The LONI QC System: A Semi-Automated, Web-Based and Freely-Available Environment for the Comprehensive Quality Control of Neuroimaging Data.

Quantifying, controlling, and monitoring image quality is an essential prerequisite for ensuring the validity and reproducibility of many types of neuroimaging data analyses. Implementation of quality control (QC) procedures is the key to ensuring that neuroimaging data are of high-quality and their validity in the subsequent analyses. We introduce the QC system of the Laboratory of Neuro Imaging (LONI): a web-based system featuring a workflow for the assessment of various modality and contrast brain imaging data. The design allows users to anonymously upload imaging data to the LONI-QC system. It then computes an exhaustive set of QC metrics which aids users to perform a standardized QC by generating a range of scalar and vector statistics. These procedures are performed in parallel using a large compute cluster. Finally, the system offers an automated QC procedure for structural MRI, which can flag each QC metric as being 'good' or 'bad.' Validation using various sets of data acquired from a single scanner and from multiple sites demonstrated the reproducibility of our QC metrics, and the sensitivity and specificity of the proposed Auto QC to 'bad' quality images in comparison to visual inspection. To the best of our knowledge, LONI-QC is the first online QC system that uniquely supports the variety of functionality where we compute numerous QC metrics and perform visual/automated image QC of multi-contrast and multi-modal brain imaging data. The LONI-QC system has been used to assess the quality of large neuroimaging datasets acquired as part of various multi-site studies such as the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study and the Alzheimer's Disease Neuroimaging Initiative (ADNI). LONI-QC's functionality is freely available to users worldwide and its adoption by imaging researchers is likely to contribute substantially to upholding high standards of brain image data quality and to implementing these standards across the neuroimaging community

Neuroimaging study designs, computational analyses and data provenance using the LONI pipeline.

Modern computational neuroscience employs diverse software tools and multidisciplinary expertise to analyze heterogeneous brain data. The classical problems of gathering meaningful data, fitting specific models, and discovering appropriate analysis and visualization tools give way to a new class of computational challenges--management of large and incongruous data, integration and interoperability of computational resources, and data provenance. We designed, implemented and validated a new paradigm for addressing these challenges in the neuroimaging field. Our solution is based on the LONI Pipeline environment [3], [4], a graphical workflow environment for constructing and executing complex data processing protocols. We developed study-design, database and visual language programming functionalities within the LONI Pipeline that enable the construction of complete, elaborate and robust graphical workflows for analyzing neuroimaging and other data. These workflows facilitate open sharing and communication of data and metadata, concrete processing protocols, result validation, and study replication among different investigators and research groups. The LONI Pipeline features include distributed grid-enabled infrastructure, virtualized execution environment, efficient integration, data provenance, validation and distribution of new computational tools, automated data format conversion, and an intuitive graphical user interface. We demonstrate the new LONI Pipeline features using large scale neuroimaging studies based on data from the International Consortium for Brain Mapping [5] and the Alzheimer's Disease Neuroimaging Initiative [6]. User guides, forums, instructions and downloads of the LONI Pipeline environment are available at http://pipeline.loni.ucla.edu

Parallel workflow tools to facilitate human brain MRI post-processing

Multi-modal magnetic resonance imaging (MRI) techniques are widely applied in human brain studies. To obtain specific brain measures of interest from MRI datasets, a number of complex image post-processing steps are typically required. Parallel workflow tools have recently been developed, concatenating individual processing steps and enabling fully automated processing of raw MRI data to obtain the final results. These workflow tools are also designed to make optimal use of available computational resources and to support the parallel processing of different subjects or of independent processing steps for a single subject. Automated, parallel MRI post-processing tools can greatly facilitate relevant brain investigations and are being increasingly applied. In this review, we briefly summarize these parallel workflow tools and discuss relevant issues

Towards structured sharing of raw and derived neuroimaging data across existing resources

