Towards an efficient segmentation of small rodents brain: a short critical review

One of the most common tasks in small rodents MRI pipelines is the voxel-wise segmentation of the volume in multiple classes. While many segmentation schemes have been developed for the human brain, fewer are available for rodent MRI, often by adaptation from human neuroimaging. Common methods include atlas-based and clustering schemes. The former labels the target volume by registering one or more pre-labeled atlases using a deformable registration method, in which case the result depends on the quality of the reference volumes, the registration algorithm and the label fusion approach, if more than one atlas is employed. The latter is based on an expectation maximization procedure to maximize the variance between voxel categories, and is often combined with Markov Random Fields and the atlas based approach to include spatial information, priors, and improve the classification accuracy. Our primary goal is to critically review the state of the art of rat and mouse segmentation of neuro MRI volumes and compare the available literature on popular, readily and freely available MRI toolsets, including SPM, FSL and ANTs, when applied to this task in the context of common pre-processing steps. Furthermore, we will briefly address the emerging Deep Learning methods for the segmentation of medical imaging, and the perspectives for applications to small rodents

Development and evaluation of biomarkers in Huntington’s Disease: furthering our understanding of the disease and preparing for clinical trials

Huntington’s Disease (HD) is a devastating hereditary neurodegenerative disease for which there are currently only symptomatic treatments. Several potentially curative pharmaceutical and genetic therapies are however in varying stages of development and therefore an increasing number of large-scale clinical trials of disease-modifying therapies are imminent. There is consequently a need for biomarkers which are sensitive to beneficial attenuation of disease-related changes. Functional, neuroimaging and biochemical biomarkers have been developed in HD (Andre et al. 2014;Weir et al. 2011). Neuroimaging biomarkers are strong candidates based on their clear relevance to the neuropathology of disease, proven precision and superior sensitivity compared with some standard functional measures (Tabrizi et al. 2011;Tabrizi et al. 2012). Their use in early-stage clinical trials, as surrogate end-points providing initial evidence of biological effect, is becoming increasingly common. Comparison of biomarkers in HD will help to clarify which measures, over varying time intervals, are most sensitive to disease progression. Additionally, the identification of robust fully-automated methods, comparable to manual and semi-automated gold-standards, would facilitate large-scale volumetric analysis. These methods however require validation in observational studies of neurodegenerative disease before they can be applied to sensitive clinical trial data. This thesis will develop and evaluate biomarkers for use in HD; both furthering our understanding of the disease and in preparation for use as end-points in clinical trials. A direct comparison of the sensitivity of diffusion and volumetric imaging biomarkers to HD-related change will be reported for the first time. Several exploratory imaging investigations are also described which enhance current knowledge of the relationship between neuroimaging metrics, brain functioning and behaviour, additionally strengthening the argument for the clinical relevance of neuroimaging measures as surrogate end-points in HD. The thesis will conclude with a comprehensive biomarker evaluation in early-stage HD, along with suggested strategies for selection of primary and secondary trial end-points based on effect sizes and corresponding sample size requirements

DEEP-AD: The deep learning model for diagnostic classification and prognostic prediction of alzheimer's disease

