title: Brain development after neonatal intermittent hyperoxia-hypoxia in the rat studied by longitudinal MRI and immunohistochemistry.
abstract: BACKGROUND
  Neonatal intermittent hyperoxia-hypoxia (IHH) is involved in the pathogenesis of retinopathy of prematurity. Whether similar oxygen fluctuations will create pathological changes in the grey and white matter of the brain is unknown.
  
  
  METHODS
  From birth until postnatal day 14 (P14), two litters (total n = 22) were reared in IHH: hyperoxia (50% O2) interrupted by three consecutive two-minute episodes of hypoxia (12% O2) every sixth hour. Controls (n = 8) were reared in room-air (20.9% O2). Longitudinal MRI (Diffusion Tensor Imaging and T2-mapping) was performed on P14 and P28 and retinal and brain tissue were examined for histopathological changes. Long-term neurodevelopment was assessed on P20 and P27.
  
  
  RESULTS
  Mean, radial and axial diffusivity were higher in white matter of IHH versus controls at P14 (p < 0.04), while fractional anisotropy (FA) was lower in the hippocampal fimbria and tended to be lower in corpus callosum (p = 0.08) and external capsule (p = 0.05). White matter diffusivity in IHH was similar to controls at P28. Higher cortical vessel density (p = 0.005) was observed at P14. Cortical and thalamic T2-relaxation time and mean diffusivity were higher in the IHH group at P14 (p ≤ 0.03), and albumin leakage was present at P28. Rats in the IHH group ran for a longer time on a Rotarod than the control group (p ≤ 0.005). Pups with lower bodyweight had more severe MRI alterations and albumin leakage.
  
  
  CONCLUSIONS
  IHH led to subtle reversible changes in brain white matter diffusivity, grey matter water content and vascular density. However, alterations in blood-brain barrier permeability may point to long-term effects. The changes seen after IHH exposure were more severe in animals with lower bodyweight and future studies should aim at exploring possible interactions between IHH and growth restriction.
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Tora Sund
authors.initials: TS
authors.lastname: Morken
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Axel Karl Gottfrid
authors.initials: AK
authors.lastname: Nyman
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Sandvig
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Sverre Helge
authors.initials: SH
authors.lastname: Torp
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway ; Department of Pediatrics, St. Olav University Hospital, Central Norway Regional Health Authority, Trondheim, Norway.
authors.forename: Jon
authors.initials: J
authors.lastname: Skranes
authors.affiliation: Department of Radiology, St. Olav University Hospital, Central Norway Regional Health Authority, Trondheim, Norway.
authors.forename: Pål Erik
authors.initials: PE
authors.lastname: Goa
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway ; Department of Pediatrics, St. Olav University Hospital, Central Norway Regional Health Authority, Trondheim, Norway.
authors.forename: Ann-Mari
authors.initials: AM
authors.lastname: Brubakk
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Marius
authors.initials: M
authors.lastname: Widerøe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018496:Hyperoxia / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D009929:Organ Size; D051381:Rats; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012166:Retinal Hemorrhage / Q000378:metabolism / Q000473:pathology; D045442:Rotarod Performance Test