Personalized noninvasive imaging of volumetric cardiac electrophysiology

Three-dimensionally distributed electrical functioning is the trigger of mechanical contraction of the heart. Disturbance of this electrical flow is known to predispose to mechanical catastrophe but, due to its amenability to certain intervention techniques, a detailed understanding of subject-specific cardiac electrophysiological conditions is of great medical interest. In current clinical practice, body surface potential recording is the standard tool for diagnosing cardiac electrical dysfunctions. However, successful treatments normally require invasive catheter mapping for a more detailed observation of these dysfunctions. In this dissertation, we take a system approach to pursue personalized noninvasive imaging of volumetric cardiac electrophysiology. Under the guidance of existing scientific knowledge of the cardiac electrophysiological system, we extract the subject specific cardiac electrical information from noninvasive body surface potential mapping and tomographic imaging data of individual subjects. In this way, a priori knowledge of system physiology leads the physiologically meaningful interpretation of personal data; at the same time, subject-specific information contained in the data identifies parameters in individual systems that differ from prior knowledge. Based on this perspective, we develop a physiological model-constrained statistical framework for the quantitative reconstruction of the electrical dynamics and inherent electrophysiological property of each individual cardiac system. To accomplish this, we first develop a coupled meshfree-BE (boundary element) modeling approach to represent existing physiological knowledge of the cardiac electrophysiological system on personalized heart-torso structures. Through a state space system approach and sequential data assimilation techniques, we then develop statistical model-data coupling algorithms for quantitative reconstruction of volumetric transmembrane potential dynamics and tissue property of 3D myocardium from body surface potential recoding of individual subjects. We also introduce a data integration component to build personalized cardiac electrophysiology by fusing tomographic image and BSP sequence of the same subject. In addition, we develop a computational reduction strategy that improves the efficiency and stability of the framework. Phantom experiments and real-data human studies are performed for validating each of the framework’s major components. These experiments demonstrate the potential of our framework in providing quantitative understanding of volumetric cardiac electrophysiology for individual subjects and in identifying latent threats in individual’s heart. This may aid in personalized diagnose, treatment planning, and fundamentally, prevention of fatal cardiac arrhythmia

Bayesian Inference with Combined Dynamic and Sparsity Models: Application in 3D Electrophysiological Imaging

Data-driven inference is widely encountered in various scientific domains to convert the observed measurements into information that cannot be directly observed about a system. Despite the quickly-developing sensor and imaging technologies, in many domains, data collection remains an expensive endeavor due to financial and physical constraints. To overcome the limits in data and to reduce the demand on expensive data collection, it is important to incorporate prior information in order to place the data-driven inference in a domain-relevant context and to improve its accuracy. Two sources of assumptions have been used successfully in many inverse problem applications. One is the temporal dynamics of the system (dynamic structure). The other is the low-dimensional structure of a system (sparsity structure). In existing work, these two structures have often been explored separately, while in most high-dimensional dynamic system they are commonly co-existing and contain complementary information. In this work, our main focus is to build a robustness inference framework to combine dynamic and sparsity constraints. The driving application in this work is a biomedical inverse problem of electrophysiological (EP) imaging, which noninvasively and quantitatively reconstruct transmural action potentials from body-surface voltage data with the goal to improve cardiac disease prevention, diagnosis, and treatment. The general framework can be extended to a variety of applications that deal with the inference of high-dimensional dynamic systems

Integrated Cardiac Electromechanics: Modeling and Personalization

Cardiac disease remains the leading cause of morbidity and mortality in the world. A variety of heart diagnosis techniques have been developed during the last century, and generally fall into two groups. The first group evaluates the electrical function of the heart using electrophysiological data such as electrocardiogram (ECG), while the second group aims to assess the mechanical function of the heart through medical imaging data. Nevertheless, the heart is an integrated electromechanical organ, where its cyclic pumping arises from the synergy of its electrical and mechanical function which requires first to be electrically excited in order to contract. At the same time, cardiac electrical function experiences feedback from mechanical contraction. This inter-dependent relationship determines that neither electrical function nor mechanical function alone can completely reflect the pathophysiological conditions of the heart. The aim of this thesis is working towards building an integrated framework for heart diagnosis through evaluation of electrical and mechanical functions simultaneously. The basic rational is to obtain quantitative interpretation of a subject-specific heart system by combining an electromechanical heart model and individual clinical measurements of the heart. To this end, we first develop a biologically-inspired mathematical model of the heart that provides a general, macroscopic description of cardiac electromechanics. The intrinsic electromechanical coupling arises from both excitation-induced contraction and deformation-induced mechano-electrical feedback. Then, as a first step towards a fully electromechanically integrated framework, we develop a model-based approach for investigating the effect of cardiac motion on noninvasive transmural imaging of cardiac electrophysiology. Specifically, we utilize the proposed heart model to obtain updated heart geometry through simulation, and further recover the electrical activities of the heart from body surface potential maps (BSPMs) by solving an optimization problem. Various simulations of the heart have been performed under healthy and abnormal conditions, which demonstrate the physiological plausibility of the proposed integrated electromechanical heart model. What\u27s more, this work presents the effect of cardiac motion to the solution of noninvasive estimation of cardiac electrophysiology and shows the importance of integrating cardiac electrical and mechanical functions for heart diagnosis. This thesis also paves the road for noninvasive evaluation of cardiac electromechanics

