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In this paper, we present an automated approach for segmenting multiple sclerosis (MS) lesions from multi-modal brain magnetic resonance images. Our method is based on a deep end-to-end 2D convolutional neural network (CNN) for slice-based segmentation of 3D volumetric data. The proposed CNN includes a multi-branch downsampling path, which enables the network to encode information from multiple modalities separately. Multi-scale feature fusion blocks are proposed to combine feature maps from different modalities at different stages of the network. Then, multi-scale feature upsampling blocks are introduced to upsize combined feature maps to leverage information from lesion shape and location. We trained and tested the proposed model using orthogonal plane orientations of each 3D modality to exploit the contextual information in all directions. The proposed pipeline is evaluated on two different datasets: a private dataset including 37 MS patients and a publicly available dataset known as the ISBI 2015 longitudinal MS lesion segmentation challenge dataset, consisting of 14 MS patients. Considering the ISBI challenge, at the time of submission, our method was amongst the top performing solutions. On the private dataset, using the same array of performance metrics as in the ISBI challenge, the proposed approach shows high improvements in MS lesion segmentation compared with other publicly available tools., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The application of structural and functional magnetic resonance imaging (MRI) techniques in patients with multiple sclerosis (MS) has certainly helped to improve our understanding of the mechanisms responsible for clinical disability and cognitive impairment in this condition. The numerous studies performed in MS patients have also provided many lessons on the structure-function relationships in the human brain, which could be applied to healthy subjects and to patients affected by other neurological conditions. The findings have allowed a better understanding of the processes involved in the loss of function after central nervous system (CNS) damage, and clarified the substrates of specific symptoms (e.g., cognitive impairment and fatigue), which should aid clinical recovery and help in the monitoring of disease progression. In this review, important examples of how the application of different MRI techniques in MS might provide relevant information on the human brain are discussed. These include how damage to strategic white matter tracts can cause symptoms due to a disconnection mechanism and how involvement of a specific brain network, independent of the underlying pathological substrate, might determine certain symptoms. The role of functional and structural plasticity in clinical recovery (following an acute relapse or promoted by rehabilitation) and the mechanisms that might become the target of treatment aimed at function recovery are also considered. The ways in which network- and system-based analysis can reshape current understanding of the brain structure-function relationships are discussed. Finally, there is speculation about the relevance of inherited or acquired factors, such as age, comorbidity, brain reserve and cognitive reserve, which are likely to influence the relation between CNS damage and disease clinical manifestations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T 1 -, T 2 -, and T 2 ∗ -weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Purpose: In vivoidentification of white matter lesions plays a key-role in evaluation of patients with multiple sclerosis (MS). Automated lesion segmentation methods have been developed to substitute manual outlining, but evidence of their performance in multi-center investigations is lacking. In this work, five research-domain automated segmentation methods were evaluated using a multi-center MS dataset., Methods: 70 MS patients (median EDSS of 2.0 [range 0.0-6.5]) were included from a six-center dataset of the MAGNIMS Study Group (www.magnims.eu) which included 2D FLAIR and 3D T1 images with manual lesion segmentation as a reference. Automated lesion segmentations were produced using five algorithms: Cascade; Lesion Segmentation Toolbox (LST) with both the Lesion growth algorithm (LGA) and the Lesion prediction algorithm (LPA); Lesion-Topology preserving Anatomical Segmentation (Lesion-TOADS); and k-Nearest Neighbor with Tissue Type Priors (kNN-TTP). Main software parameters were optimized using a training set (N = 18), and formal testing was performed on the remaining patients (N = 52). To evaluate volumetric agreement with the reference segmentations, intraclass correlation coefficient (ICC) as well as mean difference in lesion volumes between the automated and reference segmentations were calculated. The Similarity Index (SI), False Positive (FP) volumes and False Negative (FN) volumes were used to examine spatial agreement. All analyses were repeated using a leave-one-center-out design to exclude the center of interest from the training phase to evaluate the performance of the method on 'unseen' center., Results: Compared to the reference mean lesion volume (4.85 ± 7.29 mL), the methods displayed a mean difference of 1.60 ± 4.83 (Cascade), 2.31 ± 7.66 (LGA), 0.44 ± 4.68 (LPA), 1.76 ± 4.17 (Lesion-TOADS) and -1.39 ± 4.10 mL (kNN-TTP). The ICCs were 0.755, 0.713, 0.851, 0.806 and 0.723, respectively. Spatial agreement with reference segmentations was higher for LPA (SI = 0.37 ± 0.23), Lesion-TOADS (SI = 0.35 ± 0.18) and kNN-TTP (SI = 0.44 ± 0.14) than for Cascade (SI = 0.26 ± 0.17) or LGA (SI = 0.31 ± 0.23). All methods showed highly similar results when used on data from a center not used in software parameter optimization., Conclusion: The performance of the methods in this multi-center MS dataset was moderate, but appeared to be robust even with new datasets from centers not included in training the automated methods., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

