| Abstract: | Combining diffusion magnetic resonance imaging and network analysis in the adult human brain has identified a set of highly connected cortical hubs that form a “rich club”—a high-cost, high-capacity backbone thought to enable efficient network communication. Rich-club architecture appears to be a persistent feature of the mature mammalian brain, but it is not known when this structure emerges during human development. In this longitudinal study we chart the emergence of structural organization in mid to late gestation. We demonstrate that a rich club of interconnected cortical hubs is already present by 30 wk gestation. Subsequently, until the time of normal birth, the principal development is a proliferation of connections between core hubs and the rest of the brain. We also consider the impact of environmental factors on early network development, and compare term-born neonates to preterm infants at term-equivalent age. Though rich-club organization remains intact following premature birth, we reveal significant disruptions in both in cortical–subcortical connectivity and short-distance corticocortical connections. Rich club organization is present well before the normal time of birth and may provide the fundamental structural architecture for the subsequent emergence of complex neurological functions. Premature exposure to the extrauterine environment is associated with altered network architecture and reduced network capacity, which may in part account for the high prevalence of cognitive problems in preterm infants.To understand the functional properties of a complex network it is necessary to examine its structural organization and topological properties. In the human brain this can be achieved at a macroscale by tracing white matter connections between brain regions with diffusion MRI; this enables the interrogation of structural network topology in vivo with millimeter-scale spatial resolution, providing complementary evidence to experimental studies (1, 2).Network analysis of the adult human structural connectome has revealed a set of highly connected cortical “hubs” predominantly located in heteromodal association cortex, that provide a foundation for coherent neuronal activation across distal cortical regions (3–5). Further, some hub regions tend to be densely connected to each other, forming a “rich club” comprised of frontal and parietal cortex, precuneus, cingulate and the insula, as well as the hippocampus, thalamus, and putamen (6). Rich-club organization has been identified in a number of complex networks (7) and represents an attractive feature for investigation in the brain because rich-club connections tend to dominate network topology (8). Rich-club architecture appears to be a fundamental feature of the mature mammalian brain with similar organization identified in animal models (9, 10).It has been suggested that the emergence of complex neurological function is associated with the integration of major hubs across the cortex (11, 12), and that the neural connectivity underlying this undergoes substantial remodeling after birth (13, 14). Initial studies of neonatal structural networks have reported only dense local connectivity within segregated modules and few long-distance connections (12, 15). In contrast, functional MRI reveals large-scale dynamic functional networks analogous to those seen in adults (16, 17) and compatible with more advanced cerebral maturation. To address the possibility that the newborn brain may be structurally more developed than previously thought, and to understand better the role of structural network architecture in emergent neurological functions, we have developed an approach to assess the topological development of structural connectivity in the human brain up to the normal time of birth.We used this approach to define network topology at ∼30 and 40 wk of gestation and, in a group of infants studied at both time points, charted the emergence of structural organization. We also explored the specific relations of cortical and deep gray matter hubs in the network. To determine whether network development was independent of environmental factors, we compared healthy term-born subjects with infants prematurely born and exposed to the extrauterine environment. We report that highly ordered cerebral structural connectivity with rich club topology is established by 30 wk gestation; additionally, we identify aspects of network organization that develop during this period and specific features that are disturbed by premature extrauterine life. |
