Showing papers by "Maria A. Rocca published in 2014"

Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS

Abstract: Objective: Based on the theories of brain reserve and cognitive reserve, we investigated whether larger maximal lifetime brain growth (MLBG) and/or greater lifetime intellectual enrichment protect against cognitive decline over time. Methods: Forty patients with multiple sclerosis (MS) underwent baseline and 4.5-year follow-up evaluations of cognitive efficiency (Symbol Digit Modalities Test, Paced Auditory Serial Addition Task) and memory (Selective Reminding Test, Spatial Recall Test). Baseline and follow-up MRIs quantified disease progression: percentage brain volume change (cerebral atrophy), percentage change in T2 lesion volume. MLBG (brain reserve) was estimated with intracranial volume; intellectual enrichment (cognitive reserve) was estimated with vocabulary. We performed repeated-measures analyses of covariance to investigate whether larger MLBG and/or greater intellectual enrichment moderate/attenuate cognitive decline over time, controlling for disease progression. Results: Patients with MS declined in cognitive efficiency and memory ( p p = 0.031, η p 2 = 0.122), with larger MLBG protecting against decline. MLBG did not moderate memory decline ( p = 0.234, η p 2 = 0.039). Intellectual enrichment moderated decline in cognitive efficiency ( p = 0.031, η p 2 = 0.126) and memory ( p = 0.037, η p 2 = 0.115), with greater intellectual enrichment protecting against decline. MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower vs higher MLBG and intellectual enrichment. Conclusion: We provide longitudinal support for theories of brain reserve and cognitive reserve in MS. Larger MLBG protects against decline in cognitive efficiency, and greater intellectual enrichment protects against decline in cognitive efficiency and memory. Consideration of these protective factors should improve prediction of future cognitive decline in patients with MS.

Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage

Abstract: Objective In A ssessment of Ora L L aquinimod in Pr E venting Pro GR ession in Multiple Scler O sis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod9s potential effects on inflammation and neurodegeneration. Methods 1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM. Results Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p Conclusions Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMS patients. Trial registration The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.

Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration

Abstract: Background:Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease.Objectives:The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS.Methods:Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups).Results:In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-catego...

Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis.

Abstract: Objectives:Involvement of selected central nervous system (CNS) regions has been associated with depression and fatigue in MS. We assessed whether specific regional patterns of lesion distribution ...

Regional but Not Global Brain Damage Contributes to Fatigue in Multiple Sclerosis

Abstract: This multiparametric MR study supports the central origin of fatigue in multiple sclerosis by showing that regional damage to specific brain areas, in terms of lesions on T2-weighted images, white matter (WM) microstructural abnormalities, and gray matter and WM atrophy, is associated to this disabling symptom.

Cognitive rehabilitation correlates with the functional connectivity of the anterior cingulate cortex in patients with multiple sclerosis.

Abstract: We investigated how resting state (RS) functional connectivity (FC) of the anterior cingulate cortex (ACC) correlates with cognitive rehabilitation in relapsing remitting multiple sclerosis (RRMS) patients. A neuropsychological assessment and RS fMRI at baseline and after 12 weeks were obtained from 20 RRMS patients, who were assigned randomly to undergo treatment (n = 10) (treatment group-TG), which entailed computer-assisted cognitive rehabilitation of attention/information processing and executive functions for 3 days/week, or not to receive any cognitive rehabilitation (n = 10) (control group-CG). Voxel-wise changes of ACC RS FC were assessed using SPM8. In both groups, at the two study time points, ACC activity was correlated with the bilateral middle and inferior frontal gyrus, basal ganglia, posterior cingulate cortex, cerebellum, precuneus, middle temporal gyrus, and inferior parietal lobule (IPL). At follow up, compared to baseline, the TG showed an increased FC of the ACC with the right middle frontal gyrus (MFG) and right IPL, while the CG showed a decreased FC of the ACC with the right cerebellum and right inferior temporal gyrus (ITG). A significant “treatment × time” interaction was found for the increased FC of the right IPL and for the decreased FC of the right ITG. In the TG only, significant correlations (p < 0.001) were found between improvement of PASAT performance and RS FC of the ACC with the right MFG (r = 0.88) and right IPL (r = 0.76). In MS, cognitive rehabilitation correlates with changes in RS FC of brain regions subserving the trained functions. fMRI might be useful to monitor rehabilitative strategies in MS.

Functional correlates of cognitive dysfunction in multiple sclerosis: A multicenter fMRI Study.

