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Background Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. Methods We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ~2 years. Findings Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p=0.027). Interpretation Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of Bcells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of Bcells in CAL could explain our findings.

Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS.We performed 3 studies: (1) a cross-sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso-intense, hypo-intense, hyperintense, lesions with hypo-intense rims, and lesions with paramagnetic rim legions [PRLs]); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology-QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions.At baseline, hypo- and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p 0.0001). Further, at 2-year follow-up, hypo-/iso-intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo-/iso-intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%).These results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486-502.

Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.

Highlights • This is an overview of preclinical MRI studies in neuroinflammatory diseases. • We summarized experimental setup, MRI methodology, and risk of bias of these studies. • We propose guidelines to improve standardization of preclinical MRI studies. • Implementing these reporting guidelines could facilitate clinical translation. • This study can serve as a framework for future preclinical studies using MRI., Magnetic resonance imaging (MRI) is the most important paraclinical tool for assessing drug response in multiple sclerosis (MS) clinical trials. As such, MRI has also been widely used in preclinical research to investigate drug efficacy and pathogenic aspects in MS animal models. Keeping track of all published preclinical imaging studies, and possible new therapeutic approaches, has become difficult considering the abundance of studies. Moreover, comparisons between studies are hampered by methodological differences, especially since small differences in an MRI protocol can lead to large differences in tissue contrast. We therefore provide a comprehensive qualitative overview of preclinical MRI studies in the field of neuroinflammatory and demyelinating diseases, aiming to summarize experimental setup, MRI methodology, and risk of bias. We also provide estimates of the effects of tested therapeutic interventions by a meta-analysis. Finally, to improve the standardization of preclinical experiments, we propose guidelines on technical aspects of MRI and reporting that can serve as a framework for future preclinical studies using MRI in MS animal models. By implementing these guidelines, clinical translation of findings will be facilitated, and could possibly reduce experimental animal numbers.

Inflammatory destruction of iron-rich myelin is characteristic of multiple sclerosis (MS). Although iron is needed for oligodendrocytes to produce myelin during development, its deposition has also been linked to neurodegeneration and inflammation, including in MS. We report perivascular iron deposition in multiple sclerosis lesions that was mirrored in 72 lesions from 13 marmosets with experimental autoimmune encephalomyelitis. Iron accumulated mainly inside microglia/macrophages from 6 weeks after demyelination. Consistently, expression of transferrin receptor, the brain's main iron-influx protein, increased as lesions aged. Iron was uncorrelated with inflammation and postdated initial demyelination, suggesting that iron is not directly pathogenic. Iron homeostasis was at least partially restored in remyelinated, but not persistently demyelinated, lesions. Taken together, our results suggest that iron accumulation in the weeks after inflammatory demyelination may contribute to lesion repair rather than inflammatory demyelination per se.

Objectives: In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the “central vein sign”) improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). Methods: In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing–remitting MS, 3-dimensional T2*-weighted and T2–fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. Results: MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. Interpretation: The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283–294., SCOPUS: ar.j, info:eu-repo/semantics/published

Objective:To assess the prevalence and the specificity of leptomeningeal enhancement (LME) on postcontrast T2–fluid-attenuated inversion recovery (FLAIR) MRI in multiple sclerosis (MS) compared to a variety of inflammatory and noninflammatory neurologic conditions assessed in 2 academic research hospitals.Methods:On 3T postcontrast T2-FLAIR images, the presence of focal gadolinium enhancement was evaluated in the leptomeningeal compartment in 254 people with non-MS neurologic conditions or neurotropic viral infections. Based on their clinical diagnosis, patients were grouped as follows: (1) other-than-MS inflammatory neurologic diseases; (2) noninflammatory neurologic diseases; (3) human T-lymphotropic virus (HTLV)–infected; (4) HIV-infected; (5) healthy volunteers.Results:LME was detected in 56/254 non-MS cases (22%) vs 74/299 (25%) of MS cases. LME was nearly 4-fold more frequent in non-MS inflammatory neurologic conditions (18/51 cases, 35%) than in noninflammatory neurologic conditions (3/38, 8%) and healthy volunteers (5/66, 8%). The highest prevalence of LME was detected in HTLV infection (17/38 cases, 45%), particularly in the setting of HTLV-associated myelopathy (14/25 cases, 56%). LME also frequently occurred in HIV infection (13/61 cases, 21%). Unlike in MS, LME is not associated with lower brain and cortical volumes in non-MS inflammatory neurologic conditions, including HTLV and HIV infection.Conclusions:Despite its relevance to MS pathogenesis and cortical pathology, LME is not specific to MS, occurring frequently in non-MS inflammatory neurologic conditions and especially in those patients with HTLV-associated myelopathy. Overall, this strengthens the notion that LME localizes inflammation-related focal disruption of the blood–meninges barrier and associated scarring.

