Joseph J. Volpe

Joseph Volpe is generally considered to have founded the field of neonatal neurology. His research focuses on damage to the white matter of the brain in premature infants, a condition called periventricular leukomalacia (PVL). Infants with PVL have an increased risk of developing cerebral palsy and can have intellectual or learning difficulties. Volpe has sought to define the biological mechanisms of PVL and design strategies to prevent it. He has approached this goal through both basic and clinical research.

Through basic research, he has demonstrated that early differentiating oligodendrocytes (cells that compose the white matter of the brain) are exquisitely vulnerable to attack by free radicals. Volpe has discovered that this vulnerability relates to impaired antioxidant defenses, requires iron, leads to apoptotic death, is highly maturation-dependent and can be prevented with mechanism-specific interventions.

Specifically, his work has identified two major upstream mechanisms: hypoxia-ischemia and systemic infection/inflammation with activation of brain microglia. These insults activate two major downstream mechanisms--excitotoxicity and, ultimately, generation of reactive oxygen and nitrogen species. These insights have led to discovery of a variety of interventions that prevent or ameliorate the injury to early differentiating oligodendrocytes.

Volpe's clinical research has demonstrated that PVL in the premature newborn is followed by subsequent impairment of brain development. His work has also contributed to possible strategies for preventing that damage, showing that:

• Infants with a pressure-passive cerebral circulation can be identified in the first hours of life and are at very high risk for subsequent periventricular white-matter injury.
• Infants with cerebral hemodynamic disturbance can be identified prior to the occurrence of injury, raising the possibility that correcting the disturbance could prevent white-matter injury.
• The critical diffuse component of periventricular white-matter injury--invisible to conventional MRI--can be identified by diffusion-based MRI (decreased diffusion) and by proton MR spectroscopy (increased lactate).
• The disturbances of neuronal/axonal development that result from the white-matter injury involve the cerebral cortex, critical white-matter neurons (subplate neurons, late migrating GABAergic neurons), the thalamus, the basal ganglia and the cerebellum. These gray-matter lesions are likely very critical in the genesis of the cognitive/behavioral/attentional/socialization deficits observed in premature infants.