The Neonatal Connectome During Preterm Brain Development

Abstract

The human connectome is the result of an elaborate developmental trajectory. Acquiring diffusion-weighted imaging and resting-state fMRI, we studied connectome formation during the preterm phase of macroscopic connectome genesis. In total, 27 neonates were scanned at week 30 and/or week 40 gestational age (GA). Examining the architecture of the neonatal anatomical brain network revealed a clear presence of a small-world modular organization before term birth. Analysis of neonatal functional connectivity (FC) showed the early formation of resting-state networks, suggesting that functional networks are present in the preterm brain, albeit being in an immature state. Moreover, structural and FC patterns of the neonatal brain network showed strong overlap with connectome architecture of the adult brain (85 and 81%, respectively). Analysis of brain development between week 30 and week 40 GA revealed clear developmental effects in neonatal connectome architecture, including a significant increase in white matter microstructure (P < 0.01), small-world topology (P < 0.01) and interhemispheric FC (P < 0.01). Computational analysis further showed that developmental changes involved an increase in integration capacity of the connectivity network as a whole. Taken together, we conclude that hallmark organizational structures of the human connectome are present before term birth and subject to early development.

The emergence of functional architecture during early brain development

“…Most infants are scanned during natural sleep or after administering mild sedation (25-60 mg/kg oral chloral hydrate) (Doria et al, 2010a;Toulmin et al, 2015;van den Heuvel et al, 2014) and although appropriate measures are generally taken to reduce motion artifacts including feeding and swaddling (where infants are scanned during natural sleep), wrapping the infant in a vacuum fixation pillow and applying hearing protection devices to reduce exposure to acoustic noise, even subtle head movement remains a significant problem. Furthermore, the use of sedative medication -if administered -is generally confined to infants scanned in a clinical setting and may thus introduce a bias in terms of the effect of motion, as well as differences in physiological parameters and sleep state/level of consciousness between health and disease states.…”

“…With all major white matter tracts being in place by the end of normal gestation, it is not surprising that structural connectome studies -examining whole brain connectivity on a macroscopic level (Box 1) -have revealed structural network organization in the neonatal brain to show great similarity to the adult human brain Brown et al, 2014;Ratnarajah et al, 2013;Shi et al, 2012;Tymofiyeva et al, 2012;van den Heuvel et al, 2014;Yap et al, 2011). Key features of adult connectome architecture have been demonstrated in the neonatal brain, including a small world organization -combining local specialization with long-range efficiency -, a modular topology -meaning that the network constitutes smaller subnetworks for specialized information processing -, and a heavy tailed degree distribution with brain regions which show the highest number of connections forming a central core or 'rich club' (Box 1).…”

“…Although present-day findings of neuroimaging in vivo cannot be directly translated to microscopic neural circuit development, not least because of the substantial gap in spatial scale on which macro-and microscale brain network development take place, there are considerable similarities in the biological principles that both systems seem to adhere to (Scholtens et al, 2014;van den Heuvel et al, 2014). Myelination and increases in axonal diameter of white matter connections promote efficiency of axonal information transfer and may therefore be reflected in increasing integration capacity of the macroscale connectome.…”

“…The neonatal cerebral cortex displays a complex, adult-like gyrification pattern and in the underlying white matter all large-scale connections are already in place Lodygensky et al, 2010;Stiles and Jernigan, 2010;Takahashi et al, 2012;van den Heuvel et al, 2014). Historically, much of what we know about the intricate processes of early brain development came from post mortem studies in human fetuses, neonates, and non-human primates (Flechsig, 1920;Goldman-Rakic, 1987;Innocenti and Price, 2005;Kostovic, 2002;LaMantia and Rakic, 1990).…”

“…Historically, much of what we know about the intricate processes of early brain development came from post mortem studies in human fetuses, neonates, and non-human primates (Flechsig, 1920;Goldman-Rakic, 1987;Innocenti and Price, 2005;Kostovic, 2002;LaMantia and Rakic, 1990). With the increasing availability of high-quality neuroimaging techniques, including anatomical sequences customized to the developing neonatal and fetal brain, diffusion weighted imaging (DWI) and functional MRI, as well as electrophysiology recordings including electroencephalography (EEG), it has now become feasible to study early human brain development in unprecedented detail in vivo Counsell et al, 2007;Fransson et al, 2007;Huppi et al, 1998;Maas et al, 2004;Omidvarnia et al, 2014;Partridge et al, 2004;Smyser et al, 2001; Thomason et al, 2013;Toulmin et al, 2015;van den Heuvel et al, 2014). These advances have led to exciting new insights into both healthy and atypical macroscale brain network development and have paved the way to bridge the gap between the brain's neurobiological architecture and its behavioral repertoire.…”