Organ-focused mutual information for nonrigid multimodal registration of liver CT and Gd–EOB–DTPA-enhanced MRI

Accurate detection of liver lesions is of great importance in hepatic surgery planning. Recent studies have shown that the detection rate of liver lesions is significantly higher in gadoxetic acid-enhanced magnetic resonance imaging (Gd–EOB–DTPA-enhanced MRI) than in contrast-enhanced portal-phase computed tomography (CT); however, the latter remains essential because of its high specificity, good performance in estimating liver volumes and better vessel visibility. To characterize liver lesions using both the above image modalities, we propose a multimodal nonrigid registration framework using organ-focused mutual information (OF-MI). This proposal tries to improve mutual information (MI) based registration by adding spatial information, benefiting from the availability of expert liver segmentation in clinical protocols. The incorporation of an additional information channel containing liver segmentation information was studied. A dataset of real clinical images and simulated images was used in the validation process. A Gd–EOB–DTPA-enhanced MRI simulation framework is presented. To evaluate results, warping index errors were calculated for the simulated data, and landmark-based and surface-based errors were calculated for the real data. An improvement of the registration accuracy for OF-MI as compared with MI was found for both simulated and real datasets. Statistical significance of the difference was tested and confirmed in the simulated dataset (p < 0.01).

Noninvasive monitoring of serial changes in pulmonary vascular resistance and acute vasodilator testing using cardiac magnetic resonance

Objectives The study sought to evaluate the ability of cardiac magnetic resonance (CMR) to monitor acute and long-term changes in pulmonary vascular resistance (PVR) noninvasively. Background PVR monitoring during the follow-up of patients with pulmonary hypertension (PH) and the response to vasodilator testing require invasive right heart catheterization. Methods An experimental study in pigs was designed to evaluate the ability of CMR to monitor: 1) an acute increase in PVR generated by acute pulmonary embolization (n = 10); 2) serial changes in PVR in chronic PH (n = 22); and 3) changes in PVR during vasodilator testing in chronic PH (n = 10). CMR studies were performed with simultaneous hemodynamic assessment using a CMR-compatible Swan-Ganz catheter. Average flow velocity in the main pulmonary artery (PA) was quantified with phase contrast imaging. Pearson correlation and mixed model analysis were used to correlate changes in PVR with changes in CMR-quantified PA velocity. Additionally, PVR was estimated from CMR data (PA velocity and right ventricular ejection fraction) using a formula previously validated. Results Changes in PA velocity strongly and inversely correlated with acute increases in PVR induced by pulmonary embolization (r = –0.92), serial PVR fluctuations in chronic PH (r = –0.89), and acute reductions during vasodilator testing (r = –0.89, p ≤ 0.01 for all). CMR-estimated PVR showed adequate agreement with invasive PVR (mean bias –1.1 Wood units,; 95% confidence interval: –5.9 to 3.7) and changes in both indices correlated strongly (r = 0.86, p < 0.01). Conclusions CMR allows for noninvasive monitoring of acute and chronic changes in PVR in PH. This capability may be valuable in the evaluation and follow-up of patients with PH.

Self-organizing cultured neural networks: Image analysis techniques for longitudinal tracking and modeling of the underlying network structure

