title: Functional Magnetic Resonance Imaging of Rats with Experimental Autoimmune Encephalomyelitis Reveals Brain Cortex Remodeling.
abstract: Cortical reorganization occurring in multiple sclerosis (MS) patients is thought to play a key role in limiting the effect of structural tissue damage. Conversely, its exhaustion may contribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS.
  
  
  CONCLUSIONS
  Since the early 2000s, functional MRI (fMRI) has demonstrated profound modifications in the recruitment of cortical areas during motor, cognitive, and sensory tasks in multiple sclerosis (MS) patients. Experimental autoimmune encephalomyelitis (EAE) represents a reliable model of the chronic-progressive variant of MS. fMRI studies in EAE have not been performed extensively up to now. This paper reports fMRI studies in a rat model of MS with somatosensory stimulation of the forepaw. We demonstrated modifications in the recruitment of cortical areas consistent with data from MS patients. To the best of our knowledge, this is the first report of cortical remodeling in a preclinical in vivo model of MS.
authors.affiliation: Departments of Neurological and Movement Sciences and National Interuniversity Consortium of Materials Science and Technology, I-50121 Florence, Italy.
authors.forename: Stefano
authors.identifier: http://orcid.org/0000-0003-2562-1324
authors.initials: S
authors.lastname: Tambalo
authors.affiliation: Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute and National Institute for Health Research Biomedical Research Centre, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
authors.forename: Luca
authors.identifier: http://orcid.org/0000-0002-9396-5607
authors.initials: L
authors.lastname: Peruzzotti-Jametti
authors.affiliation: Experimental Neurology Unit, Department of Surgery and Translational Medicine and Center for Neuroscience of Milan, University of Milan-Bicocca, I-20900 Monza, Italy, and.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rigolio
authors.affiliation: Departments of Neurological and Movement Sciences and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fiorini
authors.affiliation: Computer Science, University of Verona, I-37134 Verona, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Bontempi
authors.affiliation: Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute and National Institute for Health Research Biomedical Research Centre, University of Cambridge, Cambridge CB2 0PY, United Kingdom, Department of Brain and Behavioural Sciences, National Neurological Institute C. Mondino, University of Pavia, I-27100 Pavia, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Mallucci
authors.affiliation: Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute and National Institute for Health Research Biomedical Research Centre, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Balzarotti
authors.affiliation: Experimental Neurology Unit, Department of Surgery and Translational Medicine and Center for Neuroscience of Milan, University of Milan-Bicocca, I-20900 Monza, Italy, and.
authors.forename: Paola
authors.identifier: http://orcid.org/0000-0002-7590-7649
authors.initials: P
authors.lastname: Marmiroli
authors.affiliation: Departments of Neurological and Movement Sciences and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sbarbati
authors.affiliation: Experimental Neurology Unit, Department of Surgery and Translational Medicine and Center for Neuroscience of Milan, University of Milan-Bicocca, I-20900 Monza, Italy, and.
authors.forename: Guido
authors.identifier: http://orcid.org/0000-0003-4128-2406
authors.initials: G
authors.lastname: Cavaletti
authors.affiliation: Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute and National Institute for Health Research Biomedical Research Centre, University of Cambridge, Cambridge CB2 0PY, United Kingdom, spp24@cam.ac.uk pasquina.marzola@univr.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
authors.affiliation: Computer Science, University of Verona, I-37134 Verona, Italy, National Interuniversity Consortium of Materials Science and Technology, I-50121 Florence, Italy, spp24@cam.ac.uk pasquina.marzola@univr.it.
authors.forename: Pasquina
authors.initials: P
authors.lastname: Marzola
mesh_terms: D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply* / Q000473:pathology*; D003337:Corpus Callosum / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D006614:Hindlimb / Q000294:innervation; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010100:Oxygen / Q000097:blood; D051381:Rats
chemical_list: D016207:Cytokines; D009419:Nerve Tissue Proteins; D010100:Oxygen
keywords: brain plasticity; cortical reorganization; experimental autoimmune encephalomyelitis; functional magnetic resonance imaging; multiple sclerosis; neuroimmunology