Fundamentals of the Development of Connectivity in the Human Fetal Brain in Late Gestation: From 24 Weeks Gestational Age to Term

During the second half of gestation, the human cerebrum undergoes pivotal histogenetic events that underlie functional connectivity. These include the growth, guidance, selection of axonal pathways, and their first engagement in neuronal networks. Here, we characterize the spatiotemporal patterns of cerebral connectivity in extremely preterm (EPT), very preterm (VPT), preterm and term babies, focusing on magnetic resonance imaging (MRI) and histological data. In the EPT and VPT babies, thalamocortical axons enter into the cortical plate creating the electrically-active, functional synapses. Additionally, the subplate zone gradually resolves in the preterm and term brain in conjunction with the growth of associative pathways leading to the activation of large-scale neural networks. We demonstrate that specific classes of axonal pathways within cerebral compartments are selectively vulnerable to temporally nested pathogenic factors. In particular, the radial distribution of axonal lesions, that is, radial vulnerability, is a robust predictor of clinical outcome. Furthermore, the subplate tangential nexus that we can visualize using MRI could be an additional marker as pivotal in the development of cortical connectivity. We suggest to direct future research toward the identification of sensitive markers of earlier lesions, the elucidation of genetic mechanisms underlying pathogenesis, and better long-term follow-up using structural and functional MRI.