Minhui Ouyang

Graduation Semester and Year

2016

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Georgios Alexandrakis

Abstract

Human brain development is structurally and functionally a nonlinear process and even with the tremendous advancements in the field of neuroimaging based on Magnetic Resonance Imaging (MRI) several significant questions remain un-answered. Although brain change and adaption are part of a lifelong process, the earliest phases of maturation, especially from birth to early childhood, are perhaps the most dramatic and important. During this early developmental period, the structural and functional organization of the brain are continuously shaped by a combination of synaptogenesis, dendritic arborization, myelination and synaptic pruning. The current research aims to use more recently developed MRI techniques of diffusion magnetic resonance imaging (dMRI) and arterial spin labeling (ASL) to study brain maturation processes in typical and atypical development. The present body of work includes the study of brain functional development and correlation between functional changes with structural changes during early development (3rd trimester), and structural changes during later development in typical and atypical condition (autism spectrum disorder (ASD)). The first project (Chapter 2) studies the brain functional development, and relationship between functional changes and the cortical microstructure changes during the early stages of development (3rd trimester). To estimate the functional changes, pseudo-continuous ASL (pCASL) method was used, which quantifies the cerebral blood flow (CBF). The adult-pCASL protocol is not optimal in the extremely slow blood flow in the brains of neonate population, which was specifically optimized for this study. To measure the cortical microstructure changes, we used dMRI to estimate fractional anisotropy (FA) on cortical skeletonized level. Based on the data acquired from 34 subjects, the global CBF measurement was found to double its value during third 3rd trimester. These CBF increase was heterogeneous across the brain, with significantly higher rate of CBF increase in the frontal lobe than in the occipital lobe. Moreover, the increasing CBF observed in frontal lobe corresponded to lower FA values in the same region, which suggests the dendritic arborization and synaptic formatting might be associated with an elevation of local CBF. In the second project (Chapter 3), dMRI was used to study the structural changes in a cohort of children with typical developing (TD) and ASD. The deep white matter (WM) voxels were surveyed to detect differences in WM microstructural development between 31 children with ASD ages of 2-7 years and 19 age-matched children with TD, using FA and radial diffusivity (RD) measures from dMRI. The anatomical locations, distribution, and extent of the core WM voxels with atypical age-dependent changes in a specific tract or tract group were delineated and evaluated by integrating the skeletonized WM with a digital atlas. Exclusively, unidirectional FA increases and RD decreases in widespread WM tracts were revealed in children with ASD before 4 years, with bi-directional changes found for children with ASD of 2-7 years. Compared to progressive development that raised FA and lowered RD during 2-7 years in the TD group, flattened curves of WM maturation were found in multiple major WM tracts of all five tract groups, particularly associational and limbic tracts, in the ASD group with trend lines of ASD and TD crossed around 4 years. Finally, a novel attempt to estimate superficial WM or short-range association fibers (SAF) in typically and atypically developmental human brain is proposed in the Chapter 4. A lot has been well characterized and understood about deep WM or longrange association fibers (LAF) in early brain development using dMRI, but very little is known about SAF. The normalized SAF (NSAF) index, defined as the ratio of the number of SAF to the number of cortico-cortical connectivity fibers (sum of SAF and LAF) traced from a given cortical gyrus based on dMRI tractography, was proposed to characterize the SAF development. Initially, dMRI data from in 21 healthy subjects, aged 2-25 years, was used to study the typically developmental trajectories of NSAF. The NSAF showed spatiotemporal heterogeneity, decreasing in early childhood and increasing with age, with lowest NSAF reached at various ages among different cortical gyri. Then, NSAF was also applied to data from to 31 children with ASD aged 2-7 years and 19 age-matched children with TD to explore its sensitivity under pathological condition. The decrease of whole brain NSAF was highly correlated with global network efficiency increase (calculated from structural network based on graph theory) in young children with TD but not with ASD, indicating the important role of balance between SAF and LAF during the brain network reconfiguration process. Moreover, significant age dependent NSAF in prefrontal and default-mode network hub regions were observed in TD but not ASD group. In conclusion, the present research work demonstrates the feasibility of using ASL to study the regional CBF of neonates during 3rd trimester under normal or pathological conditions (e.g. hypoxic-ischemic encephalopathy or neonatal congenital heart disease) on a 3T MRI scanner. Secondly, the work showed the atypical agedependent changes of FA and RD widely in ASD and these converging findings from both group comparisons at different age ranges and trajectory analyses may help elucidate the seemingly non-uniform WM finding of children with ASD reported in prior studies. Last, altered maturation of short-range connection in higher-order brain regions were found in children with ASD, which may offer structural basis for the functional over-connectivity of short-range connection in ASD and also suggest the NSAF could be a potential biomarker for delineation normal brain development and diagnosis of several mental disorders.

Keywords

Brain development, Autism spectrum disorder, Short-range association fibers, Magnetic resonance imaging, Diffusion tensor imaging, Arterial spin labeling

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

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