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 1 min. Using 3-D acquired T(1)-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 T(2)-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., (Copyright 2010 Elsevier Inc. All rights reserved.)

Longitudinal voxel-based morphometry studies have demonstrated morphological changes in cortical structures following motor and cognitive learning. In this study, we applied, for the first time, tensor-based morphometry (TBM) to assess the short-term structural brain gray matter (GM) changes associated with cognitive learning in healthy subjects. Using a 3 T scanner, a 3D T1-weighted sequence was acquired from 32 students at baseline and after two weeks. Students were separated into two groups: 13 defined as "students in cognitive training", who underwent a two-week cognitive learning period, and 19 "students not in cognitive training", who were not involved in any teaching activity. GM changes were assessed using TBM and statistical parametric mapping. Baseline regional GM volume did not differ between the two groups. At follow up, compared to "students not in cognitive training", the "students in cognitive training" had a significant GM volume increase in the dorsomedial frontal cortex, the orbitofrontal cortex, and the precuneus (p<0.001). These results suggest that cognitive learning results in short-term structural GM changes of neuronal networks of the human brain, which are known to be involved in cognition. This may have important implications for the development of rehabilitation strategies in patients with neurological diseases.

To assess regional grey matter (GM) changes in a large cohort of multiple sclerosis (MS) patients with different clinical phenotypes, using voxel-based morphometry (VBM) and their correlation with the extent of global and regional T2 lesion volumes (LV), we acquired conventional MRI scans from 71 MS patients with different clinical phenotypes (26 with relapsing-remitting [RR] MS, 27 with secondary progressive [SP] MS and 18 with primary progressive [PP] MS), 28 patients with a clinically isolated syndrome (CIS) suggestive of MS, and 21 controls. No GM loss was found in CIS patients. Compared to CIS patients, those with RRMS had a significant GM loss in the right pre and postcentral gyri. Compared to RRMS, SPMS patients had a significant GM loss in several regions of the fronto-parieto-temporo-occipital lobes, the cerebellum and superior and inferior colliculus, bilaterally, and deep GM structures. Compared to PPMS, SPMS patients had a significant GM loss in the postcentral gyrus, the cuneus, the middle occipital gyrus, the thalamus, the cerebellum, and the superior and inferior colliculus. In all MS groups, regional GM loss was strongly/moderately correlated with brain T2 LV. In SPMS and PPMS patients, a correlation was found between cortical regional GM loss and T2 LV of the corresponding or adjacent lobes. In MS patients, GM volume loss follows different patterns of regional distribution according to the clinical phenotype of the disease, is likely secondary to the presence and topography of focal WM inflammatory-demyelinating lesions, and is more evident in the progressive forms of the disease.

Although age-related effects on brain volume have been extensively investigated post mortem and in vivo using magnetic resonance imaging (MRI), regional and temporal patterns of white matter (WM) volume changes with aging are not defined yet. The aim of this study was to assess the topographical distribution of age-related WM volume changes using a recently developed voxel-based method to obtain estimates of WM fiber bundle volumes using diffusion tensor (DT) MRI. Brain conventional and DT MRI were obtained from 84 healthy subjects (mean age=44 years, range=13-70). Linear and non-linear relationships between age and WM fiber bundle volume changes were tested. A negative linear correlation was found between age and WM volume decline in the corona radiata, anterior cingulum, body and crus of the fornix and left superior cerebellar peduncle. A positive linear correlation was found between age and volume increase of the right deep temporal association fibers. The non-linear regression analysis also showed age-related changes of the genu of the corpus callosum and fitted better the volume changes of the right deep temporal association fibers. WM volume decline with age is unevenly distributed across brain regions. Our approach holds promise to gain additional information on the pathological changes associated to neurological disorders of the elderly.