Meshfree and Particle Methods in Biomechanics: Prospects and Challenges

The use of meshfree and particle methods in the field of bioengineering and biomechanics has significantly increased. This may be attributed to their unique abilities to overcome most of the inherent limitations of mesh-based methods in dealing with problems involving large deformation and complex geometry that are common in bioengineering and computational biomechanics in particular. This review article is intended to identify, highlight and summarize research works on topics that are of substantial interest in the field of computational biomechanics in which meshfree or particle methods have been employed for analysis, simulation or/and modeling of biological systems such as soft matters, cells, biological soft and hard tissues and organs. We also anticipate that this review will serve as a useful resource and guide to researchers who intend to extend their work into these research areas. This review article includes 333 references

-Norm Regularization in Volumetric Imaging of Cardiac Current Sources

Advances in computer vision have substantially improved our ability to analyze the structure and mechanics of the heart. In comparison, our ability to observe and analyze cardiac electrical activities is much limited. The progress to computationally reconstruct cardiac current sources from noninvasive voltage data sensed on the body surface has been hindered by the ill-posedness and the lack of a unique solution of the reconstruction problem. Common L2- and L1-norm regularizations tend to produce a solution that is either too diffused or too scattered to reflect the complex spatial structure of current source distribution in the heart. In this work, we propose a general regularization with Lp-norm () constraint to bridge the gap and balance between an overly smeared and overly focal solution in cardiac source reconstruction. In a set of phantom experiments, we demonstrate the superiority of the proposed Lp-norm method over its L1 and L2 counterparts in imaging cardiac current sources with increasing extents. Through computer-simulated and real-data experiments, we further demonstrate the feasibility of the proposed method in imaging the complex structure of excitation wavefront, as well as current sources distributed along the postinfarction scar border. This ability to preserve the spatial structure of source distribution is important for revealing the potential disruption to the normal heart excitation

Uncertainty Quantification and Reduction in Cardiac Electrophysiological Imaging

Cardiac electrophysiological (EP) imaging involves solving an inverse problem that infers cardiac electrical activity from body-surface electrocardiography data on a physical domain defined by the body torso. To avoid unreasonable solutions that may fit the data, this inference is often guided by data-independent prior assumptions about different properties of cardiac electrical sources as well as the physical domain. However, these prior assumptions may involve errors and uncertainties that could affect the inference accuracy. For example, common prior assumptions on the source properties, such as fixed spatial and/or temporal smoothness or sparseness assumptions, may not necessarily match the true source property at different conditions, leading to uncertainties in the inference. Furthermore, prior assumptions on the physical domain, such as the anatomy and tissue conductivity of different organs in the thorax model, represent an approximation of the physical domain, introducing errors to the inference. To determine the robustness of the EP imaging systems for future clinical practice, it is important to identify these errors/uncertainties and assess their impact on the solution. This dissertation focuses on the quantification and reduction of the impact of uncertainties caused by prior assumptions/models on cardiac source properties as well as anatomical modeling uncertainties on the EP imaging solution. To assess the effect of fixed prior assumptions/models about cardiac source properties on the solution of EP imaging, we propose a novel yet simple Lp-norm regularization method for volumetric cardiac EP imaging. This study reports the necessity of an adaptive prior model (rather than fixed model) for constraining the complex spatiotemporally changing properties of the cardiac sources. We then propose a multiple-model Bayesian approach to cardiac EP imaging that employs a continuous combination of prior models, each re-effecting a specific spatial property for volumetric sources. The 3D source estimation is then obtained as a weighted combination of solutions across all models. Including a continuous combination of prior models, our proposed method reduces the chance of mismatch between prior models and true source properties, which in turn enhances the robustness of the EP imaging solution. To quantify the impact of anatomical modeling uncertainties on the EP imaging solution, we propose a systematic statistical framework. Founded based on statistical shape modeling and unscented transform, our method quantifies anatomical modeling uncertainties and establish their relation to the EP imaging solution. Applied on anatomical models generated from different image resolutions and different segmentations, it reports the robustness of EP imaging solution to these anatomical shape-detail variations. We then propose a simplified anatomical model for the heart that only incorporates certain subject-specific anatomical parameters, while discarding local shape details. Exploiting less resources and processing for successful EP imaging, this simplified model provides a simple clinically-compatible anatomical modeling experience for EP imaging systems. Different components of our proposed methods are validated through a comprehensive set of synthetic and real-data experiments, including various typical pathological conditions and/or diagnostic procedures, such as myocardial infarction and pacing. Overall, the methods presented in this dissertation for the quantification and reduction of uncertainties in cardiac EP imaging enhance the robustness of EP imaging, helping to close the gap between EP imaging in research and its clinical application