Esta tesis estudia la evolución estructural de conjuntos de neuronas como la capacidad de auto-organización desde conjuntos de neuronas separadas hasta que forman una red (clusterizada) compleja. Esta tesis contribuye con el diseño e implementación de un algoritmo no supervisado de segmentación basado en grafos con un coste computacional muy bajo. Este algoritmo proporciona de forma automática la estructura completa de la red a partir de imágenes de cultivos neuronales tomadas con microscopios de fase con una resolución muy alta. La estructura de la red es representada mediante un objeto matemático (matriz) cuyos nodos representan a las neuronas o grupos de neuronas y los enlaces son las conexiones reconstruidas entre ellos. Este algoritmo extrae también otras medidas morfológicas importantes que caracterizan a las neuronas y a las neuritas. A diferencia de otros algoritmos hasta el momento, que necesitan de fluorescencia y técnicas inmunocitoquímicas, el algoritmo propuesto permite el estudio longitudinal de forma no invasiva posibilitando el estudio durante la formación de un cultivo. Además, esta tesis, estudia de forma sistemática un grupo de variables topológicas que garantizan la posibilidad de cuantificar e investigar la progresión de las características principales durante el proceso de auto-organización del cultivo. Nuestros resultados muestran la existencia de un estado concreto correspondiente a redes con configuracin small-world y la emergencia de propiedades a micro- y meso-escala de la estructura de la red. Finalmente, identificamos los procesos físicos principales que guían las transformaciones morfológicas de los cultivos y proponemos un modelo de crecimiento de red que reproduce el comportamiento cuantitativamente de las observaciones experimentales. ABSTRACT The thesis analyzes the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. In particular, it contributes with the design and implementation of a graph-based unsupervised segmentation algorithm, having an associated very low computational cost. The processing automatically retrieves the whole network structure from large scale phase-contrast images taken at high resolution throughout the entire life of a cultured neuronal network. The network structure is represented by a mathematical object (a matrix) in which nodes are identified neurons or neurons clusters, and links are the reconstructed connections between them. The algorithm is also able to extract any other relevant morphological information characterizing neurons and neurites. More importantly, and at variance with other segmentation methods that require fluorescence imaging from immunocyto- chemistry techniques, our measures are non invasive and entitle us to carry out a fully longitudinal analysis during the maturation of a single culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main networks characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graphs micro- and meso-scale properties emerge. Finally, we identify the main physical processes taking place during the cultures morphological transformations, and embed them into a simplified growth model that quantitatively reproduces the overall set of experimental observations.

Self-organizing cultured neural networks: Image analysis techniques for longitudinal tracking and modeling of the underlying network structure (versión actualizada)

Esta tesis estudia la evolución estructural de conjuntos de neuronas como la capacidad de auto-organización desde conjuntos de neuronas separadas hasta que forman una red (clusterizada) compleja. Esta tesis contribuye con el diseño e implementación de un algoritmo no supervisado de segmentación basado en grafos con un coste computacional muy bajo. Este algoritmo proporciona de forma automática la estructura completa de la red a partir de imágenes de cultivos neuronales tomadas con microscopios de fase con una resolución muy alta. La estructura de la red es representada mediante un objeto matemático (matriz) cuyos nodos representan a las neuronas o grupos de neuronas y los enlaces son las conexiones reconstruidas entre ellos. Este algoritmo extrae también otras medidas morfológicas importantes que caracterizan a las neuronas y a las neuritas. A diferencia de otros algoritmos hasta el momento, que necesitan de fluorescencia y técnicas inmunocitoquímicas, el algoritmo propuesto permite el estudio longitudinal de forma no invasiva posibilitando el estudio durante la formación de un cultivo. Además, esta tesis, estudia de forma sistemática un grupo de variables topológicas que garantizan la posibilidad de cuantificar e investigar la progresión de las características principales durante el proceso de auto-organización del cultivo. Nuestros resultados muestran la existencia de un estado concreto correspondiente a redes con configuracin small-world y la emergencia de propiedades a micro- y meso-escala de la estructura de la red. Finalmente, identificamos los procesos físicos principales que guían las transformaciones morfológicas de los cultivos y proponemos un modelo de crecimiento de red que reproduce el comportamiento cuantitativamente de las observaciones experimentales. ABSTRACT The thesis analyzes the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. In particular, it contributes with the design and implementation of a graph-based unsupervised segmentation algorithm, having an associated very low computational cost. The processing automatically retrieves the whole network structure from large scale phase-contrast images taken at high resolution throughout the entire life of a cultured neuronal network. The network structure is represented by a mathematical object (a matrix) in which nodes are identified neurons or neurons clusters, and links are the reconstructed connections between them. The algorithm is also able to extract any other relevant morphological information characterizing neurons and neurites. More importantly, and at variance with other segmentation methods that require fluorescence imaging from immunocyto- chemistry techniques, our measures are non invasive and entitle us to carry out a fully longitudinal analysis during the maturation of a single culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main networks characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graphs micro- and meso-scale properties emerge. Finally, we identify the main physical processes taking place during the cultures morphological transformations, and embed them into a simplified growth model that quantitatively reproduces the overall set of experimental observations.