We compared the global and regional distribution of white matter (WM) and gray matter (GM) damage and T2-visible lesion between patients with benign (B) and relapsing remitting (RR) multiple sclerosis (MS). BMS and RRMS patients did not differ in terms of global volumes and diffusion tensor (DT) MRI metrics of the WM and GM. Compared to controls, BMS and RRMS patients had bilateral thalamic loss. Compared to controls, BMS and RRMS patients had lower WM fractional anisotropy (FA) in the corpus callosum (CC) and in several regions of temporal and occipital lobes. BMS also had a decreased WM FA in the parietal lobes. RRMS patients had also lower WM FA in several regions of the frontal lobes. Compared to BMS, RRMS patients had decreased WM FA in the frontal lobes, while the opposite comparison showed lower WM FA in the CC, the temporal lobes and the cuneus in BMS. Contrasted to controls, both MS groups showed several regions of increased MD in WM and GM, but no difference was found between MS sub-groups. T2-visible lesions were mainly located in the posterior regions of the brain in BMS patients, while they involved also regions in the frontal lobes, in RRMS patients. BMS and RRMS patients differ in terms of the topographical distribution of WM damage rather than in the overall extent of brain structural changes. The less prominent involvement of the frontal lobe WM and of the NAWM in general in BMS might be associated to their favorable clinical status.

Using fMRI, an increased recruitment of the ipsilateral primary sensorimotor cortex (SMC), supplementary motor area, and middle frontal gyrus has been detected in patients with cervical cord myelitis of possible demyelinating origin. The aim of this study was to evaluate, using fMRI, whether the level of cord involvement influences cortical reorganization by comparing patients with isolated myelitis of the cervical and the dorsal portions of the cord, and to investigate whether the extent of cortical reorganization is associated with the extent of cervical cord pathology measured using magnetization transfer (MT) MRI. We studied 24 right-handed patients (14 with a previous involvement of the cervical cord and 10 with an involvement of the dorsal cord) in a chronic and clinically stable phase following an isolated myelitis of possible demyelinating origin and 15 sex- and age-matched healthy controls. During a single session, we obtained fMRI during repetitive flexion-extension of the last four fingers of the right and left hands and cervical cord MT MRI. Average cord MTR was lower in patients with cervical (P < 0.0001) and dorsal (P = 0.0001) myelitis than in controls. Compared to controls and for both tasks, patients with myelitis had an increased recruitment of the ipsilateral primary SMC, which was independent of the level of cord involvement. On the contrary, patients with cervical myelitis had a more widespread recruitment of frontal and parietal regions, whereas those with dorsal myelitis had a more widespread recruitment of temporal and cerebellar regions. Strong correlations (r values ranging from -0.72 to -0.88) were found between relative activations of cortical areas and the severity of cervical cord damage. Patients with isolated myelitis have different patterns of movement-associated cortical activations according to the level of cord involvement. This "level-dependent" functional reorganization of the cortex is likely to have an adaptive role in limiting the clinical outcome of cord damage and should be considered when designing rehabilitation strategies for these patients.