Abstract: In this multicenter study, we applied functional magnetic resonance imaging (fMRI) to define the functional correlates of cognitive dysfunction in patients with multiple sclerosis (MS). fMRI scans during the performance of the N-back task were acquired from 42 right-handed relapsing remitting (RR) MS patients and 52 sex-matched right-handed healthy controls, studied at six European sites using 3.0 Tesla scanners. Patients with at least two abnormal (<2 standard deviations from the normative values) neuropsychological tests at a standardized evaluation were considered cognitively impaired (CI). FMRI data were analyzed using the SPM8 software, modeling regions showing load-dependent activations/deactivations with increasing task difficulty. Twenty (47%) MS patients were CI. During the N-back load condition, compared to controls and CI patients, cognitively preserved (CP) patients had increased recruitment of the right dorsolateral prefrontal cortex. As a function of increasing task difficulty, CI MS patients had reduced activations of several areas located in the fronto-parieto-temporal lobes as well as reduced deactivations of regions which are part of the default mode network compared to the other two groups. Significant correlations were found between abnormal fMRI patterns of activations and deactivations and behavioral measures, cognitive performance, and brain T2 and T1 lesion volumes. This multicenter study supports the theory that a preserved fMRI activity of the frontal lobe is associated with a better cognitive profile in MS patients. It also indicates the feasibility of fMRI to monitor disease evolution and treatment effects in future studies.

Structural brain MRI abnormalities in pediatric patients with migraine

Abstract: Morphometric MRI studies in adult patients with migraine have consistently demonstrated atrophy of several gray matter (GM) regions involved in pain processing. We explored the regional distribution of GM and white matter (WM) abnormalities in pediatric patients with episodic migraine and their correlations with disease clinical manifestations. Using a 3.0 T scanner, brain T2-weighted and 3D T1-weighted scans were acquired from 12 pediatric migraine patients and 15 age-matched healthy controls. GM and WM volumetric abnormalities were estimated using voxel-based morphometry (p < 0.05, family-wise error corrected). Compared to controls, pediatric migraine patients experienced a significant GM atrophy of several regions of the frontal and temporal lobes which are part of the pain-processing network. They also had an increased volume of the right putamen. The left fusiform gyrus had an increased volume in patients with aura compared to patients without aura and controls, whereas it was significantly atrophied in patients without aura when compared to the other two groups. No abnormalities of WM volume were detected. In migraine patients, regional GM atrophy was not correlated with disease duration and attack frequency, whereas a negative correlation was found between increased volume of the putamen and disease duration (r = −0.95, p < 0.05). These results show that GM morphometric abnormalities do occur in pediatric patients with migraine. The presence of such abnormalities early in the disease course, and the absence of correlation with patient clinical characteristics suggest that they may represent a phenotypic biomarker of this condition.

Changes of brain resting state functional connectivity predict the persistence of cognitive rehabilitation effects in patients with multiple sclerosis.

Abstract: Objective:We investigated whether the efficacy of 12-week cognitive rehabilitation in MS patients persists six months after treatment termination and, together with resting state (RS) functional co...

Magnetic resonance outcome measures in multiple sclerosis trials: time to rethink?

Abstract: Purpose of reviewWe summarize MRI measures currently available to assess treatment efficacy and safety in multiple sclerosis (MS) clinical trials and discuss novel metrics that could enter the clinical arena in the near future.Recent findingsIn relapsing remitting MS, MRI measures of disease activit

Ultra-high-field MR imaging in multiple sclerosis

Abstract: In multiple sclerosis (MS), MRI is the most important paraclinical tool used to inform diagnosis and for monitoring disease evolution, either natural or modified by treatment. The increased availability of ultra-high-field magnets (7 Tesla or higher) gives rise to questions about the main benefits of and challenges for their use in patients with MS. The main advantages of ultra-highfield MRI are the improved signal-to-noise ratio, greater chemical shift dispersion, and improved contrast due to magnetic susceptibility variations, which lead to increased sensitivity to the heterogeneous pathological substrates of the disease. At present, ultra-high-field MRI is mainly used to improve our understanding of MS pathogenesis. This review discusses the main achievements that have so far come from the use of these scanners, which are: better visualisation of white matter lesions and their morphological characteristics; an improvement in the ability to visualise grey matter lesions and their exact location; the quantification of ‘novel’ metabolites which may have a role in axonal degeneration; and greater sensitivity to iron accumulation. The application of ultra-high-field systems in standard clinical practice is still some way off since their role in the diagnostic work-up of patients at presentation with clinically isolated syndromes, or in monitoring disease progression or treatment response in patients with definite MS, needs to be established. Additional challenges remain in the development of morphological, quantitative and functional imaging methods at these field strengths, techniques which may ultimately lead to novel biomarkers for monitoring disease evolution and treatment response.

