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Background: Actual and imagined cued gait trainings have not been compared in people with multiple sclerosis (MS)., Objective: To analyze the effects of cued motor imagery (CMI), cued gait training (CGT), and combined CMI and cued gait training (CMI-CGT) on motor, cognitive, and emotional functioning, and health-related quality of life in people with MS., Methods: In this double-blind randomized parallel-group multicenter trial, people with MS were randomized (1:1:1) to CMI, CMI-CGT, or CGT for 30 minutes, 4×/week for 4 weeks. Patients practiced at home, using recorded instructions, and supported by ≥6 phone calls. Data were collected at weeks 0, 4, and 13. Co-primary outcomes were walking speed and distance, analyzed by intention-to-treat. Secondary outcomes were global cognitive impairment, anxiety, depression, suicidality, fatigue, HRQoL, motor imagery ability, music-induced motivation, pleasure and arousal, self-efficacy, and cognitive function. Adverse events and falls were continuously monitored., Results: Of 1559 screened patients, 132 were randomized: 44 to CMI, 44 to CMI-CGT, and 44 to CGT. None of the interventions demonstrated superiority in influencing walking speed or distance, with negligible effects on walking speed (η 2  = 0.019) and distance (η 2  = 0.005) observed in the between-group comparison. Improvements in walking speed and walking distance over time corresponded to large effects for CMI, CMI-CGT, and CGT (η 2  = 0.348 and η 2  = 0.454 respectively). No severe study-related adverse events were reported., Conclusions: CMI-GT did not lead to improved walking speed and distance compared with CMI and CGT alone in people with MS. Lack of a true control group represents a study limitation., Trial Registration: German Clinical Trials Register, DRKS00023978., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To explore the experiences and acceptability of music-cued motor imagery (MCMI), music-cued gait training (MCGT), and combined MCMI and MCGT (MCMI-MCGT) in people with multiple sclerosis (pwMS). We also aimed to explore participants' self-rated health status postintervention and gather recommendations for further programme development., Design: Qualitative study alongside the double-blind randomised controlled real and imagined gait training with music-cueing (RIGMUC) multicentre trial of MCMI, MCGT and MCMI-MCGT., Setting: PwMS recruited for the RIGMUC trial from Departments of Neurology at Medical Universities of Innsbruck and Graz and Clinic for Rehabilitation Muenster, Austria., Participants: All 132 pwMS with mild to moderate disability randomised into the trial were included in the analysis., Methods: Participants practised home-based MCMI, MCGT or MCMI-MCGT for 30 min, 4×/week, for 4 weeks. Three trained researchers conducted weekly semistructured telephone interviews during the intervention period, supporting adherence, addressing problems, sharing experiences and assessing intervention acceptability. Follow-up interviews at 4-week postintervention aimed to understand participants' self-rated changes in walking, fatigue and overall health compared with their prestudy condition. Investigator triangulation was employed among the researchers to enhance trustworthiness and credibility., Results: Using thematic analysis, we identified five themes: (1) empowerment, (2) remaining in sync, (3) interconnection between imagined and actual walking, (4) sustaining focus and (5) real-world transfer. Participants appreciated and found the imagined and actual MCGT innovative. Problems included concentration issues, early fatigue in advanced disability and difficulty synchronising with music cues. Positive changes in walking, fatigue and overall health postinterventions were reported offering valuable insights for programme development., Conclusions: A participatory study to codevelop a music-cued exercise programme for pwMS seems appropriate as participants appreciated the innovation and effectiveness of both imagined and actual MCGT. Future studies should also investigate pwMS' potential and limitations in enhancing their MCMI abilities with intensive therapist-supported practice., Trial Registration Number: DRKS00023978., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A central role for vitamin D (VD) in immune modulation has recently been recognized linking VD insufficiency to autoimmune disorders that commonly exhibit sex-associated differences. Similar to other autoimmune diseases, there is a higher incidence of multiple sclerosis (MS) in women, but a poorer prognosis in men, often characterized by a more rapid progression. Although sex hormones are most likely involved, this phenomenon is still poorly understood. Oxidative stress, modulated by VD serum levels as well as sex hormones, may act as a contributing factor to demyelination and axonal damage in both MS and the corresponding preclinical models. In this study, we analyzed sex-associated differences and VD effects utilizing an animal model that recapitulates histopathological features of the progressive MS phase (PMS). In contrast to relapsing-remitting MS (RRMS), PMS has been poorly investigated in this context. Male ( n = 50) and female ( n = 46) Dark Agouti rats received either VD (400 IU per week; VD + ) or standard rodent food without extra VD (VD - ) from weaning onwards. Myelination, microglial activation, apoptotic cell death and neuronal viability were assessed using immunohistochemical markers in brain tissue. Additionally, we also used two different histological markers against oxidized lipids along with colorimetric methods to measure protective polyphenols (PP) and total antioxidative capacity (TAC) in serum. Neurofilament light chain serum levels (sNfL) were analyzed using single-molecule array (SIMOA) analysis. We found significant differences between female and male animals. Female rats exhibited a better TAC and higher amounts of PP. Additionally, females showed higher myelin preservation, lower microglial activation and better neuronal survival while showing more apoptotic cells than male rats. We even found a delay in reaching the peak of the disease in females. Overall, both sexes benefitted from VD supplementation, represented by significantly less cortical, neuroaxonal and oxidative damage. Unexpectedly, male rats had an even higher overall benefit, most likely due to differences in oxidative capacity and defense systems.

