Multivariate Modeling of longitudinal MRI in early brain development with confidence measures

pre-printThe human brain undergoes rapid organization and structuring early in life. Longitudinal imaging enables the study of these changes over a developmental period within individuals through estimation of population growth trajectory and its variability. In this paper, we focus on maturation of white and gray matter depicted in structural and diffusion MRI of healthy subjects with repeated scans. We provide a framework for joint analysis of both structural MRI and DTI (Diffusion Tensor Imaging) using multivariate nonlinear mixed effect modeling of temporal changes. Our framework constructs normative growth models for all the modalities, taking into account the correlation among the modalities and individuals, along with estimation of the variability of the population trends. We apply our method to study early brain development, and to our knowledge this is the first multimodel longitudinal modeling of diffusion and signal intensity changes for this growth stage. Results show the potential of our framework to study growth trajectories, as well as neurodevelopmental disorders through comparison against the constructed normative models of multimodal 4D MRI

Predicting the course of Alzheimer's progression.

Alzheimer's disease is the most common neurodegenerative disease and is characterized by the accumulation of amyloid-beta peptides leading to the formation of plaques and tau protein tangles in brain. These neuropathological features precede cognitive impairment and Alzheimer's dementia by many years. To better understand and predict the course of disease from early-stage asymptomatic to late-stage dementia, it is critical to study the patterns of progression of multiple markers. In particular, we aim to predict the likely future course of progression for individuals given only a single observation of their markers. Improved individual-level prediction may lead to improved clinical care and clinical trials. We propose a two-stage approach to modeling and predicting measures of cognition, function, brain imaging, fluid biomarkers, and diagnosis of individuals using multiple domains simultaneously. In the first stage, joint (or multivariate) mixed-effects models are used to simultaneously model multiple markers over time. In the second stage, random forests are used to predict categorical diagnoses (cognitively normal, mild cognitive impairment, or dementia) from predictions of continuous markers based on the first-stage model. The combination of the two models allows one to leverage their key strengths in order to obtain improved accuracy. We characterize the predictive accuracy of this two-stage approach using data from the Alzheimer's Disease Neuroimaging Initiative. The two-stage approach using a single joint mixed-effects model for all continuous outcomes yields better diagnostic classification accuracy compared to using separate univariate mixed-effects models for each of the continuous outcomes. Overall prediction accuracy above 80% was achieved over a period of 2.5 years. The results further indicate that overall accuracy is improved when markers from multiple assessment domains, such as cognition, function, and brain imaging, are used in the prediction algorithm as compared to the use of markers from a single domain only

Multivariate MR Biomarkers Better Predict Cognitive Dysfunction in Mouse Models of Alzheimers Disease

To understand multifactorial conditions such as Alzheimers disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included the hippocampus, olfactory areas, entorhinal cortex and cerebellum. The image based properties of these regions were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.Comment: 23 pages, 3 Tables, 6 Figures; submitted for publicatio

Doctor of Philosophy

dissertationMany mental illnesses are thought to have their origins in early stages of development, encouraging increased research efforts related to early neurodevelopment. Magnetic resonance imaging (MRI) has provided us with an unprecedented view of the brain in vivo. More recently, diffusion tensor imaging (DTI/DT-MRI), a magnetic resonance imaging technique, has enabled the characterization of the microstrucutral organization of tissue in vivo. As the brain develops, the water content in the brain decreases while protein and fat content increases due to processes such as myelination and axonal organization. Changes of signal intensity in structural MRI and diffusion parameters of DTI reflect these underlying biological changes. Longitudinal neuroimaging studies provide a unique opportunity for understanding brain maturation by taking repeated scans over a time course within individuals. Despite the availability of detailed images of the brain, there has been little progress in accurate modeling of brain development or creating predictive models of structure that could help identify early signs of illness. We have developed methodologies for the nonlinear parametric modeling of longitudinal structural MRI and DTI changes over the neurodevelopmental period to address this gap. This research provides a normative model of early brain growth trajectory as is represented in structural MRI and DTI data, which will be crucial to understanding the timing and potential mechanisms of atypical development. Growth trajectories are described via intuitive parameters related to delay, rate of growth, and expected asymptotic values, all descriptive measures that can answer clinical questions related to quantitative analysis of growth patterns. We demonstrate the potential of the framework on two clinical studies: healthy controls (singletons and twins) and children at risk of autism. Our framework is designed not only to provide qualitative comparisons, but also to give researchers and clinicians quantitative parameters and a statistical testing scheme. Moreover, the method includes modeling of growth trajectories of individuals, resulting in personalized profiles. The statistical framework also allows for prediction and prediction intervals for subject-specific growth trajectories, which will be crucial for efforts to improve diagnosis for individuals and personalized treatment

