title: 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.
authors.affiliation: Neurosciences and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Akbar
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giorgio
authors.affiliation: Department of Psychology, York University, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Till
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.affiliation: Neurosciences and Mental Health Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Doesburg
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.affiliation: Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
authors.forename: Brenda
authors.initials: B
authors.lastname: Banwell
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D005260:Female; D006179:Gyrus Cinguli / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000473:pathology*; D009415:Nerve Net / Q000473:pathology; D055815:Young Adult