Functional cortical changes have been demonstrated in patients with several neurological conditions, including stroke, tumors and MS. The correlation found between the extent of fMRI activations and the extent and severity of brain structural damage suggests an adaptive role of these functional changes. In this study, we assess, using fMRI, the brain pattern of movement-associated cortical activations in neuropsychiatric systemic lupus erythematosus (NPSLE) patients and investigate whether the extent of cortical reorganization is associated with the extent of brain pathology, measured on dual-echo and diffusion tensor (DT) MR images. From 14 right-handed NPSLE patients and 14 matched controls, we obtained: (a) fMRI during the performance of repetitive flexion-extension of the last four fingers of the right hand; (b) dual-echo and (c) pulsed-gradient spin-echo echo-planar sequence to calculate DT MRI maps of the normal-appearing white (NAWM) and gray (NAGM) matter. Brain T2-visible abnormalities were detected in 11 NPSLE patients. Compared with controls, NPSLE patients had significantly higher NAWM fractional anisotropy histogram peak height (P = 0.005), and more significant activations of the contralateral primary sensorimotor cortex, putamen and dentate nucleus. They also had more significant activations of several regions located in the frontal and parietal lobes as well as of MT/V5 and the middle occipital gyrus, bilaterally. Strong correlations (r values ranging from 0.79 to 0.87) were found between relative activations of sensorimotor areas and the extent and severity of brain damage. Movement-associated functional cortical changes do occur in patients with NPSLE and might contribute to the maintenance of their normal functional capacities.

The spinal cord is frequently involved in multiple sclerosis (MS), and cord damage may be an important contributor to disability. Diffusion tensor magnetic resonance imaging (DT-MRI) provides quantitative information about the structural and orientational features of the central nervous system. In order to assess whether diffusion tensor-derived measures of cord tissue damage are related to clinical disability, mean diffusivity (MD) and fractional anisotropy (FA) histograms from the cervical cord were acquired from a large cohort of MS patients. Diffusion-weighted sensitivity-encoded (SENSE) echo planar images of the cervical cord, and brain dual-echo and diffusion-weighted scans were acquired from 44 patients with MS and 17 healthy controls. Cord and brain MD and FA histograms were produced. An analysis of variance model, adjusting for cord volume and patient age, was used to compare cord DT-MRI parameters from controls and patients. A multivariate linear regression model was used to identify DT-MRI variables independently associated with disability. Average cervical cord FA was significantly lower in MS patients compared to controls. Cord cross-sectional area, average FA and average MD were all significantly correlated with the degree of disability (r values ranging from 0.36 to 0.51). The multivariate linear regression model retained average cord FA and average brain MD as variables independently associated with disability, with a correlation coefficient of 0.73 (P < 0.001). DT-MRI reveals a loss of cervical cord tissue structure in MS patients. The strong correlation found between a composite DT-MRI score and disability suggests that a full and accurate assessment of cervical cord damage in MS provides information that usefully contributes to an explanation of the clinical manifestations of the disease.

The aim of this study was to investigate whether neurological symptoms related to a specific axonal fiber tract in brain white matter were associated with a higher degree of tissue damage in that region, in patients at presentation with clinically isolated syndromes (CIS) suggestive of multiple sclerosis. To this end, a magnetic resonance imaging (MRI) method to segment and evaluate the fiber bundle of interest was implemented, taking care to circumvent the problems caused by pathology. Diffusion tensor (DT) MRI tractography was used to construct, from healthy volunteer data, a probability map for the pyramidal tract (PYT), and this map was applied to patients to calculate DT-derived metrics inside the PYT. In CIS patients with clinical symptoms related to motor function, the DT-derived mean diffusivity and the lesion volume in the PYT were found to be increased, while the fractional anisotropy was no different, when compared to those patients without motor symptoms. These results may be explained by several microstructural changes in the damaged tissue, such as changes in the permeability of axonal cell membranes, decreases of axonal density and edema. The approach taken to analyze a specific fiber tract was possible because the axons in the tract have a high orientational coherence, allowing tissue structure changes to be isolated from the tissue architecture. Its extension to other white matter fiber bundles is therefore limited to bundles with high orientational coherence.