Geotechnical Analysis of Contaminated Sand by Light Non-Aquous Phase Liquids

Contaminated soil reuse was investigated, with higher profusion, throughout the early 90’s, coinciding with the 1991 Gulf War, when efforts to amend large crude oil releases began in geotechnical assessment of contaminated soils. Isolated works referring to geotechnical testing with hydrocarbon ground contaminants are described in the state-of-the-art, which have been extended to other type of contaminated soil references. Contaminated soils by light non-aquous phase liquids (LNAPL) bearing capacity reduction has been previously investigated from a forensic point of view. To date, all the research works have been published based on the assumption of constant contaminant saturation for the entire soil mass. In contrast, the actual LNAPLs distribution plumes exhibit complex flow patterns which are subject to physical and chemical changes with time and distance travelled from the release source. This aspect has been considered along the present text. A typical Madrid arkosic soil formation is commonly known as Miga sand. Geotechnical tests have been carried out, with Miga sand specimens, in incremental series of LNAPL concentrations in order to observe the soil engineering properties variation due to a contamination increase. Results are discussed in relation with previous studies and as a matter of fact, soil mechanics parameters change in the presence of LNAPL, showing different tendencies according to each test and depending on the LNAPL content, as well as to the specimen’s initially planned relative density, dense or loose. Geotechnical practical implications are also commented on and analyzed. Variation on geotechnical properties may occur only within the external contour of contamination distribution plume. This scope has motivated the author to develop a physical model based on transparent soil technology. The model aims to reproduce the distribution of LNAPL into the ground due to an accidental release from a storage facility. Preliminary results indicate that the model is a potentially complementary tool for hydrogeological applications, site-characterization and remediation treatment testing within the framework of soil pollution events. A description of the test setup of an innovative three dimensional physical model for the flow of two or more phases, in porous media, is presented herein, along with a summary of the advantages, limitations and future applications for modeling with transparent material. En los primeros años de la década de los años 90, del siglo pasado, coincidiendo con la Guerra del Golfo en 1991, se investigó intensamente sobre la reutilización de suelos afectados por grandes volúmenes de vertidos de crudo, fomentándose la evaluación geotécnica de los suelos contaminados. Se describen, en el estado del arte de esta tésis, una serie de trabajos aislados en relación con la caracterización geotécnica de suelos contaminados con hidrocarburos, descripción ampliada mediante referencias relacionadas con otros tipos de contaminación de suelos. Existen estudios previos de patología de cimentaciones que analizan la reducción de la capacidad portante de suelos contaminados por hidrocarburos líquidos ligeros en fase no acuosa (acrónimo en inglés: LNAPL de “Liquid Non-Aquous Phase Liquid”). A fecha de redacción de la tesis, todas las publicaciones anteriores estaban basadas en la consideración de una saturación del contaminante constante en toda la extensión del terreno de cimentación. La distribución real de las plumas de contaminante muestra, por el contrario, complejas trayectorias de flujo que están sujetas a cambios físico-químicos en función del tiempo y la distancia recorrida desde su origen de vertido. Éste aspecto ha sido considerado y tratado en el presente texto. La arena de Miga es una formación geológica típica de Madrid. En el ámbito de esta tesis se han desarrollado ensayos geotécnicos con series de muestras de arena de Miga contaminadas con distintas concentraciones de LNAPL con el objeto de estimar la variación de sus propiedades geotécnicas debido a un incremento de contaminación. Se ha realizado una evaluación de resultados de los ensayos en comparación con otros estudios previamente analizados, resultando que las propiedades mecánicas del suelo, efectivamente, varían en función del contenido de LNAPL y de la densidad relativa con la que se prepare la muestra, densa o floja. Se analizan y comentan las implicaciones de carácter práctico que supone la mencionada variación de propiedades geotécnicas. El autor ha desarrollado un modelo físico basado en la tecnología de suelos transparentes, considerando que las variaciones de propiedades geotécnicas únicamente deben producirse en el ámbito interior del contorno de la pluma contaminante. El objeto del modelo es el de reproducir la distribución de un LNAPL en un terreno dado, causada por el vertido accidental de una instalación de almecenamiento de combustible. Los resultados preliminares indican que el modelo podría emplearse como una herramienta complementaria para el estudio de eventos contaminantes, permitiendo el desarrollo de aplicaciones de carácter hidrogeológico, caracterización de suelos contaminados y experimentación de tratamientos de remediación. Como aportación de carácter innovadora, se presenta y describe un modelo físico tridimensional de flujo de dos o más fases a través de un medio poroso transparente, analizándose sus ventajas e inconvenientes así como sus limitaciones y futuras aplicaciones.