Posterior brain damage and cognitive impairment in pediatric multiple sclerosis

Abstract: Objective: We combined structural and functional MRI to better understand the mechanisms responsible for cognitive impairment in pediatric patients with multiple sclerosis (MS). Methods: Brain dual-echo, diffusion tensor, 3D T1-weighted, and resting-state (RS) fMRI scans were acquired from 35 consecutive pediatric patients with MS and 16 sex- and age-matched healthy controls. Patients with abnormalities in ≥2 neuropsychological tests were classified as cognitively impaired. The regional distribution of white matter (WM) and gray matter (GM) damage was assessed using voxel-wise analyses. Default mode network (DMN) RS functional connectivity (FC) was also measured. Results: Sixteen patients (45%) were classified as cognitively impaired. Compared to cognitively preserved (CP) patients, cognitively impaired patients with MS had higher occurrence of T2 lesions as well as more severe damage to the WM and GM, as measured by atrophy and diffusivity abnormalities, in the posterior regions of the parietal lobes close to the midline (precuneus, posterior cingulum, and corpus callosum). Compared to the other study groups, they also showed reduced RS FC of the precuneus, whereas CP patients experienced an increased RS FC of the anterior cingulate cortex. A multivariable model identified diffusivity abnormalities of the cingulum and corpus callosum and RS FC of the precuneus as the covariates more strongly associated with cognitive impairment (C-index = 0.99). Conclusions: In pediatric patients with MS, cognitive dysfunction is associated with structural and functional abnormalities of the posterior core regions of the DMN. WM structural abnormalities co-occurring at this level are likely to be the substrate of such modifications.

Forceps minor damage and co-occurrence of depression and fatigue in multiple sclerosis.

Abstract: Objective:Using diffusion tensor magnetic resonance imaging (DT MRI), we analyzed the architectural integrity of the brain white matter (WM) from a large cohort of MS patients to identify the structural substrates of the concomitant presence of depression and fatigue.Methods:Brain dual-echo, 3D T1-weighted and DT MRI scans were acquired from 147 MS patients and 90 gender- and age-matched healthy controls (HCs). Patients were stratified by the presence of depression (92 depressed (D), 55 not depressed (nD)) and fatigue (81 fatigued (F), 66 not fatigued (nF)). Sixty-five patients had co-occurrence of depression and fatigue (DF). Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). Tract-specific analyses were run in brain WM tracts using standard-space templates.Results:Whole-brain voxel-wise analysis yielded no significant differences between patient subgroups. At tract-specific analysis, DF patients had reduced fractional anisotropy (FA)...

Relationship between Damage to the Cerebellar Peduncles and Clinical Disability in Multiple Sclerosis

Abstract: Compared with volumetric measures of lesions or cerebellar atrophy, measures of structural damage to the middle and superior cerebellar peduncles were more strictly related to impairment of ambulation and cerebellar and brainstem functional system scores, thus supporting the notion that the measurement of structural involvement of clinically relevant tracts by using quantitative MR techniques is a powerful strategy for improving the strength of the correlation between MR imaging and clinical measures in multiple sclerosis.

Determinants of iron accumulation in deep grey matter of multiple sclerosis patients

Abstract: Background:Iron accumulation in deep grey matter (GM) structures is a consistent finding in multiple sclerosis (MS) patients. This study focused on the identification of independent determinants of iron accumulation using R2* mapping.Subjects and methods:Ninety-seven MS patients and 81 healthy controls were included in this multicentre study. R2* mapping was performed on 3T MRI systems. R2*in deep GM was corrected for age and was related to disease duration, disability, T2 lesion load and brain volume.Results:Compared to controls, R2* was increased in all deep GM regions of MS patients except the globus pallidus and the substantia nigra. R2* increase was most pronounced in the progressive stage of the disease and independently predicted by disease duration and disability. Reduced cortical volume was not associated with iron accumulation in the deep GM with the exception of the substantia nigra and the red nucleus. In lesions, R2* was inversely correlated with disease duration and higher total lesion load....

Intranetwork and internetwork functional connectivity abnormalities in pediatric multiple sclerosis

Abstract: 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.