Data sharing efforts increasingly contribute to the acceleration of scientific discovery. Neuroimaging data is accumulating in distributed domain-specific databases and there is currently no integrated access mechanism nor an accepted format for the critically important meta-data that is necessary for making use of the combined, available neuroimaging data. In this manuscript, we present work from the Derived Data Working Group, an open-access group sponsored by the Biomedical Informatics Research Network (BIRN) and the International Neuroimaging Coordinating Facility (INCF) focused on practical tools for distributed access to neuroimaging data. The working group develops models and tools facilitating the structured interchange of neuroimaging meta-data and is making progress towards a unified set of tools for such data and meta-data exchange. We report on the key components required for integrated access to raw and derived neuroimaging data as well as associated meta-data and provenance across neuroimaging resources. The components include (1) a structured terminology that provides semantic context to data, (2) a formal data model for neuroimaging with robust tracking of data provenance, (3) a web service-based application programming interface (API) that provides a consistent mechanism to access and query the data model, and (4) a provenance library that can be used for the extraction of provenance data by image analysts and imaging software developers. We believe that the framework and set of tools outlined in this manuscript have great potential for solving many of the issues the neuroimaging community faces when sharing raw and derived neuroimaging data across the various existing database systems for the purpose of accelerating scientific discovery

ARIANNA: A research environment for neuroimaging studies in autism spectrum disorders

The complexity and heterogeneity of Autism Spectrum Disorders (ASD) require the implementation of dedicated analysis techniques to obtain the maximum from the interrelationship among many variables that describe affected individuals, spanning from clinical phenotypic characterization and genetic profile to structural and functional brain images. The ARIANNA project has developed a collaborative interdisciplinary research environment that is easily accessible to the community of researchers working on ASD (https://arianna.pi.infn.it). The main goals of the project are: to analyze neuroimaging data acquired in multiple sites with multivariate approaches based on machine learning; to detect structural and functional brain characteristics that allow the distinguishing of individuals with ASD from control subjects; to identify neuroimaging-based criteria to stratify the population with ASD to support the future development of personalized treatments. Secure data handling and storage are guaranteed within the project, as well as the access to fast grid/cloud-based computational resources. This paper outlines the web-based architecture, the computing infrastructure and the collaborative analysis workflows at the basis of the ARIANNA interdisciplinary working environment. It also demonstrates the full functionality of the research platform. The availability of this innovative working environment for analyzing clinical and neuroimaging information of individuals with ASD is expected to support researchers in disentangling complex data thus facilitating their interpretation

Towards Individualized Transcranial Electric Stimulation Therapy through Computer Simulation

