Extracting Vascular Networks under Physiological Constraints via Integer Programming

Abstract. We introduce an integer programming-based approach to vessel net-work extraction that enforces global physiological constraints on the vessel struc-ture and learn this prior from a high-resolution reference network. The method accounts for both image evidence and geometric relationships between vessels by formulating and solving an integer programming problem. Starting from an over-connected network, it is pruning vessel stumps and spurious connections by evaluating bifurcation angle and connectivity of the graph. We utilize a high-resolution micro computed tomography (µCT) dataset of a cerebrovascular corro-sion cast to obtain a reference network, perform experiments on micro magnetic resonance angiography (µMRA) images of mouse brains and discuss properties of the networks obtained under different tracking and pruning approaches.

Anatomical Modeling of Cerebral Microvascular Structures: Application to Identify Biomarkers of Microstrokes

Les réseaux microvasculaires corticaux sont responsables du transport de l’oxygène et des substrats énergétiques vers les neurones. Ces réseaux réagissent dynamiquement aux demandes énergétiques lors d’une activation neuronale par le biais du couplage neurovasculaire. Afin d’élucider le rôle de la composante microvasculaire dans ce processus de couplage, l’utilisation de la modélisation in-formatique pourrait se révéler un élément clé. Cependant, la manque de méthodologies de calcul appropriées et entièrement automatisées pour modéliser et caractériser les réseaux microvasculaires reste l’un des principaux obstacles. Le développement d’une solution entièrement automatisée est donc important pour des explorations plus avancées, notamment pour quantifier l’impact des mal-formations vasculaires associées à de nombreuses maladies cérébrovasculaires. Une observation courante dans l’ensemble des troubles neurovasculaires est la formation de micro-blocages vascu-laires cérébraux (mAVC) dans les artérioles pénétrantes de la surface piale. De récents travaux ont démontré l’impact de ces événements microscopiques sur la fonction cérébrale. Par conséquent, il est d’une importance vitale de développer une approche non invasive et comparative pour identifier leur présence dans un cadre clinique. Dans cette thèse,un pipeline de traitement entièrement automatisé est proposé pour aborder le prob-lème de la modélisation anatomique microvasculaire. La méthode de modélisation consiste en un réseau de neurones entièrement convolutif pour segmenter les capillaires sanguins, un générateur de modèle de surface 3D et un algorithme de contraction de la géométrie pour produire des mod-èles graphiques vasculaires ne comportant pas de connections multiples. Une amélioration de ce pipeline est développée plus tard pour alléger l’exigence de maillage lors de la phase de représen-tation graphique. Un nouveau schéma permettant de générer un modèle de graphe est développé avec des exigences d’entrée assouplies et permettant de retenir les informations sur les rayons des vaisseaux. Il est inspiré de graphes géométriques déformants construits en respectant les morpholo-gies vasculaires au lieu de maillages de surface. Un mécanisme pour supprimer la structure initiale du graphe à chaque exécution est implémenté avec un critère de convergence pour arrêter le pro-cessus. Une phase de raffinement est introduite pour obtenir des modèles vasculaires finaux. La modélisation informatique développée est ensuite appliquée pour simuler les signatures IRM po-tentielles de mAVC, combinant le marquage de spin artériel (ASL) et l’imagerie multidirectionnelle pondérée en diffusion (DWI). L’hypothèse est basée sur des observations récentes démontrant une réorientation radiale de la microvascularisation dans la périphérie du mAVC lors de la récupéra-tion chez la souris. Des lits capillaires synthétiques, orientés aléatoirement et radialement, et des angiogrammes de tomographie par cohérence optique (OCT), acquis dans le cortex de souris (n = 5) avant et après l’induction d’une photothrombose ciblée, sont analysés. Les graphes vasculaires informatiques sont exploités dans un simulateur 3D Monte-Carlo pour caractériser la réponse par résonance magnétique (MR), tout en considérant les effets des perturbations du champ magnétique causées par la désoxyhémoglobine, et l’advection et la diffusion des spins nucléaires. Le pipeline graphique proposé est validé sur des angiographies synthétiques et réelles acquises avec différentes modalités d’imagerie. Comparé à d’autres méthodes effectuées dans le milieu de la recherche, les expériences indiquent que le schéma proposé produit des taux d’erreur géométriques et topologiques amoindris sur divers angiogrammes. L’évaluation confirme également l’efficacité de la méthode proposée en fournissant des modèles représentatifs qui capturent tous les aspects anatomiques des structures vasculaires. Ensuite, afin de trouver des signatures de mAVC basées sur le signal IRM, la modélisation vasculaire proposée est exploitée pour quantifier le rapport de perte de signal intravoxel minimal lors de l’application