Introduction: Brain viscoelasticity as assessed by magnetic resonance elastography (MRE) has been discussed as a promising surrogate of microstructural alterations due to neurodegenerative processes. Existing studies indicate that multiple sclerosis (MS) is associated with a global reduction in brain stiffness. However, no study to date systematically investigated the MS-related characteristics of brain viscoelasticity separately in normal-appearing white matter (NAWM), deep gray matter (DGM) and T2-hyperintense white matter (WM) lesions., Methods: 70 MS patients and 42 healthy volunteers underwent whole-cerebral MRE using a stimulated echo sequence (DENSE) with a low-frequency mechanical excitation at 20 Hertz. The magnitude |G ∗ | (Pa) and phase angle φ (rad) of the complex shear modulus G ∗ were reconstructed by multifrequency dual elasto-visco (MDEV) inversion and related to structural imaging and clinical parameters., Results: We observed φ in the thalamus to be higher by 4.3 % in patients relative to healthy controls (1.11 ± 0.07 vs. 1.06 ± 0.07, p < 0.0001). Higher Expanded Disability Status Scale (EDSS) scores were negatively associated with φ in the basal ganglia (p = 0.01). We measured φ to be lower in MS lesions compared to surrounding NAWM (p = 0.001), which was most prominent for lesions in the temporal lobe (1.01 ± 0.22 vs. 1.06 ± 0.19, p = 0.003). Age was associated with lower values of |G ∗ | (p = 0.04) and φ (p = 0.004) in the thalamus of patients. No alteration in NAWM stiffness relative to WM in healthy controls was observed., Conclusion: Low-frequency elastography in MS patients reveals age-independent alterations in the viscoelasticity of deep gray matter at early stages of disease., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Vitamin D (VD) is the most discussed antioxidant supplement for multiple sclerosis (MS) patients and many studies suggest correlations between a low VD serum level and onset and progression of the disease. While many studies in animals as well as clinical studies focused on the role of VD in the relapsing-remitting MS, knowledge is rather sparse for the progressive phase of the disease and the development of cortical pathology. In this study, we used our established rat model of cortical inflammatory demyelination, resembling features seen in late progressive MS, to address the question about whether VD could have positive effects on reducing cortical pathology, oxidative stress, and neurofilament light chain (NfL) serum levels. For this purpose, we used male Dark Agouti (DA) rats, with one group being supplemented with VD (400 IE per week; VD + ) from the weaning on at age three weeks; the other group received standard rodent food. The rat brains were assessed using immunohistochemical markers against demyelination, microglial activation, apoptosis, neurons, neurofilament, and reactive astrocytes. To evaluate the effect of VD on oxidative stress and the antioxidant capacity, we used two different oxidized lipid markers (anti- Cu ++ and HOCl oxidized LDL antibodies) along with colorimetric methods for protective polyphenols (PP) and total antioxidative capacity (TAC). NfL serum levels of VD + and VD - animals were analyzed by fourth generation single-molecule array (SIMOA) analysis. We found significant differences between the VD + and VD - animals both in histopathology as well as in all serum markers. Myelin loss and microglial activation is lower in VD + animals and the number of apoptotic cells is significantly reduced with a higher neuronal survival. VD + animals show significantly lower NfL serum levels, a higher TAC, and more PP. Additionally, there is a significant reduction of oxidized lipid markers in animals under VD supplementation. Our data thus show a positive effect of VD on cellular features of cortical pathology in our animal model, presumably due to protection against reactive oxygen species. In this study, VD enhanced remyelination and prevented neuroaxonal and oxidative damage, such as demyelination and neurodegeneration. However, more studies on VD dose relations are required to establish an optimal response while avoiding overdosing.

