Abnormal cervical cord function contributes to fatigue in multiple sclerosis.

UNLABELLED: BACKGROUND/OBJECTIVE We aimed to investigate whether cervical cord damage and dysfunction is associated with the presence and severity of fatigue in multiple sclerosis (MS) using a multiparametric magnetic resonance (MR) approach. METHODS: Cervical cord functional magnetic resonance imaging (fMRI) during a tactile stimulation of the right hand, and structural brain and cord MRI were acquired from 20 controls, 15 MS patients without fatigue (NF) and 20 MS patients with fatigue (F). Between-group differences in the extent of focal lesions and diffusivity abnormalities in the brain and cord, cord-normalized cross-sectional area (CSAn) and fMRI activity were assessed. RESULTS: All structural MRI measures differed significantly among groups, except for cord lesion number and CSAn. Compared with controls, NF-MS patients experienced higher cord recruitment (p=0.04). Compared with F-MS, NF-MS patients had a lower brain normal-appearing white matter average fractional anisotropy (p=0.001) and increased cord recruitment (p=0.02). In patients with MS, the extent of cord recruitment was correlated with the severity of fatigue (r=-0.34, p=0.04). Compared with the other two groups, F-MS patients had a more diffuse recruitment of cord quadrants on the axial and longitudinal planes. CONCLUSIONS: Abnormalities of function, but not of structure, of the cervical cord are likely to contribute to the pathogenesis of fatigue in MS.

Sensorimotor functional connectivity changes in amyotrophic lateral sclerosis.

We investigated whether the functional connections to the primary sensorimotor cortex (SMC) at rest are abnormal in 26 patients with amyotrophic lateral sclerosis (ALS) and whether such changes are related to the corticospinal tract (CST) damage, measured using diffusion tensor magnetic resonance imaging (DT MRI). ALS patients versus controls showed a significantly increased functional connectivity between the left SMC and the right cingulate cortex, parahippocampal gyrus, and cerebellum-crus II. No right SMC connectivity changes were found. The pattern of increased functional connectivity to the left SMC was more widespread when considering only patients with no CST DT MRI abnormalities than the whole group of patients. In this patient group, functional connectivity was also increased between the right SMC and the right parahippocampal gyrus. On the contrary, in ALS patients with CST damage (as assessed using DT MRI) versus controls, functional connectivity was increased between the left SMC and the right cingulate cortex only, while it was decreased between the right SMC and the right cerebellum-lobule VI. In ALS patients, disease severity correlated with reduced SMC functional connectivity. Functional brain changes do occur in ALS with mild disability. These changes might have a role in compensating for (limited) structural damage and might exhaust with increasing burden of disease pathology.

Cervical cord functional MRI changes in relapse-onset MS patients.

OBJECTIVE: To investigate whether (1) the tactile-associated cord functional MRI (fMRI) changes vary in the different clinical stages of relapse-onset multiple sclerosis (MS), and (2) the pattern of cord fMRI changes relates to severity of MS clinical disability. METHODS: Cervical cord fMRI was acquired from 49 MS patients (30 relapsing-remitting (RR), 19 secondary progressive (SP)), and 19 controls, during a tactile stimulation of the right hand. Task-related cord mean signal change and occurrence of fMRI activity at each cord quadrant and level were measured. MRI quantities were compared between groups using an univariate analysis. Between-group differences in topographical distribution of fMRI activity were evaluated using random-effect logistic regression models. RESULTS: Compared with controls, both RRMS (p=0.05) and secondary progressive multiple sclerosis (p=0.02) patients showed a higher cord fMRI activity, whereas no difference was found between patient groups. Severely disabled patients (26/49) showed a cord overactivation relative to controls (p=0.004) and patients with mild disability (p=0.04). Both controls and MS patients showed a functional lateralisation of cord activity, which was predominant in the cord side ipsilateral to the stimulus, and a more frequent activation of the posterior than of the anterior cord quadrants. DISCUSSION: This study shows that tactile-associated cervical cord fMRI activity is increased in relapse-onset MS patients. Such an overactivation is more prominent in patients with more severe locomotor disability. This suggests that an abnormality of cord functional properties may be among the factors associated with the clinical status of MS patients.