de plusieurs directions de gradient, à des paramètres de séquence variables avec et sans ASL. Avec l’ASL, les résultats démontrent une dif-férence significative (p <0,05) entre le signal calculé avant et 3 semaines après la photothrombose. La puissance statistique a encore augmenté (p <0,005) en utilisant des angiogrammes capturés à la semaine suivante. Sans ASL, aucun changement de signal significatif n’est trouvé. Des rapports plus élevés sont obtenus à des intensités de champ magnétique plus faibles (par exemple, B0 = 3) et une lecture TE plus courte (<16 ms). Cette étude suggère que les mAVC pourraient être carac-térisés par des séquences ASL-DWI, et fournirait les informations nécessaires pour les validations expérimentales postérieures et les futurs essais comparatifs.----------ABSTRACT Cortical microvascular networks are responsible for carrying the necessary oxygen and energy substrates to our neurons. These networks react to the dynamic energy demands during neuronal activation through the process of neurovascular coupling. A key element in elucidating the role of the microvascular component in the brain is through computational modeling. However, the lack of fully-automated computational frameworks to model and characterize these microvascular net-works remains one of the main obstacles. Developing a fully-automated solution is thus substantial for further explorations, especially to quantify the impact of cerebrovascular malformations associ-ated with many cerebrovascular diseases. A common pathogenic outcome in a set of neurovascular disorders is the formation of microstrokes, i.e., micro occlusions in penetrating arterioles descend-ing from the pial surface. Recent experiments have demonstrated the impact of these microscopic events on brain function. Hence, it is of vital importance to develop a non-invasive and translatable approach to identify their presence in a clinical setting. In this thesis, a fully automatic processing pipeline to address the problem of microvascular anatom-ical modeling is proposed. The modeling scheme consists of a fully-convolutional neural network to segment microvessels, a 3D surface model generator and a geometry contraction algorithm to produce vascular graphical models with a single connected component. An improvement on this pipeline is developed later to alleviate the requirement of water-tight surface meshes as inputs to the graphing phase. The novel graphing scheme works with relaxed input requirements and intrin-sically captures vessel radii information, based on deforming geometric graphs constructed within vascular boundaries instead of surface meshes. A mechanism to decimate the initial graph struc-ture at each run is formulated with a convergence criterion to stop the process. A refinement phase is introduced to obtain final vascular models. The developed computational modeling is then ap-plied to simulate potential MRI signatures of microstrokes, combining arterial spin labeling (ASL) and multi-directional diffusion-weighted imaging (DWI). The hypothesis is driven based on recent observations demonstrating a radial reorientation of microvasculature around the micro-infarction locus during recovery in mice. Synthetic capillary beds, randomly- and radially oriented, and op-tical coherence tomography (OCT) angiograms, acquired in the barrel cortex of mice (n=5) before and after inducing targeted photothrombosis, are analyzed. The computational vascular graphs are exploited within a 3D Monte-Carlo simulator to characterize the magnetic resonance (MR) re-sponse, encompassing the effects of magnetic field perturbations caused by deoxyhemoglobin, and the advection and diffusion of the nuclear spins. The proposed graphing pipeline is validated on both synthetic and real angiograms acquired with different imaging modalities. Compared to other efficient and state-of-the-art graphing schemes, the experiments indicate that the proposed scheme produces the lowest geometric and topological error rates on various angiograms. The evaluation also confirms the efficiency of the proposed scheme in providing representative models that capture all anatomical aspects of vascular struc-tures. Next, searching for MRI-based signatures of microstokes, the proposed vascular modeling is exploited to quantify the minimal intravoxel signal loss ratio when applying multiple gradient di-rections, at varying sequence parameters with and without ASL. With ASL, the results demonstrate a significant difference (p<0.05) between the signal-ratios computed at baseline and 3 weeks after photothrombosis. The statistical power further increased (p<0.005) using angiograms captured at week 4. Without ASL, no reliable signal change is found. Higher ratios with improved significance are achieved at low magnetic field strengths (e.g., at 3 Tesla) and shorter readout TE (<16 ms). This study suggests that microstrokes might be characterized through ASL-DWI sequences, and provides necessary insights for posterior experimental validations, and ultimately, future transla-tional trials

Using deep learning for an automatic detection and classification of the vascular bifurcations along the Circle of Willis