Introduction: Motor imagery (MI) refers to the mental rehearsal of a physical action without muscular activity. Our previous studies showed that MI combined with rhythmic-auditory cues improved walking, fatigue and quality of life (QoL) in people with multiple sclerosis (pwMS). Largest improvements were seen after music and verbally cued MI. It is unclear whether actual cued gait training achieves similar effects on walking as cued MI in pwMS. Furthermore, in pwMS it is unknown whether any of these interventions leads to changes in brain activation. The purpose of this study is therefore to compare the effects of imagined and actual cued gait training and a combination thereof on walking, brain activation patterns, fatigue, cognitive and emotional functioning in pwMS., Methods and Analysis: A prospective double-blind randomised parallel multicentre trial will be conducted in 132 pwMS with mild to moderate disability. Randomised into three groups, participants will receive music, metronome and verbal cueing, plus MI of walking (1), MI combined with actual gait training (2) or actual gait training (3) for 30 min, 4× per week for 4 weeks. Supported by weekly phone calls, participants will practise at home, guided by recorded instructions. Primary endpoints will be walking speed (Timed 25-Foot Walk) and distance (2 min Walk Test). Secondary endpoints will be brain activation patterns, fatigue, QoL, MI ability, anxiety, depression, cognitive functioning, music-induced motivation-to-move, pleasure, arousal and self-efficacy. Data will be collected at baseline, postintervention and 3-month follow-up. MRI reference values will be generated using 15 matched healthy controls., Ethics and Dissemination: This study follows the Standard Protocol Items: Recommendations for Interventional Trials-PRO Extension. Ethical approval was received from the Ethics Committees of the Medical Universities of Innsbruck (1347/2020) and Graz (33-056 ex 20/21), Austria. Results will be disseminated via national and international conferences and published in peer-reviewed journals., Trial Registration Number: DRKS00023978., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Recent studies suggested that CSF-mediated factors contribute to periventricular (PV) T2-hyperintense lesion formation in multiple sclerosis (MS) and this in turn correlates with cortical damage. We thus investigated if such PV-changes are observable microstructurally in early-MS and if they correlate with cortical damage., Methods: We assessed the magnetisation transfer ratio (MTR) in PV normal-appearing white matter (NAWM) and in MS lesions in 44 patients with a clinically isolated syndrome (CIS) suggestive of MS and 73 relapsing-remitting MS (RRMS) patients. Band-wise MTR values were related to cortical mean thickness (CMT) and compared with 49 healthy controls (HCs). For each band, MTR changes were assessed relative to the average MTR values of all HCs., Results: Relative to HCs, PV-MTR was significantly reduced up to 2.63% in CIS and 5.37% in RRMS (p < 0.0001). The MTR decreased towards the lateral ventricles with 0.18%/mm in CIS and 0.31%/mm in RRMS patients, relative to HCs. In RRMS, MTR-values adjacent to the ventricle and in PV-lesions correlated positively with CMT and negatively with EDSS., Conclusion: PV-MTR gradients are present from the earliest stage of MS, consistent with more pronounced microstructural WM-damage closer to the ventricles. The positive association between reduced CMT and lower MTR in PV-NAWM suggests a common pathophysiologic mechanism. Together, these findings indicate the potential use of multimodal MRI as refined marker for MS-related tissue changes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantitative susceptibility mapping (QSM) has been successfully applied to study changes in deep grey matter nuclei as well as in lesional tissue, but its application to white matter has been complicated by the observed orientation dependence of gradient echo signal. The anisotropic susceptibility tensor is thought to be at the origin of this orientation dependence, and magnetic susceptibility anisotropy (MSA) derived from this tensor has been proposed as a marker of the state and integrity of the myelin sheath and may therefore be of particular interest for the study of demyelinating pathologies such as multiple sclerosis (MS). Reconstruction of the susceptibility tensor, however, requires repeated measurements with multiple head orientations, rendering the approach impractical for clinical applications. In this study, we combined single-orientation QSM with fibre orientation information to assess apparent MSA in three white matter tracts, i.e., optic radiation (OR), splenium of the corpus callosum (SCC), and superior longitudinal fascicle (SLF), in two cohorts of 64 healthy controls and 89 MS patients. The apparent MSA showed a significant decrease in optic radiation in the MS cohort compared with healthy controls. It decreased in the MS cohort with increasing lesion load in OR and with disease duration in the splenium. All of this suggests demyelination in normal appearing white matter. However, the apparent MSA observed in the SLF pointed to potential systematic issues that require further exploration to realize the full potential of the presented approach. Despite the limitations of such single-orientation ROI-specific estimation, we believe that our clinically feasible approach to study degenerative changes in WM is worthy of further investigation., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Oxidative stress-induced neuronal damage in multiple sclerosis (MS) results from an imbalance between toxic free radicals and counteracting antioxidants, i.e., antioxidative capacity (AOC). The relation of AOC to outcome measures in MS still remains inconclusive. We aimed to compare AOC in cerebrospinal fluid (CSF) and serum between early MS and controls and assess its correlation with clinical/radiological measures. Methods: We determined AOC (ability of CSF and serum of patients to inhibit 2,2'-azobis(2-amidinopropane) dihydrochloride-induced oxidation of dihydrorhodamine) in clinically isolated syndrome (CIS)/early relapsing-remitting MS (RRMS) ( n = 55/11) and non-inflammatory neurological controls ( n = 67). MS patients underwent clinical follow-up (median, 4.5; IQR, 5.2 years) and brain MRI at 3 T (baseline/follow-up n = 47/34; median time interval, 3.5; IQR, 2.1 years) to determine subclinical disease activity. Results: CSF AOC was differently regulated among CIS, RRMS and controls ( p = 0.031) and lower in RRMS vs. CIS ( p = 0.020). Lower CSF AOC correlated with physical disability ( r = -0.365, p = 0.004) and risk for future relapses (exp(β) = 0.929, p = 0.033). No correlations with MRI metrics were found. Conclusion: Decreased CSF AOC was associated with increased disability and clinical disease activity in MS. While our finding cannot prove causation, they should prompt further investigations into the role of AOC in the evolution of MS.