Disentangling causal webs in the brain using functional Magnetic Resonance Imaging: A review of current approaches

In the past two decades, functional Magnetic Resonance Imaging has been used to relate neuronal network activity to cognitive processing and behaviour. Recently this approach has been augmented by algorithms that allow us to infer causal links between component populations of neuronal networks. Multiple inference procedures have been proposed to approach this research question but so far, each method has limitations when it comes to establishing whole-brain connectivity patterns. In this work, we discuss eight ways to infer causality in fMRI research: Bayesian Nets, Dynamical Causal Modelling, Granger Causality, Likelihood Ratios, LiNGAM, Patel's Tau, Structural Equation Modelling, and Transfer Entropy. We finish with formulating some recommendations for the future directions in this area

A model of brain morphological changes related to aging and Alzheimer's disease from cross-sectional assessments

In this study we propose a deformation-based framework to jointly model the influence of aging and Alzheimer's disease (AD) on the brain morphological evolution. Our approach combines a spatio-temporal description of both processes into a generative model. A reference morphology is deformed along specific trajectories to match subject specific morphologies. It is used to define two imaging progression markers: 1) a morphological age and 2) a disease score. These markers can be computed locally in any brain region. The approach is evaluated on brain structural magnetic resonance images (MRI) from the ADNI database. The generative model is first estimated on a control population, then, for each subject, the markers are computed for each acquisition. The longitudinal evolution of these markers is then studied in relation with the clinical diagnosis of the subjects and used to generate possible morphological evolution. In the model, the morphological changes associated with normal aging are mainly found around the ventricles, while the Alzheimer's disease specific changes are more located in the temporal lobe and the hippocampal area. The statistical analysis of these markers highlights differences between clinical conditions even though the inter-subject variability is quiet high. In this context, the model can be used to generate plausible morphological trajectories associated with the disease. Our method gives two interpretable scalar imaging biomarkers assessing the effects of aging and disease on brain morphology at the individual and population level. These markers confirm an acceleration of apparent aging for Alzheimer's subjects and can help discriminate clinical conditions even in prodromal stages. More generally, the joint modeling of normal and pathological evolutions shows promising results to describe age-related brain diseases over long time scales.Comment: NeuroImage, Elsevier, In pres

Doctor of Philosophy

dissertationAn important aspect of medical research is the understanding of anatomy and its relation to function in the human body. For instance, identifying changes in the brain associated with cognitive decline helps in understanding the process of aging and age-related neurological disorders. The field of computational anatomy provides a rich mathematical setting for statistical analysis of complex geometrical structures seen in 3D medical images. At its core, computational anatomy is based on the representation of anatomical shape and its variability as elements of nonflat manifold of diffeomorphisms with an associated Riemannian structure. Although such manifolds effectively represent natural biological variability, intrinsic methods of statistical analysis within these spaces remain deficient at large. This dissertation contributes two critical missing pieces for statistics in diffeomorphisms: (1) multivariate regression models for cross-sectional study of shapes, and (2) generalization of classical Euclidean, mixed-effects models to manifolds for longitudinal studies. These models are based on the principle that statistics on manifold-valued information must respect the intrinsic geometry of that space. The multivariate regression methods provide statistical descriptors of the relationships of anatomy with clinical indicators. The novel theory of hierarchical geodesic models (HGMs) is developed as a natural generalization of hierarchical linear models (HLMs) to describe longitudinal data on curved manifolds. Using a hierarchy of geodesics, the HGMs address the challenge of modeling the shape-data with unbalanced designs typically arising as a result of follow-up medical studies. More generally, this research establishes a mathematical foundation to study dynamics of changes in anatomy and the associated clinical progression with time. This dissertation also provides efficient algorithms that utilize state-of-the-art high performance computing architectures to solve models on large-scale, longitudinal imaging data. These manifold-based methods are applied to predictive modeling of neurological disorders such as Alzheimer's disease. Overall, this dissertation enables clinicians and researchers to better utilize the structural information available in medical images