Dataset Information

Alterations in Functional and Structural Connectivity in Pediatric-Onset Multiple Sclerosis.

ABSTRACT:

Background

Reduced white matter (WM) integrity is a fundamental aspect of pediatric multiple sclerosis (MS), though relations to resting-state functional MRI (fMRI) connectivity remain unknown. The objective of this study was to relate diffusion-tensor imaging (DTI) measures of WM microstructural integrity to resting-state network (RSN) functional connectivity in pediatric-onset MS to test the hypothesis that abnormalities in RSN reflects changes in structural integrity.

Methods

This study enrolled 19 patients with pediatric-onset MS (mean age = 19, range 13-24 years, 14 female, mean disease duration = 65 months, mean age of disease onset = 13 years) and 16 age- and sex-matched healthy controls (HC). All subjects underwent 3.0T anatomical and functional MRI which included DTI and resting-state acquisitions. DTI processing was performed using Tract-Based Spatial Statistics (TBSS). RSNs were identified using Independent Components Analysis, and a dual regression technique was used to detect between-group differences in the functional connectivity of RSNs. Correlations were investigated between DTI measures and RSN connectivity.

Results

Lower fractional anisotropy (FA) was observed in the pediatric-onset MS group compared to HC group within the entire WM skeleton, and particularly the corpus callosum, posterior thalamic radiation, corona radiata and sagittal stratum (all p < .01, corrected). Relative to HCs, MS patients showed higher functional connectivity involving the anterior cingulate cortex and right precuneus of the default-mode network, as well as involving the anterior cingulate cortex and left middle frontal gyrus of the frontoparietal network (all p < .005 uncorrected, k?30 voxels). Higher functional connectivity of the right precuneus within the default-mode network was associated with lower FA of the entire WM skeleton (r = -.525, p = .02), genu of the corpus callosum (r = -.553, p = .014), and left (r = -.467, p = .044) and right (r = -.615, p = .005) sagittal stratum.

Conclusions

Loss of WM microstructural integrity is associated with increased resting-state functional connectivity in pediatric MS, which may reflect a diffuse and potentially compensatory activation early in MS.

SUBMITTER: Akbar N

PROVIDER: S-EPMC4701472 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Alterations in Functional and Structural Connectivity in Pediatric-Onset Multiple Sclerosis.

Akbar Nadine N Giorgio Antonio A Till Christine C Sled John G JG Doesburg Sam M SM De Stefano Nicola N Banwell Brenda B

PloS one 20160105 1

<h4>Background</h4>Reduced white matter (WM) integrity is a fundamental aspect of pediatric multiple sclerosis (MS), though relations to resting-state functional MRI (fMRI) connectivity remain unknown. The objective of this study was to relate diffusion-tensor imaging (DTI) measures of WM microstructural integrity to resting-state network (RSN) functional connectivity in pediatric-onset MS to test the hypothesis that abnormalities in RSN reflects changes in structural integrity.<h4>Methods</h4>T ...[more]

PMID: 26731278

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Project description:Background: Advanced imaging techniques such as diffusion and functional MRI can be used to identify pathology-related changes to the brain's structural and functional connectivity (SC and FC) networks and mapping of these changes to disability and compensatory mechanisms in people with multiple sclerosis (pwMS). No study to date performed a comparison study to investigate which connectivity type (SC, static or dynamic FC) better distinguishes healthy controls (HC) from pwMS and/or classifies pwMS by disability status. Aims: We aim to compare the performance of SC, static FC, and dynamic FC (dFC) in classifying (a) HC vs. pwMS and (b) pwMS who have no disability vs. with disability. The secondary objective of the study is to identify which brain regions' connectome measures contribute most to the classification tasks. Materials and Methods: One hundred pwMS and 19 HC were included. Expanded Disability Status Scale (EDSS) was used to assess disability, where 67 pwMS who had EDSS<2 were considered as not having disability. Diffusion and resting-state functional MRI were used to compute the SC and FC matrices, respectively. Logistic regression with ridge regularization was performed, where the models included demographics/clinical information and either pairwise entries or regional summaries from one of the following matrices: SC, FC, and dFC. The performance of the models was assessed using the area under the receiver operating curve (AUC). Results: In classifying HC vs. pwMS, the regional SC model significantly outperformed others with a median AUC of 0.89 (p <0.05). In classifying pwMS by disability status, the regional dFC and dFC metrics models significantly outperformed others with a median AUC of 0.65 and 0.61 (p < 0.05). Regional SC in the dorsal attention, subcortical and cerebellar networks were the most important variables in the HC vs. pwMS classification task. Increased regional dFC in dorsal attention and visual networks and decreased regional dFC in frontoparietal and cerebellar networks in certain dFC states was associated with being in the group of pwMS with evidence of disability. Discussion: Damage to SCs is a hallmark of MS and, unsurprisingly, the most accurate connectomic measure in classifying patients and controls. On the other hand, dynamic FC metrics were most important for determining disability level in pwMS, and could represent functional compensation in response to white matter pathology in pwMS.