Objective: To determine the frequency and nature of leptomeningeal contrast enhancement in multiple sclerosis (MS) via in vivo 3-tesla postcontrast T2-weighted, fluid-attenuated inversion recovery (FLAIR) MRI and 7-tesla postmortem MRI–pathology correlation. Methods: Brain MRI, using the postcontrast T2-weighted, FLAIR technique, was prospectively collected in 299 MS cases and 37 age-matched neurologically healthy controls. Expert raters evaluated focal gadolinium enhancement in the leptomeningeal compartment. Two progressive MS cases came to autopsy after in vivo MRI characterization. Pathologic and immunohistochemical examination assessed the association of enhancement with leptomeningeal inflammation and adjacent cortical demyelination. Results: Focal contrast enhancement was detected in the leptomeningeal compartment in 74 of 299 MS cases (25%) vs 1 of 37 neurologically healthy controls (2.7%; p = 0.001). Enhancement was nearly twice as frequent ( p = 0.009) in progressive MS (39/118 cases, 33%) as in relapsing-remitting MS (35/181, 19%). Enhancing foci generally remained stable throughout the evaluation period (up to 5.5 years). Pathology showed perivascular lymphocytic and mononuclear infiltration in the enhancing areas in association with flanking subpial cortical demyelination. Conclusion: Leptomeningeal contrast enhancement occurs frequently in MS and is a noninvasive, in vivo marker of inflammation and associated subpial demyelination. It might therefore enable testing of new treatments aimed at eliminating this inflammation and potentially arresting progressive MS.

Active motor functional magnetic resonance imaging (fMRI) studies have shown that pediatric multiple sclerosis (MS) patients have a strictly lateralized pattern of activations and a preserved functional connectivity (FC) within the motor system when compared to age-matched healthy controls. However, it is still not clear whether a preserved FC in pediatric MS is present only in the motor system, or involves other relevant functional system. Resting-state (RS) fMRI is a valuable tool for an unbiased investigation of FC abnormalities of multiple networks. This study explored abnormalities of RS FC within and between large-scale neuronal networks from 44 pediatric MS patients and 27 controls and their correlation with clinical, neuropsychological, and conventional MRI measures. Compared to controls, pediatric MS patients had a decreased FC of several regions of the sensorimotor, secondary visual, default-mode (DMN), executive control, and bilateral working memory (WMN) networks. They also experienced an increased FC in the right medial frontal gyrus of the attention network, which was correlated with T2 lesion volume. Cognitively impaired patients had decreased RS FC of the right precuneus of the left WMN. An increased FC between the sensorimotor network and the DMN, and between the L WMN and the attention network as well as a decreased FC between L WMN and the DMN were also found. A distributed pattern of FC abnormalities within large-scale neuronal networks occurs in pediatric MS patients, contributes to their cognitive status, and is partially driven by focal white matter lesions. Internetwork connectivity is relatively preserved in these patients. Hum Brain Mapp 35:4180–4192, 2014. © 2014 Wiley Periodicals, Inc.