Insights from magnetic resonance imaging

Abstract: Recent years have witnessed impressive advancements in the use of magnetic resonance imaging (MRI) for the assessment of patients with multiple sclerosis (MS). Complementary to the clinical evaluation, conventional MRI (cMRI) provides crucial pieces of information for the diagnosis of MS, the understanding of its natural history, and monitoring the efficacy of experimental treatments. Measures derived from cMRI present clear advantages over the clinical assessment, including their more objective nature and an increased sensitivity to MS-related changes. However, the correlation between these measures and the clinical manifestations of the disease remains weak, and this can be explained, at least partially, by the limited ability of cMRI to characterize and quantify the heterogeneous features of MS pathology. Quantitative MR-based techniques have the potential to overcome the limitations of cMRI. Magnetization transfer MRI, diffusion-weighted and diffusion tensor MRI with fiber tractography, proton magnetic resonance spectroscopy, T1 and T2 relaxation time measurement, and functional MRI are contributing to elucidate the mechanisms that underlie injury, repair, and functional adaptation in patients with MS. All conventional and nonconventional MR techniques will benefit from the use of high-field MR systems (3.0T or more).

Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes:

Abstract: Background:Non-enhancing black holes (neBHs) are more common in multiple sclerosis (MS) patients with longer disease durations and progressive disease subtypes.Objective:Our aim was to analyse the ...

Multicenter R-2* Mapping in the Healthy Brain

Abstract: Purpose The relaxation rate constant has been suggested as a sensitive measure for iron accumulation The aim of this multi-center study was to assess the inter-scanner and inter-subject variability of mapping and to investigate the relationship between brain volume and in specific structures Methods mapping was performed in 81 healthy subjects in seven centers using different 3 T systems was calculated from a dual-echo gradient echo sequence and was assessed in several deep gray matter structures The inter-scanner and inter-subject variability of was calculated by means of the coefficient of variation before and after correcting for age Results Significant center effects were seen in some regions which get lost after age correction The coefficient of variation for the inter-center variability was much lower (<56%) than for the intra-subject variability (67%–117%) in the putamen and red nucleus scaled with cortical volume while in the globus pallidus and the substantia nigra was negatively associated with white matter volume Conclusion is a robust and reproducible measure in a multicenter setting provided that a standardized MRI protocol is used The relationship between iron concentration in deep gray matter and volume of specific brain compartments needs further investigation Magn Reson Med 71:1103–1107, 2014 © 2013 Wiley Periodicals, Inc

Brain connectivity abnormalities extend beyond the sensorimotor network in peripheral neuropathy.

Abstract: Objectives: To investigate, using resting state (RS) functional connectivity (FC), the selectivity of involvement of the sensorimotor network in patients with acquired (A) and with hereditary (H) peripheral neuropathies (PN) and the correlations of RS FC abnormalities with clinical impairment and structural brain damage. Temporal associations among RS networks were also explored. Experimental design: RS fMRI scans were acquired from 13 APN, 12 HPN, and 18 age- and sex-matched healthy controls. Independent component analysis and functional network connectivity were used to investigate RS FC within and among RS networks with potential functional relevance. Principal observations: Compared to controls, patients had a decreased FC of the right precentral gyrus and an increased RS FC of the precuneus within the sensorimotor network. Both decreased and increased RS FC also involved the visual and auditory networks, which additionally had an increased coherence of function with the sensorimotor network (more pronounced in HPN). RS FC modifications in patients extended to several cognitive networks and were correlated with disease duration. In APN, they were also correlated with the severity of clinical impairment and corpus callosum atrophy. Conclusions: In PN, RS FC modifications extend beyond the sensorimotor network and involve other sensory and cognitive networks. The correlations between RS FC patterns and disease duration in patients as well as with clinical impairment in patients with APN suggest that modifications of FC might reflect an adaptive mechanism, which takes time to occur and helps to limit the clinical consequences of peripheral damage. Hum Brain Mapp 35:513–526, 2014. © 2012 Wiley Periodicals, Inc.

KIR4.1: another misleading expectation in multiple sclerosis?

Abstract: www.thelancet.com/neurology Vol 13 August 2014 753 diabetes, hypertension, and depression, the question of when to intervene might be less relevant, because these disorders are already targets for treatment and prevention. In these cases, the question is whether we should and can do a better job with our treatments. Apart from timing of interventions, a question is whether prevention programmes should be population wide or target specifi c high-risk subgroups, as is now common in the prevention of cardiovascular disease. To target individuals at increased risk of Alzheimer’s disease, these individuals would need to be identifi ed at a very early stage, well before the disease process commences. In my view, a key message of the Article by Norton and colleagues is that maintaining mental health up to late life requires a lifespan perspective on prevention (fi gure). In their Article, Norton and colleagues show that Alzheimer’s disease, just like many other disorders in late life, is at least partially preventable and that several known risk factors for poor health also substantially contribute to dementia risk. In fact, the potential for prevention might be even larger if other modifi able risk factors for dementia (eg, diet and leisure activities) are considered. In this respect, encouragingly, population trends in longevity and health status already seem to be accompanied by a reduction in age-specifi c prevalence of dementia, possibly because of more intensive management of vascular risk factors over the past few decades. These latter fi ndings give hope that with the right approaches we can capitalise on the potential for dementia prevention.

