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Title: Cortical microstructural maturation in the typical and atypical developing brain
Author: Dimitrova, Ralica Vladimirova
ISNI:       0000 0004 7970 072X
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Many neurodevelopmental disorders (NDD) including autism spectrum (ASD) are diagnosed in early childhood. However, the pathophysiological mechanisms underpinning vulnerability to these conditions operate from much earlier, with foetal and early postnatal development representing a sensitive period to adverse environmental exposures and genetic risks. Unfortunately, very little is known about normal human brain development during this period, let along the impact of NDD risk factors on brain maturation. Most of the current knowledge of typical and atypical early brain development comes from animal and post-mortem work. Preclinical studies argue that genetic risk factors for ASD and related NDD act upon fundamental biological processes governing early brain maturation, including dendritic development. How these findings translate to the living human brain remains poorly understood. Advances in diffusion magnetic resonance imaging (MRI) and their application to human neonatal cohorts have provided a unique opportunity to probe the developing cortical microstructure in vivo. However, such research to date has mainly focused on preterm born infants. Preterm infants are known to be at risk of atypical development including a wide-range of brain alterations and behavioural deficits, and thus findings might not necessary generalise to the term-born brain of either typical infants, or those with genetic risk factors for NDD. This work aimed to advance current understanding about typical and atypical cortical microstructural maturation during early human brain development (term birth to 6 months of age). Specifically, (i) to describe typical neurite development in the term-born brain and (ii) to test the hypothesis that vulnerability to NDD is associated with altered dendritic maturation during this period. This was achieved by applying advanced diffusion MRI analyses to characterise neurite maturation in neonates and 6-month-old infants with and without NDD risk factors, namely familial history of ASD/ADHD. First, cortical microstructural maturation within the first month of life was examined in a sample of term-born neonates. The relative spatial distribution of diffusion metrics previously reported across the adult cortex was already evident within the first month of life, although quantitative values were consistent with the more immature state of the newborn cortex. Lower-level sensory cortices were better 'developed' than higher order regions, characterised by lower anisotropy and higher measures of neurite density and orientation dispersion. Age-related changes in neurite composition were observed in a fall in cortical anisotropy and tissue-water content together with an increase in neurite orientation dispersion and density, likely to be associated with rapid dendritic outgrowth. However, the pattern of cortical development observed in term-born 4 neonates was distinct from that recorded in studies of preterm cohorts of the same postmenstrual age. Second, consistent with findings from preclinical studies, a familial risk of NDD was associated with atypical cortical microstructure in early postnatal life. Neonates vulnerable to NDD had altered neurite geometry in cortical regions involved in lower-level sensory processing and multisensory integration, abilities known to be altered in high risk infants and individuals with a diagnosis of NDD. This abnormality was present in the absence of any atypical neurite density or altered macrostructural features, including cortical volume, thickness and curvature. Last, cortical microstructure was examined in the typical and atypical infant brain. For the first time, the spatial pattern of cortical diffusion was described in 6-month-old term-born infants. Consistent with findings from the neonatal study in this thesis, the primary sensory areas continued to show a more 'mature' state than higher-order cortices. Furthermore, vulnerability to NDD was also associated with altered neurite geometry in cortical regions governing lower-level sensory processing and multi-sensory integration, showing a substantial overlap with observations in at-risk neonates. Taken together, the work presented here shows that early postnatal life is characterised by dynamic changes in cortical microstructural composition. Furthermore, building on preclinical research it suggests that dendritic pathology represents a primary mechanism underlying vulnerability to ASD and related NDD.
Supervisor: McAlonan, Grainne Mary ; Edwards, Anthony David ; Murphy, Declan G. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available