Objective In multiple sclerosis (MS), accurate, in vivo characterization of dynamic inflammatory pathological changes occurring in newly forming lesions could have major implications for understanding disease pathogenesis and mechanisms of tissue destruction. Here, we investigated the potential of ultrahigh-field magnetic resonance imaging (MRI; 7T), particularly phase imaging combined with dynamic contrast enhancement, to provide new insights in acute MS lesions. Methods Sixteen active MS patients were studied at 7T. Noncontrast, high-resolution T2* magnitude and phase scans, T1 scans before/after gadolinium contrast injection, and dynamic contrast-enhanced (DCE) T1 scans were acquired. T2*/phase features and DCE pattern were determined for acute and chronic lesions. When possible, 1-year follow-up 7T MRI was performed. Results Of 49 contrast-enhancing lesions, 44 could be analyzed. Centrifugal DCE lesions appeared isointense or hypointense on phase images, whereas centripetal DCE lesions showed thin, hypointense phase rims that clearly colocalized with the initial site of contrast enhancement. This pattern generally disappeared once enhancement resolved. Conversely, in 43 chronic lesions also selected for the presence of hypointense phase rims, the findings were stable over time, and the rims were typically thicker and darker. These considerations suggest different underlying pathological processes in the 2 lesion types. Interpretation Ultrahigh-field MRI and, especially, phase contrast, are highly sensitive to tissue changes in acute MS lesions, which differ from the patterns seen in chronic lesions. In acute lesions, the hypointense phase rim reflects the expanding inflammatory edge and may directly correspond to inflammatory byproducts and sequelae of blood–brain barrier opening. Ann Neurol 2013;74:669–678

Using resting state (RS) functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), we identified the predictors of clinical improvement following constraint-induced movement therapy (CIMT) in pediatric patients with chronic hemiplegia.From 14 children with congenital or acquired brain injury and 10 sex- and age-matched healthy controls, brain dual-echo, DTI and RS fMRI sequences were acquired before CIMT. The Quality of Upper Extremities Skills Test and the Gross Motor Function Measure (GMFM) were administered at baseline, at the end of CIMT (10 weeks), and after 6 months. Mean diffusivity and fractional anisotropy (FA) were measured in the lesion responsible for the clinical symptomatology, the affected and unaffected corticospinal tract (CST), motor transcallosal fibers, and uncinate fasciculus (as an internal control). Independent component analysis was used to identify the sensorimotor RS network. The ability of baseline MRI variables to predict clinical changes over time was assessed using multivariate linear models. At baseline, patients had increased mean diffusivity in the symptomatic lesion and decreased FA in the symptomatic lesion, affected corticospinal tract, and motor transcallosal fibers. A reduced RS functional connectivity was found in the bilateral cerebellum, left precentral gyrus, and right secondary sensorimotor cortex. At follow up, Quality of Upper Extremities Skills Test and GMFM scales improved significantly. Baseline average lesion FA predicted clinical improvement at week 10, and baseline functional connectivity of the right secondary sensorimotor cortex and cerebellum predicted GMFM improvement at month 6. DTI and RS fMRI offer promising and objective markers to predict clinical outcomes following CIMT in pediatric patients with congenital or acquired hemiplegia.

"Abstract Primary progressive multiple sclerosis (PPMS) is characterized by a steady progression of irreversible disability from the onset of the disease. Although magnetic resonance imaging (MRI) is a valuable tool to quantify the disease burden in the brain and spinal cord of patients with MS, measures derived from conventional MRI, including T2-visible lesions, gadolinium-enhancing lesions and atrophy, are correlated only weakly with the clinical manifestations of PPMS. On the contrary, advanced MRI techniques are contributing significantly to the understanding of the mechanisms underlying the irreversible accumulation of disability in PPMS patients. Data from quantitative MRI studies suggest that the extent and topography of ‘‘diffuse’’ damage in different central nervous system (CNS) compartments (i.e. normal-appearing brain white matter and grey matter and the spinal cord) is associated with the severity of disability in PPMS and can predict subsequent medium-term disease evolution. Functional MRI studies have shown that the impairment of the adaptive capacity of the cortex to limit the clinical consequences of structural CNS damage is yet another factor contributing to the manifestations of this condition."