Patterns of regional gray matter and white matter atrophy in cortical multiple sclerosis.

Abstract: We investigated the patterns of regional distribution of focal lesions, white matter (WM) and gray matter (GM) atrophy in patients with cortical (cort) MS in comparison to classical (c) MS patients. Nine cort-MS, nine c-MS and nine age-matched healthy controls (HC) underwent a brain MRI exam, including FLAIR and high-resolution T1-weighted scans. MS patients underwent neurological and neuropsychological assessment. Between-group differences of GM and WM volumes and their correlations with neuropsychological performances were assessed with voxel-based morphometry. FLAIR and T1 lesion probability maps (LPMs) were also obtained. Performance at neuropsychological tests was worse in cort-MS than in c-MS patients. Compared to HC, MS patients had a distributed pattern of GM and WM atrophy. No GM/WM area was more atrophic in c-MS vs cort-MS patients. Compared to c-MS, cort-MS patients experienced GM atrophy of frontal–temporal–parietal areas and cingulate cortex and WM atrophy of the cingulum bundle, bilateral cerebral peduncles, right inferior longitudinal fasciculus and left superior longitudinal fasciculus. FLAIR and T1 LPMs did not differ between c-MS vs cort-MS patients. A higher susceptibility to neurodegenerative processes in key brain regions known to be related to cognitive functions is likely to underlie the clinical manifestations of cort-MS.

Abnormalities of the Brain Functional Connectome in Pediatric Patients with Multiple Sclerosis (P3.336)

Abstract: OBJECTIVE: To investigate the functional organization of large-scale brain networks (connectome) in pediatric patients with multiple sclerosis (MS) using resting state functional MRI (RS fMRI) and graph theory. BACKGROUND: Distinct modifications of brain network topology have been identified during development and normal aging. DESIGN/METHODS: Fifty-two pediatric MS patients and 16 age- and sex-matched healthy controls were studied. Whole-brain networks were constructed using graph theory. The overall topology of functional brain connectivity was examined by computing the average network degree (D), clustering coefficient (C), characteristic path length (L), global and local efficiencies (E g and E l ) and assortativity. Between-group differences of global and local network connectivity metrics were investigated with a two-sample t-test. Brain regions were ranked according to their importance in explaining between-group differences by using the positive false-discovery rate method. RESULTS: Significant abnormalities of global network metrics in pediatric MS patients compared with controls were found only for the assortativity (p ranging from 0.008 to 0.04). However, there were trends (p ranging from 0.07 to 0.09 for all metrics) towards a decrease of D and E g , and an increase of L in pediatric MS patients vs controls. The bilateral middle cingulate cortex and middle temporal gyrus, right inferior temporal gyrus and bilateral cerebellum were hubs in both controls and pediatric MS patients. The right anterior cingulate cortex, bilateral thalamus and some occipital regions were hubs in controls only. Compared with controls, pediatric MS patients had a decreased nodal degree of several regions of the occipital and temporal lobes, the basal ganglia and the cerebellum. The bilateral thalamus, right cuneus, bilateral lingual gyrus, the left middle and superior occipital gyrus, and the bilateral cerebellum were ranked as the most important regions in explaining between-group differences. CONCLUSIONS: The global topology of functional network organization is relatively preserved in pediatric MS patients. Study Supported by: This study has been partially supported by a grant from Italian Ministry of Health (GR-2009-1529671) Disclosure: Dr. Filippi has received personal compensation for activities with Teva Neuroscience and Genmab AS as a member of scientific advisory boards, and Bayer Pharmaceuticals Corp. as a consultant. Dr. Filippi has received research support from Bayer Schering, Biogen Idec, Genmab AS, Merck Serono, Teva Neuroscience, the Italian Ministry of Health, and the Fondazione Italiana Sclerosi Mult. Dr. Valsasina has nothing to disclose. Dr. Sala has nothing to disclose. Dr. Martinelli has received personal compensation for activities with Biogen Idec, Merck Serono, and Bayer Schering. Dr. Ghezzi has received personal compensation for activities with Merck Serono, Teva Neuroscience, Biogen Idec, Bayer Schering, Novartis, and Actelion Pharmaceuticals. Dr. Veggiotti has nothing to disclose. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Novartis, Merck Serono, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, and Actellion. Dr. Rocca has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation.

