well-known in definite MS, occurs early in the disease course. Increases in thalamic iron are associated with worsened clinical status. Decreased white matter R2* may be interpreted as diffuse damage to normal appearing white matter, not often reported in CIS. Observations do not support a role for venous abnormalities in either iron accumulation or white matter damage. [Copyright &y& Elsevier]

Objective: The objective of this study is to determine the effect of low resolution in the estimation of iron content in deep grey matter of brain using quantitative susceptibility mapping. Methodology: Six females with mean age 43.16, S.D= 20, age range (23-66) and 13 males with mean age 28.92 ± 8.14 were scanned with 3D SWI sequence at 3 Tesla (Trio-Seimens, Erlangen, Germany). The caudate nucleus, red nucleus, globus pallidus, putamen, white matter, thalamus and substantia nigra of brain were drawn manually based on their anatomical locations in Signal Processing in Nuclear Magnetic Resonance (SPIN). Magnitude and phase images of high resolution (HR) (0.5x0.5x2 mm³) were processed in SPIN using collapsing parameter to generate the low resolution (LR) (1x1x2 mm³) susceptibility mapping. Data was analyzed using paired t-test. Results: A strong linear correlation (R²=0.99, p ≤ 0.05) was found between the susceptibilities of Deep Grey Matter (DGM) at low resolution versus high resolution which showed the consistency of susceptibility at both resolution. When the susceptibilities in ppb of DGM were correlated with iron content (mgFe/100g), a positive correlation was found with R-saqure (R²=0.67, p ≥ 0.05 at HR, R²=0.66, p = 0.05 at LR). The slope of the above linear correlation was consistent with the equivalent susceptibility trend at low and high resolution QSM. Conclusion: Linear correlation between susceptibility and iron content at HR and LR has demonstrated that low resolution QSM holds the consistency of susceptibility and does not affect the estimation of iron content in deep grey matter of brain. [ABSTRACT FROM AUTHOR]

The article presents a study which determine the impact of changes on iron content that occur in demyelinating disease to patients with Clinically Isolated Syndrome (CIS). The study uses the ultra-high field magnetic resonance imaging (MRI) to compare 10 CIS patients with 20 age-matched healthy individual. Result shows that there is no consistent trends between susceptibility and age. It concludes that CIS patients showed an increase in iron accumulation considering the deep grey matter.

Objective: T2 hypo-intensity on magnetic resonance imaging scans is thought to reflect pathological iron deposition in the presence of disease. In this pilot study, we evaluated the utility of the quantification of T2 hypo-intensities in paediatric patients by estimating deep grey matter (DGM) T2 hypo-intensities in paediatric patients with multiple sclerosis (MS) or clinically isolated syndromes (CIS), and their changes over 1 year.Methods: A dual-echo sequence was obtained from 45 paediatric patients (10 with CIS, 35 with relapsing–remitting MS, 8 with an onset of the disease before the age of 10 and 37 during adolescence) and 14 age-matched healthy controls (HC). Eleven patients were reassessed both clinically and with MRI after 1 year. Normalized T2 intensity in the basal ganglia and thalamus was quantified.Results: At baseline, DGM T2 intensity was similar between paediatric patients and HC in all the structures analysed, except for the head of the left caudate nucleus (p = 0.001). DGM T2 intensity of the head of the left caudate nucleus was similar between paediatric CIS and RRMS patients, but it was reduced in adolescent-onset paediatric patients versus HC (p = 0.002). In all patients, DGM T2 intensity of the head of the left caudate nucleus was correlated with T2 lesion volume (r = −0.39, p = 0.007). DGM T2 intensity in all the structures analysed with longitudinal assessment remained stable over the follow-up in the cohort of patients.Conclusions: The quantification of DGM T2 intensity in paediatric patients may provide surrogate markers of neurodegeneration. In paediatric MS, DGM is likely to be affected by iron-related changes, which are likely to be, at least partially, secondary to WM damage. [ABSTRACT FROM AUTHOR]

