Growth of the Human Corpus Callosum: Modular and Laminar Morphogenetic Zones

The purpose of this focused review is to present and discuss recent data on the changing organization of cerebral midline structures that support the growth and development of the largest commissure in humans, the corpus callosum. We will put an emphasis on the callosal growth during the period between 20 and 45 postconceptual weeks (PCW) and focus on the advantages of a correlated histological/magnetic resonance imaging (MRI) approach. The midline structures that mediate development of the corpus callosum in rodents, also mediate its early growth in humans. However, later phases of callosal growth in humans show additional medial transient structures: grooves made up of callosal septa and the subcallosal zone. These modular (septa) and laminar (subcallosal zone) structures enable the growth of axons along the ventral callosal tier after 18 PCW, during the rapid increase in size of the callosal midsagittal cross-section area. Glial fibrillary acidic protein positive cells, neurons, guidance molecule semaphorin3A in cells and extracellular matrix (ECM), and chondroitin sulfate proteoglycan in the ECM have been identified along the ventral callosal tier in the protruding septa and subcallosal zone. Postmortem MRI at 3 T can demonstrate transient structures based on higher water content in ECM, and give us the possibility to follow the growth of the corpus callosum in vivo, due to the characteristic MR signal. Knowledge about structural properties of midline morphogenetic structures may facilitate analysis of the development of interhemispheric connections in the normal and abnormal fetal human brain

Data quality in diffusion tensor imaging studies of the preterm brain: a systematic review

Background: To study early neurodevelopment in preterm infants, evaluation of brain maturation and injury is increasingly performed using diffusion tensor imaging, for which the reliability of underlying data is paramount. Objective: To review the literature to eva

Role of perinatal inflammation in preterm brain injury

Perinatal inflammation is associated with an increased risk of brain injury and neurodevelopmental impairment in preterm infants but the immune mediators driving this association are not well understood. This PhD thesis seeks to further characterise the inflammatory response associated with preterm birth, describe the relationship between perinatal inflammation and white matter development and explore the effect of specific inflammation-associated proteins on the development of human cortical neurons derived from induced pluripotent stem cells (iPSCs). In the first study, I investigated the inflammatory profile at birth in 55 very preterm infants, compared to 59 term-born controls and then used this profile to predict exposure to intrauterine inflammation in the preterm group. Preterm infants had a distinct pro-inflammatory profile in umbilical cord blood at delivery when compared to term-born controls and IL-8 was found to be the strongest predictor of intrauterine inflammation. In the second study, I investigated the association between specific inflammation-associated proteins and white matter microstructure in 71 very preterm infants using structural MRI and diffusion-weighted imaging of the brain. Elevated IL-8 in the first week of life was associated with white matter dysmaturation at term-equivalent age. Following this discovery, I investigated the effect of IL-8 on the maturation and morphology of iPSC-derived cortical neurons and found that exposure was associated with impaired neurite outgrowth. This thesis provides further evidence to support the role of inflammation in the aetiology of preterm brain injury and suggests that IL-8 dysregulation may link systemic inflammation with atypical cortical development and white matter disease in preterm infants

Effect of preterm birth on white matter tracts and infant cognition

Preterm birth (defined as birth before 37 weeks) is a leading cause of neurocognitive impairment in childhood, including difficulties in social cognition and executive function. Microstructural divergence from typical brain development in the preterm brain can be quantified using diffusion magnetic resonance imaging (dMRI) tractography during the neonatal period. The relationship between dMRI tractography metrics and later cognitive difficulties remains inconclusive. A general measure of white matter microstructure (gWM) offers a neural basis for cognitive processes in adults, however it remains unclear when gWM is first detectable in the developmental trajectory. Eye-tracking is a technique which assesses eye-gaze behaviour in response to visual stimuli, which permits inference about underlying cognitive processes, such as social cognition and executive function in infancy. The primary aims of this thesis were to test the hypotheses: dMRI tractography reveals significant differences in tract-average fractional anisotropy (FA) and mean diffusivity (MD) between preterm and term infants, and variance in tract-average FA and MD is shared across major tracts. Secondly, infants born preterm have altered social cognition and executive function compared to term born peers, assessed by eye-tracking and finally, neonatal MRI gWM is associated with cognitive function in infancy. Preterm (birth weight ≤ 1500g) and term infants (born ≥ 37 weeks’ post-menstrual age [PMA]) were recruited and underwent a MRI scan at term equivalent age (between 38 - 42 weeks’ PMA) and an eye-tracking assessment six to nine months later. Preterm infants were assessed at two years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). dMRI tractography metrics were generated using probabilistic neighbourhood tractography (PNT) in eight pre-defined tracts-of-interest. Principal component analyses (PCA) were used to determine the correlations between the eight tracts-of-interest for four tract-averaged water diffusion parameters. dMRI metrics were compared to the eye-tracking performance and two year outcome data. Quantitative microstructural changes were identifiable within the preterm brain when compared to infants born at term. PCA revealed a single variable that accounts for nearly 50% of shared variance between tracts-of-interest, and all tracts showed positive loadings. Eye-tracking revealed group-wise differences in infant social cognition, attributable to preterm birth, but executive functions inferred from eye-tracking did not differ between groups. dMRI tractography metrics within the neonatal period did not relate to later outcome measures. This thesis shows that variance in dMRI parameters is substantially shared across white matter tracts of the developing brain and suggests that anatomical foundations of later intelligence are present by term equivalent age. Social cognition is altered by preterm birth, however social cognitive ability in infancy is independent of gWM

