Spatio-temporal Modeling and Analysis of Brain Development

The incidence of preterm birth is increasing and has emerged as a leading cause of neurodevelopmental impairment in childhood. In early development, defined here as the period before and around birth, the brain undergoes significant morphological, functional and appearance changes. The scope and rate of change is arguably greater than at any other time in life, but quantitative markers of this period of development are limited. Improved understanding of cerebral changes during this critical period is important for mapping normal growth, and for investigating mechanisms of injury associated with risk factors for maldevelopment such as premature birth. The objective of this thesis is the development of methods for spatio-temporal modeling and quantitative measures of brain development that can assist understanding the patterns of normal growth and can guide interventions designed to reduce the burden of preterm brain injury. An approach for constructing high-definition spatio-temporal atlases of the developing brain is introduced. A novelty in the proposed approach is the use of a time-varying kernel width, to overcome the variations in the distribution of subjects at different ages. This leads to an atlas that retains a consistent level of detail at every time-point. The resulting 4D fetal and neonatal average atlases have greater anatomic definition than currently available 4D atlases, an important factor in improving registrations between the atlas and individual subjects with clear anatomical structures and atlas-based automatic segmentation. The fetal atlas provides a natural benchmark for assessing preterm born neonates and gives some insight into differences between the groups. Also, a novel framework for longitudinal registration which can accommodate large intra-subject anatomical variations is introduced. The framework exploits previously developed spatio-temporal atlases, which can aid the longitudinal registration process as it provides prior information about the missing anatomical evolution between two scans taken over large time-interval. Finally, a voxel-wise analysis framework is proposed which complements the analysis of changes in brain morphology by the study of spatio-temporal signal intensity changes in multi-modal MRI, which can offer a useful marker of neurodevelopmental changes

A normative spatiotemporal MRI atlas of the fetal brain for automatic segmentation and analysis of early brain growth.

Longitudinal characterization of early brain growth in-utero has been limited by a number of challenges in fetal imaging, the rapid change in size, shape and volume of the developing brain, and the consequent lack of suitable algorithms for fetal brain image analysis. There is a need for an improved digital brain atlas of the spatiotemporal maturation of the fetal brain extending over the key developmental periods. We have developed an algorithm for construction of an unbiased four-dimensional atlas of the developing fetal brain by integrating symmetric diffeomorphic deformable registration in space with kernel regression in age. We applied this new algorithm to construct a spatiotemporal atlas from MRI of 81 normal fetuses scanned between 19 and 39 weeks of gestation and labeled the structures of the developing brain. We evaluated the use of this atlas and additional individual fetal brain MRI atlases for completely automatic multi-atlas segmentation of fetal brain MRI. The atlas is available online as a reference for anatomy and for registration and segmentation, to aid in connectivity analysis, and for groupwise and longitudinal analysis of early brain growth

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

Interpreting Age Effects of Human Fetal Brain from Spontaneous fMRI using Deep 3D Convolutional Neural Networks

Understanding human fetal neurodevelopment is of great clinical importance as abnormal development is linked to adverse neuropsychiatric outcomes after birth. Recent advances in functional Magnetic Resonance Imaging (fMRI) have provided new insight into development of the human brain before birth, but these studies have predominately focused on brain functional connectivity (i.e. Fisher z-score), which requires manual processing steps for feature extraction from fMRI images. Deep learning approaches (i.e., Convolutional Neural Networks) have achieved remarkable success on learning directly from image data, yet have not been applied on fetal fMRI for understanding fetal neurodevelopment. Here, we bridge this gap by applying a novel application of deep 3D CNN to fetal blood oxygen-level dependence (BOLD) resting-state fMRI data. Specifically, we test a supervised CNN framework as a data-driven approach to isolate variation in fMRI signals that relate to younger v.s. older fetal age groups. Based on the learned CNN, we further perform sensitivity analysis to identify brain regions in which changes in BOLD signal are strongly associated with fetal brain age. The findings demonstrate that deep CNNs are a promising approach for identifying spontaneous functional patterns in fetal brain activity that discriminate age groups. Further, we discovered that regions that most strongly differentiate groups are largely bilateral, share similar distribution in older and younger age groups, and are areas of heightened metabolic activity in early human development.Comment: 9 page