In vivo assessment of cervical cord damage in MS patients: a longitudinal diffusion tensor MRI study.

Cervical cord damage is likely to contribute to the accumulation of disability in multiple sclerosis (MS) and can be quantified in vivo using MRI. We used conventional and diffusion tensor (DT) MRI to: (a) define the temporal evolution of intrinsic tissue injury and atrophy in the cervical cord from MS patients, (b) investigate how these two aspects of cord damage are interrelated and (c) assess the correlation of cord MRI metrics with concomitant brain damage and disability. Conventional and DT MRI of the brain and cervical cord were obtained from 42 MS patients and 9 healthy controls at baseline and after a mean follow-up of 2.4 years. At each time-point, we measured: cervical cord lesion number, cross-sectional area, mean diffusivity (MD) and fractional anisotropy (FA). Brain T2 lesion volume, grey matter MD, normal appearing white matter (NAWM) MD and FA, as well as longitudinal normalized percentage brain volume changes were also measured. In MS patients, cervical cord cross-sectional area (P < 0.001) and FA (P = 0.01) decreased, and cervical cord MD increased (P < 0.001) during follow-up. Cord FA decrease, but not cord cross-sectional area and MD, was significantly higher (P = 0.05) in primary progressive MS patients than in those with either relapsing-remitting or secondary progressive MS. At baseline and follow-up, moderate correlations were found between intrinsic cord diffusivity abnormalities and cord cross-sectional area (r values ranging from 0.34 to 0.58), but not between their changes over time. No cross-sectional and longitudinal correlations were found between these MRI metrics and the number of cord T2-visible lesions. Brain NAWM MD (P = 0.03) and brain volume (P < 0.001) also changed in patients. There was no significant correlation between cord and brain MRI metrics at both time-points, as well as between their changes occurred over the follow-up. Baseline cord cross-sectional area (r = -0.40, P = 0.01) and FA (r = -0.40, P = 0.03) correlated with increase in disability at follow-up. This study shows that both progressive tissue loss and injury to the remaining tissue occur in the cervical cord of MS patients, and that these two components of cord damage are not strictly interrelated, thus suggesting that a multiparametric MRI approach is needed to achieve more accurate estimates of such a damage. MS cord pathology also seems to be independent of concomitant brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual.

Identification of Chronic Active Multiple Sclerosis Lesions on 3T MRI.

BACKGROUND AND PURPOSE: MR imaging-pathologic studies have reported that paramagnetic rims on 7T susceptibility-based MR imaging identify, in vivo, the subset of MS lesions with compartmentalized inflammation at the lesion edge and associated remyelination failure. Here, we assessed the reliability of detecting these rims on high-resolution 3T phase images. MATERIALS AND METHODS: High-resolution T2* and phase MR imaging was collected in 20 patients with MS at 3T (3D segmented EPI, 0.65 mm3) and 7T (2D gradient-echo, 0.2 × 0.2 × 1 mm) MR imaging. In each case, 5 discrete chronic (nonenhancing) MS lesions were selected on T2 FLAIR images for rim evaluation. Five raters experienced in MS imaging contributed to the rim assessment, of whom 3 worked independently on 3T data, and 2, on 7T data. Consensus agreement was reached for both 3T and 7T rim evaluations. Discrepancies between 3T and 7T were discussed, and consensus was reached. RESULTS: Phase rims were seen in 34 lesions at 7T and in 36 lesions at 3T by consensus. Inter- and intrarater reliability were "substantial/good" both at 3T and 7T analysis (Cohen κ, >0.71). Based on consensus agreement, the reliability of rim visualization at 3T versus 7T was 0.78 (κ) with a pair-wise agreement of 90%. More lesions were judged to be false-positive or false-negative at 3T than at 7T. CONCLUSIONS: Nearly all 7T paramagnetic rims can also be seen at 3T. Imaging at 3T opens the possibility of implementing paramagnetic rims as an outcome measure in multicenter, MR imaging-based clinical trials aimed at treating perilesional persistent inflammation and its potential effects on remyelination.