Cortical functional changes, with the potential to limit the functional consequences of tissue injury, have been shown in patients with multiple sclerosis (MS). In this study, we assessed the influence of MS-related tissue damage of the brain portion of the left pyramidal tract on the corresponding movement-associated patterns of cortical recruitment in a large sample of MS patients when performing a simple motor task with their fully normal functioning right upper limbs. We investigated 76 right-handed patients with definite MS. In each subject, functional magnetic resonance imaging (fMRI) was acquired during the performance of a simple motor task with the dominant, right upper limb. During the same session, dual-echo, magnetization transfer (MT) and diffusion tensor (DT) MRI sequences were also obtained to quantify the extent and the severity of pyramidal tract damage. Lesions along the left pyramidal tract were identified in 43 patients. Compared to patients without pyramidal tract lesions, patients with such lesions had more significant activations of the contralateral primary sensorimotor cortex (SMC), secondary sensorimotor cortex (SII), inferior central sulcus, and cingulate motor area (CMA). They also showed more significant activations of several regions of the ipsilateral hemisphere, including the primary SMC and the precuneus. In these patients, T2 lesion load of left pyramidal tract was correlated with the extent of activation of the contralateral primary SMC (r2 = 0.25, P < 0.0001), whereas no correlations were found between the extent of fMRI activations and the severity of intrinsic lesion damage, as well as with left pyramidal tract normal-appearing white matter damage. This study shows that, in patients with MS, following injury of the motor pathways, there is an increased recruitment of a widespread sensorimotor network, which is likely to contribute to limit the appearance of overt clinical deficits.

Movement-associated cortical changes have been shown in several neurological conditions and were found to be associated to the extent of brain and cord damage. Devic's neuromyelitis optica (DNO) is characterized by a severe involvement of the cord and optic nerve, with sparing of the brain. To assess the actual role of cord pathology on the pattern of movement-associated cortical recruitment, we obtained functional magnetic resonance imaging (fMRI) from patients with DNO and investigated whether the extent of brain activation is correlated with the extent of cervical cord damage. We studied 10 right-handed DNO patients and 15 sex- and age-matched healthy controls. The MRI assessment consisted of the following: (a) fMRI during repetitive flexion extension of the last four fingers of the right and left hand, (b) brain and cervical cord conventional MRI, and (c) cervical cord magnetization transfer (MT) MRI. Compared to controls and for both tasks, DNO patients had an increased recruitment of several regions of the sensorimotor network (primary sensorimotor cortex, postcentral gyrus, middle frontal gyrus, rolandic operculum, secondary sensorimotor cortex, precuneus, and cerebellum) and of several other regions mainly in the temporal and occipital lobes, such as MT/V5, the fusiform gyrus, the cuneus, and the parahippocampal gyrus. For both tasks, strong correlations (r values ranging from -0.76 to -0.85) were found between relative activations of cortical sensorimotor areas and the severity of cervical cord damage. This study shows an abnormal pattern of movement-associated cortical activations in patients with DNO, which extends beyond the 'classical' sensorimotor network and also involves visual areas devoted to motion processing. The correlation found between fMRI changes and the extent of cord damage suggests that such functional cortical changes might have an adaptive role in limiting the clinical outcome of DNO structural pathology.

Previous functional magnetic resonance imaging (fMRI) studies of simple motor tasks have shown that in patients with multiple sclerosis (MS), there is an increased recruitment of several regions part of a complex sensorimotor network. These studies have suggested that this might be the case because patients tend to activate, when performing a simple motor task, regions that are usually activated in healthy subjects during the performance of more complex tasks due to the presence of subcortical structural damage. In this study, we tested this hypothesis by comparing the patterns of cortical activations during the performance of two tasks with different levels of complexity from 16 MS patients and 16 age- and sex-matched controls. The first task (simple) consisted of flexion-extension of the last four fingers of the right hand, and the second task (complex) consisted of object manipulation. During the simple task, MS patients had, when compared to controls, more significant activations of the supplementary motor area (SMA), secondary sensorimotor area, posterior lobe of the cerebellum, superior parietal gyrus (SPG), and inferior frontal gyrus (IFG). These three latter regions are part of a fronto-parietal circuit, whose activation occurs typically in the contralateral hemisphere of healthy subjects during object manipulation, as shown also by the present study. During the performance of the complex task, MS patients showed an increased bilateral recruitment of several areas of the fronto-parietal circuit associated with object manipulation, as well of several other areas, which were mainly in the frontal lobes. This study confirms that some of the regions that are activated by MS patients during the performance of simple motor tasks are part of more complex pathways, recruited by healthy subjects when more complex and difficult tasks have to be performed.

