The immature brain is uniquely and exquisitely sensitive to oxidative stress which accounts for the cell death seen after hypoxia-ischemia. As in all neurological diseases, there are vulnerable regions of injury and these regions are damaged in an age-dependent manner. For example, in the premature brain, we see injury in the periventricular white matter that reflect damage to the developing oligodendrocytes, but we also have new data to suggest that subplate neurons are involved as well . In the term baby, we see a different pattern of vulnerability, with damage to the deep gray nuclei and this pattern of vulnerability can be used to predict neurodevelopmental outcome later in life (see human studies below). This pattern may be due to the unique distribution of a network of cells with a rich supply of glutamate receptors that parallels the distribution of a population of neurons containing neuronal nitric oxide synthase that are uniquely spared after hypoxia-ischemia at this age. Since these cells are spared, they are available to signal relentlessly and release the free radical nitric oxide and oxidatively challenge the newborn brain. Selective destructive or targeted elimination of the nitric oxide synthase neurons results in protection in animal models, although pharmacological inhibition of the enzyme has not been satisfactory due to the non-selectivity of the compounds and to the fact that there is some depression of enzymatic activity immediately after the insult. We have also shown that hypoxic-ischemic injury results in prolonged and delayed cell death both locally and in remote regions after the insult.These data have important consequences for future studies because they suggest that there is prolonged window of opportunity for the administration of neuroprotective agents. We have shown that therapies used for the adult nervous system must not be assumed to work for the newborn brain. For example, overexpression of superoxide dismutase had been successful in treating adult stroke in animal models, but in the immature animal, this overexpression leads to more injury because the neonatal animals have less antioxidant reserve . This was the first example where therapy assumed to be neuroprotective for all ages actually had deleterious effects in the immature brain. Subsequently, other reports followed for other agents (Ikonomidou et al, Science 283, 1999).

Currently, we have two prospective human research studies ongoing to delineate injury patterns and identify prognostic factors that will determine neurodevelopmental outcome in babies with neonatal encephalopathy. We have studied over 150 preterm (PREMRI - Premature Asphyxia Magnetic Resonance Imaging) and 200 term (BAMRI -Brain Asphyxia Magnetic Resonance Imaging) infants using state-of-the art magnetic resonance (MR) imaging modalities such as spectroscopy, diffusion tensor imaging, and perfusion mapping.