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. 2016 Jan 5;11(1):e0145906.
doi: 10.1371/journal.pone.0145906. eCollection 2016.

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

Nadine Akbar  1   2 , Antonio Giorgio  3 , Christine Till  4 , John G Sled  5   6 , Sam M Doesburg  1   2 , Nicola De Stefano  3 , Brenda Banwell  7
Affiliations

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

Nadine Akbar et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: NA has received speaker honoraria from EMD Serono outside of the submitted work. NDS has received honoraria from Schering, Biogen-Idec, Teva, Novartis, Genzyme, and Merck Serono S.A. for consulting services, speaking and travel support. He serves on advisory boards for Merck Serono S.A. and Novartis. He has received research grant support from the Italian MS Society. BB serves as an advisor to Biogen Idec, Novartis, Eli Lilly, and Sanofi-Aventis; she does not receive any financial remuneration for her advisory role but is remunerated for work pertaining to centralized imaging analyses by Novartis. BB also serves as a chief editor for Multiple Sclerosis and Related Disorders and is on the editorial board for Neurology. AG, CT, JGS, and SMD report no disclosures. All reported disclosures do not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Differences between groups in white matter FA.
(a) WM skeleton (green) depicting areas in which the pediatric-onset MS group demonstrated lower FA (blue) compared to the healthy control group (p < .01, corrected). (b) Mean lesion map of the pediatric MS group with brighter (yellow) areas representing voxels with higher probability of lesion occurrence. MNI152 template slice coordinates are also reported.
Fig 2
Fig 2. Differences between groups in functional connectivity of resting-state networks.
Group ICA components (3D volumes) including (a) default mode network, (b) primary visual network, (c) secondary visual network, (d) salience network, (e) right frontoparietal network, (f) left frontoparietal network, (g) sensorimotor network, and (h) dorsal attention network. The ICA components are shown in FSL red-yellow encoding using a 3< z-score <10 threshold. The (i) bilateral frontoparietal and (j) precuneus (posterior default-mode) networks were the only networks which demonstrated significant differences between groups (p < .005 uncorrected, cluster size> 30 voxels). Areas in blue below these networks (k), with numbered clusters 1–4, indicate those areas within these networks in which the pediatric-onset MS group demonstrated higher connectivity compared to healthy controls. C1 indicates the anterior cingulate cluster and C2 the left middle frontal gyrus cluster of the bilateral frontoparietal network. C3 indicates the right precuneus and C4 the anterior cingulate cluster of the precuneus posterior default-mode network. Statistics for the connectivity values of these clusters are referred to throughout the text. All images are displayed in radiological convention. (Left = Right, Right = Left). The most informative slices are shown.
See this image and copyright information in PMC

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