The third important factor in the pathogenesis of periventricular white matter injury relates to an intrinsic vulnerability of neonatal cerebral white matter. Such an intrinsic vulnerability of the immature oligodendrocyte in cerebral white matter of the human infant, particularly regarding the more diffuse component of periventricular white matter injury, is suggested by experimental studies, by the rarity of the lesion at later ages, and by the relative cellular specificity of the diffuse injury, ie, involving oligodendrocytes but not astrocytes or other cellular elements.1,12 Recent immunocytochemical studies of developing human brain suggest that the cellular target for diffuse oligodendroglial injury in periventricular leukomalacia is an early differentiating oligodendrocyte, ie, at a developmental stage prior to the acquisition of myelin basic protein staining typical of the mature oligodendrocyte.12 Studies in cell culture demonstrate that this early differentiating oligodendrocyte, but not the mature oligodendrocyte, is extremely vulnerable to free radical attack.13,14 This vulnerability, of course, is of great interest because periventricular leukomalacia is considered to be an ischemic lesion, and an elevation in a variety of reactive oxygen species is a well-established sequela of ischemia and/or reperfusion. In 2 model systems of free radical accumulation, my colleagues and I have shown that early differentiating oligodendrocytes are very vulnerable to free radical attack.13,14 In one model, oligodendrocytes were shown to undergo free radical–mediated cell death by exposure to glutamate.13 The mechanism of the glutamate-induced cell death was related to glutathione depletion caused by intracellular cystine depletion, in turn related to activation of a glutamate-cystine exchange transport system. Glutamate entry caused cystine efflux, glutathione depletion, and free radical–mediated cell death. Clinically safe free radical scavengers, eg, vitamin E, totally prevented the oligodendroglial death caused by glutamate.