'Enhancement of the crystallization process of TbxFe1-x thin films upon the formation of alpha-Tb phase'

TbxFe1−x thin films deposited by sputtering on Mo were investigated structurally and magnetically. The microstructure consists of TbFe2 nanoparticles embedded in an amorphous matrix, and the Tb content can be correlated with an increase in the volume of these nanoparticles. Similar microstructure and behavior were found when TbFe2 was deposited on glass and on a Pt buffer layer. Nevertheless, thermal treatments promote a different effect, depending on the mechanical stiffness of the buffer layer. The layers deposited on Mo, a rigid material, show crystalline TbFe2 together with α-Tb phase upon thermal treatment. In contrast, TbFe2 does not crystallize properly on Pt, a material with a lower stiffness than Mo. Intermediate results were observed on the film deposited on glass. Experimental results show the impact of the buffer stiffness on the crystallization process. Moreover, the formation of α-Tb appears to be fundamental to crystallized TbFe2 on layers deposited on rigid buffers

Super-Resolution in Respiratory Synchronized Positron Emission Tomography

Respiratory motion is a major source of reduced quality in positron emission tomography (PET). In order to minimize its effects, the use of respiratory synchronized acquisitions, leading to gated frames, has been suggested. Such frames, however, are of low signal-to-noise ratio (SNR) as they contain reduced statistics. Super-resolution (SR) techniques make use of the motion in a sequence of images in order to improve their quality. They aim at enhancing a low-resolution image belonging to a sequence of images representing different views of the same scene. In this work, a maximum a posteriori (MAP) super-resolution algorithm has been implemented and applied to respiratory gated PET images for motion compensation. An edge preserving Huber regularization term was used to ensure convergence. Motion fields were recovered using a B-spline based elastic registration algorithm. The performance of the SR algorithm was evaluated through the use of both simulated and clinical datasets by assessing image SNR, as well as the contrast, position and extent of the different lesions. Results were compared to summing the registered synchronized frames on both simulated and clinical datasets. The super-resolution image had higher SNR (by a factor of over 4 on average) and lesion contrast (by a factor of 2) than the single respiratory synchronized frame using the same reconstruction matrix size. In comparison to the motion corrected or the motion free images a similar SNR was obtained, while improvements of up to 20% in the recovered lesion size and contrast were measured. Finally, the recovered lesion locations on the SR images were systematically closer to the true simulated lesion positions. These observations concerning the SNR, lesion contrast and size were confirmed on two clinical datasets included in the study. In conclusion, the use of SR techniques applied to respiratory motion synchronized images lead to motion compensation combined with improved image SNR and contrast, without any increase in the overall acquisition times.

