Abstract
During the third trimester, rapid and complex neurodevelopmental processes leave the developing brain vulnerable to insult and at risk of structural alterations and developmental delays in the event that birth is premature. As such, there is increasing interest in the quality of life of those surviving preterm birth — who are at risk of developing neurological disorders andneuropsychological impairments in childhood and later life. In particular, difficulties in behaviour and cognition are among the developmental sequelae associated with preterm birth — specifically very preterm birth (VPT; prior to 33 weeks’ gestation). Yet, despite existing research dedicated to understanding behavioural development in VPT children, the underlying neural substrates associated with this population’s increased vulnerability to developing such difficulties remain unclear. To date, only a few studies have rigorously investigated the association between behavioural problems following VPT birth and structural and functional brain alterations that could contribute to the development of such problems.The overall aim of this thesis was to increase our understanding of the neurodevelopmental mechanisms associated with behavioural outcomes following VPT birth. Specifically, structural and functional brain connectivities, both in the whole-brain and within specific tracts, were investigated. This thesis also aims to determine whether data acquired in the neonatal period can be used to identify those VPT children at a greater risk of experiencing behavioural difficulties. This was achieved through multimodal neuroimaging in a cohort of 511 VPT children, recruited at birth into the ePrime study, who underwent magnetic resonance imaging (MRI) at term-equivalent age. At 4–7 years, 251 participants were followed up for neurodevelopmental assessments. At 7–10 years, 64 of these children were followed up with multimodal MRI and neurodevelopmental assessments. Additionally, 46 full-term control children were recruited from the community.
Chapter 1 provides a general overview of preterm birth and brain development, as well as an introduction to neuroimaging methods used in their investigation in neonates and children. Chapter 2 includes a comprehensive review of cognitive and socio-emotional difficulties in VPT children and their neural correlates. Chapter 3 presents an overview of the current thesis, including aims and hypotheses. Chapter 4 includes the overall methodology for the included studies.
Chapters 5 and 6 include studies of neonatal MRI data and socio-emotional outcomes, as measured by parental questionnaires, in the VPT group only. In Chapter 5, associations between neonatal structural connectivity in specific white matter (WM) tracts (uncinate fasciculus, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and inferior longitudinal fasciculus), measured with diffusion characteristics (fractional anisotropy and radial diffusivity), and childhood socio-emotional outcomes are discussed. Chapter 6 examines associations between neonatal restingstate functional connectivity (rs-FC) of the amygdalae and childhood socio-emotional outcomes. Amygdalae rs-FC was estimated using seed-based connectivity analysis, with the bilateral amygdalae as seed region of interest. Results from both studies indicated an association between neonatal frontotemporal connectivity (structural and functional) in the right hemisphere and childhood socioemotional outcomes.
Chapter 7 presents a study of VPT children compared to age-matched term-born controls. Differences in WM between VPT and full-term children were explored using diffusion MRI data analysed with both voxel- and fixel-based analysis, the latter a method that measures both the microstructure (fibre density) and macrostructure (fibre cross-section) of WM tracts. Associations between childhood WM structure and behavioural outcomes in both VPT and control groups were also studied. Voxel- and fixel-based results showed alterations in the structure of several WM tracts in VPT children when compared to controls. Moreover, associations between specific WM tract structure in the corpus callosum and corticospinal tract, as measured by fixel-based analysis, and verbal comprehension were found in all children.
Taken together, the findings of this thesis deepen our understanding of the impact of VPT birth on behavioural outcomes during childhood. By combining neuroimaging techniques with behavioural tests and questionnaires to isolate specific brain mechanisms associated with behaviours of interest, further research in this field can allow for the identification of children at a greater risk of developing difficulties in later life, and thus the implementation of strategies that can prevent their emergence.
Date of Award | 1 Jul 2022 |
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Original language | English |
Awarding Institution |
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Supervisor | Chiara Nosarti (Supervisor) & Serena Counsell (Supervisor) |