Optimized T1-MPRAGE sequence for better visualization of spinal cord multiple sclerosis lesions at 3T.

BACKGROUND AND PURPOSE: Spinal cord lesions are highly prevalent in MS, and their visualization can help both in diagnosis and patient follow-up. However, the sensitivity of MR imaging to spinal cord lesions remains poor, primarily because of suboptimal contrast between lesions and a normal-appearing cord. Here, we propose an optimized 3D MPRAGE sequence for improved detection of MS lesions in the spinal cord at 3T. MATERIALS AND METHODS: Images were acquired by use of T2 FSE, STIR, T1-gradient recalled-echo (for T1 mapping), and T1-MPRAGE in the sagittal plane, and T2*-weighted scans in the axial plane, on 40 patients with MS and 7 healthy volunteers. Two observers qualitatively evaluated the images for lesion conspicuity. Lesions seen between the C1 and C4 segments in 10 randomly selected patients with MS were further evaluated quantitatively for contrast-to-noise ratio between the lesion and normal-appearing cord, and for lesion burden. RESULTS: Spinal cord lesions were more conspicuous on the optimized T1-MPRAGE sequence than on any other sequence tested. Detailed analysis revealed that lesions were almost 3 times more conspicuous (P < .01), and the total lesion volume was 2 times greater (P < .05, n=10), in the T1-MPRAGE sequence compared with the standard STIR sequence. Correlation of clinical disability (Expanded Disability Status Score) with lesion load from each sequence also demonstrated the importance of the improved lesion conspicuity with T1-MPRAGE. CONCLUSIONS: The optimized T1-MPRAGE sequence described here improves the reliability of lesion visualization and estimation of lesion burden, especially when used in conjunction with other well-established clinical sequences.

Future MRI tools in multiple sclerosis.

Magnetic resonance imaging (MRI) is extremely sensitive in detecting multiple sclerosis (MS)-related abnormalities. As a consequence, it has become an established tool to diagnose the disease and to monitor its evolution. In patients at presentation with clinically isolated syndromes suggestive of MS, MRI has been formally included in the diagnostic work up and ad hoc criteria have been proposed and are updated on a regular basis. However, in patients with definite MS, the strength of the relationship between conventional MRI findings and subsequent clinical manifestations of the disease remains modest. This is likely due to the relatively lack of specificity of conventional MRI to the heterogeneous pathological substrates of the disease and its inability to provide accurate estimates of such a damage outside focal lesions as well as to define the mechanisms through which the central nervous system recovers after tissue injury has occurred. Non-conventional MRI techniques offer new biomarkers more closely linked to the pathological features of the disease, which are likely to contribute to overcome, at least partially, these limitations. This review summarizes how MRI has improved our ability to diagnose MS and to predict its course, as well as how it is changing our understanding of the factors associated with the accumulation of irreversible disability in this condition.

Spatial normalization and regional assessment of cord atrophy: voxel-based analysis of cervical cord 3D T1-weighted images.

BACKGROUND AND PURPOSE: VBM is widely applied to characterize regional differences in brain volume among groups of subjects. The aim of this study was to develop and validate a method for voxelwise statistical analysis of cord volume and to test, with this method, the correlation between cord tissue loss and aging. MATERIALS AND METHODS: 3D T1-weighted scans of the spinal cord were acquired from 90 healthy subjects spanning several decades of life. Using an AS method, we outlined the cord surface and created output images reformatted with image planes perpendicular to the estimated cord centerline. Unfolded cervical cord images were coregistered into a common standard space, and smoothed cord binary masks, produced by using the cord outlines estimated by the AS approach, were used as input images for spatial statistics. RESULTS: High spatial correlation between normalized images was observed. Averaging of the normalized scans allowed the creation of a cervical cord template and of a standardized region-of-interest atlas. VBM analysis showed some significant associations between a decreased probability of cord tissue and aging. Results were robust across different smoothing levels, but the use of an anisotropic Gaussian kernel gave the optimal trade-off between spatial resolution and the requirements of the Gaussian random field theory. CONCLUSIONS: VBM analysis of the cervical cord was feasible and holds great promise for accurate localization of regional cord atrophy in several neurologic conditions.