Mejoras en el procesamiento de imágenes de TC para el tratamiento con radioterapia adaptativa del cáncer de próstata

El cáncer de próstata es el tipo de cáncer con mayor prevalencia entre los hombres del mundo occidental y, pese a tener una alta tasa de supervivencia relativa, es la segunda mayor causa de muerte por cáncer en este sector de la población. El tratamiento de elección frente al cáncer de próstata es, en la mayoría de los casos, la radioterapia externa. Las técnicas más modernas de radioterapia externa, como la radioterapia modulada en intensidad, permiten incrementar la dosis en el tumor mientras se reduce la dosis en el tejido sano. Sin embargo, la localización del volumen objetivo varía con el día de tratamiento, y se requieren movimientos muy pequeños de los órganos para sacar partes del volumen objetivo fuera de la región terapéutica, o para introducir tejidos sanos críticos dentro. Para evitar esto se han desarrollado técnicas más avanzadas, como la radioterapia guiada por imagen, que se define por un manejo más preciso de los movimientos internos mediante una adaptación de la planificación del tratamiento basada en la información anatómica obtenida de imágenes de tomografía computarizada (TC) previas a la sesión terapéutica. Además, la radioterapia adaptativa añade la información dosimétrica de las fracciones previas a la información anatómica. Uno de los fundamentos de la radioterapia adaptativa es el registro deformable de imágenes, de gran utilidad a la hora de modelar los desplazamientos y deformaciones de los órganos internos. Sin embargo, su utilización conlleva nuevos retos científico-tecnológicos en el procesamiento de imágenes, principalmente asociados a la variabilidad de los órganos, tanto en localización como en apariencia. El objetivo de esta tesis doctoral es mejorar los procesos clínicos de delineación automática de contornos y de cálculo de dosis acumulada para la planificación y monitorización de tratamientos con radioterapia adaptativa, a partir de nuevos métodos de procesamiento de imágenes de TC (1) en presencia de contrastes variables, y (2) cambios de apariencia del recto. Además, se pretende (3) proveer de herramientas para la evaluación de la calidad de los contornos obtenidos en el caso del gross tumor volumen (GTV). Las principales contribuciones de esta tesis doctoral son las siguientes: _ 1. La adaptación, implementación y evaluación de un algoritmo de registro basado en el flujo óptico de la fase de la imagen como herramienta para el cálculo de transformaciones no-rígidas en presencia de cambios de intensidad, y su aplicabilidad a tratamientos de radioterapia adaptativa en cáncer de próstata con uso de agentes de contraste radiológico. Los resultados demuestran que el algoritmo seleccionado presenta mejores resultados cualitativos en presencia de contraste radiológico en la vejiga, y no distorsiona la imagen forzando deformaciones poco realistas. 2. La definición, desarrollo y validación de un nuevo método de enmascaramiento de los contenidos del recto (MER), y la evaluación de su influencia en el procedimiento de radioterapia adaptativa en cáncer de próstata. Las segmentaciones obtenidas mediante el MER para la creación de máscaras homogéneas en las imágenes de sesión permiten mejorar sensiblemente los resultados de los algoritmos de registro en la región rectal. Así, el uso de la metodología propuesta incrementa el índice de volumen solapado entre los contornos manuales y automáticos del recto hasta un valor del 89%, cercano a los resultados obtenidos usando máscaras manuales para el registro de las dos imágenes. De esta manera se pueden corregir tanto el cálculo de los nuevos contornos como el cálculo de la dosis acumulada. 3. La definición de una metodología de evaluación de la calidad de los contornos del GTV, que permite la representación de la distribución espacial del error, adaptándola a volúmenes no-convexos como el formado por la próstata y las vesículas seminales. Dicha metodología de evaluación, basada en un nuevo algoritmo de reconstrucción tridimensional y una nueva métrica de cuantificación, presenta resultados precisos con una gran resolución espacial en un tiempo despreciable frente al tiempo de registro. Esta nueva metodología puede ser una herramienta útil para la comparación de distintos algoritmos de registro deformable orientados a la radioterapia adaptativa en cáncer de próstata. En conclusión, el trabajo realizado en esta tesis doctoral corrobora las hipótesis de investigación postuladas, y pretende servir como cimiento de futuros avances en el procesamiento de imagen médica en los tratamientos de radioterapia