Background: The COVID-19 pandemic challenges neurologists in counselling patients with multiple sclerosis (pwMS) regarding their risk by SARS-CoV-2 and in guiding disease-modifying treatment (DMT)., Objective: To characterize the prevalence and outcome of COVID-19 in pwMS specifically associated with different DMT in a nationwide population-based study., Methods: We included patients aged ≥18 years with a confirmed diagnosis of MS and a diagnosis of COVID-19 established between January 1, 2020 and December 31, 2020. We classified COVID-19 course as either mild, severe or fatal. Impact of DMT and specifically immunosuppressants (alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab) on COVID-19 outcome was determined by multivariable models, adjusted for a-priori-risk., Results: Of 126 MS patients with COVID-19 (mean age 43.2 years [SD 13.4], 71% female), 86.5% had a mild course, 9.5% a severe course and 3.2% died from COVID-19. A-priori-risk significantly predicted COVID-19 severity (R2 0.814; p<0.001) and mortality (R2 0.664; p<0.001). Adjusting for this a-priori-risk, neither exposure to any DMT nor exposure to specific immunosuppressive DMT were significantly associated with COVID-19 severity (odds ratio [OR] 1.6; p = 0.667 and OR 1.9; p = 0.426) or mortality (OR 0.5; p = 0.711 and 2.1; 0.233) when compared to no DMT., Conclusions: In a population-based MS cohort, COVID-19 outcome was not associated with exposure to DMT and immunosuppressive DMT when accounting for other already known risk factors. This provides reassuring evidence that COVID-19 risk can be individually anticipated in MS and-except for a very small proportion of high-risk patients-treatment decisions should be primarily focused on treating MS rather than the pandemic., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Gabriel Bsteh: has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Roche and Teva. Hamid Assar: has participated in meetings sponsored by, received honoraria (advisory boards, consultations) or travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Harald Hegen: has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Siemens and Teva, and received honoraria for consulting Biogen, Novartis and Teva. Bettina Heschl: has nothing to disclose. Fritz Leutmezer: has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Franziska Di Pauli: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. Christiane Gradl: has participated in meetings sponsored by, received honoraria (lectures, consultations) and/or travel funding from Biogen, D-Pharma, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Gerhard Traxler: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Gudrun Zulehner: has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Paulus Rommer: has received honoraria for consultancy/speaking from AbbVie, Allmiral, Alexion, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi Genzyme, has received research grants from Amicus, Biogen, Merck, Roche. Peter Wipfler: has received funding for travel and honoraria (lectures, advisory boards) from Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Michael Guger: has received support and honoraria for research, consultation, lectures and education from Almirall, Bayer, Biogen, Celgene, Genzyme, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Shire and Teva. Christian Enzinger: has received funding for travel and speaker honoraria from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Shire and Teva. has received research support from Biogen, Celgene, Merck, and Teva; is serving on scientific advisory boards for Bayer, Biogen, Celgene, Merck, Novartis, Roche and Teva. Thomas Berger: has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, Celgene, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. His institution has received financial support in the past 12 months by unrestricted research grants (Bayer, Biogen, Merck, Novartis, Sanofi Aventis, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Quantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure.