Transkranielle Elektrostimulation (tES) beschreibt eine Gruppe von Hirnstimulationstechniken, die einen schwachen elektrischen Strom über zwei nicht-invasiv am Kopf angebrachten Elektroden applizieren. Handelt es sich dabei um einen Gleichstrom, spricht man von transkranieller Gleichstromstimulation, auch tDCS abgekürzt. Die allgemeine Zielstellung aller Hirnstimulationstechniken ist Hirnfunktion durch ein Verstärken oder Dämpfen von Hirnaktivität zu beeinflussen. Unter den Stimulationstechniken wird die transkranielle Gleichstromstimulation als ein adjuvantes Werkzeug zur Unterstützung der mikroskopischen Reorganisation des Gehirnes in Folge von Lernprozessen und besonders der Rehabilitationstherapie nach einem Schlaganfall untersucht. Aktuelle Herausforderungen dieser Forschung sind eine hohe Variabilität im erreichten Stimulationseffekt zwischen den Probanden sowie ein unvollständiges Verständnis des Zusammenspiels der der Stimulation zugrundeliegenden Mechanismen. Als Schlüsselkomponente für das Verständnis der Stimulationsmechanismen wird das zwischen den Elektroden im Kopf des Probanden aufgebaute elektrische Feld erachtet. Einem grundlegenden Konzept folgend wird angenommen, dass Hirnareale, die einer größeren elektrischen Feldstärke ausgesetzt sind, ebenso einen höheren Stimulationseffekt erfahren. Damit kommt der Positionierung der Elektroden eine entscheidende Rolle für die Stimulation zu. Allerdings verteilt sich das elektrische Feld wegen des heterogenen elektrischen Leitfähigkeitsprofil des menschlichen Kopfes nicht uniform im Gehirn der Probanden. Außerdem ist das Verteilungsmuster auf Grund anatomischer Unterschiede zwischen den Probanden verschieden. Die triviale Abschätzung der Ausbreitung des elektrischen Feldes anhand der bloßen Position der Stimulationselektroden ist daher nicht ausreichend genau für eine zielgerichtete Stimulation. Computerbasierte, biophysikalische Simulationen der transkraniellen Elektrostimulation ermöglichen die individuelle Approximation des Verteilungsmusters des elektrischen Feldes in Probanden basierend auf deren medizinischen Bildgebungsdaten. Sie werden daher zunehmend verwendet, um tDCS-Anwendungen zu planen und verifizieren, und stellen ein wesentliches Hilfswerkzeug auf dem Weg zu individualisierter Schlaganfall-Rehabilitationstherapie dar. Softwaresysteme, die den dahinterstehenden individualisierten Verarbeitungsprozess erleichtern und für ein breites Feld an Forschern zugänglich machen, wurden in den vergangenen Jahren für den Anwendungsfall in gesunden Erwachsenen entwickelt. Jedoch bleibt die Simulation von Patienten mit krankhaftem Hirngewebe und strukturzerstörenden Läsionen eine nicht-triviale Aufgabe. Daher befasst sich das hier vorgestellte Projekt mit dem Aufbau und der praktischen Anwendung eines Arbeitsablaufes zur Simulation transkranieller Elektrostimulation. Dabei stand die Anforderung im Vordergrund medizinische Bildgebungsdaten insbesondere neurologischer Patienten mit krankhaft verändertem Hirngewebe verarbeiten zu können. Der grundlegende Arbeitsablauf zur Simulation wurde zunächst für gesunde Erwachsene entworfen und validiert. Dies umfasste die Zusammenstellung medizinischer Bildverarbeitungsalgorithmen zu einer umfangreichen Verarbeitungskette, um elektrisch relevante Strukturen in den Magnetresonanztomographiebildern des Kopfes und des Oberkörpers der Probanden zu identifizieren und zu extrahieren. Die identifizierten Strukturen mussten in Computermodelle überführt werden und das zugrundeliegende, physikalische Problem der elektrischen Volumenleitung in biologischen Geweben mit Hilfe numerischer Simulation gelöst werden. Im Verlauf des normalen Alterns ist das Gehirn strukturellen Veränderungen unterworfen, unter denen ein Verlust des Hirnvolumens sowie die Ausbildung mikroskopischer Veränderungen seiner Nervenfaserstruktur die Bedeutendsten sind. In einem zweiten Schritt wurde der Arbeitsablauf daher erweitert, um diese Phänomene des normalen Alterns zu berücksichtigen. Die vordergründige Herausforderung in diesem Teilprojekt war die biophysikalische Modellierung der veränderten Hirnmikrostruktur, da die resultierenden Veränderungen im Leitfähigkeitsprofil des Gehirns bisher noch nicht in der Literatur quantifiziert wurden. Die Erweiterung des Simulationsablauf zeichnete sich vorrangig dadurch aus, dass mit unsicheren elektrischen Leitfähigkeitswerten gearbeitet werden konnte. Damit war es möglich den Einfluss der ungenau bestimmbaren elektrischen Leitfähigkeit der verschiedenen biologischen Strukturen des menschlichen Kopfes auf das elektrische Feld zu ermitteln. In einer Simulationsstudie, in der Bilddaten von 88 Probanden einflossen, wurde die Auswirkung der veränderten Hirnfaserstruktur auf das elektrische Feld dann systematisch untersucht. Es wurde festgestellt, dass sich diese Gewebsveränderungen hochgradig lokal und im Allgemeinen gering auswirken. Schließlich wurden in einem dritten Schritt Simulationen für Schlaganfallpatienten durchgeführt. Ihre großen, strukturzerstörenden Läsionen wurden dabei mit einem höheren Detailgrad als in bisherigen Arbeiten modelliert und physikalisch abermals mit unsicheren Leitfähigkeiten gearbeitet, was zu unsicheren elektrischen Feldabschätzungen führte. Es wurden individuell berechnete elektrische Felddaten mit der Hirnaktivierung von 18 Patienten in Verbindung gesetzt, unter Berücksichtigung der inhärenten Unsicherheit in der Bestimmung der elektrischen Felder. Das Ziel war zu ergründen, ob die Hirnstimulation einen positiven Einfluss auf die Hirnaktivität der Patienten im Kontext von Rehabilitationstherapie ausüben und so die Neuorganisierung des Gehirns nach einem Schlaganfall unterstützen kann. Während ein schwacher Zusammenhang hergestellt werden konnte, sind weitere Untersuchungen nötig, um diese Frage abschließend zu klären.:Kurzfassung Abstract Contents 1 Overview 2 Anatomical structures in magnetic resonance images 2 Anatomical structures in magnetic resonance images 2.1 Neuroanatomy 2.2 Magnetic resonance imaging 2.3 Segmentation of MR images 2.4 Image morphology 2.5 Summary 3 Magnetic resonance image processing pipeline 3.1 Introduction to human body modeling 3.2 Description of the processing pipeline 3.3 Intermediate and final outcomes in two subjects 3.4 Discussion, limitations & future work 3.5 Conclusion 4 Numerical simulation of transcranial electric stimulation 4.1 Electrostatic foundations 4.2 Discretization of electrostatic quantities 4.3 The numeric solution process 4.4 Spatial discretization by volume meshing 4.5 Summary 5 Simulation workflow 5.1 Overview of tES simulation pipelines 5.2 My implementation of a tES simulation workflow 5.3 Verification & application examples 5.4 Discussion & Conclusion 6 Transcranial direct current stimulation in the aging brain 6.1 Handling age-related brain changes in tES simulations 6.2 Procedure of the simulation study 6.3 Results of the uncertainty analysis 6.4 Findings, limitations and discussion 7 Transcranial direct current stimulation in stroke patients 7.1 Bridging