Original Article

Delayed neural network degeneration after neonatal hypoxia-ischemia†

  1. Brian S. Stone MD1,
  2. Jiangyang Zhang PhD2,
  3. Devin W. Mack BS1,
  4. Susumu Mori PhD2,3,
  5. Lee J. Martin PhD4,
  6. Frances J. Northington MD1,*

Article first published online: 9 DEC 2008

DOI: 10.1002/ana.21517

Issue

Annals of Neurology

Annals of Neurology

Volume 64, Issue 5, pages 535–546, November 2008

Additional Information

How to Cite

Stone, B. S., Zhang, J., Mack, D. W., Mori, S., Martin, L. J. and Northington, F. J. (2008), Delayed neural network degeneration after neonatal hypoxia-ischemia. Annals of Neurology, 64: 535–546. doi: 10.1002/ana.21517

Author Information

  1. 1

    Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Neonatal Research Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD

  2. 2

    Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD

  3. 3

    F.M. Kirby Functional Imaging Center, Kennedy Krieger Institute, Baltimore, MD

  4. 4

    Departments of Pathology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD

*Eudowood Neonatal Pulmonary Division, Department of Pediatrics, CMSC 6-104, 600 North Wolfe Street, Baltimore, MD 21287

  1. †

    Potential conflict of interest; Nothing to report.

Publication History

  1. Issue published online: 9 DEC 2008
  2. Article first published online: 9 DEC 2008
  3. Manuscript Accepted: 7 AUG 2008
  4. Manuscript Revised: 24 JUL 2008
  5. Manuscript Received: 25 JAN 2008

Funded by

  • March of Dimes Foundation. Grant Number: 6-08-275
  • National Institutes of Health. Grant Numbers: AG16282, AG 20012 (NINDS), NS 45059, EB 003543, ES 012665, NS 059529
  • Lehmann Brothers Foundation

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Abstract

Objective

Clinical magnetic resonance studies show delayed and ongoing neurodegeneration after neonatal hypoxia-ischemia (HI), but the mechanisms and timing of this neurodegeneration remain unclear. We used ex vivo diffusion tensor imaging (DTI) and brain neuropathology to determine whether selective injury to white matter tracts occurs after neonatal HI in mice resulting in neural system–associated attrition in remote regions and at delayed times.

Methods

The Rice–Vannucci model (unilateral carotid ligation + 45 minutes of hypoxia FiO2 = 0.08) was used to cause brain injury in postnatal day 7 (p7) C57BL6 mice, and ex vivo DTI and correlative neuropathology were performed at p8, p11, p15, p21, p28, and p42.

Results

DTI provides excellent contrast visualization of unmyelinated white matter in the immature mouse brain. Severe ipsilateral injury to the hippocampus is seen with both histopathology and diffusion-weighted magnetic resonance imaging 24 hours after injury. Injury to axons is evident 24 hours after HI in the hippocampal alveus. By p11 and continuing until p28, the ipsilateral fimbria fornix degenerates. At p15, there is injury and loss of axons entering the ipsilateral septal nucleus followed by ipsilateral septal atrophy. Volume loss in the hippocampus is rapid and severe, but is subacute and significantly slower in the ipsilateral septum. Neonatal HI also interrupts the normal developmental increase in fractional anisotropy in the ipsilateral fimbria but not in the contralateral fimbria from p8 to p42.

Interpretation

In neonatal brain, there is progressive systems-preferential injury after HI. DTI allows unparalleled visualization of this neural network–associated attrition so that it can be followed longitudinally in developing brain. Ann Neurol 2008;64:535–546

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