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.)

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 < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings., Conclusion: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety., Methods: Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions., Results: In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup ( p = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning ( r = -0.950, p = 0.001) and memory ( r = -0.813; p = 0.026) disappeared when further controlling for age, educational level, and sex., Conclusions: In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS). In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions - the pathological hallmark of MS. However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability. The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI. MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses. In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures. On the basis of this review, the group makes consensus statements and recommendations for future research.

We aimed to assess differences in resting-state functional connectivity (FC) between distinct morphological MRI-phenotypes in multiple sclerosis (MS). Out of 180 MS patients, we identified those with high T2-hyperintense lesion load (T2-LL) and high normalized brain volume (NBV; a predominately white matter damage group, WMD; N = 37) and patients with low T2-LL and low NBV (N = 37; a predominately grey matter damage group; GMD). Independent component analysis of resting-state fMRI was used to test for differences in the sensorimotor network (SMN) between MS MRI-phenotypes and compared to 37 age-matched healthy controls (HC). The two MS groups did not differ regarding EDSS scores, disease duration and distribution of clinical phenotypes. WMD compared to GMD patients showed increased FC in all sub-units of the SMN (sex- and age-corrected). WMD patients had increased FC compared to HC and GMD patients in the central SMN (leg area). Only in the WMD group, higher EDSS scores and T2-LL correlated with decreased connectivity in SMN sub-units. MS patients with distinct morphological MRI-phenotypes also differ in brain function. The amount of focal white matter pathology but not global brain atrophy affects connectivity in the central SMN (leg area) of the SMN, consistent with the notion of a disconnection syndrome.