Cortical lesions in children with multiple sclerosis.

OBJECTIVE: Double inversion recovery (DIR) sequences have improved the detection of cortical lesions (CLs) in adult patients with multiple sclerosis (MS). We evaluated the presence and frequency of CLs in pediatric patients with relapsing-remitting MS (RRMS) in comparison to adult patients with MS with the same clinical phenotype. METHODS: Using a 3.0-T scanner, brain DIR, dual-echo, and 3-dimensional T1-weighted scans were acquired from 24 pediatric patients with RRMS, 15 adult patients with RRMS, and 10 pediatric healthy controls. CLs and white matter (WM) lesions were identified, and their volumes measured. Brain gray matter and WM volumes were also calculated. Between-group comparisons were performed using χ(2), Mann-Whitney, and analysis of variance tests. Poisson regressions for count data were used to model the number of lesions of the 2 groups of patients. RESULTS: Compared to adults, pediatric patients had shorter disease duration and lower disability. WM lesion number and volume did not differ between pediatric and adult patients with MS. CLs were detected in 2 (8%) pediatric and 10 (66%) adult patients. Median CL volume was lower in pediatric than adult patients with RRMS (p = 0.0003). Regression analysis showed that pediatric patients had a lower number of CLs than adults (p = 0.0003), after adjusting for age, gender, Expanded Disability Status Scale score, and disease duration. CONCLUSION: CLs are rare in pediatric patients with MS. Since pediatric patients with MS have a clinical onset closer to the biological onset of the disease than adult patients with MS, our findings indicate that CL formation is likely not to be an initial event in this disease.

Overcoming the clinical-MR imaging paradox of multiple sclerosis: MR imaging data assessed with a random forest approach.

BACKGROUND AND PURPOSE: In MS, the relation between clinical and MR imaging measures is still suboptimal. We assessed the correlation of disability and specific impairment of the clinical functional system with overall and regional CNS damage in a large cohort of patients with MS with different clinical phenotypes by using a random forest approach. MATERIALS AND METHODS: Brain conventional MR imaging and DTI were performed in 172 patients with MS and 46 controls. Cervical cord MR imaging was performed in a subgroup of subjects. To evaluate whether MR imaging measures were able to correctly classify impairment in specific clinical domains, we performed a random forest analysis. RESULTS: Between-group differences were found for most of the MR imaging variables, which correlated significantly with clinical measures (r ranging from -0.57 to 0.55). The random forest analysis showed a high performance in identifying impaired versus unimpaired patients, with a global error between 7% (pyramidal functional system) and 31% (Ambulation Index) in the different outcomes considered. When considering the performance in the unimpaired and impaired groups, the random forest analysis showed a high performance in identifying patients with impaired sensory, cerebellar, and brain stem functions (error below 10%), while it performed poorly in defining impairment of visual and mental systems (error of 91% and 70%, respectively). In analyses with a good level of classification, for most functional systems, damage of the WM fiber bundles subserving their function, measured by using DTI tractography, had the highest classification power. CONCLUSIONS: Random forest analysis, especially if applied to DTI tractography data, is a valuable approach, which might contribute to overcoming the MS clinical-MR imaging paradox.

Default-mode network dysfunction and cognitive impairment in progressive MS.