EHMTI-0084. Resting state functional connectivity abnormalities in pediatric patients with migraine

Abstract: Previous resting state (RS) functional magnetic resonance imaging (fMRI) studies in adult patients with migraine have demonstrated abnormal functional connectivity (FC) of brain networks involved in pain processing, including the default mode (DMN), the salience (SN) and the executive control (ECN) network.

Thalamic Dysfunction Is Associated with Fatigue in Patients with Multiple Sclerosis: A Graph Theory Study (S13.003)

Abstract: OBJECTIVE: To explore abnormalities of large-scale brain networks (connectome) in patients with multiple sclerosis (MS) and fatigue, using resting state (RS) functional MRI (fMRI) and graph theory. BACKGROUND: Fatigue affects a large proportion of patients with MS. The definition of its physiopathology might contribute to develop tailored treatments. DESIGN/METHODS: Graph theoretical analysis was applied to RS fMRI data from 64 MS patients with fatigue (F) according to the Fatigue Severity Scale. As control groups, 60 MS patients without fatigue (NF) matched for disease duration and brain T2 lesion volume with F-MS patients and 59 gender and age-matched healthy controls (HC) were included. Functional connectivity between 116 cortical and subcortical brain regions was estimated using a bivariate correlation analysis. Small-worldness properties were tested by comparison with matched random networks. Hubs were defined as regions having either degree or betweeness centrality one standard deviation greater than network average. Between-group differences of global and local network metrics were investigated using ANOVA models. RESULTS: Small-worldness (i.e., high clustering and short paths) was verified in all study groups. All global network parameters were significantly altered in F-MS patients and NF-MS patients compared with HC, with no significant differences between F- and NF-MS patients. The cerebellum (right lobule VI and bilateral crus I), and bilateral middle and inferior temporal gyri were hubs in all study groups. F- and NF-MS patients lost hubs in the bilateral anterior cingulate cortex and cerebellar regions (lobule VII-VIII, crus II). F-MS patients also lost hubs in the thalami and middle cingulate cortex. Compared to HC, F- and NF-MS patients had a decreased degree in the bilateral caudate nucleus. F-MS patients also experienced a decreased degree in the bilateral thalamus. CONCLUSIONS: Fatigue in MS is related to a functional disruption of the thalamic connector, which should be the target of potential therapeutic interventions. Study Supported by: This study has been partially supported by a grant from Italian Ministry of Health (GR-2008-1138784). Disclosure: Dr. Filippi has received personal compensation for activities with Teva Neuroscience and Genmab AS as a member of scientific advisory boards, and Bayer Pharmaceuticals Corp. as a consultant. Dr. Filippi has received research support from Bayer Schering, Biogen Idec, Genmab AS, Merck Serono, Teva Neuroscience, the Italian Ministry of Health, and the Fondazione Italiana Sclerosi Mult. Dr. Valsasina has nothing to disclose. Dr. Bisecco has nothing to disclose. Dr. Meani has nothing to disclose. Dr. Parisi has nothing to disclose. Dr. Messina has nothing to disclose. Dr. Colombo has nothing to disclose. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Novartis, Merck Serono, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, and Actellion. Dr. Rocca has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation.

Regional Hippocampal Involvement in Paediatric Multiple Sclerosis: A Radial Mapping MR Study (P2.336)

