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In vivo assessment of the developing brain using diffusion magnetic resonance imaging

Student thesis: Doctoral ThesisDoctor of Philosophy

An estimated 15 million infants are born preterm every year and, thanks to improvements in neonatal care, mortality rates have decreased. However, preterm infants remain at risk of a wide spectrum of neurodevelopmental impairments including cognitive, motor and language deficits. The substantial personal and societal cost of preterm birth underscores the importance of identifying infants at risk, and those who may benefit from early interventional therapies.

Diffusion-weighted magnetic resonance imaging (dMRI) studies have provided valuable insights into the effects of maturation and injury on brain development in infant populations. The cerebral white matter is particularly vulnerable to injury and previous studies of preterm infants have demonstrated that altered white matter microstructure observed at term equivalent age is associated with developmental performance in later life. dMRI analysis of the developing white matter in this population may provide biomarkers of neurodevelopmental impairment.

Through the application of novel approaches to white matter analysis in neonates, this thesis investigates the effects of perinatal risk factors on the developing brain in preterm infants and the relationship between white matter microstructure in the perinatal period and subsequent neurodevelopmental performance. This work evaluated a new approach for neonatal dMRI analysis, tract-specific analysis (TSA). The evaluation of this method demonstrated that TSA provides improved spatial alignment of white matter tracts and better approximation of native space diffusion data than tract-based spatial statistics, a similar, widely used method.

TSA was applied to assess the relationship between diffusion tensor imaging (DTI) metrics in white matter fasciculi in 407 preterm infants at term-equivalent age and neurodevelopmental performance at 20 months, and to assess the effects of prematurity and maturation. Higher motor and cognitive scores assessed using the Bayley Scales of Infant and Toddler Development, 3rd edition, were associated with increased fractional anisotropy (FA) and decreased diffusivity in projection, commissural and association fibres, while the associations between language performance and DTI metrics were limited. Higher diffusivity and lower FA was associated with increased prematurity, and lower diffusivity and increased FA was associated with increasing age at scan, in agreement with previous studies.

Moving beyond the standard diffusion tensor model, novel higher-order diffusion models were applied for the first time to the preterm infant population to provide deeper insight into the relationship between white matter microstructure and perinatal risk factors, neurodevelopmental performance and brain maturation by identifying specific fibre pathways within regions of complex white matter configurations. The diffusion tensor model fails to adequately represent white matter anatomy in regions of crossing fibres. Therefore, fixel-based analysis (FBA) was applied to estimate fibre density and fibre-cross section for each distinct fibre population within a voxel, where a ‘fixel’ refers to a single fibre population. The association between perinatal risk factors and fibre cross-section was more extensive than with fibre density, implying a greater effect on white matter morphology than microstructure. Higher motor and cognitive scores were associated with increases in fibre cross-section while language performance was positively correlated with fibre density.

Finally, the methods explored in this thesis were applied to assess normal brain maturation in term infants from the Developing Human Connectome Project (dHCP). State-of-the-art diffusion imaging data from the dHCP were analysed to characterise healthy human brain development. TSA was combined with DTI, neurite orientation dispersion and density imaging (NODDI) and fixel-derived metrics. This study presented the first application of NODDI and FBA to healthy termborn infants. The results reveal that lateralisation of white matter fasciculi, observed in adults and associated with functional specialisation, is not present at birth in healthy term-born infants and most likely emerges later in life, also demonstrating a maturation-related increase in intra-axonal density and fibre cross-section in the perinatal period. Analysis of high quality, multi-shell diffusion data from the dHCP demonstrates the potential of advanced dMRI, which may provide a deeper understanding of the environmental and biological factors influencing brain development and the pathophysiology of preterm brain injury.
Original languageEnglish
Awarding Institution
Award date2018


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