Learning to synthesise the ageing brain without longitudinal data

How will my face look when I get older? Or, for a more challenging question: How will my brain look when I get older? To answer this question one must devise (and learn from data) a multivariate auto-regressive function which given an image and a desired target age generates an output image. While collecting data for faces may be easier, collecting longitudinal brain data is not trivial. We propose a deep learning-based method that learns to simulate subject-specific brain ageing trajectories without relying on longitudinal data. Our method synthesises images conditioned on two factors: age (a continuous variable), and status of Alzheimer's Disease (AD, an ordinal variable). With an adversarial formulation we learn the joint distribution of brain appearance, age and AD status, and define reconstruction losses to address the challenging problem of preserving subject identity. We compare with several benchmarks using two widely used datasets. We evaluate the quality and realism of synthesised images using ground-truth longitudinal data and a pre-trained age predictor. We show that, despite the use of cross-sectional data, our model learns patterns of gray matter atrophy in the middle temporal gyrus in patients with AD. To demonstrate generalisation ability, we train on one dataset and evaluate predictions on the other. In conclusion, our model shows an ability to separate age, disease influence and anatomy using only 2D cross-sectional data that should be useful in large studies into neurodegenerative disease, that aim to combine several data sources. To facilitate such future studies by the community at large our code is made available at https://github.com/xiat0616/BrainAgeing

Computerized Analysis of Magnetic Resonance Images to Study Cerebral Anatomy in Developing Neonates

The study of cerebral anatomy in developing neonates is of great importance for the understanding of brain development during the early period of life. This dissertation therefore focuses on three challenges in the modelling of cerebral anatomy in neonates during brain development. The methods that have been developed all use Magnetic Resonance Images (MRI) as source data. To facilitate study of vascular development in the neonatal period, a set of image analysis algorithms are developed to automatically extract and model cerebral vessel trees. The whole process consists of cerebral vessel tracking from automatically placed seed points, vessel tree generation, and vasculature registration and matching. These algorithms have been tested on clinical Time-of- Flight (TOF) MR angiographic datasets. To facilitate study of the neonatal cortex a complete cerebral cortex segmentation and reconstruction pipeline has been developed. Segmentation of the neonatal cortex is not effectively done by existing algorithms designed for the adult brain because the contrast between grey and white matter is reversed. This causes pixels containing tissue mixtures to be incorrectly labelled by conventional methods. The neonatal cortical segmentation method that has been developed is based on a novel expectation-maximization (EM) method with explicit correction for mislabelled partial volume voxels. Based on the resulting cortical segmentation, an implicit surface evolution technique is adopted for the reconstruction of the cortex in neonates. The performance of the method is investigated by performing a detailed landmark study. To facilitate study of cortical development, a cortical surface registration algorithm for aligning the cortical surface is developed. The method first inflates extracted cortical surfaces and then performs a non-rigid surface registration using free-form deformations (FFDs) to remove residual alignment. Validation experiments using data labelled by an expert observer demonstrate that the method can capture local changes and follow the growth of specific sulcus

Flexible Bayesian Dynamic Modeling of Correlation and Covariance Matrices

Modeling correlation (and covariance) matrices can be challenging due to the positive-definiteness constraint and potential high-dimensionality. Our approach is to decompose the covariance matrix into the correlation and variance matrices and propose a novel Bayesian framework based on modeling the correlations as products of unit vectors. By specifying a wide range of distributions on a sphere (e.g. the squared-Dirichlet distribution), the proposed approach induces flexible prior distributions for covariance matrices (that go beyond the commonly used inverse-Wishart prior). For modeling real-life spatio-temporal processes with complex dependence structures, we extend our method to dynamic cases and introduce unit-vector Gaussian process priors in order to capture the evolution of correlation among components of a multivariate time series. To handle the intractability of the resulting posterior, we introduce the adaptive $\Delta$-Spherical Hamiltonian Monte Carlo. We demonstrate the validity and flexibility of our proposed framework in a simulation study of periodic processes and an analysis of rat's local field potential activity in a complex sequence memory task.Comment: 49 pages, 15 figure