the gap between simulated electric fields and brain activation in stroke patients 7.2 Methodology for relating simulated electric fields to functional MRI data 7.3 Evaluation of the simulation study and correlation analysis 7.4 Discussion & Conclusion 8 Outlooks for simulations of transcranial electric stimulation List of Figures List of Tables Glossary of Neuroscience Terms Glossary of Technical Terms BibliographyTranscranial electric current stimulation (tES) denotes a group of brain stimulation techniques that apply a weak electric current over two or more non-invasively, head-mounted electrodes. When employing a direct-current, this method is denoted transcranial direct current stimulation (tDCS). The general aim of all tES techniques is the modulation of brain function by an up- or downregulation of brain activity. Among these, transcranial direct current stimulation is investigated as an adjuvant tool to promote processes of the microscopic reorganization of the brain as a consequence of learning and, more specifically, rehabilitation therapy after a stroke. Current challenges of this research are a high variability in the achieved stimulation effects across subjects and an incomplete understanding of the interplay between its underlying mechanisms. A key component to understanding the stimulation mechanism is considered the electric field, which is exerted by the electrodes and distributes in the subjects' heads. A principle concept assumes that brain areas exposed to a higher electric field strength likewise experience a higher stimulation. This attributes the positioning of the electrodes a decisive role for the stimulation. However, the electric field distributes non-uniformly across subjects' brains due to the heterogeneous electrical conductivity profile of the human head. Moreover, the distribution pattern is variable between subjects due to their individual anatomy. A trivial estimation of the distribution of the electric field solely based on the position of the stimulating electrodes is, therefore, not precise enough for a well-targeted stimulation. Computer-based biophysical simulations of transcranial electric stimulation enable the individual approximation of the distribution pattern of the electric field in subjects based on their medical imaging data. They are, thus, increasingly employed for the planning and verification of tDCS applications and constitute an essential tool on the way to individualized stroke rehabilitation therapy. Software pipelines facilitating the underlying individualized processing for a wide range of researchers have been developed for use in healthy adults over the past years, but, to date, the simulation of patients with abnormal brain tissue and structure disrupting lesions remains a non-trivial task. Therefore, the presented project was dedicated to establishing and practically applying a tES simulation workflow. The processing of medical imaging data of neurological patients with abnormal brain tissue was a central requirement in this process. The basic simulation workflow was first designed and validated for the simulation of healthy adults. This comprised compiling medical image processing algorithms into a comprehensive workflow to identify and extract electrically relevant physiological structures of the human head and upper torso from magnetic resonance images. The identified structures had to be converted to computational models. The underlying physical problem of electric volume conduction in biological tissue was solved by means of numeric simulation. Over the course of normal aging, the brain is subjected to structural alterations, among which a loss of brain volume and the development of microscopic alterations of its fiber structure are the most relevant. In a second step, the workflow was, thus, extended to incorporate these phenomena of normal aging. The main challenge in this subproject was the biophysical modeling of the altered brain microstructure as the resulting alterations to the conductivity profile of the brain were so far not quantified in the literature. Therefore, the augmentation of the workflow most notably included the modeling of uncertain electrical properties. With this, the influence of the uncertain electrical conductivity of the biological structures of the human head on the electric field could be assessed. In a simulation study, including imaging data of 88 subjects, the influence of the altered brain fiber structure on the electric field was then systematically investigated. These tissue alterations were found to exhibit a highly localized and generally low impact. Finally, in a third step, tDCS simulations of stroke patients were conducted. Their large, structure-disrupting lesions were modeled in a more detailed manner than in previous stroke simulation studies, and they were physically, again, modeled by uncertain electrical conductivity resulting in uncertain electric field estimates. Individually simulated electric fields were related to the brain activation of 18 patients, considering the inherently uncertain electric field estimations. The goal was to clarify whether the stimulation exerts a positive influence on brain function in the context of rehabilitation therapy supporting brain reorganization following a stroke. While a weak correlation could be established, further investigation will be necessary to answer that research question.:Kurzfassung Abstract Contents 1 Overview 2 Anatomical structures in magnetic resonance images 2 Anatomical structures in magnetic resonance images 2.1 Neuroanatomy 2.2 Magnetic resonance imaging 2.3 Segmentation of MR images 2.4 Image morphology 2.5 Summary 3 Magnetic resonance image processing pipeline 3.1 Introduction to human body modeling 3.2 Description of the processing pipeline 3.3 Intermediate and final outcomes in two subjects 3.4 Discussion, limitations & future work 3.5 Conclusion 4 Numerical simulation of transcranial electric stimulation 4.1 Electrostatic foundations 4.2 Discretization of electrostatic quantities 4.3 The numeric solution process 4.4 Spatial discretization by volume meshing 4.5 Summary 5 Simulation workflow 5.1 Overview of tES simulation pipelines 5.2 My implementation of a tES simulation workflow 5.3 Verification & application examples 5.4 Discussion & Conclusion 6 Transcranial direct current stimulation in the aging brain 6.1 Handling age-related brain changes in tES simulations 6.2 Procedure of the simulation study 6.3 Results of the uncertainty analysis 6.4 Findings, limitations and discussion 7 Transcranial direct current stimulation in stroke patients 7.1 Bridging the gap between simulated electric fields and brain activation in stroke patients 7.2 Methodology for relating simulated electric fields to functional MRI data 7.3 Evaluation of the simulation study and correlation analysis 7.4 Discussion & Conclusion 8 Outlooks for simulations of transcranial electric stimulation List of Figures List of Tables Glossary of Neuroscience Terms Glossary of Technical Terms Bibliograph