Machine learning classification is an attractive approach to automatically differentiate patients from healthy subjects, and to predict future disease outcomes. A clinically isolated syndrome (CIS) is often the first presentation of multiple sclerosis (MS), but it is difficult at onset to predict who will have a second relapse and hence convert to clinically definite MS. In this study, we thus aimed to distinguish CIS converters from non-converters at onset of a CIS, using recursive feature elimination and weight averaging with support vector machines. We also sought to assess the influence of cohort size and cross-validation methods on the accuracy estimate of the classification. We retrospectively collected 400 patients with CIS from six European MAGNIMS MS centres. Patients underwent brain MRI at onset of a CIS according to local standard-of-care protocols. The diagnosis of clinically definite MS at one-year follow-up was the standard against which the accuracy of the model was tested. For each patient, we derived MRI-based features, such as grey matter probability, white matter lesion load, cortical thickness, and volume of specific cortical and white matter regions. Features with little contribution to the classification model were removed iteratively through an interleaved sample bootstrapping and feature averaging approach. Classification of CIS outcome at one-year follow-up was performed with 2-fold, 5-fold, 10-fold and leave-one-out cross-validation for each centre cohort independently and in all patients together. The estimated classification accuracy across centres ranged from 64.9% to 88.1% using 2-fold cross-validation and from 73% to 92.9% using leave-one-out cross-validation. The classification accuracy estimate was higher in single-centre, smaller data sets than in combinations of data sets, being the lowest when all patients were merged together. Regional MRI features such as WM lesions, grey matter probability in the thalamus and the precuneus or cortical thickness in the cuneus and inferior temporal gyrus predicted the occurrence of a second relapse in patients at onset of a CIS using support vector machines. The increased accuracy estimate of the classification achieved with smaller and single-centre samples may indicate a model bias (overfitting) when data points were limited, but also more homogeneous. We provide an overview of classifier performance from a range of cross-validation schemes to give insight into the variability across schemes. The proposed recursive feature elimination approach with weight averaging can be used both in single- and multi-centre data sets in order to bridge the gap between group-level comparisons and making predictions for individual patients., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation. In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres. Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97). Disability was scored using the Expanded Disability Status Scale. We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions. Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation. The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis. Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry. All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls. T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed. The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001). The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes. The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS.

MRI red flags proposed over a decade ago by the European Magnetic Resonance Network in MS (MAGNIMS) have guided clinicians in the diagnosis of multiple sclerosis (MS). However, the past 10 years have seen increased recognition that vascular disease can coexist and possibly interact with MS, improvements in the reliability of ways to differentiate MS from novel antibody-mediated CNS disorders (such as anti-aquaporin-4 antibody and myelin-oligodendrocyte glycoprotein antibody-associated diseases) and advances in MRI techniques. In this Review, MAGNIMS updates the imaging features that differentiate the most common mimics of MS, particularly age-related cerebrovascular disease and neuromyelitis optica, from MS itself. We also provide a pragmatic summary of the clinically useful MRI features that distinguish MS from its mimics and discuss the future of nonconventional techniques that have identified promising disease-specific features.

In a multicenter setting, we applied voxel-based methods to different structural MR imaging modalities to define the relative contributions of focal lesions, normal-appearing white matter (NAWM), and gray matter (GM) damage and their regional distribution to cognitive deficits as well as impairment of specific cognitive domains in multiple sclerosis (MS) patients. Approval of the institutional review boards was obtained, together with written informed consent from all participants. Standardized neuropsychological assessment and conventional, diffusion tensor and volumetric brain MRI sequences were collected from 61 relapsing-remitting MS patients and 61 healthy controls (HC) from seven centers. Patients with ≥2 abnormal tests were considered cognitively impaired (CI). The distribution of focal lesions, GM and WM atrophy, and microstructural WM damage were assessed using voxel-wise approaches. A random forest analysis identified the best imaging predictors of global cognitive impairment and deficits of specific cognitive domains. Twenty-three (38%) MS patients were CI. Compared with cognitively preserved (CP), CI MS patients had GM atrophy of the left thalamus, right hippocampus and parietal regions. They also showed atrophy of several WM tracts, mainly located in posterior brain regions and widespread WM diffusivity abnormalities. WM diffusivity abnormalities in cognitive-relevant WM tracts followed by atrophy of cognitive-relevant GM regions explained global cognitive impairment. Variable patterns of NAWM and GM damage were associated with deficits in selected cognitive domains. Structural, multiparametric, voxel-wise MRI approaches are feasible in a multicenter setting. The combination of different imaging modalities is needed to assess and monitor cognitive impairment in MS., (© 2016 Wiley Periodicals, Inc.)