adaptativa en cáncer de próstata. Asimismo, se siguen abriendo nuevas líneas de aplicación futura de métodos de procesamiento de imágenes médicas con el fin de mejorar los procesos de radioterapia adaptativa en presencia de cambios de apariencia de los órganos, e incrementar la seguridad del paciente. I.2 Inglés Prostate cancer is the most prevalent cancer amongst men in the Western world and, despite having a relatively high survival rate, is the second leading cause of cancer death in this sector of the population. The treatment of choice against prostate cancer is, in most cases, external beam radiation therapy. The most modern techniques of external radiotherapy, as intensity modulated radiotherapy, allow increasing the dose to the tumor whilst reducing the dose to healthy tissue. However, the location of the target volume varies with the day of treatment, and very small movements of the organs are required to pull out parts of the target volume outside the therapeutic region, or to introduce critical healthy tissues inside. Advanced techniques, such as the image-guided radiotherapy (IGRT), have been developed to avoid this. IGRT is defined by more precise handling of internal movements by adapting treatment planning based on the anatomical information obtained from computed tomography (CT) images prior to the therapy session. Moreover, the adaptive radiotherapy adds dosimetric information of previous fractions to the anatomical information. One of the fundamentals of adaptive radiotherapy is deformable image registration, very useful when modeling the displacements and deformations of the internal organs. However, its use brings new scientific and technological challenges in image processing, mainly associated to the variability of the organs, both in location and appearance. The aim of this thesis is to improve clinical processes of automatic contour delineation and cumulative dose calculation for planning and monitoring of adaptive radiotherapy treatments, based on new methods of CT image processing (1) in the presence of varying contrasts, and (2) rectum appearance changes. It also aims (3) to provide tools for assessing the quality of contours obtained in the case of gross tumor volume (GTV). The main contributions of this PhD thesis are as follows: 1. The adaptation, implementation and evaluation of a registration algorithm based on the optical flow of the image phase as a tool for the calculation of non-rigid transformations in the presence of intensity changes, and its applicability to adaptive radiotherapy treatment in prostate cancer with use of radiological contrast agents. The results demonstrate that the selected algorithm shows better qualitative results in the presence of radiological contrast agents in the urinary bladder, and does not distort the image forcing unrealistic deformations. 2. The definition, development and validation of a new method for masking the contents of the rectum (MER, Spanish acronym), and assessing their impact on the process of adaptive radiotherapy in prostate cancer. The segmentations obtained by the MER for the creation of homogenous masks in the session CT images can improve significantly the results of registration algorithms in the rectal region. Thus, the use of the proposed methodology increases the volume overlap index between manual and automatic contours of the rectum to a value of 89%, close to the results obtained using manual masks for both images. In this way, both the calculation of new contours and the calculation of the accumulated dose can be corrected. 3. The definition of a methodology for assessing the quality of the contours of the GTV, which allows the representation of the spatial distribution of the error, adapting it to non-convex volumes such as that formed by the prostate and seminal vesicles. Said evaluation methodology, based on a new three-dimensional reconstruction algorithm and a new quantification metric, presents accurate results with high spatial resolution in a time negligible compared to the registration time. This new approach may be a useful tool to compare different deformable registration algorithms oriented to adaptive radiotherapy in prostate cancer In conclusion, this PhD thesis corroborates the postulated research hypotheses, and is intended to serve as a foundation for future advances in medical image processing in adaptive radiotherapy treatment in prostate cancer. In addition, it opens new future applications for medical image processing methods aimed at improving the adaptive radiotherapy processes in the presence of organ’s appearance changes, and increase the patient safety.