Transferring Generalized Knowledge from Physics-based Simulation to Clinical Domain

A primary factor for the success of machine learning is the quality of labeled training data. However, in many fields, labeled data can be costly, difficult, or even impossible to acquire. In comparison, computer simulation data can now be generated at a much higher abundance with a much lower cost. These simulation data could potentially solve the problem of data deficiency in many machine learning tasks. Nevertheless, due to model assumptions, simplifications and possible errors, there is always a discrepancy between simulated and real data. This discrepancy needs to be addressed when transferring the knowledge from simulation to real data. Furthermore, simulation data is always tied to specific settings of models parameters, many of which have a considerable range of variations yet not necessarily relevant to the machine learning task of interest. The knowledge extracted from simulation data must thus be generalizable across these parameter variations before being transferred. In this dissertation, we address the two outlined challenges in leveraging simulation data to overcome the shortage of labeled real data, . We do so in a clinical task of localizing the origin of ventricular activation from 12 lead electrocardiograms (ECGs), where the clinical ECG data with labeled sites of origin in the heart can only be invasively available. By adopting the concept of domain adaptation, we address the discrepancy between simulated and clinical ECG data by learning the shift between the two domains using a large amount of simulation data and a small amount of clinical data. By adopting the concept of domain generalization, we then address the reliance of simulated ECG data on patient-specific geometrical models by learning to generalize simulated ECG data across subjects, before transferring them to clinical data. Evaluated on in-vivo premature ventricular contraction (PVC) patients, we demonstrate the feasibility of utilizing a large number of offline simulated ECG datasets to enable the prediction of the origin of arrhythmia with only a small number of clinical ECG data on a new patient

Kalbin Elektriksel Aktivitesinin 3 Boyutlu Transmembran Potansiyel Dağılımları Cinsinden Girişimsiz Olarak Görüntülenmesi