Given increasing efforts to use resting-state fMRI (rfMRI) as a biomarker of disease progression in multiple sclerosis (MS) we here explored the reproducibility of longitudinal rfMRI over three months in patients with clinically and radiologically stable MS. To pursue this aim, two approaches were applied in nine rfMRI networks: First, the intraclass correlation coefficient (ICC 3,1) was assessed for the mean functional connectivity maps across the entire network and a region of interest (ROI). Second, the ratio of overlap between Z-thresholded connectivity maps for each network was assessed. We quantified between-session functional reproducibility of rfMRI for 20 patients with stable MS and 14 healthy controls (HC). Nine rfMRI networks (RSNs) were examined at baseline and after 3 months of follow-up: three visual RSNs, the default-mode network, sensorimotor-, auditory-, executive control, and the left and right fronto-parietal RSN. ROI analyses were constrained to thresholded overlap masks for each individual (Z>0) at baseline and follow-up.In both stable MS and HC mean functional connectivity across the entire network did not reach acceptable ICCs for several networks (ICC<0.40) but we found a high reproducibility of ROI ICCs and of the ratio of overlap. ROI ICCs of all nine networks were between 0.98 and 0.99 for HC and ranged from 0.88 to 0.99 in patients with MS, respectively. The ratio of overlap for all networks was similar for both groups, ranging from 0.60 to 0.75.Our findings attest to a high reproducibility of rfMRI networks not only in HC but also in patients with stable MS when applying ROI analysis. This supports the utility of rfMRI to monitor functional changes related to disease progression or therapeutic interventions in MS.

MRI has become the most important paraclinical tool for diagnosing and monitoring patients with multiple sclerosis (MS). However, conventional MRI sequences are largely nonspecific in the pathology they reveal, and only provide a limited view of the complex morphological changes associated with MS. Nonconventional MRI techniques, such as magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) promise to complement existing techniques by revealing more-specific information on microstructural tissue changes. Past years have witnessed dramatic advances in the acquisition and analysis of such imaging data, and numerous studies have used these tools to probe tissue alterations associated with MS. Other MRI-based techniques-such as myelin-water imaging, (23)Na imaging, magnetic resonance elastography and magnetic resonance perfusion imaging-might also shed new light on disease-associated changes. This Review summarizes the rapid technical progress in the use of MRI in patients with MS, with a focus on nonconventional structural MRI. We critically discuss the present utility of nonconventional MRI in MS, and provide an outlook on future applications, including clinical practice. This information should allow appropriate selection of advanced MRI techniques, and facilitate their use in future studies of this disease.

Objective: While many studies correlated cognitive function with changes in brain morphology in multiple sclerosis (MS), few of them used a multi-parametric approach in a single dataset so far. We thus here assessed the predictive value of different conventional and quantitative MRI-parameters both for overall and domain-specific cognitive performance in MS patients from a single center., Methods: 69 patients (17 clinically isolated syndrome, 47 relapsing-remitting MS, 5 secondary-progressive MS) underwent the "Brief Repeatable Battery of Neuropsychological Tests" assessing overall cognition, cognitive efficiency and memory function as well as MRI at 3 Tesla to obtain T2-lesion load (T2-LL), normalized brain volume (global brain volume loss), normalized cortical volume (NCV), normalized thalamic volume (NTV), normalized hippocampal volume (NHV), normalized caudate nuclei volume (NCNV), basal ganglia R2* values (iron deposition) and magnetization transfer ratios (MTRs) for cortex and normal appearing brain tissue (NABT)., Results: Regression models including clinical, demographic variables and MRI-parameters explained 22-27% of variance of overall cognition, 17-26% of cognitive efficiency and 22-23% of memory. NCV, T2-LL and MTR of NABT were the strongest predictors of overall cognitive function. Cognitive efficiency was best predicted by NCV, T2-LL and iron deposition in the basal ganglia. NTV was the strongest predictor for memory function and NHV was particularly related to memory function., Conclusions: The predictive value of distinct MRI-parameters differs for specific domains of cognitive function, with a greater impact of cortical volume, focal and diffuse white matter abnormalities on overall cognitive function, an additional role of basal ganglia iron deposition on cognitive efficiency, and thalamic and hippocampal volume on memory function. This suggests the usefulness of using multiparametric MRI to assess (micro)structural correlates of different cognitive constructs.