Abstract: OBJECTIVE: To assess the patterns of global and regional hippocampal volume (HV) changes in paediatric multiple sclerosis (MS) patients, and their correlations with clinical, neuropsychological and MRI metrics. BACKGROUND: Hippocampal demyelination and neurodegeneration occur early in MS. DESIGN/METHODS: From 53 paediatric MS patients and 18 healthy controls (HC), brain dual-echo and 3DT1-weighted images were acquired. Global HV was computed using a manual tracing procedure. Regional HV changes were assessed using a radial mapping analysis. Patients with abnormal performance in 蠅2 tests of the Brief Neuropsychological Battery for Children were classified as cognitively impaired (CI). Global and regional HV changes were compared between groups and correlated with disease duration, EDSS, BRBC tests scores, T2- and T1-lesion volume (LV), normalized brain (NBV), gray matter (GMV) and white matter volumes (WMV). RESULTS: Global HV was reduced, bilaterally, in patients versus HC (p<0.001), but not significantly correlated with clinical and MRI measures. In patients, radial atrophy affected the cornu Ammonis (CA1), subiculum and dentate gyrus (DG) subfields of both hippocampi, mostly on the right side (p<0.001). Radial hypetrophy of the DG subfield was found in both hippocampi, mostly on the left side. Significant correlations were found between regional HV changes and clinical and MRI metrics. Twenty-one (39.6%) patients were CI. Global HV did not differ between CI versus CP MS patients. Compared to CP patients, CI ones had areas of radial atrophy of the subiculum and DG subfields of the right hippocampus (p<0.001). Significant correlations were found between regional HV changes and memory, attention and language abilities. CONCLUSIONS: Hippocampal subregions have a different vulnerability to MS-related damage, possibly reflecting differential susceptibility to inflammatory insults and neurodegenerative processes of the hippocampal subfields. These results support the feasibility of MR-based radial mapping for the development of reliable markers of disease progression in MS. Study Supported by: a grant from Italian Ministry of Health (GR-2009-1529671) Disclosure: Dr. Morelli has nothing to disclose. Dr. Rocca has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation. Dr. Pagani has nothing to disclose. Dr. Moiola has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., and Biogen Idec., Dr. Ghezzi has received personal compensation for activities with Merck Serono, Teva Neuroscience, Biogen Idec, Bayer Schering, Novartis, and Actelion Pharmaceuticals. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Novartis, Merck Serono, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, and Actellion. Dr. Filippi has received personal compensation for activities with Teva Neuroscience and Genmab AS as a member of scientific advisory boards, and Bayer Pharmaceuticals Corp. as a consultant. Dr. Filippi has received research support from Bayer Schering, Biogen Idec, Genmab AS, Merck Serono, Teva Neuroscience, the Italian Ministry of Health, and the Fondazione Italiana Sclerosi Mult.

A fMRI Graph Theory Study of the Effect of Gender and Aging on Topology of Functional Brain Networks (P6.310)

Abstract: OBJECTIVE: To analyze age- and gender-related effects on large-scale functional brain networks using a graph theory approach. BACKGROUND: Previous studies detected an association between aging and abnormal long- and short-range functional connectivities of the human brain. The combined effect of aging and gender on functional network measures has not been investigated yet. DESIGN/METHODS: Graph theoretical analysis was applied to resting state (RS) functional MRI data from 132 healthy controls (62 men and 70 women, mean age=40.6 years, range=8-84 years). The global topology of functional networks was examined by computing the average degree, clustering coefficient, characteristic path length, global and local efficiency, hierarchy and assortativity. Regional network properties, including the integrated degree and local efficiency of each network node, were also assessed. The effects of age, gender and “age x gender” interactions on global functional network measures were assessed by using linear regression models. Correlations between aging and regional network properties were assessed by using the Spearman’s Rank correlation coefficient. RESULTS: Significant age-related abnormalities (i.e., lower degree, clustering coefficient, local and global efficiency and hierarchy; and higher path length and assortativity) were detected in both genders. Males showed higher average network values than females. Both genders experienced a significant age-related decline of nodal degree and local efficiency of several regions of the frontal lobe (including the bilateral anterior cingulate cortex, middle and superior frontal gyrus, orbitofrontal cortex, precentral gyrus and supplementary motor area), temporal regions, posterior cingulate cortex/precuneus and deep gray matter nuclei. No significant “age x gender” interaction was found for global and regional network metrics. CONCLUSIONS: Age-related decline of functional network measures were detected in both genders. The effect of aging was more severe in regions of the frontal lobes and the basal ganglia than in the other brain areas. Gender does not influence such an altered network connectivity with aging. Study Supported by: Disclosure: Dr. Riccitelli has nothing to disclose. Dr. Rocca has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation. Dr. Valsasina has nothing to disclose. Dr. Meani has nothing to disclose. Dr. Agosta has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Sanofi-Aventis Pharmaceuticals Inc., and Serono Symposia International Foundation. Dr. Agosta has received personal compensation in an editorial capacity for the Journal of Neurology. Dr. Agosta has received research support from the Italian Ministry of Health, and Teva Neuroscience. Dr. Filippi has received personal compensation for activities with Teva Neuroscience and Genmab AS as a member of scientific advisory boards, and Bayer Pharmaceuticals Corp. as a consultant. Dr. Filippi has received research support from Bayer Schering, Biogen Idec, Genmab AS, Merck Serono, Teva Neuroscience, the Italian Ministry of Health, and the Fondazione Italiana Sclerosi Mult.

