Primary neuronal dysmaturation in preterm brain: Important and likely modifiable.

Abstract

The purpose of this Commentary is to discuss recent evidence that primary impairment of neuronal maturation of gray matter structures in the human preterm infant is common, important and likely modifiable. The major cellular element of gray matter structures in the human brain is the neuron. The principal gray matter structures, especially the cerebral cortex, basal ganglia, and thalamus, are crucial determinants of cognitive and related higher functions, developing subsequent to the newborn period. Impaired cognitive functions, including overall intellect, language, behavior, and socialization, occur in at least 50% of survivors of very preterm birth [1]. In the last trimester of human gestation, development of the cerebral cortex is especially prominent [2]. The principal anatomic features are development of a complex dendritic arbor, elaboration of axonal ramifications, onset of synaptogenesis and establishment of connectivity between cortical regions and deep nuclear structures. A variety of imaging studies in survivors of preterm birth have shown disturbances in maturation of gray matter structures [1], manifested by deficits in volumetric growth, microstructure and functional connectivity. The prevailing concept has been that injury to the vulnerable developing cerebral white matter leads secondarily to neuronal dysmaturation [3]. This secondary neuronal dysmaturation results because the pre-oligodendrocyte fails to ensheath axons, thereby causing, by anterograde and retrograde mechanisms, impairment of neuronal maturation. Recent experimental studies, however, suggest that impaired neuronal maturation also may be a primary event (see later), not related to white matter injury. Moreover, studies of very preterm human infants have shown impaired cognitive functions in the absence of definite white matter injury (see later). The occurrence of primary neuronal dysmaturation has important implications for elucidating the anatomic substrate for the cognitive deficits observed in survivors of preterm birth, and, critically for interventions to restore normal maturation and improve outcome. The following will review the principal experimental and human studies supportive of primary neuronal dysmaturation in the very preterm infant and of potential restorative interventions,