In terms of context, the aim of this dissertation is to aid neuroradiologists in their clinical judgment regarding the early detection of AD by using DL. To that aim, the system design research methodology is suggested in this dissertation for achieving three goals. The first goal is to investigate the DL models that have performed well at identifying patterns associated with AD, as well as the accuracy so far attained, limitations, and gaps. A systematic review of the literature (SLR) revealed a shortage of empirical studies on the early identification of AD through DL. In this regard, thirteen empirical studies were identified and examined. We concluded that three-dimensional (3D) DL models have been generated far less often and that their performance is also inadequate to qualify them for clinical trials. The second goal is to provide the neuroradiologist with the computer-interpretable information they need to analyze neuroimaging biomarkers. Given this context, the next step in this dissertation is to find the optimum DL model to analyze neuroimaging biomarkers. It has been achieved in two steps. In the first step, eight state-of-the-art DL models have been implemented by training from scratch using end-to-end learning (E2EL) for two binary classification tasks (AD vs. CN and AD vs. stable MCI) and compared by utilizing MRI scans from the publicly accessible datasets of neuroimaging biomarkers. Comparative analysis is carried out by utilizing efficiency-effects graphs, comprehensive indicators, and ranking mechanisms. For the training of the AD vs. sMCI task, the EfficientNet-B0 model gets the highest value for the comprehensive indicator and has the fewest parameters. DenseNet264 performed better than the others in terms of evaluation matrices, but since it has the most parameters, it costs more to train. For the AD vs. CN task by DenseNet264, we achieved 100% accuracy for training and 99.56% accuracy for testing. However, the classification accuracy was still only 82.5% for the AD vs. sMCI task. In the second step, fusion of transfer learning (TL) with E2EL is applied to train the EfficientNet-B0 for the AD vs. sMCI task, which achieved 95.29% accuracy for training and 93.10% accuracy for testing. Additionally, we have also implemented EfficientNet-B0 for the multiclass AD vs. CN vs. sMCI classification task with E2EL to be used in ensemble of models and achieved 85.66% training accuracy and 87.38% testing accuracy. To evaluate the model’s robustness, neuroradiologists must validate the implemented model. As a result, the third goal of this dissertation is to create a tool that neuroradiologists may use at their convenience. To achieve this objective, this dissertation proposes a web-based application (DEEP-AD) that has been created by making an ensemble of Efficient-Net B0 and DenseNet 264 (based on the contribution of goal 2). The accuracy of a DEEP-AD prototype has undergone repeated evaluation and improvement. First, we validated 41 subjects of Spanish MRI datasets (acquired from HT Medica, Madrid, Spain), achieving an accuracy of 82.90%, which was later verified by neuroradiologists. The results of these evaluation studies showed the accomplishment of such goals and relevant directions for future research in applied DL for the early detection of AD in clinical settings.En términos de contexto, el objetivo de esta tesis es ayudar a los neurorradiólogos en su juicio clínico sobre la detección precoz de la AD mediante el uso de DL. Para ello, en esta tesis se propone la metodología de investigación de diseño de sistemas para lograr tres objetivos. El segundo objetivo es proporcionar al neurorradiólogo la información interpretable por ordenador que necesita para analizar los biomarcadores de neuroimagen. Dado este contexto, el siguiente paso en esta tesis es encontrar el modelo DL óptimo para analizar biomarcadores de neuroimagen. Esto se ha logrado en dos pasos. En el primer paso, se han implementado ocho modelos DL de última generación mediante entrenamiento desde cero utilizando aprendizaje de extremo a extremo (E2EL) para dos tareas de clasificación binarias (AD vs. CN y AD vs. MCI estable) y se han comparado utilizando escaneos MRI de los conjuntos de datos de biomarcadores de neuroimagen de acceso público. El análisis comparativo se lleva a cabo utilizando gráficos de efecto-eficacia, indicadores exhaustivos y mecanismos de clasificación. Para el entrenamiento de la tarea AD vs. sMCI, el modelo EfficientNet-B0 obtiene el valor más alto para el indicador exhaustivo y tiene el menor número de parámetros. DenseNet264 obtuvo mejores resultados que los demás en términos de matrices de evaluación, pero al ser el que tiene más parámetros, su entrenamiento es más costoso. Para la tarea AD vs. CN de DenseNet264, conseguimos una accuracy del 100% en el entrenamiento y del 99,56% en las pruebas. Sin embargo, la accuracy de la clasificación fue sólo del 82,5% para la tarea AD vs. sMCI. En el segundo paso, se aplica la fusión del aprendizaje por transferencia (TL) con E2EL para entrenar la EfficientNet-B0 para la tarea AD vs. sMCI, que alcanzó una accuracy del 95,29% en el entrenamiento y del 93,10% en las pruebas. Además, también hemos implementado EfficientNet-B0 para la tarea de clasificación multiclase AD vs. CN vs. sMCI con E2EL para su uso en conjuntos de modelos y hemos obtenido una accuracy de entrenamiento del 85,66% y una precisión de prueba del 87,38%. Para evaluar la solidez del modelo, los neurorradiólogos deben validar el modelo implementado. Como resultado, el tercer objetivo de esta disertación es crear una herramienta que los neurorradiólogos puedan utilizar a su conveniencia. Para lograr este objetivo, esta disertación propone una aplicación basada en web (DEEP-AD) que ha sido creada haciendo un ensemble de Efficient-Net B0 y DenseNet 264 (basado en la contribución del objetivo 2). La accuracy del prototipo DEEP-AD ha sido sometida a repetidas evaluaciones y mejoras. En primer lugar, validamos 41 sujetos de conjuntos de datos de MRI españoles (adquiridos de HT Medica, Madrid, España), logrando una accuracy del 82,90%, que posteriormente fue verificada por neurorradiólogos. Los resultados de estos estudios de evaluación mostraron el cumplimiento de dichos objetivos y las direcciones relevantes para futuras investigaciones en DL, aplicada en la detección precoz de la AD en entornos clínicos.Escuela de DoctoradoDoctorado en Tecnologías de la Información y las Telecomunicacione

Preprocessing methods for morphometric brain analysis and quality assurance of structural magnetic resonance images