Functional Correlates of Impaired Working Memory in MS Patients: A Multicentre Study (P6.123)

Abstract: OBJECTIVE: To assess the functional MRI (fMRI) correlates of frontal lobe dysfunction in multiple sclerosis (MS) patients with and without cognitive impairment. Background. BACKGROUND: Cognitive impairment in MS seems to be associated with a disconnection between the frontal lobes and other regions subserving cognitive functioning. DESIGN/METHODS: This study was conducted at six European sites using 3.0 Tesla scanners. FMRI scans during a N-back task were acquired from 42 right-handed relapsing remitting (RR) MS patients and 52 sex-matched right-handed healthy controls (HC). MS patients underwent the Rao battery and the Wisconsin Card Sorting test. Patients with at least two abnormal tests were considered as cognitively impaired (CI). FMRI data were analysed modelling regions showing a load-dependent activation/deactivation with increasing task difficulty. FMRI activity was compared between HC and all MS, as well as between HC, cognitively preserved (CP) and CI patients. Correlations of fMRI activity with clinical, neuropsychological and conventional MRI variables were also assessed. RESULTS: Twenty-two MS patients were cognitively preserved (CP) and 20 (47%) were CI. Task-related activations/deactivations were found in similar regions for HC and MS. Compared to HC, MS showed a reduction of fMRI activity with increasing task difficulty in the bilateral parietal, left inferior frontal and left middle frontal regions. While CP showed fMRI patterns similar to those detected in HC, CI patients had a distributed reduced fMRI activity (in bilateral parietal and frontal regions, and in the bilateral insula) and fMRI deactivations (in the bilateral precuneus, posterior cingulate cortex and parahyppocampal gyrus) compared to HC and CP patients. A failure of activation of frontal regions was correlated with a longer disease duration, higher T2/T1-lesion volumes, lower Z-score of global cognitive, attention-executive and visual functions. CONCLUSIONS: This multicenter study support the theory that preserved fMRI activity of the frontal lobe is associated with a better cognitive profile in MS. Study Supported by: Disclosure: Dr. Bisecco has nothing to disclose. Dr. Rocca has received personal compensation for activities with Biogen Idec and Serono Symposia International Foundation. Dr. Valsasina has nothing to disclose. Dr. Abdel-Aziz has nothing to disclose. Dr. Barkhof has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Biogen Idec, Teva Neuroscience, Merck & Co. Inc., Novartis, Synthon BV, Janssen, Genzyme Inc., and Roche Diagnostics Corporation. Dr. Enzinger has received personal compensation for activities with Biogen Idec, Bayer Schering, Merck Serono and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Enzinger has received research support from Merck Serono and Biogen Idec. Dr. Fazekas has received personal compensation for activities with Biogen Idec, Merck Serono, and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Fazekas has received research support from Biogen Idec, and Merck Serono. Dr. Gallo has nothing to disclose. Dr. Hulst has nothing to disclose. Dr. Montalban has received personal compensation for activities with Bayer Pharmaceuticals Corp., BIogen Idec, EMD Serono, and Genente. Dr. Muhlert has nothing to disclose. Dr. Riccitelli has nothing to disclose. Dr. Rovira has received personal compensation for activities with Bayer Schering, Sanofi-Aventis Pharmaceuticals Inc., Bracco, Merck Serono, Teva Neurosciences, Novartis, and Biogen Idec. Dr. Rovira has received personal compensation in an editorial capacity for the American Journal of Neuroradiology, and Neuroradiology. Dr. Rovira has received research support from Bayer Schering. Dr. Tedeschi has received research support from Biogen Idec, Merck Serono, Sanofi-Aventis Pharmaceuticals Inc., and Novartis. Dr. Comi has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals Inc., Novartis, Merck Serono, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, and Actellion. Dr. Filippi has received personal compensation for activities with Teva Neuroscience and Genmab AS as a member of scientific advisory boards, and Bayer Pharmaceuticals Corp. as a consultant. Dr. Filippi has received research support from Bayer Schering, Biogen Idec, Genmab AS, Merck Serono, Teva Neuroscience, the Italian Ministry of Health, and the Fondazione Italiana Sclerosi Mult.

Imaging of Migraine and Vestibular Migraine

Abstract: In the past few years, the application of magnetic resonance imaging (MRI) techniques to study patients with migraine has changed our view of migraine from primarily a vascular disorder to a neurovascular disease and currently to a central nervous system (CNS) disorder. Abnormal function of key brain areas and networks, mainly involved in pain processing, has been shown to occur in the brain of migraineurs. Numerous studies demonstrated also relevant and diffuse structural abnormalities of the brain gray (GM) and white matter (WM). What is now established is that migraine is not simply a disease related to pain occurring intermittently, but a process that over time either affects the brain or acts on a predisposed brain that may have an underlying difference in function or structure. Given the fact that criteria for the diagnosis of vestibular migraine have been proposed only recently and the relative rarity of this condition, only a few studies have applied neuroimaging techniques in patients suffering of vestibular migraine. However, the potential of the use of these techniques, in the context of the current knowledge on migraine, will be discussed.