Quantifying age-related differences in diffusion tensor imaging biomarkers for the male urethral sphincter of prostate cancer patients

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Sinais e Imagens Médicas) Universidade de Lisboa, Faculdade de Ciências, 2019For the past years, radical prostatectomy (RP) has been the treatment of choice for locally advanced prostate cancer (PC) because of its high accuracy in tumor removal. However, the surgical techniques performed tend to be invasive, with a complete removal of the proximal lisso-sphincter and partial removal of the distal rhabdosphincter. Whereas the former has been related with maintenance of continence at rest, the latter is related with active continence. Between 4 to 69 % [1] of patients undergoing RP develop urinary incontinence, with a reported decrease in quality of life. This can be a consequence, not only from the surgical technique used, but from other factors including the competence of the sphincter function, that it is expected to decrease with age [2]. It is important to find preoperative imaging biomarkers that can help predict the risk of the patient developing postoperative urinary incontinence. The TransDouglas project, approved by the Ethics Committee of Champalimaud Foundation since July 2018, aims at validating the implementation of a new surgical procedure for RP, which is an improved version of the robotic-assisted laparoscopic radical prostatectomy (RALRP) procedure. Preoperative anatomical parameters are extracted from the T2-weighted magnetic resonance imaging (MRI) that can be related with urinary incontinence after the new surgical technique, and to construct a model that can help predict the likely time until urinary continence recovery. Diffusion tensor imaging (DTI) is a MRI-based technique that allows the quantification of anisotropic movement of water molecules. It has been proven [3] that this technique can be used to visualize the microarchitecture of the urethral sphincters, and to extract relevant diffusion metrics. DTI metrics can be incorporated in the model to predict urinary incontinence recovery after RP. Considering this, an addendum to the TransDouglas project that requests the acquisition of an additional DTI sequence to the standard multiparametric (mpMRI) of the prostate has been approved this January, enabling the use of DTI to study the microarchitecture of the urethral sphincters in vivo and non-invasively. However, since parameters of sphincter function significantly change with age [2], it is important to study the influence of patient age at scan on these parameters prior to predicting the likely chance of continence recovery after RP. Therefore, the main goal of this thesis was to investigate age-related differences in DTI metrics of the male urethral sphincter complex. Furthermore, the influence of a prostate condition, including PC and benign prostatic hyperplasia (BPH), was studied. The proximal and distal sphincters, as well as the membranous urethra, were reconstructed for 95 subjects by using the deterministic tractography algorithm in DSIStudio software [4]. DTI metrics were extracted including tract length and density, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) and additional histogram parameters for each DTI metric, namely standard deviation, median, trimmed mean, median absolute deviation, minimum, maximum, range, skewness, kurtosis, standard error and the 5th, 25th, 75th and 95th percentiles. The influence of subject motion and eddy currents corrections on the extracted DTI metrics was investigated. Linear regressions and Pearson or Spearman correlations were performed between age and each of the DTI metrics. Additionally, analysis of variance (ANOVA), or the non-parametric Kruskal-Wallis test, were used to compare DTI metrics between four age groups (from 50 to 59, 60 to 69, 70 to 79 and 80 to 89 years old). For a subset of the 69 subjects with a confirmed diagnosis for PC, BPH and the absence of any of both, ANOVA testing was used to compare between disease groups, and t-tests, or the nonparametric Wilcoxon test, to compare between cancer status. For statistically significant ANOVA test results, post-hoc t-tests were used to investigate the groups between which the difference lied. No statistically significant differences were found on DTI metrics with and without motion and eddy currents corrections, so the non-corrected DTI data was used for the subsequent analysis. In this study, it was found that MD and RD distributions statistical significantly changed with age. In particular, older subjects evidenced lower RD kurtosis in the proximal sphincter, lower MD maximum in the distal sphincter and higher MD median absolute deviation in the membranous urethra. On the other hand, further investigations are needed to understand if the presence of a prostate condition affects the DTI metrics of the sphincters and membranous urethra. This project was the first to examine age related differences in the urethral sphincter complex