Gegenstand der Dissertation ist die Neuentwicklung und Validierung von Verfahren zur Aufbereitung von anatomischen Daten, die mittels Magnetresonanztomographie gewonnen wurden. Ziel ist dabei die Erfassung von morphometrischen Kennwerten zur Beschreibung der Struktur und Form des Gehirns, wie beispielsweise Volumen, Fläche, Dicke oder Faltung der Großhirnrinde. Die Kennwerte erlauben sowohl die Erforschung individueller gesunder und pathologischer Entwicklung als auch der evolutionären Anpassung des Gehirns. Die zur Datenanalyse notwendige Vorverarbeitung beinhaltet dabei die Angleichung von Bildeigenschaften und individueller Anatomie. Die fortlaufende Weiterentwicklung der Scanner- und Rechentechnik ermöglicht eine zunehmend genauere Bildgebung, erfordert aber die kontinuierliche Anpassung existierender Verfahren. Die Schwerpunkte dieser Dissertation lagen in der Entwicklung neuer Verfahren zur (i) Klassifikation der Hirngewebe (Segmentierung), (ii) räumlichen Abbildung des individuellen Gehirns auf ein Durchschnittsgehirn (Registrierung), (iii) Bestimmung der Dicke der Großhirnrinde und Rekonstruktion einer repräsentativen Oberfläche und (iv) Qualitätssicherung der Eingangsdaten. Die Segmentierung gleicht die Bildeigenschaften unterschiedlicher Protokolle an, während die Registrierung anatomische Merkmale normalisiert und so den Vergleich verschiedener Gehirne ermöglicht. Die Rekonstruktion von Oberflächen erlaubt wiederum die Gewinnung einer Vielzahl weiterer morphometrischer Maße zur spezifischen Charakterisierung des Gehirns und seiner Entwicklung. Anhand von simulierten und realen Daten wird die Validität der neuen Methoden belegt und mit anderen Ansätzen verglichen. Die Verfahren sind Bestandteil der Computational Anatomy Toolbox (CAT; http://dbm.neuro.uni-jena.de/cat), deren Schwerpunkt die Vorverarbeitung von strukturellen Daten ist und die Teil des Statistical Parametric Mapping (SPM) Softwarepaketes in MATLAB ist.This Ph.D. thesis focuses on the development, optimization and validation of preprocessing methods of structural magnetic resonance images of the brain. The preprocessing describes the creation of morphometric data that support a statistical analysis of brain anatomy. Image interferences have to be removed to allow a tissue classification (segmentation). In order to compare different subjects a spatial normalization to an average-shaped brain (template) is required, where atlas maps allow identification of specific brain structures and regions of interest. Beside the analysis in a voxel-grid, the cortex can be represented by surfaces that allow further measures such as the cortical thickness or folding. The derived brain features (such as volume, area, and thickness) permit the individual study of normal and pathological development during the lifespan but also of the evolutionary adaption of the brain. The ongoing progress of imaging and computing technology demands continous enhancement of preprocessing tools but also facilitates the exploration of novel approaches and models. The basis of this thesis is the development of a method that uses a tissue segmentation to estimate the cortical thickness and the central surface in one integrated step. Further essential improvements of surface reconstruction algorithms were achieved by specific refinement of processing steps such as (i) the classification of brain tissue (segmentation), (ii) the spatial mapping of the individual brain to an average brain (registration), (iii) determining the thickness of the cerebral cortex and reconstructing a representative surface and (iv) the quality assurance of input data. The validity of the new methods is proven and compared with other approaches by simulated and real data. The procedures are part of the Computational Anatomy Toolbox (CAT; http://dbm.neuro.uni-jena.de/cat), which focuses on the preprocessing of structural data and is part of the Statistical Parametric Mapping (SPM) software package in MATLAB

AN EDGE-CENTRIC PERSPECTIVE FOR BRAIN NETWORK COMMUNITIES

Thesis (Ph.D.) - Indiana University, Department of Psychological and Brain Sciences and Program in Neuroscience, 2021The brain is a complex system organized on multiple scales and operating in both a local and distributed manner. Individual neurons and brain regions participate in specific functions, while at the same time existing in the context of a larger network, supporting a range of different functionalities. Building brain networks comprised of distinct neural elements (nodes) and their interrelationships (edges), allows us to model the brain from both local and global perspectives, and to deploy a wide array of computational network tools. A popular network analysis approach is community detection, which aims to subdivide a network’s nodes into clusters that can used to represent and evaluate network organization. Prevailing community detection approaches applied to brain networks are designed to find densely interconnected sets of nodes, leading to the notion that the brain is organized in an exclusively modular manner. Furthermore, many brain network analyses tend to focus on the nodes, evidenced by the search for modular groupings of neural elements that might serve a common function. In this thesis, we describe the application of community detection algorithms that are sensitive to alternative cluster configurations, enhancing our understanding of brain network organization. We apply a framework called the stochastic block model, which we use to uncover evidence of non-modular organization in human anatomical brain networks across the life span, and in the informatically-collated rat cerebral cortex. We also propose a framework to cluster functional brain network edges in human data, which naturally results in an overlapping organization at the level of nodes that bridges canonical functional systems. These alternative methods utilize the connection patterns of brain network edges in ways that prevailing approaches do not. Thus, we motivate an alternative outlook which focuses on the importance of information provided by the brain’s interconnections, or edges. We call this an edge-centric perspective. The edge-centric approaches developed here offer new ways to characterize distributed brain organization and contribute to a fundamental change in perspective in our thinking about the brain