Abstract: Cortical and subcortical atrophy occurs in multiple sclerosis (MS) and relates to clinical outcomes. FreeSurfer, a voxel-based automated software for brain reconstruction was used to investigate the extent of subcortical and cortical atrophy in 71 MS and 17 clinically isolated syndrome (CIS) patients, and 38 normal controls (NC), and to relate group differences to disease type and severity. Segmentation was performed on 3D SPGR T1-weighted MRI 1.5T images. Region-specific subcortical tissue volumes were calculated in mm3 and cortical thickness in mm. Logistic regression and general linear model analyses, adjusted for age and intracranial volume, examined differences between NC, MS and CIS patients and disease subtypes. The MS group was characterized by significantly lower volumes of thalamus (left and right p <0.0001), left inferior lateral ventricle, third ventricle (p <0.0001), ventral diencephalon, pallidum and putamen bilaterally, as well as of right accumbens and brainstem with corresponding bilateral increase in volumes of lateral ventricles (p <0.01). Focal cortical atrophy areas in the thalamus, inferior parietal lobule of left hemisphere and in right precuneus were also significant in the MS sample. Versus CIS patients, RR or progressive MS patients showed significantly lower volumes of subcortical regions and cortical thinning. Hippocampal atrophy appeared only in advanced disease stages. Cerebellum WM volumes were significantly lower in MS and CIS patients vs. NC. Subcortical and cortical atrophy correlated with higher disability as measured by EDSS. This study confirmed selective deep gray matter atrophy (mostly thalamic), revealed cerebellum WM atrophy from the earliest clinical stages, and showed that cortical thinning advances with disease progression. [Copyright &y& Elsevier]

Abstract: Background: The aim of this study was to assess the correlation of overall survival with tumor location (lobar vs. deep grey matter) and with other clinical and imaging variables in a cohort of patients with high grade gliomas. Methods: Adult patients with newly diagnosed supratentorial WHO grade 3 and 4 gliomas were evaluated. Clinical data included demographics, symptoms at presentation, treatment variables, and overall survival. Radiological data included tumor side, site (deep vs. lobar) and size, extent of peritumoral edema, and presence of midline shift. Biostatistics were carried out using log rank tests and univariate and multivariate Cox regression models. Results: A total of 121 patients were investigated, 23 (19.0%) with WHO grade 3 and 98 (81.0%) with WHO grade 4 gliomas. Tumors had lobar location in 96 cases (79.3%) and deep grey matter location in 25 cases (20.7%). Median survival time for all patients was 26 weeks (IQR: 14–53). Patients with deep tumors survived significantly longer than those with lobar gliomas (log rank test, p =0.0083). Extensive brain edema significantly shortened survival (log rank test, p =0.0003). Presence of midline shift (>1 cm) was a statistically significant risk factor for shorter survival (log rank test, p <0.0001). The univariate Cox regression model demonstrated statistical significance for the variables age, side, site and size of tumor, presence of extensive edema, and presence of mass effect (>1 cm). In the multivariate Cox models, tumor grade, site and size showed statistical significance. Conclusions: This study suggests that patients with deep grey matter gliomas may survive significantly longer after the initial diagnosis than those with tumors in a lobar location. This is a potentially novel finding, which may corroborate the theory of differential invasion of glioma cells in different microenvironments of the brain, but remains to be confirmed in future prospective studies. [Copyright &y& Elsevier]

T2 hypointensity (black T2, BT2) in the deep grey matter of multiple sclerosis (MS) patients correlate weakly with disability at 1.5 T. BT2 is likely to be caused by abnormal iron deposition. We compared the correlation between disability and deep grey matter BT2 measured on 3 T MRI and on 1.5 T MRI in 17 MS patients. We observed a significant correlation between expanded disability status scale and signal intensity on 3 T MRI in the globus pallidus and the caudate nucleus (r = -0.5, P < 0.05). BT2 at 3 T may be a useful MRI measure associated with disability in MS and warrants further study. [ABSTRACT FROM AUTHOR]