Using compartment models of diffusion MRI to investigate the preterm brain

Preterm birth is the leading cause of neonatal mortality, with survivors experiencing motor, cognitive and other deficits at increased rates. In preterm infancy, the developing brain undergoes folding, myelination, and rapid cellular growth. Diffusion-Weighted Magnetic Resonance Imaging (DW MRI) is an imaging modality that allows noninvasive inference of cellular microstructure in living tissue, and its parameters reflect changes in brain tissue composition. In this thesis, we employ compartment models of DW MRI to investigate the microstructure in preterm-born subjects at different ages. Within infants, we have used the NODDI model to investigate longitudinal changes in neurite density and orientation dispersion within the white matter, cerebral cortex and thalamus, explaining known trends in diffusion tensor parameters with greater specificity. We then used a quantitative T2 sequence to develop and investigate a novel, multi-modal parameter known as the ‘g-ratio’. We have also investigated changing microstructural geometry within the cortex. Immediately after preterm birth, the highly-ordered underlying cellular structure makes diffusion in the cortex almost entirely radial. This undergoes a transition to a disordered and isotropic state over the first weeks of life, which we have used the DIAMOND model to quantify. This radiality decreases at a rate that depends on the cortical lobe. In a cohort of young adults born extremely preterm, we have quantified differences in brain microstructure compared to term-born controls. In preterm subjects, the brain structures are smaller than for controls, leading to increased partial volume in some regions of interest. We introduce a method to infer diffusion parameters in partial volume, even for regions which are smaller than the diffusion resolution. Overall, this thesis utilises and evaluates a variety of compartment models of DW MRI. By developing and applying principled and robust methodology, we present new insights into microstructure within the preterm-born brain

Longitudinal analysis of extreme prematurity: a neuroimage investigation of early brain development

Brain development is a complex process, and disruptions from its normal course may affect the later neurological outcome of an individual. Preterm infants are at higher risk of disability, since a substantial part of brain development happens outside the mother’s womb, making it vulnerable to a range of insults. Understanding the early brain development during the preterm period is of critical importance and magnetic resonance imaging (MRI) allows us to investigate this. Methodologically, this is a challenging task, as classical approaches of studying longitudinal development over this period do not cope with the large changes taking place. This thesis focuses on the development of tools to study the changes in cortical folding, shape of different brain structures and microstructural changes over the preterm period from longitudinal data of extremely preterm-born infants. It describes a tissue segmentation pipeline, optimised on a postmortem fetal dataset, and then focuses on finding longitudinal correspondences between the preterm and termequivalent brain regions and structures in extremely preterm-born infants using MRI. Three novel registration techniques are proposed for longitudinal registration of this challenging data. These are based on matching the spectral components associated with either the cortical surfaces, diffusion tensor images, or both. These allow us to quantify longitudinal changes in different brain regions and structures. We investigated changes in cortical folding of different lobes, microstructural changes and tracts in the white matter, cortical thickness and changes in cortical fractional anisotropy and mean diffusivity. We used cortical surface registration to look at shape differences between controls and extremely preterm-born young adults to gain an insight into the long-term impact of prematurity. This research may contribute to the development of early biomarkers for predicting the neurological outcome of preterm infants and illuminate our understanding of brain development during this crucial period

Quantification of cortical folding using MR image data

The cerebral cortex is a thin layer of tissue lining the brain where neural circuits perform important high level functions including sensory perception, motor control and language processing. In the third trimester the fetal cortex folds rapidly from a smooth sheet into a highly convoluted arrangement of gyri and sulci. Premature birth is a high risk factor for poor neurodevelopmental outcome and has been associated with abnormal cortical development, however the nature of the disruption to developmental processes is not fully understood. Recent developments in magnetic resonance imaging have allowed the acquisition of high quality brain images of preterms and also fetuses in-utero. The aim of this thesis is to develop techniques which quantify folding from these images in order to better understand cortical development in these two populations. A framework is presented that quantifies global and regional folding using curvature-based measures. This methodology was applied to fetuses over a wide gestational age range (21.7 to 38.9 weeks) for a large number of subjects (N = 80) extending our understanding of how the cortex folds through this critical developmental period. The changing relationship between the folding measures and gestational age was modelled with a Gompertz function which allowed an accurate prediction of physiological age. A spectral-based method is outlined for constructing a spatio-temporal surface atlas (a sequence of mean cortical surface meshes for weekly intervals). A key advantage of this method is the ability to do group-wise atlasing without bias to the anatomy of an initial reference subject. Mean surface templates were constructed for both fetuses and preterms allowing a preliminary comparison of mean cortical shape over the postmenstrual age range 28-36 weeks. Displacement patterns were revealed which intensified with increasing prematurity, however more work is needed to evaluate the reliability of these findings.Open Acces