Most of the intracranial aneurysms (ICA) occur on a specific portion of the cerebral vascular tree named the Circle of Willis (CoW). More particularly, they mainly arise onto fifteen of the major arterial bifurcations constituting this circular structure. Hence, for an efficient and timely diagnosis it is critical to develop some methods being able to accurately recognize each Bifurcation of Interest (BoI). Indeed, an automatic extraction of the bifurcations presenting the higher risk of developing an ICA would offer the neuroradiologists a quick glance at the most alarming areas. Due to the recent efforts on Artificial Intelligence, Deep Learning turned out to be the best performing technology for many pattern recognition tasks. Moreover, various methods have been particularly designed for medical image analysis purposes. This study intends to assist the neuroradiologists to promptly locate any bifurcation presenting a high risk of ICA occurrence. It can be seen as a Computer Aided Diagnosis scheme, where the Artificial Intelligence facilitates the access to the regions of interest within the MRI. In this work, we propose a method for a fully automatic detection and recognition of the bifurcations of interest forming the Circle of Willis. Several neural networks architectures have been tested, and we thoroughly evaluate the bifurcation recognition rate

Segmentation of Peripheral Nerves From Magnetic Resonance Neurography: A Fully-Automatic, Deep Learning-Based Approach

Diagnosis of peripheral neuropathies relies on neurological examinations, electrodiagnostic studies, and since recently magnetic resonance neurography (MRN). The aim of this study was to develop and evaluate a fully-automatic segmentation method of peripheral nerves of the thigh. T2-weighted sequences without fat suppression acquired on a 3 T MR scanner were retrospectively analyzed in 10 healthy volunteers and 42 patients suffering from clinically and electrophysiologically diagnosed sciatic neuropathy. A fully-convolutional neural network was developed to segment the MRN images into peripheral nerve and background tissues. The performance of the method was compared to manual inter-rater segmentation variability. The proposed method yielded Dice coefficients of 0.859 ± 0.061 and 0.719 ± 0.128, Hausdorff distances of 13.9 ± 26.6 and 12.4 ± 12.1 mm, and volumetric similarities of 0.930 ± 0.054 and 0.897 ± 0.109, for the healthy volunteer and patient cohorts, respectively. The complete segmentation process requires less than one second, which is a significant decrease to manual segmentation with an average duration of 19 ± 8 min. Considering cross-sectional area or signal intensity of the segmented nerves, focal and extended lesions might be detected. Such analyses could be used as biomarker for lesion burden, or serve as volume of interest for further quantitative MRN techniques. We demonstrated that fully-automatic segmentation of healthy and neuropathic sciatic nerves can be performed from standard MRN images with good accuracy and in a clinically feasible time

Vessel-CAPTCHA: An efficient learning framework for vessel annotation and segmentation

Deep learning techniques for 3D brain vessel image segmentation have not been as successful as in the segmentation of other organs and tissues. This can be explained by two factors. First, deep learning techniques tend to show poor performances at the segmentation of relatively small objects compared to the size of the full image. Second, due to the complexity of vascular trees and the small size of vessels, it is challenging to obtain the amount of annotated training data typically needed by deep learning methods. To address these problems, we propose a novel annotation-efficient deep learning vessel segmentation framework. The framework avoids pixel-wise annotations, only requiring weak patch-level labels to discriminate between vessel and non-vessel 2D patches in the training set, in a setup similar to the CAPTCHAs used to differentiate humans from bots in web applications. The user-provided weak annotations are used for two tasks: (1) to synthesize pixel-wise pseudo-labels for vessels and background in each patch, which are used to train a segmentation network, and (2) to train a classifier network. The classifier network allows to generate additional weak patch labels, further reducing the annotation burden, and it acts as a second opinion for poor quality images. We use this framework for the segmentation of the cerebrovascular tree in Time-of-Flight angiography (TOF) and Susceptibility-Weighted Images (SWI). The results show that the framework achieves state-of-the-art accuracy, while reducing the annotation time by ∼77% w.r.t. learning-based segmentation methods using pixel-wise labels for training

Vessel-CAPTCHA: An efficient learning framework for vessel annotation and segmentation

Deep learning techniques for 3D brain vessel image segmentation have not been as successful as in the segmentation of other organs and tissues. This can be explained by two factors. First, deep learning techniques tend to show poor performances at the segmentation of relatively small objects compared to the size of the full image. Second, due to the complexity of vascular trees and the small size of vessels, it is challenging to obtain the amount of annotated training data typically needed by deep learning methods. To address these problems, we propose a novel annotation-efficient deep learning vessel segmentation framework. The framework avoids pixel-wise annotations, only requiring weak patch-level labels to discriminate between vessel and non-vessel 2D patches in the training set, in a setup similar to the CAPTCHAs used to differentiate humans from bots in web applications. The user-provided weak annotations are used for two tasks: (1) to synthesize pixel-wise pseudo-labels for vessels and background in each patch, which are used to train a segmentation network, and (2) to train a classifier network. The classifier network allows to generate additional weak patch labels, further reducing the annotation burden, and it acts as a second opinion for poor quality images. We use this framework for the segmentation of the cerebrovascular tree in Time-of-Flight angiography (TOF) and Susceptibility-Weighted Images (SWI). The results show that the framework achieves state-of-the-art accuracy, while reducing the annotation time by 77% w.r.t. learning-based segmentation methods using pixel-wise labels for training