Background: Iron accumulates in brain tissue in healthy subjects during aging. Our goal was to conduct a detailed analysis of iron deposition patterns in the cerebral deep grey matter and cortex using region-based and whole-brain analyses of brain magnetic susceptibility., Methods: Brain MRI was performed in 95 healthy individuals aged between 21 and 58 years on a 3T scanner. MRI protocol included T1-weighted (T1W) magnetization-prepared rapid acquisition with gradient echo images and 3D flow-compensated multi-echo gradient-echo images for quantitative susceptibility mapping (QSM). In the region-based analysis, QSM and T1W images entered an automated multi-atlas segmentation pipeline and regional mean bulk susceptibility values were calculated. The whole-brain analysis included a non-linear transformation of QSM images to the standard MNI template. For the whole-brain analysis voxel-wise maps of linear regression slopes β and P values were calculated. Regional masks of cortical voxels with a significant association between susceptibility and age were created and further analyzed., Results: In cortical regions, the highest increase of susceptibility values with age was found in areas involved in motor functions (precentral and postcentral areas, premotor cortex), in cognitive processing (prefrontal cortex, superior temporal gyrus, insula, precuneus), and visual processing (occipital gyri, cuneus, posterior cingulum, fusiform, calcarine and lingual gyrus). Thalamic susceptibility increased until the fourth decade and decreased thereafter with the exception of the pulvinar where susceptibility increase was observed throughout the adult lifespan. Deep grey matter structures with the highest increase of susceptibility values with age included the red nucleus, putamen, substantia nigra, dentate nucleus, external globus pallidus, caudate nucleus, and the subthalamic nucleus in decreasing order., Conclusions: Accumulation of iron in basal ganglia follows a linear pattern whereas in the thalamus, pulvinar, precentral cortex, and precuneus, it follows a quadratic or exponential pattern. Age-related changes of iron content are different in the pulvinar and the rest of the thalamus as well as in internal and external globus pallidus. In the cortex, areas involved in motor and cognitive functions and visual processing show the highest iron increase with aging. We suggest that the departure from normal patterns of regional brain iron trajectories during aging may be helpful in the detection of subtle neurodegenerative and neuroinflammatory processes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-21-87). Dr. PD reports funding from Czech Ministry of Health, grant No. NU21-04-00535 and European Union’s Horizon 2020 research and innovation programme, grant No. 633190, and advisory board payment from Alexion Pharmaceuticals. Dr. MV reports funding from Czech Ministry of Health, grant No. NV 18-04-00168, honoraria for lectures and presentation from Biogen Idec, Novartis, Sanofi Genzyme, Merck Serono and Teva and support for attending meetings and/or travel from Biogen Idec, Novartis, Sanofi Genzyme. Dr. DH reports honoraria for lectures and presentation from Biogen Idec, Novartis, Sanofi, Roche and Merck and support for attending meetings and/or travel from Biogen Idec, Novartis, Sanofi, Roche and Merck. Dr. JK reports funding from Czech Ministry of Health, grant No. NV 18-04-00168 and support for attending meetings and/or travel Biogen Idec, Novartis, Sanofi Genzyme. Dr. LL serves as an unpaid editorial board member of Quantitative Imaging in Medicine and Surgery. The other authors have no conflicts of interest to declare., (2021 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

• Bipolar disorder (BD) is frequently observed in multiple sclerosis (MS). • Largely unexplored is the brain damage related to BD in MS. • We found smaller nucleus accumbens, putamen and pallidus in MS patients with BD. • Deep grey matter alterations may influence the BD occurrence in MS. Bipolar disorder (BD) is frequently observed in patients affected by multiple sclerosis (MS), presenting a lifetime estimate of around 8%. However, uncertainty exists on the brain damage associated with this psychiatric comorbidity. This study aimed to investigate the effect of brain atrophy, particularly that of the subcortical grey matter (scGM) structures that notoriously regulate the affective functioning, on the co-occurrence of BD in patients with MS. A group of patients with MS affected by BD and a control group of patients with MS without any mood/psychiatric disorder, as defined using standardised diagnostic tools (Advanced Neuropsychiatric Tools and Assessment Schedule), were recruited. The patients underwent brain MRI, and the volumes of the whole brain (WB), white matter (WM), and grey matter (GM) were estimated using SIENAX. Thus, the scGM volumes of the putamen, caudate, thalamus, hippocampus, amygdala, nucleus accumbens, and pallidus were estimated using the FIRST tool. The sample included 61 patients with MS, amongst whom 15 (24.6%) had BD. No differences in the WB, WM, and cortical GM volumes were observed between the patients with MS with and without BD. Conversely, the multiple regression analysis revealed a significant association of BD with lower volumes of the putamen (p = 0.032), nucleus accumbens (p = 0.029), and pallidus (p = 0.061; with a trend towards significance), independently from the demographic and MS clinical features. Our preliminary results indicated that the nucleus accumbens and putamen are smaller in MS patients with BD. Further investigations in larger cohorts of MS patients with affective disorders are necessary to confirm these data and understand the structural brain damage underlying this psychiatric comorbidity. [ABSTRACT FROM AUTHOR]