Background: Previous work suggested greater intellectual enrichment might moderate the negative impact of brain atrophy on cognition. This awaits confirmation in independent cohorts including investigation of the role of T2-lesion load (T2-LL), which is another important determinant of cognition in MS. We here thus aimed to test this cognitive reserve hypothesis by investigating whether educational attainment (EA) moderates the negative effects of both brain atrophy and T2-LL on cognitive function in a large sample of MS patients., Methods: 137 patients participated in the study. Cognition was assessed by the "Brief Repeatable Battery of Neuropsychological Tests." T2-LL, normalized brain volume (global volume loss) and third ventricle width (regional volume loss) served as MRI markers., Results: Both T2-LL and atrophy predicted worse cognition, with a stronger effect of T2-LL. Higher EA (as assessed by years of education) also predicted better cognition. Interactions showed that the negative effects of T2-LL and regional brain atrophy were moderated by EA., Conclusions: In a cohort with different stages of MS, higher EA attenuated the negative effects of white matter lesion burden and third ventricle width (suggestive of thalamic atrophy) on cognitive performance. Actively enhancing cognitive reserve might thus be a means to reduce or prevent cognitive problems in MS in parallel to disease modifying drugs.

Objectives: Resting state (RS) functional MRI recently identified default network abnormalities related to cognitive impairment in MS. fMRI can also be used to map functional connectivity (FC) while the brain is at rest and not adhered to a specific task. Given the importance of the anterior cingulate cortex (ACC) for higher executive functioning in MS, we here used the ACC as seed-point to test for differences and similarities in RS-FC related to sustained attention between MS patients and controls., Design: Block-design rest phases of 3 Tesla fMRI data were analyzed to assess RS-FC in 31 patients (10 clinically isolated syndromes, 16 relapsing-remitting, 5 secondary progressive MS) and 31 age- and gender matched healthy controls (HC). Participants underwent extensive cognitive testing., Observations: In both groups, signal changes in several brain areas demonstrated significant correlation with RS-activity in the ACC. These comprised the posterior cingulate cortex (PCC), insular cortices, the right caudate, right middle temporal gyrus, angular gyri, the right hippocampus, and the cerebellum. Compared to HC, patients showed increased FC between the ACC and the left angular gyrus, left PCC, and right postcentral gyrus. Better cognitive performance in the patients was associated with increased FC to the cerebellum, middle temporal gyrus, occipital pole, and the angular gyrus., Conclusion: We provide evidence for adaptive changes in RS-FC in MS patients compared to HC in a sustained attention network. These results extend and partly mirror findings of task-related fMRI, suggesting FC may increase our understanding of cognitive dysfunction in MS.

Several relaxation mapping techniques have been proposed to quantitatively assess disease-related brain tissue changes in multiple sclerosis. Newer developments also account for the distribution of hydrogen protons in different tissue compartments, and therefore provide markers for myelin and macromolecular content. This article will cover the broad spectrum of the pulse sequences and analysis techniques related to this topic that are currently available. Various technical and practical limitations linked with specific approaches will be discussed. These include acquisition time, accuracy and precision, radiofrequency absorption and limited coverage of the brain. Finally, the application of these techniques in the context of multiple sclerosis will be reviewed.

In this multicenter study, we used dynamic causal modeling to characterize the abnormalities of effective connectivity of the sensorimotor network in 61 patients with multiple sclerosis (MS) compared with 74 age-matched healthy subjects. We also investigated the correlation of such abnormalities with findings derived from structural MRI. In a subgroup of subjects, diffusion tensor (DT) MRI metrics of the corpus callosum and the left corticospinal tract (CST) were also assessed. MS patients showed increased effective connectivity relative to controls between: (a) the left primary SMC and the left dorsal premotor cortex (PMd), (b) the left PMd and the supplementary motor areas (SMA), (c) the left secondary sensorimotor cortex (SII) and the SMA, (d) the right SII and the SMA, (e) the left SII and the right SII, and (f) the right SMC and the SMA. MS patients had relatively reduced effective connectivity between the left SMC and the right cerebellum. No interaction was found between disease group and center. Coefficients of altered connectivity were weakly correlated with brain T2 LV, but moderately correlated with DT MRI-measured damage of the left CST. In conclusion, large multicenter fMRI studies of effective connectivity changes in diseased people are feasible and can facilitate studies with sample size large enough for robust outcomes. Increased effective connectivity in the patients for the simple motor task suggests local network modulation contributing to enhanced long-distance effective connectivity in MS patients. This extends and generalizes previous evidence that enhancement of effective connectivity may provide an important compensatory mechanism in MS., ((c) 2008 Wiley-Liss, Inc.)