Project description:ImportancePediatric-onset multiple sclerosis (PoMS) is associated with significant cognitive and physical disability. Whether this disability translates into differences in educational achievements and earnings is unknown.ObjectiveTo evaluate the association between PoMS and educational level and income throughout adulthood.Design, setting, and participantsA prospective register-based cohort study of individuals with PoMS and a population-based matched reference cohort was conducted using nationwide microdata from linked registers in Sweden from January 1, 1990, to December 31, 2016; analyses were completed from May 1, 2019, to September 1, 2020. Of 772 persons with PoMS identified in the Swedish MS registry, 485 had an onset during the period from 1980 to 2014 and had socioeconomic data available. The general population reference cohort without multiple sclerosis (MS) (n = 4850) was randomly selected from the full Swedish population, matched 10:1 on age, sex, and country of birth.ExposurePediatric-onset MS, diagnosed by a neurologist, with onset before 18 years of age.Main outcomes and measuresHighest educational level (elementary school, high school, or university) was assessed using logistic regression. Income, measured as the mean annual earnings from paid work in US dollars, was compared using Tobit models, and net annual sickness absence and disability pension days were compared using zero-inflated negative binomial regression. Earnings and days receiving disability benefits were compared within 4 age periods (19-24, 25-34, 35-44, and 45-54 years).ResultsThe median age of the cohort with PoMS (n = 485) and the matched reference cohort (n = 4850) in 2016 was 32 years (interquartile range, 26-40 years), and most participants were women (348 [71.8%] in the PoMS cohort and 3480 [71.8%] in the matched reference cohort). Persons with PoMS were less likely than persons in the matched reference cohort to attend university (odds ratio, 0.80 [95% CI, 0.66-0.97]) and had significantly lower annual earnings than the reference cohort, ranging from -$1618 (95% CI, -$2558 to -$678) in the youngest age period to -$10 683 (95% CI, -$18 187 to -$3178) in the eldest. Persons with PoMS received higher rates of disability benefits, as sickness absence days in the youngest age period (rate ratio, 3.06 [95% CI, 2.08-4.52]) and disability pension days in the oldest age period (rate ratio, 1.43 [95% CI, 1.11-1.85]).Conclusions and relevanceThis study suggests that having PoMS is associated with less educational achievement, lower earnings, and greater use of disability benefits throughout the working-age life span. As adults, persons with PoMS never earned as much as their counterparts without MS, and they exhibited a heavier reliance on disability benefits.

Project description:Resting state functional MRI (rs-fMRI) has provided important insights into functional reorganization in subjects with Multiple Sclerosis (MS) at different stage of disease. In this cross-sectional study we first assessed, by means of rs-fMRI, the impact of overall T2 lesion load (T2LL) and MS severity score (MSSS) on resting state networks (RSNs) in 62 relapsing remitting MS (RRMS) patients with mild disability (MSSS < 3). Independent Component Analysis (ICA) followed by dual regression analysis confirmed functional connectivity (FC) alterations of many RSNs in RRMS subjects compared to healthy controls. The anterior default mode network (DMNa) and the superior precuneus network (PNsup) showed the largest areas of decreased FC, while the sensory motor networks area M1 (SMNm1) and the medial visual network (MVN) showed the largest areas of increased FC. In order to better understand the nature of these alterations as well as the mechanisms of functional alterations in MS we proposed a method, based on linear regression, that takes into account FC changes and their correlation with T2LL and MSSS. Depending on the sign of the correlation between FC and T2LL, and furthermore the sign of the correlation with MSSS, we suggested the following possible underlying mechanisms to interpret altered FC: (1) FC reduction driven by MS lesions, (2) "true" functional compensatory mechanism, (3a) functional compensation attempt, (3b) "false" functional compensation, (4a) neurodegeneration, (4b) pre-symptomatic condition (damage precedes MS clinical manifestation). Our data shows areas satisfying 4 of these 6 conditions (i.e., 1,2,3b,4b), supporting the suggestion that increased FC has a complex nature that may exceed the simplistic assumption of an underlying compensatory mechanism attempting to limit the brain damage caused by MS progression. Exploring differences between RRMS subjects with short disease duration (MSshort) and RRMS with similar disability but longer disease duration (MSlong), we found that MSshort and MSlong were characterized by clearly distinct pattern of FC, involving predominantly sensory and cognitive networks respectively. Overall, these results suggest that the analysis of FC alterations in multiple large-scale networks in relation to radiological (T2LL) and clinical (MSSS, disease duration) status may provide new insights into the pathophysiology of relapse onset MS evolution.

Dataset Information

Alterations in Functional and Structural Connectivity in Pediatric-Onset Multiple Sclerosis.

Background

Methods

Results

Conclusions

Publications

Alterations in Functional and Structural Connectivity in Pediatric-Onset Multiple Sclerosis.

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