Background: Deep grey matter (dGM) structures, particularly the thalamus, are clinically relevant in multiple sclerosis (MS). However, segmentation of dGM in MS is challenging; labeled MS-specific reference sets are needed for objective evaluation and training of new methods., Objectives: This study aimed to (i) create a standardized protocol for manual delineations of dGM; (ii) evaluate the reliability of the protocol with multiple raters; and (iii) evaluate the accuracy of a fast-semi-automated segmentation approach (FASTSURF)., Methods: A standardized manual segmentation protocol for caudate nucleus, putamen, and thalamus was created, and applied by three raters on multi-center 3D T1-weighted MRI scans of 23 MS patients and 12 controls. Intra- and inter-rater agreement was assessed through intra-class correlation coefficient (ICC); spatial overlap through Jaccard Index (JI) and generalized conformity index (CIgen). From sparse delineations, FASTSURF reconstructed full segmentations; accuracy was assessed both volumetrically and spatially., Results: All structures showed excellent agreement on expert manual outlines: intra-rater JI > 0.83; inter-rater ICC ≥ 0.76 and CIgen ≥ 0.74. FASTSURF reproduced manual references excellently, with ICC ≥ 0.97 and JI ≥ 0.92., Conclusions: The manual dGM segmentation protocol showed excellent reproducibility within and between raters. Moreover, combined with FASTSURF a reliable reference set of dGM segmentations can be produced with lower workload., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The deep grey matter (DGM) nuclei of the brain play a crucial role in learning, behaviour, cognition, movement and memory. Although automated segmentation strategies can provide insight into the impact of multiple neurological conditions affecting these structures, such as Multiple Sclerosis (MS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Cerebral Palsy (CP), there are a number of technical challenges limiting an accurate automated segmentation of the DGM. Namely, the insufficient contrast of T1 sequences to completely identify the boundaries of these structures, as well as the presence of iso-intense white matter lesions or extensive tissue loss caused by brain injury. Therefore in this systematic review, 269 eligible studies were analysed and compared to determine the optimal approaches for addressing these technical challenges. The automated approaches used among the reviewed studies fall into three broad categories, atlas-based approaches focusing on the accurate alignment of atlas priors, algorithmic approaches which utilise intensity information to a greater extent, and learning-based approaches that require an annotated training set. Studies that utilise freely available software packages such as FIRST, FreeSurfer and LesionTOADS were also eligible, and their performance compared. Overall, deep learning approaches achieved the best overall performance, however these strategies are currently hampered by the lack of large-scale annotated data. Improving model generalisability to new datasets could be achieved in future studies with data augmentation and transfer learning. Multi-atlas approaches provided the second-best performance overall, and may be utilised to construct a "silver standard" annotated training set for deep learning. To address the technical challenges, providing robustness to injury can be improved by using multiple channels, highly elastic diffeomorphic transformations such as LDDMM, and by following atlas-based approaches with an intensity driven refinement of the segmentation, which has been done with the Expectation Maximisation (EM) and level sets methods. Accounting for potential lesions should be achieved with a separate lesion segmentation approach, as in LesionTOADS. Finally, to address the issue of limited contrast, R2*, T2* and QSM sequences could be used to better highlight the DGM due to its higher iron content. Future studies could look to additionally acquire these sequences by retaining the phase information from standard structural scans, or alternatively acquiring these sequences for only a training set, allowing models to learn the "improved" segmentation from T1-sequences alone. • We present a comprehensive review of deep grey matter segmentation methods. • We detail each of the methodologies and software, and compare their performance. • We outline the advantages and limitations of the different approaches. • We discuss future directions to account for brain injury and dataset limitations. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Previous studies have detected abnormal iron deposition in the deep grey matter (DGM) of multiple sclerosis (MS). The regional specificity of the DGM iron deposition in neuromyelitis optica (NMO) is still unclear. We compared the differences in the DGM iron concentration between MS and NMO patients. Methods: We enrolled 42 relapsing–remitting MS (RRMS) patients, 42 NMO patients and 42 healthy controls undergoing brain conventional MRI and three-dimensional (3D)-enhanced T2*-weighted angiography (ESWAN) sequences. We obtained the mean phase values (MPVs) for ESWAN-filtered phase images. An analysis of covariance (ANCOVA) was used to compare MPVs among three groups. The correlations of MPVs changes with disease duration and expanded disability status scale (EDSS) were analyzed. Results: The RRMS patients had higher DGM iron concentration than did the NMO and control groups, but only the bilateral substantia nigra (SN) showed a significant statistical difference among three groups (p <0.05). In the RRMS group, the iron concentration in the bilateral head of the caudate nucleus (HCN) (left: p <0.0001; right: p =0.0134) and the dentate nucleus (DN) (p <0.05 for both) were correlated with disease duration. In the NMO group, no correlation was found between the DGM iron concentration and disease duration (p >0.05). Furthermore, no correlations were found between the DGM iron concentration and EDSS (p >0.05). Conclusions: We confirm the iron concentration in the DGM iron content of MS patients is more than NMO patients and healthy controls in the same age range. Furthermore, the disease duration was found to be a significant contributor to patients with MS. [Copyright &y& Elsevier]