title: Diffusion fMRI detects white-matter dysfunction in mice with acute optic neuritis.
abstract: Optic neuritis is a frequent and early symptom of multiple sclerosis (MS). Conventional magnetic resonance (MR) techniques provide means to assess multiple MS-related pathologies, including axonal injury, demyelination, and inflammation. A method to directly and non-invasively probe white-matter function could further elucidate the interplay of underlying pathologies and functional impairments. Previously, we demonstrated a significant 27% activation-associated decrease in the apparent diffusion coefficient of water perpendicular to the axonal fibers (ADC⊥) in normal C57BL/6 mouse optic nerve with visual stimulation using diffusion fMRI. Here we apply this approach to explore the relationship between visual acuity, optic nerve pathology, and diffusion fMRI in the experimental autoimmune encephalomyelitis (EAE) mouse model of optic neuritis. Visual stimulation produced a significant 25% (vs. baseline) ADC⊥ decrease in sham EAE optic nerves, while only a 7% (vs. baseline) ADC⊥ decrease was seen in EAE mice with acute optic neuritis. The reduced activation-associated ADC⊥ response correlated with post-MRI immunohistochemistry determined pathologies (including inflammation, demyelination, and axonal injury). The negative correlation between activation-associated ADC⊥ response and visual acuity was also found when pooling EAE-affected and sham groups under our experimental criteria. Results suggest that reduction in diffusion fMRI directly reflects impaired axonal-activation in EAE mice with optic neuritis. Diffusion fMRI holds promise for directly gauging in vivo white-matter dysfunction or therapeutic responses in MS patients.
authors.affiliation: Department of Physics, Washington University, St. Louis, MO 63130, USA.
authors.forename: Tsen-Hsuan
authors.initials: TH
authors.lastname: Lin
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Spees
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Chiang
authors.affiliation: Department of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Trinkaus
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Cross
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: ssong@wustl.edu.
authors.forename: Sheng-Kwei
authors.initials: SK
authors.lastname: Song
mesh_terms: D000208:Acute Disease; D000818:Animals; D001931:Brain Mapping; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology*; D009902:Optic Neuritis / Q000473:pathology / Q000503:physiopathology*; D014792:Visual Acuity / Q000502:physiology
keywords: Diffusion fMRI; EAE; Optic neuritis; Visual acuity; White matter