Comi, Giancarlo Jeffery, Douglas Kappos, Ludwig Montalban, Xavier Boyko, Alexey Rocca, Maria A Filippi, Massimo ALLEGRO Study Group Clinical Trial, Phase III Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't United States The New England journal of medicine N Engl J Med. 2012 Mar 15;366(11):1000-9.; BACKGROUND: Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis. METHODS: We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging. RESULTS: Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (+/-SE) annualized relapse rate (0.30+/-0.02 vs. 0.39+/-0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33+/-0.14 vs. 2.12+/-0.22 and 5.03+/-0.08 vs. 7.14+/-0.07, respectively; P

Objective: Aim of this study was to compare tactile-associated cervical cord fMRI activity between primary progressive (PP) and secondary progressive (SP) MS patients and to investigate whether cord recruitment was associated with structural brain and cord damage. Experimental Design: Cervical cord fMRI during a tactile stimulation of the right hand was acquired from 17 healthy controls, 18 SPMS patients, and 16 PPMS patients. Average fMRI activity and its topographical distribution in cord sectors (left vs. right, posterior vs. anterior) were assessed. Correlations between cord recruitment and structural cord and brain MRI were estimated. Principal Observations: Progressive MS patients showed an increased cord recruitment compared with controls (P = 0.003). Despite a similar structural cord damage, cord activity was increased in SPMS compared to PPMS patients (P = 0.05). Regional analysis showed a non-lateralized pattern of cord recruitment in MS patients. Compared to PPMS, SPMS patients had grey matter (GM) atrophy in several cortical and subcortical regions. In SPMS patients, atrophy of the left postcentral gyrus was correlated with cord activity (r = −0.48, P = 0.04). Conclusions: Patients with progressive MS had an over-recruitment of the cervical cord, which was more pronounced in SPMS than PPMS, despite similar cord structural damage. The alteration of the complex modulation of spinal cord interneurons possibly due to a loss of supratentorial inhibition secondary to brain injury might contribute to explain the observed functional cord abnormalities. Hum Brain Mapp 33:2072–2080, 2012. © 2011 Wiley Periodicals, Inc.

Aim: We assessed the pattern of regional white matter and grey matter abnormalities in patients with cluster headache (CH), using tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM). Methods: Using a 3.0 Tesla scanner, dual-echo, diffusion tensor and 3D T1-weighted scan were acquired from 15 patients with episodic CH and 19 healthy controls. TBSS analysis was performed using the FMRIB's Diffusion Toolbox. VBM was performed on the 3D T1-weighted images using SPM8. Results: No diffusivity and volumetry abnormalities of brain white matter were detected in CH patients. Compared with controls, CH patients showed decreased grey matter volume in the right thalamus, head of the right caudate nucleus, right precentral gyrus, right posterior cingulate cortex, bilateral middle frontal gyrus, right middle temporal gyrus, left inferior parietal lobule and left insula (p Conclusion: CH patients experience tissue abnormalities of grey matter regions that are part of the antinociceptive system, which is shared with other chronic pain conditions.

Objectives: A growing body of evidence suggests that, independent of localized brain lesions, mood disorders can be associated with dysfunction of brain networks involved in the modulation of emotional and cognitive behavior. We used diffusion tensor (DT) tractography to quantify the presence and extent of structural injury to the connections between the amygdala and other brain regions, which included the subgenual, the supragenual and posterior cingulate, the parahippocampal, the orbitofrontal and dorsolateral prefrontal cortices, as well as the insula. Methods: Using a 3.0 Tesla scanner, conventional and DT magnetic resonance imaging sequences of the brain were acquired from 15 adult patients with major depressive disorder (MDD), 15 with bipolar disorder (BD), and 21 age-matched healthy controls. Using FSL software, diffusivity changes of the white matter (WM) fiber bundles belonging to the emotional network were measured. Results: Compared to controls and MDD patients, BD patients had significantly decreased average fractional anisotropy, increased average mean diffusivity, and increased average axial and radial diffusivity values in the majority of the WM fiber bundles connecting structures of the anterior limbic network (p-values ranging from 0.002 to 0.040). Medication load did not influence the results with the exception of lithium, which was associated with normal diffusivity values in tracts connecting the amygdala with the subgenual cingulate cortex. Conclusions: We detected specific WM abnormalities, suggestive of disrupted integrity of fiber bundles in the brains of patients with BD. These abnormalities might contribute to understanding both mood dysregulation and cognitive disturbances in BD, and might provide an objective marker to monitor treatment efficacy in this condition. ""Objectives: A growing body of evidence suggests that, independent of localized brain lesions, mood disorders can be associated with dysfunction of brain networks involved in the modulation of emotional and cognitive behavior. We used diffusion tensor (DT) tractography to quantify the presence and extent of structural injury to the connections between the amygdala and other brain regions, which included the subgenual, the supragenual and posterior cingulate, the parahippocampal, the orbitofrontal and dorsolateral prefrontal cortices, as well as the insula. Methods: Using a 3.0 Tesla scanner, conventional and DT magnetic resonance imaging sequences of the brain were acquired from 15 adult patients with major depressive disorder (MDD), 15 with bipolar disorder (BD), and 21 age-matched healthy controls. Using FSL software, diffusivity changes of the white matter (WM) fiber bundles belonging to the emotional network were measured. Results: Compared to controls and MDD patients, BD patients had significantly decreased average fractional anisotropy, increased average mean diffusivity, and increased average axial and radial diffusivity values in the majority of the WM fiber bundles connecting structures of the anterior limbic network (p-values ranging from 0.002 to 0.040). Medication load did not influence the results with the exception of lithium, which was associated with normal diffusivity values in tracts connecting the amygdala with the subgenual cingulate cortex. Conclusions: We detected specific WM abnormalities, suggestive of disrupted integrity of fiber bundles in the brains of patients with BD. These abnormalities might contribute to understanding both mood dysregulation and cognitive disturbances in BD, and might provide an objective marker to monitor treatment efficacy in this condition.""