OBJECTIVE: This study explores default-mode network (DMN) abnormalities in patients with secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) and whether such abnormalities correlate with cognitive impairment and damage to selected white matter (WM) fiber bundles, quantified using diffusion tensor (DT) MRI tractography. METHODS: Resting state (RS) functional MRI and DT MRI data were acquired from 33 patients with SPMS, 24 patients with PPMS, and 24 controls. Independent component analysis (ICA) was used to identify the DMN. SPM5 was used to assess within- and between-group activations. RESULTS: Between-group differences in DMN activity were found in the left medial prefrontal cortex (mPFC), left precentral gyrus (PcG), and anterior cingulate cortex (ACC). Compared to controls, patients with SPMS had reduced activity in the mPFC (p = 0.01) and PcG (p = 0.02), while patients with PPMS had reduced activity in the PcG (p = 0.008) and the ACC (p = 0.002). Compared to patients with PPMS, patients with SPMS had increased ACC activity (p = 0.04). Reduction of RS activity in the ACC was more pronounced in cognitively impaired vs cognitively preserved patients with MS (p = 0.02). In patients with MS, DMN abnormalities correlated with the PASAT and word list test scores (r values ranging from 0.35 to 0.45) and DT MRI changes in the corpus callosum and the cingulum (r values ranging from 0.82 to 0.87). CONCLUSION: These results suggest that a dysfunction of the anterior components of the default-mode network may be among the factors responsible for the accumulation of cognitive deficits in patients with progressive multiple sclerosis.

Evidence of thalamic gray matter loss in pediatric multiple sclerosis.

OBJECTIVE: We used voxel-based morphometry (VBM) to assess the pattern of regional gray matter (GM) loss in patients with pediatric multiple sclerosis (MS) and its relation with the Expanded Disability Status Scale (EDSS) score, disease duration, and the extent of T2 lesion load (LL). METHODS: From 28 patients with pediatric relapsing-remitting MS (16 girls; mean age = 14.4 years, range = 7 to 16 years) and 21 matched controls, dual-echo and three-dimensional T1-weighted magnetization prepared rapid acquisition gradient echo sequences were acquired. T2 LL was measured using a local thresholding segmentation technique. Data were analyzed using an optimized VBM analysis and statistical parametric mapping. RESULTS: In pediatric patients with MS, mean brain T2 LL was 7.8 mL +/- 11.3. Intracranial volume did not differ between patients and controls. Compared to controls, patients with pediatric MS had significant GM loss in the thalamus, bilaterally, which was significantly correlated with T2 LL (r = -0.80 for the right thalamus, r = -0.74 for the left thalamus, p < 0.05, corrected for multiple comparisons). No correlation was found between thalamic GM loss, disease duration, and disability. CONCLUSIONS: In patients with pediatric multiple sclerosis (MS), differently from what happens in adult-onset MS, gray matter (GM) atrophy seems to involve the thalamus only, with sparing of the cortex and other deep GM nuclei. The correlation found between atrophy and T2 lesion load suggests transsynaptic and Wallerian degenerations as the most likely substrate of tissue loss in the thalamus of these patients.

Altered functional and structural connectivities in patients with MS: a 3-T study.

OBJECTIVE: To determine the functional and structural substrates of motor network dysfunction in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Using a 3-T scanner, in 12 right-handed RRMS patients and 14 matched controls, we acquired diffusion tensor (DT) MRI and functional MRI during the performance of a simple motor task with the right (R) hand. Using DT MRI tractography, we calculated DT-derived metrics from several motor and nonmotor white matter (WM) fiber bundles. Functional connectivity analysis was performed using SPM2. RESULTS: Compared with control, MS patients had abnormal DT MRI metrics of all the WM bundles studied. Compared with controls, MS patients had more significant activations of the left (L) supplementary motor area (SMA), the L primary sensorimotor cortex (SMC), and the R cerebellum. They also had increased functional connectivity between the R primary SMC and the R cerebellum (p = 0.01) and the L SMA and the L primary SMC (p = 0.04). Coefficients of altered connectivity were correlated with structural MRI metrics of tissue damage of the corticospinal and the dentatorubrothalamic tract (r values ranging from -0.73 to 0.85). CONCLUSIONS: The correlations found between measures of functional connectivity and structural damage to some of the major brain motor white matter bundles suggest an adaptive role of functional connectivity changes in limiting the clinical consequences of structural damage in patients with relapsing-remitting multiple sclerosis. Combining measures of altered functional and structural connectivities of specific brain networks is a promising tool to elucidate the mechanisms responsible for clinical manifestations of CNS damage.