TÜBİTAK EEEAG Proje01.04.2015Vücut yüzeyi potansiyel (VYP) ölçümlerinden kalpteki elektriksel kaynakların kestirilmesine ters elektrokardiografi (EKG) problemi denir. Bu yöntem, ölümcül de olabilecek kalp hastalıklarının teşhisinde ve tedavi planlamasında hekimlere yol gösterme potansiyeline sahiptir. Ancak, bu problem kötü konumlanmış bir problemdir ve ölçümlerdeki az miktarda gürültü bile sınırsız çözümler bulunmasına yol açmaktadır. Bunun üstesinden gelebilmek için literatürde, başta Tikhonov düzenlileştirmesi olmak üzere çeşitli düzenlileştirme yöntemleri uygulanmıştır. Ancak uygulanan her yöntem farklı durumlarda test edilmiştir; henüz hangi yöntemin en iyi yöntem olduğu konusunda fikir birliği sağlanamamıştır. Son zamanlarda, üç boyutlu miyokart dokusunda da detaylı bilgi verebildiği için, transmembran potansiyelleri (TMP) cinsinden ters EKG çözümleri popülerleşmiştir. Ancak henüz bu alanda az sayıda çalışma vardır ve özellikle farklı kalp aritmilerinde farklı yöntemlerin nasıl performans sergileyeceği bilinmemektedir. Bu projede temel amaç, bu açığı kapatmak, farklı elektriksel dağılımlar için literatürdeki belli başlı yöntemlerle ters EKG problemini çözmektir. Bu projede, kapsamlı bir çalışmayla, önerilen yöntemlerin performansları aynı test verisiyle ve aynı kriterler kullanılarak objektif bir şekilde karşılaştırılabilmiştir. Ayrıca farklı aritmiler için TMP benzetimleri ve buna bağlı VYPler elde edildiği için, yöntemlerin bu farklı aritmiler karşısında nasıl bir performans sergilediği de araştırılmıştır. Öncelikle Aliev-Panfilov yöntemiyle farklı kalp aktiviteleri için TMP benzetimleri yapılmış, ardından ileri EKG problemi çözülerek bu dağılımlardan VYP dağılımları bulunmuştur. Bu dağılımlar ters EKG çözümlerinde kullanılmıştır. Uygulanan beş değişik ters EKG çözüm yönteminden her durumda en başarılı yöntemin Bayesian MAP olduğu gözlenmiştir. TTLS, LTTLS ve LSQR yöntemlerinin de uyarım noktalarını ve dalga önünü bulmakta çok kötü performans sergilemediği görülmüştür. Bu proje kapsamında iki ayrı dalda daha literatüre katkı sağlanmıştır. Bunlardan ilki, fiber yönelimlerinin TMP dağılımlarına etkilerinin incelenmesidir. Başka bir kalpten aktarılan fiber yönelimini kullanmanın izotropik varsayım kullanmaktan daha doğru sonuçlar verdiği gözlenmiştir. İkinci katkı da, TMP dağılımları cinsinden FEM yöntemi ile ileri problem çözümünün doğrulamasıdır. Uygun ağ sıklığına ulaşıldığında sayısal çözümün analitik çözüme yakınsadığı gösterilmiştir.Inverse electrocardiography is the estimation of cardiac electrical sources from body surface potential (BSP) measurements. Inverse solutions can guide the physicians for diagnosis and treatment planning of lethal heart diseases. However, inverse problem is ill-posed and even small perturbations in the measurements yield unbounded errors in the solutions. To overcome this difficulty, many regularization approaches have been proposed in literature. However, these methods have been applied and tested under varying conditions in different studies; there is no consensus among researchers on the method with the best performance. Lately, solutions in terms of transmembrane potentials (TMP) have become popular, since they provide information about the electrical activity of the three dimensional myocardium. There are few studies in this area and it is still an open question how different methods will perform under different arrythmia conditions. The main goal in this project is to solve the inverse problem in terms of TMPs, using different approaches but under the same (and diverse) cardiac conditions. First, we obtained TMP distributions for various cardiac electrical activity assumptions using Aliev-Panfilov model. Then we solved the forward ECG problem to obtain the corresponding BSPs, which were later used in the inverse problem solutions. Among the five inverse approaches, Bayesian MAP estimation had the best performance under all conditions. TTLS, LTTLS and LSQR were also successful in finding the initial stimulation points and recovering the wavefront. We made contributions in two more areas in this project. The first one is our study of fiber orientation effects on TMP distributions. We found that even using fiber orientations from a different heart is much better than using the isotropic assumption. The second one is the analytical verification of the FEM based forward problem; with an appropriate mesh size, we showed that the numerical solution converges to the analytical solution

On Learning and Generalization to Solve Inverse Problem of Electrophysiological Imaging

In this dissertation, we are interested in solving a linear inverse problem: inverse electrophysiological (EP) imaging, where our objective is to computationally reconstruct personalized cardiac electrical signals based on body surface electrocardiogram (ECG) signals. EP imaging has shown promise in the diagnosis and treatment planning of cardiac dysfunctions such as atrial flutter, atrial fibrillation, ischemia, infarction and ventricular arrhythmia. Towards this goal, we frame it as a problem of learning a function from the domain of measurements to signals. Depending upon the assumptions, we present two classes of solutions: 1) Bayesian inference in a probabilistic graphical model, 2) Learning from samples using deep networks. In both of these approaches, we emphasize on learning the inverse function with good generalization ability, which becomes a main theme of the dissertation. In a Bayesian framework, we argue that this translates to appropriately integrating different sources of knowledge into a common probabilistic graphical model framework and using it for patient specific signal estimation through Bayesian inference. In learning from samples setting, this translates to designing a deep network with good generalization ability, where good generalization refers to the ability to reconstruct inverse EP signals in a distribution of interest (which could very well be outside the sample distribution used during training). By drawing ideas from different areas like functional analysis (e.g. Fenchel duality), variational inference (e.g. Variational Bayes) and deep generative modeling (e.g. variational autoencoder), we show how we can incorporate different prior knowledge in a principled manner in a probabilistic graphical model framework to obtain a good inverse solution with generalization ability. Similarly, to improve generalization of deep networks learning from samples, we use ideas from information theory (e.g. information bottleneck), learning theory (e.g. analytical learning theory), adversarial training, complexity theory and functional analysis (e.g. RKHS). We test our algorithms on synthetic data and real data of the patients who had undergone through catheter ablation in clinics and show that our approach yields significant improvement over existing methods. Towards the end of the dissertation, we investigate general questions on generalization and stabilization of adversarial training of deep networks and try to understand the role of smoothness and function space complexity in answering those questions. We conclude by identifying limitations of the proposed methods, areas of further improvement and open questions that are specific to inverse electrophysiological imaging as well as broader, encompassing theory of learning and generalization