Longitudinal brain development in extremely preterm newborns

Abstract

To unravel the pathophysiology underlying the large percentage of preterm born infants that will demonstrate neurodevelopmental impairments during childhood, a better understanding of brain development during what would have been the third trimester of pregnancy is needed. The aim of this thesis was to study longitudinal brain development in extremely preterm infants. We did so by utilizing serial MRI scans of a cohort of preterm infants born before a gestation of 28 weeks, that were scanned around 30 weeks postmenstrual age and again around term-equivalent age.

In this thesis, we show that volumetric measurements, the progression of cortical folding, microstructural development of the white matter and functional connectivity networks all confirm the central-peripheral and occipital-frontal gradient of brain development. Several clinical risk factors for deviations in brain development were studied and prolonged mechanical ventilation, whether as a representative of lung damage or of overall severity of illness, has the most severe negative influence on brain development throughout the different studies. By utilizing serial scans, we show that the remote effects of brain injury will become evident in the period between 30 and 40 weeks gestation, whereas the direct effects are already established by 30 weeks. Relating these findings to neurodevelopmental outcome around two years of age showed significant but modest effects, suggesting that outcome at a later age is needed to find deficits caused by mild brain injury.

Punctate white matter lesions, nowadays the most common form of white matter injury in preterm infants, were seen in two distinctive patterns, suggestive of a difference in underlying pathology. Additional sequences (diffusion and susceptibility weighted imaging) are needed to reliably distinguish both. Volumetric growth showed regional differences with by far the largest growth in the cerebellum, which is also affected most by brain damage. The use of hydrocortisone for developing chronic lung disease, however, did not influence overall brain size or cerebellar volumes. While studying the progression of cortical folding, adult brain asymmetries were shown to develop already during the last ten weeks of gestation. In addition, cortical surface area and depth were correlated with neurodevelopmental outcomes at two years of age. Utilizing diffusion tensor imaging showed increases of fractional anisotropy in the white matter, but decreases in the cortex, fitting with the theory of cortical development. Damage to the corticospinal tracts in infants with cystic periventricular leukomalacia was seen within weeks after the insult, while the remote effects on thalamic volume develop over time and become clear at term-equivalent age. Finally, immature functional networks were already present at 30 weeks and were similar to adult networks. Both structural and functional connectivity networks develop between 30 weeks and term-equivalent age leading to an increase in integration capacity.

Identifying these processes in brain development, taking place while preterm infants are cared for in a neonatal intensive care environment with all its stressors and complications, as well as the deviations caused by preterm birth, will help in finding better predictive strategies and protective therapies to improve cognitive and behavioural outcome for this vulnerable population.