using DTI, as well as, the first time a DTI sequence for the prostate was implemented at Champalimaud Centre for the Unknown (CCU). It was concluded that age should be used as a covariate in a model that makes use of DTI biomarkers representative of the male urethral complex microstructure to predict the likely time of post-surgical continence recovery. Ultimately, this investigation should be a starting point for helping clinicians in the prediction of the risk of complications for each patient before undergoing RP, and balance the advantages and disadvantages comparing with other available treatment options for PC.Segundo dados de 2016, no sexo masculino e em paises desenvolvidos, o cancro da prostata foi o cancro que registou maior incidencia [5]. Apos uma detecao atraves do aumento da evolucao dos niveis do antigenio especifico da prostata (PSA) no sangue e/ou de realizacao do teste do toque retal, o método de diagnostico mais comum e a biopsia, que pode ser auxiliada por ultrassons ou por ressonância magnetica multiparametrica. A escolha do tratamento adequado para cada paciente depende do estadio da doenca e das suas preferencias individuais, que geralmente pretendem equiponderar a esperanca de vida para o paciente e a qualidade de vida apos tratamento. Geralmente, as opcoes de tratamento mais adequadas para um paciente com PSA > 10 ng/mL e nodulos palpaveis sao: acompanhamento e tratamento dos sintomas a medida que estes surgem, radioterapia ou braquiterapia, e cirurgia [6]. A ultima opcao, em particular a prostatectomia radical, tem demonstrado maior precisao na remocao de tecido maligno e no aumento da esperanca media de vida para os pacientes operados [7]. Mais recentemente, tecnicas laparoscopicas convencionais tem vindo a ser substituidas por tecnicas robóticas que oferecem maiores vantagens no pos-operatorio. No entanto, a incontinencia urinaria e a disfunção eretil continuam a ser complicacoes reportadas por uma percentagem significativa de pacientes submetidos a cirurgia. Relativamente ao primeiro, afeta cerca de 4 a 69 % dos pacientes [1], e a sua ocorrencia esta intimamente ligada a remocao do esfincter proximal ou liso, que ocorre aquando da remocao da prostata, e consequente dano no esfincter distal ou rabdoesfincter. A construcao de um modelo preditivo da recuperacao da continencia pos-cirurgica com base na utilizacao de biomarcadores do esfincter, pode permitir aos prospetivos pacientes uma escolha ponderada do tipo de tratamento. No entanto, e sabido que a microestrutura do esfincter varia com a idade [2], logo e necessario conhecer o padrao de variacao dos biomarcadores do esfincter com a idade, no sentido de avaliar a recuperacao pos-cirurgica da continencia. Para estudar a microestrutura do esfincter tem sido utilizadas diversas tecnicas in vivo [8]–[13] que, no entanto, nao fornecem informacao tridimensional da estrutura e orientacao das fibras que o compoem. Contrariamente, imagem por tensor de difusao (DTI) e uma tecnica nao invasiva baseada em ressonância magnetica que permite quantificar o movimento das moleculas de agua nos tecidos, atraves da aplicação de gradientes em varias direcoes nao colineares [14]. Relacionando o gradiente aplicado com o sinal medido, obtem-se em cada voxel informacao sobre a magnitude e direcao da difusao. A partir da diagonalizacao do tensor de difusao e possivel calcular eigenvalues e eigenvectors. Enquanto que os ultimos refletem a direccionalidade, os primeiros quantificam a magnitude da difusao e combinados entre si permitem obter um conjunto de metricas – que inclui a anisotropia fracional (FA), difusibilidade axial (AD), difusibilidade media (MD) e difusibilidade radial (RD) – que permitem estudar a organizacao estrutural das fibras. Apesar das aplicacoes de DTI se focarem essencialmente em estudos de conectividade da substancia branca do cerebro, tem progressivamente sido alargadas ao estudo de outros orgaos, como o rim [15], o coracao [16] e a prostata. Relativamente ao uso de DTI para o estudo da prostata, esta tecnica tem sido utilizada para estudar este orgao em condicoes normais [17] e para definir metricas que permitam distinguir tecido saudavel de tumoral [18]. Ademais, estudos tem avaliado os feixes neuro-vasculares da prostata antes e apos a cirurgia e correlacionado com a disfunção eretil pos-prostatectomia radical [7]. Para alem de um estudo que investigou o esfincter uretral feminino usando DTI [19], que se tenha conhecimento, existe apenas um estudo que conseguiu utilizar DTI para estudo da microarquitectura do esfincter masculino em sujeitos jovens e sem patologia [3]. Assim, o principal objetivo da presente tese de mestrado e investigar variacoes derivadas da idade no complexo do esfincter uretral, que compreende os esfincteres proximais e distais e a uretra membranosa – correspondente ao segmento da uretra que se estende desde o apice da prostata ate ao bulbo peniano. No sentido de estudar o efeito da presenca de uma condicao da prostata, incluindo cancro da prostata e