A new semi-automatic method for segmenting the spinal cord from MR images is presented. The method is based on an active surface (AS) model of the cord surface, with intrinsic smoothness constraints. The model is initialized by the user marking the approximate cord center-line on a few representative slices, and the compact surface parametrization results in a rapid segmentation, taking on the order of one minute. Using 3-D acquired T1-weighted images of the cervical spine from human controls and patients with multiple sclerosis, the intra- and inter-observer reproducibilities were evaluated, and compared favorably with an existing cord segmentation method. While the AS method overestimated the cord area by approximately 14% compared to manual outlining, correlations between cord cross-sectional area and clinical disability scores confirmed the relevance of the new method in measuring cord atrophy in multiple sclerosis. Segmentation of the cord from 2-D multi-slice T2-weighted images is also demonstrated over the cervical and thoracic region. Since the cord center-line is an intrinsic parameter extracted as part of the segmentation process, the image can be resampled such that the center-line forms one coordinate axis of a new image, allowing simple visualization of the cord structure and pathology; this could find wider application in standard radiological practice.

This study aimed at elucidating whether (a) brain areas associated with motor function show a change in functional magnetic resonance imaging (fMRI) signal in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), (b) such change is linear over the course of the disease, and (c) fMRI changes in aMCI and AD are driven by hippocampal atrophy, or, conversely, reflect a nonspecific neuronal network rewiring generically associated to brain tissue damage. FMRI during the performance of a simple motor task with the dominant right‐hand, and structural MRI (i.e., dual‐echo, 3D T1‐weighted, and diffusion tensor [DT] MRI sequences) were acquired from 10 AD patients, 15 aMCI patients, and 11 healthy controls. During the simple‐motor task, aMCI patients had decreased recruitment of the left (L) inferior frontal gyrus compared to controls, while they showed increased recruitment of L postcentral gyrus and head of L caudate nucleus, and decreased activation of the cingulum compared with AD patients. Effective connectivity was altered between primary sensorimotor cortices (SMC) in aMCI patients vs. controls, and between L SMC, head of L caudate nucleus, and cingulum in AD vs. aMCI patients. Altered fMRI activations and connections were correlated with the hippocampal atrophy in aMCI and with the overall GM microstructural damage in AD. Motor‐associated functional cortical changes in aMCI and AD mirror fMRI changes of the cognitive network, suggesting the occurrence of a widespread brain rewiring with increasing structural damage rather than a specific response of cognitive network. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.