Although several functional magnetic resonance imaging (fMRI) studies have shown adaptive cortical changes in patients with early multiple sclerosis (MS), the presence of brain plasticity and its role in limiting the functional consequences of brain tissue damage in patients with secondary progressive (SP) MS have not been fully investigated yet. In this study, we assessed the movement-associated brain pattern of cortical activations in patients with SPMS and investigated whether the extent of cortical brain activations is correlated with the extent of brain structural changes. From 13 right-handed SPMS patients and 15 sex- and age-matched healthy volunteers, we obtained: (a) brain dual-echo scans; (b) brain mean diffusivity and fractional anisotropy maps of the normal-appearing white (NAWM) and gray matter (NAGM); (c) fMRI during the performance of simple motor tasks [flexion-extension of the last four fingers of the right hand (task 1) and flexion-extension of the right foot (task 2)]. Compared to healthy volunteers, during task 1 performance, SPMS patients showed more significant activations of the ipsilateral inferior frontal gyrus, middle frontal gyrus, bilaterally, and contralateral intraparietal sulcus. During task 2 performance, SPMS patients had more significant activations of the contralateral primary sensorimotor cortex and thalamus and of the ipsilateral upper bank of sylvian fessure. For both tasks, strong correlations (r values ranging from -0.83 to 0.88) were found between relative activations of cortical areas of the motor network and the severity of structural changes of the NAWM and NAGM. This study demonstrates that cortical plasticity does occur in patients with SPMS and that it might have a role in limiting the clinical impact of MS-related damage. It also suggests that, in these patients, functional abilities are sustained by increased recruitment of highly specialized cortical areas.

Recent functional magnetic resonance imaging (fMRI) work has suggested that cortical reorganisation might have an adaptive role in limiting the clinical impact of multiple sclerosis (MS) structural damage. In this study, we investigated whether, in patients with MS, the presence and extent of structural damage of the normal-appearing brain tissue are associated with the extent of the movement-associated pattern of cortical activations. Using fMRI and a general search method, we assessed the patterns of brain activations associated with simple motor tasks in 12 right-handed patients with clinically definite MS and nonspecific T2-weighted abnormalities on conventional MRI scans of the brain and compared them with those from 12 sex- and age-matched right- handed healthy controls. Also investigated were the extent to which the fMRI changes correlated with normal-appearing white matter and grey matter (GM) pathology, measured using diffusion tensor MRI. When performing the simple motor task with the dominant hand, MS patients had more significant activations of the ipsilateral supplementary motor area (SMA), the ipsilateral superior frontal sulcus, the contralateral superior temporal gyrus, and the thalamus than controls. On the contrary, healthy subjects showed more significant activations of the medial part of the contralateral parieto-occipital fissure and the ipsilateral primary sensorimotor cortex (SMC) than patients with MS. In patients with MS, the relative activation of the ipsilateral SMA was correlated with the peak height (r = -0.88, P < 0.001) and position (r = 0.87, P < 0.001) of the GM mean diffusivity histogram. This study shows that cortical reorganisation occurs over a rather distributed sensorimotor network even in patients with MS and nonspecific abnormalities on conventional brain MRI scans. This suggests that, in patients with MS, an increased recruitment of movement-associated cortical network can be elicited by the presence of normal-appearing tissue pathology, which is independent of macroscopic T2-weighted abnormalities.

Previous work has suggested that functional reorganization of cortical areas might have a role in limiting the clinical impact of axonal pathology in patients with established multiple sclerosis (MS). Since there is evidence for irreversible tissue damage even in patients with early MS, we assessed, using functional MRI (fMRI) and a general search method, the brain pattern of movement-associated cortical activations in patients at presentation with clinically isolated syndromes (CIS) suggestive of MS. To elucidate the role of cortical reorganization in these patients, we also investigated the extent to which the fMRI changes correlated with the extent of overall axonal injury of the brain. From 16 right-handed patients at presentation with CIS and 15 right-handed, age- and sex-matched healthy volunteers, we obtained: (1). fMRI (repetitive flexion-extension of the last four fingers of the right hand), (2). conventional MRI scans, and (3). a new, unlocalized proton MR spectroscopy ((1)HMRS) sequence to measure the concentration of N-acetylaspartate of the whole brain (WBNAA). Compared to controls, patients with CIS had more significant activations of the contralateral primary somatomotor cortex (SMC), secondary somatosensory cortex, and inferior frontal gyrus. They also had significant decreased WBNAA concentration. Relative activation of the contralateral primary SMC was strongly correlated with WBNAA levels (r = -0.78, P < 0.001). This study shows that axonal pathology and functional cortical changes over a rather distributed sensorimotor network occur in patients at presentation with CIS suggestive of MS and that these two aspects of the disease are strictly correlated. This suggests that the increased functional recruitment of the cortex in these patients might have an adaptive role in limiting the clinical impact of irreversible tissue damage.