hiperplasia benigna da prostata (HBP), a variacao das metricas de DTI do esfincter para o grupo de pacientes diagnosticados foi tambem avaliada. Como objetivo secundario, que teve importancia na etapa de processamento dos dados de DTI, foi investigado se a correcao de movimento durante a aquisicao e correcao de correntes de Foucault afetava significativamente as metricas de DTI em estudo, para cada uma das estruturas. Para tal, os esfincteres proximal e distal, bem como a uretra membranosa, foram reconstruidos para 95 individuos usando o algoritmo deterministico de tractografia no software DSIStudio [4]. Previamente foram definidas manualmente um conjunto de regioes de interesse nos mapas coloridos de FA para os esfincteres proximal e distal, e na imagem anatomica em T2 para a uretra membranosa. Para a tractografia, foram otimizados alguns parametros segundo uma abordagem de tentativa e erro, que acabou por estabelecer um valor limite de anisotropia fracional de 0.15, e um limite angular de 75o e 45o, respetivamente para os esfincteres e para a uretra. As metricas de DTI foram extraidas para cada uma das estruturas reconstruidas, incluindo o comprimento e densidade das fibras, FA, AD, MD e RD e parametros adicionais do histograma para cada metrica de DTI, ou seja, desvio padrao, mediana, media aparada, desvio absoluto mediano, minimo, maximo, amplitude, assimetria, curtose, erro padrao e os percentis 5, 25, 75 e 95. A influencia do movimento e da presenca de correntes de Foucault nas métricas de DTI extraidas foram investigadas. Regressoes lineares e correlacoes de Pearson ou Spearman foram realizadas entre a idade e cada uma das metricas de DTI. Alem disso, uma analise de variância (ANOVA) – ou o equivalente teste nao parametrico de Kruskal-Wallis –, foram realizados para comparar metricas de DTI entre quatro faixas etarias (de 50 a 59, 60 a 69, 70 a 79 e 80 a 89 anos). Para um subconjunto dos 69 individuos com diagnostico confirmado de cancro de prostata, HBP ou da ausencia de qualquer um dos dois, o teste ANOVA foi usado para comparar entre grupos de doenca. Adicionalmente, testes t-student – ou o teste nao parametrico de Wilcoxon – foram utilizados para comparar a presenca vs. ausencia de cancro. Para resultados estatisticamente significativos do teste ANOVA, foram posteriormente empregues testes t-student para investigar entre que grupos se encontrava a diferenca. Nao foram encontradas diferencas estatisticamente significativas nas metricas de DTI com e sem correcao de movimento e correntes de Foucault, logo, os dados de DTI sem correcao foram utilizados para a analise subsequente. Neste estudo, verificou-se que as distribuicoes de MD e RD variaram significativamente com a idade. Em particular, individuos mais velhos evidenciaram menor curtose da RD no esfincter proximal, menor valor maximo de MD no esfincter distal e maior desvio absoluto mediano de MD na uretra membranosa. Por outro lado, sao necessarias investigacoes adicionais para entender se a presenca de uma condicao da prostata pode afetar as metricas de DTI dos esfincteres e da uretra membranosa. Tal acontece, pois os resultados obtidos neste estudo para a presenca de doença estao limitados pela heterogeneidade da amostra em termos das diferentes condicoes que cada individuo pode apresentar. Julga-se que este estudo foi o primeiro a identificar variacoes com a idade nas metricas de DTI do esfincter. Alem disso, definiu a inclusao de uma sequencia de DTI a ressonancia magnética multiparametrica da pratica clinica da Fundacao Champalimaud. Por se tratar de um estudo prospetivo, foi possivel definir os parametros de aquisicao – nomeadamente o valor de b (em s/mm2), o numero de direcoes da aplicacao do gradiente, o numero de cortes adquiridos e a extensao da aquisicao - otimospara a visualizacao das estruturas do complexo uretral masculino, com o melhor compromisso entre duracao da aquisicao (em minutos) e a resolucao espacial (em milimetros). Esta nova sequencia so comecou a ser incluida na clinica desde Janeiro 2019, o que representa cerca de 14 pacientes operados, dos 45 diagnosticados com cancro da prostata. Assim que for possivel aumentar a amostra de pacientes operados com um intervalo de tempo pos-cirurgico de 3 a 6 meses, sera possivel utilizar os resultados dos testes de incontinencia, os dados de DTI do esfincter corrigidos da idade e as medidas do comprimento da uretra em T2, para prever o tempo de recuperacao de continencia pos-cirurgica. No futuro, esperamos poder extrair os biomarcadores de DTI para o complexo do esfincter uretral de cada paciente e usa-los como um preditor da taxa de incontinencia pos-cirurgica. No entanto, e importante que este modelo tenha em conta alteracoes nas metricas de DTI do complexo uretral masculino que são influenciadas pelo envelhecimento. Esse modelo preditivo pode orientar os pacientes na escolha informada da melhor opcao de tratamento personalizado para tratar o tumor da prostata e, simultaneamente, proporcionar uma qualidade de vida satisfatoria