Objective To characterise, using conventional and diffusion tensor (DT) MRI, the nature and distribution of lesions and the extent of damage in the brain normal-appearing white matter (NAWM) and grey matter (GM) from a relatively large population of paediatric multiple sclerosis (MS) patients. Methods Brain conventional and DT MRI scans were acquired from 48 patients with paediatric MS (10 clinically isolated syndromes (CIS), 38 relapsing remitting (RR) MS), 30 adult CIS, 27 adult RRMS, 15 paediatric healthy controls (HC) and 18 adult HC. T2-lesion probability maps and DT MRI of lesions, NAWM and GM were compared among controls and MS groups. Results T2-visible lesion volumes did not differ among patient groups, but T2 lesions were more frequently located in the posterior periventricular regions in adult RRMS patients than in adult CIS and paediatric RRMS patients. Adult RRMS patients had a significantly higher lesion average mean diffusivity than paediatric RRMS patients. No DT MRI changes in the NA tissues were found in paediatric and adult CIS patients. DT MRI abnormalities were limited to the NAWM in paediatric RRMS patients, while they involved the NAWM and GM in adult RRMS patients. The extent of NAWM involvement was similar between adult and paediatric RRMS patients and was significantly correlated with T2-visible lesion burden. Conclusions A less severe intrinsic lesion damage, a less frequent lesion occurrence in the posterior periventricular WM and the sparing of GM may help to explain the favourable short-/medium-term disease outcome of paediatric MS.

We evaluated the functional magnetic resonance imaging (fMRI) correlates of simple movement performance in patients with pediatric multiple sclerosis (MS) and their relation with the extent of T2 lesion volume (LV), to improve our understanding of the mechanisms leading to their short/medium term favorable clinical course. We obtained fMRI during repetitive flexion‐extension of the last four fingers of the right hand and brain dual‐echo scans from 17 right‐handed patients with pediatric relapsing‐remitting MS and 9 sex‐ and age‐matched right‐handed healthy controls. T2 LV was measured using a local thresholding segmentation technique. fMRI activations and functional connectivity analysis were performed using SPM2. Compared to controls, pediatric MS patients had an increased recruitment of the left (L) primary sensorimotor cortex (SMC). They also showed reduced functional connectivity between the L primary SMC and the L thalamus (P = 0.03), the L insula and the L secondary sensorimotor cortex (SII) (P = 0.02), the supplementary motor area and the L SII (P = 0.02), the L thalamus and the L insula (P = 0.01) and the L thalamus and the L SII (P = 0.003). In patients with pediatric MS, the activity of the L primary SMC was significantly correlated with brain T2 LV (r = 0.78). No correlation was found between coefficients of abnormal connectivity and structural MRI measures. The maintenance of a selective and strictly lateralized pattern of movement‐associated brain activations and a modulation of its functional connections suggest a preserved functional reserve in patients with pediatric MS, which, in turn, might contribute to explain their favorable clinical evolution at short/medium term. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

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. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

The objective of this study was to assess the functional and structural substrates of cognitive network changes in patients with benign multiple sclerosis (BMS), using an analysis of effective connectivity and MR tractography. Using a 3-Tesla scanner, we acquired dual-echo, diffusion tensor (DT) and functional MRI during the performance of the Stroop task from 15 BMS patients and 19 healthy controls. DT MRI tractography was used to calculate DT derived metrics from several white matter (WM) fiber bundles, thought to be involved in cognitive performance. DT MRI metrics from WM fiber bundles not directly related with cognitive performance were also derived. Effective connectivity analysis was performed using statistical parametric mapping. MS patients had significantly abnormal DT MRI metrics in all the structures analyzed. Compared with controls, MS patients had more significant activations of several areas of the cognitive network involved in Stroop performance, bilaterally. Compared with controls, BMS patients also had increased connectivity strengths between several cortical areas of the sensorimotor network and the right (R) inferior frontal gyros and the R cerebellum, as well as decreased connectivity strengths with the anterior cingulate cortex. Coefficients of altered connectivity were moderately correlated with structural MRI metrics of tissue damage within intra- and inter-hemispheric cognitive-related WM fiber bundles, while no correlations were found with the remaining fiber bundles studied, suggesting that functional cortical changes in patients with BMS might represent an adaptive response driven by damage of specific WM structures. Hum Brain Mapp 30:276-290, 2009. (c) 2007 Wiley-Liss, Inc.