Although it is accepted that functional changes of the cortex can occur in patients with white matter diseases of the brain and might have an adaptive role in limiting the clinical consequences of subcortical injury, the pathological substrates able to elicit such cortical changes are still unknown. This multiparametric magnetic resonance study of a patient with an early diagnosis of subacute combined degeneration suggests that demyelination alone does not necessarily induce adaptive functional changes of the cerebral cortex.

In patients with primary progressive multiple sclerosis (PPMS), we investigated whether brain and cervical cord structural changes in lesions and normal-appearing brain tissue (NABT), measured using conventional, magnetization transfer (MT), and diffusion tensor (DT) MRI, are correlated with movement-associated cortical activations measured using functional magnetic resonance imaging (fMRI). From 26 right-handed PPMS patients and 15 right-handed, sex- and age-matched healthy controls, we obtained: (a) brain and cervical cord dual-echo scans and MT ratio (MTR) maps; (b) brain mean diffusivity (D(-)) maps, and (c) f-MRI (flexion-extension of the last four fingers of the right hand). All PPMS patients had no previous symptoms affecting their right upper limbs, which were functionally normal. Healthy volunteers showed more significant activation in the ipsilateral cerebellar hemisphere than PPMS patients. PPMS patients showed greater activation bilaterally in the superior temporal gyrus, ipsilaterally in the middle frontal gyrus, and, contralaterally in the insula/claustrum. In PPMS patients, moderate to strong correlations (r values ranging from 0.59 to 0.68) were found between relative activations of cortical areas located in a widespread network for sensory-motor and multimodal integration and the severity of structural changes of the NABT (as measured using MT and DT MRI) and the severity of cervical cord damage (as measured using MT MRI). This study shows that the pattern of cortical activation of PPMS patients is different from that of normal controls even when performing a motor task with clinically unaffected limbs. It also suggests that cortical reorganization might be able to limit the consequences of MS injury in the brain and cervical cord., (©2002 Elsevier Science (USA).)

Although fatigue is a common and troublesome symptom of multiple sclerosis (MS), its pathogenesis is poorly understood. In this study, we used functional magnetic resonance imaging (fMRI) to test whether a different pattern of movement-associated cortical and subcortical activations might contribute to the development of fatigue in patients with MS. We obtained fMRI during the execution of a simple motor task with completely normally functioning hands from 15 MS patients with fatigue (F), 14 MS patients without fatigue (NF), and 15 sex- and age-matched healthy volunteers. F and NF MS patients were also matched for major clinical and MRI variables. FMRI data were analyzed using statistical parametric mapping. In all patients, severity of fatigue was rated using the Fatigue Severity Scale (FSS). Compared to healthy subjects, MS patients showed more significant activations of the contralateral primary somatomotor cortex, the contralateral ascending limb of the Sylvian fissure, the contralateral intraparietal sulcus (IPS), the contralateral supplementary motor area, and the ipsilateral and contralateral cingulate motor area (CMA). Compared to F MS patients, NF patients showed more significant activations of the ipsilateral cerebellar hemisphere, the ipsilateral rolandic operculum, the ipsilateral precuneus, the contralateral thalamus, and the contralateral middle frontal gyrus. In contrast, F MS patients had a more significant activation of the contralateral CMA. Significant inverse correlations were found between FSS scores and relative activations of the contralateral IPS (r = -0.63), ipsilateral rolandic operculum (r = -0.61), and thalamus (r = -0.62). This study provides additional evidence that fatigue in MS is related to impaired interactions between functionally related cortical and subcortical areas. It also suggests that fMRI might be a valuable tool to monitor the efficacy of treatment aimed at reducing MS-related fatigue., (©2002 Elsevier Science (USA).)