A formal architecture-centric and model driven approach for the engineering of science gateways

From n-Tier client/server applications, to more complex academic Grids, or even the most recent and promising industrial Clouds, the last decade has witnessed significant developments in distributed computing. In spite of this conceptual heterogeneity, Service-Oriented Architecture (SOA) seems to have emerged as the common and underlying abstraction paradigm, even though different standards and technologies are applied across application domains. Suitable access to data and algorithms resident in SOAs via so-called ‘Science Gateways’ has thus become a pressing need in order to realize the benefits of distributed computing infrastructures.In an attempt to inform service-oriented systems design and developments in Grid-based biomedical research infrastructures, the applicant has consolidated work from three complementary experiences in European projects, which have developed and deployed large-scale production quality infrastructures and more recently Science Gateways to support research in breast cancer, pediatric diseases and neurodegenerative pathologies respectively. In analyzing the requirements from these biomedical applications the applicant was able to elaborate on commonly faced issues in Grid development and deployment, while proposing an adapted and extensible engineering framework. Grids implement a number of protocols, applications, standards and attempt to virtualize and harmonize accesses to them. Most Grid implementations therefore are instantiated as superposed software layers, often resulting in a low quality of services and quality of applications, thus making design and development increasingly complex, and rendering classical software engineering approaches unsuitable for Grid developments.The applicant proposes the application of a formal Model-Driven Engineering (MDE) approach to service-oriented developments, making it possible to define Grid-based architectures and Science Gateways that satisfy quality of service requirements, execution platform and distribution criteria at design time. An novel investigation is thus presented on the applicability of the resulting grid MDE (gMDE) to specific examples and conclusions are drawn on the benefits of this approach and its possible application to other areas, in particular that of Distributed Computing Infrastructures (DCI) interoperability, Science Gateways and Cloud architectures developments