In-silico-Systemanalyse von Biopathways

Chen M. In silico systems analysis of biopathways. Bielefeld (Germany): Bielefeld University; 2004.In the past decade with the advent of high-throughput technologies, biology has migrated from a descriptive science to a predictive one. A vast amount of information on the metabolism have been produced; a number of specific genetic/metabolic databases and computational systems have been developed, which makes it possible for biologists to perform in silico analysis of metabolism. With experimental data from laboratory, biologists wish to systematically conduct their analysis with an easy-to-use computational system. One major task is to implement molecular information systems that will allow to integrate different molecular database systems, and to design analysis tools (e.g. simulators of complex metabolic reactions). Three key problems are involved: 1) Modeling and simulation of biological processes; 2) Reconstruction of metabolic pathways, leading to predictions about the integrated function of the network; and 3) Comparison of metabolism, providing an important way to reveal the functional relationship between a set of metabolic pathways. This dissertation addresses these problems of in silico systems analysis of biopathways. We developed a software system to integrate the access to different databases, and exploited the Petri net methodology to model and simulate metabolic networks in cells. It develops a computer modeling and simulation technique based on Petri net methodology; investigates metabolic networks at a system level; proposes a markup language for biological data interchange among diverse biological simulators and Petri net tools; establishes a web-based information retrieval system for metabolic pathway prediction; presents an algorithm for metabolic pathway alignment; recommends a nomenclature of cellular signal transduction; and attempts to standardize the representation of biological pathways. Hybrid Petri net methodology is exploited to model metabolic networks. Kinetic modeling strategy and Petri net modeling algorithm are applied to perform the processes of elements functioning and model analysis. The proposed methodology can be used for all other metabolic networks or the virtual cell metabolism. Moreover, perspectives of Petri net modeling and simulation of metabolic networks are outlined. A proposal for the Biology Petri Net Markup Language (BioPNML) is presented. The concepts and terminology of the interchange format, as well as its syntax (which is based on XML) are introduced. BioPNML is designed to provide a starting point for the development of a standard interchange format for Bioinformatics and Petri nets. The language makes it possible to exchange biology Petri net diagrams between all supported hardware platforms and versions. It is also designed to associate Petri net models and other known metabolic simulators. A web-based metabolic information retrieval system, PathAligner, is developed in order to predict metabolic pathways from rudimentary elements of pathways. It extracts metabolic information from biological databases via the Internet, and builds metabolic pathways with data sources of genes, sequences, enzymes, metabolites, etc. The system also provides a navigation platform to investigate metabolic related information, and transforms the output data into XML files for further modeling and simulation of the reconstructed pathway. An alignment algorithm to compare the similarity between metabolic pathways is presented. A new definition of the metabolic pathway is proposed. The pathway defined as a linear event sequence is practical for our alignment algorithm. The algorithm is based on strip scoring the similarity of 4-hierarchical EC numbers involved in the pathways. The algorithm described has been implemented and is in current use in the context of the PathAligner system. Furthermore, new methods for the classification and nomenclature of cellular signal transductions are recommended. For each type of characterized signal transduction, a unique ST number is provided. The Signal Transduction Classification Database (STCDB), based on the proposed classification and nomenclature, has been established. By merging the ST numbers with EC numbers, alignments of biopathways are possible. Finally, a detailed model of urea cycle that includes gene regulatory networks, metabolic pathways and signal transduction is demonstrated by using our approaches. A system biological interpretation of the observed behavior of the urea cycle and its related transcriptomics information is proposed to provide new insights for metabolic engineering and medical care

Wavelet transform methods for identifying onset of SEMG activity

Quantifying improvements in motor control is predicated on the accurate identification of the onset of surface electromyograpic (sEMG) activity. Applying methods from wavelet theory developed in the past decade to digitized signals, a robust algorithm has been designed for use with sEMG collected during reaching tasks executed with the less-affected arm of stroke patients. The method applied both Discretized Continuous Wavelet Transforms (CWT) and Discrete Wavelet Transforms (DWT) for event detection and no-lag filtering, respectively. Input parameters were extracted from the assessed signals. The onset times found in the sEMG signals using the wavelet method were compared with physiological instants of motion onset, determined from video data. Robustness was evaluated by considering the response in onset time with variations of input parameter values. The wavelet method found physiologically relevant onset times in all signals, averaging 147 ms prior to motion onset, compared to predicted onset latencies of 90-110 ins. Latency exhibited slight dependence on subject, but no other variables