Development and Evaluation of Quantitative Methods of Analysing Single Photon Emission Computed Tomography Blood Flow Images of the Brain

Development and evaluation of quantitative methods of analysing single photon emission computed tomography blood flow images of the brain. This thesis presents the investigations carried out on a particular method of functional human brain mapping (FHBM) analysis (SPM)1 as to its applicability to a routine nuclear medicine neuroimaging department. Principally designed for the investigation into positron emission tomography (PET) radiolabelled water studies of normal brain function during neuroactivation experiments the technique is still relatively novel for the purposes of interpreting single photon emission computed tomography (SPECT) images of brain function. This thesis investigates whether the functional brain mapping technique (SPM) can be extended to embrace the widely available imaging technique of SPECT and to determine whether this combination can contribute to routine diagnosis of abnormalities in brain function and to research investgiations involving functional neuroactivation. Validation of the image standardisation facility of SPM96 applied to oblique or incomplete image data sets. The image standardisation component of SPM96 was validated by subjecting it to a series of challenge conditions created from simulated data. The challenge conditions were chosen to reflect those that occur in clinical scans, for example, extreme misalignments to a standard reference orientation resulting in axial truncation of the image volume. The results of the software performance under these challenges showed that the image standardisation component of this software had particular problems correcting for large (1

Developing advanced mathematical models for detecting abnormalities in 2D/3D medical structures.

Detecting abnormalities in two-dimensional (2D) and three-dimensional (3D) medical structures is among the most interesting and challenging research areas in the medical imaging field. Obtaining the desired accurate automated quantification of abnormalities in medical structures is still very challenging. This is due to a large and constantly growing number of different objects of interest and associated abnormalities, large variations of their appearances and shapes in images, different medical imaging modalities, and associated changes of signal homogeneity and noise for each object. The main objective of this dissertation is to address these problems and to provide proper mathematical models and techniques that are capable of analyzing low and high resolution medical data and providing an accurate, automated analysis of the abnormalities in medical structures in terms of their area/volume, shape, and associated abnormal functionality. This dissertation presents different preliminary mathematical models and techniques that are applied in three case studies: (i) detecting abnormal tissue in the left ventricle (LV) wall of the heart from delayed contrast-enhanced cardiac magnetic resonance images (MRI), (ii) detecting local cardiac diseases based on estimating the functional strain metric from cardiac cine MRI, and (iii) identifying the abnormalities in the corpus callosum (CC) brain structure—the largest fiber bundle that connects the two hemispheres in the brain—for subjects that suffer from developmental brain disorders. For detecting the abnormal tissue in the heart, a graph-cut mathematical optimization model with a cost function that accounts for the object’s visual appearance and shape is used to segment the the inner cavity. The model is further integrated with a geometric model (i.e., a fast marching level set model) to segment the outer border of the myocardial wall (the LV). Then the abnormal tissue in the myocardium wall (also called dead tissue, pathological tissue, or infarct area) is identified based on a joint Markov-Gibbs random field (MGRF) model of the image and its region (segmentation) map that accounts for the pixel intensities and the spatial interactions between the pixels. Experiments with real in-vivo data and comparative results with ground truth (identified by a radiologist) and other approaches showed that the proposed framework can accurately detect the pathological tissue and can provide useful metrics for radiologists and clinicians. To estimate the strain from cardiac cine MRI, a novel method based on tracking the LV wall geometry is proposed. To achieve this goal, a partial differential equation (PDE) method is applied to track the LV wall points by solving the Laplace equation between the LV contours of each two successive image frames over the cardiac cycle. The main advantage of the proposed tracking method over traditional texture-based methods is its ability to track the movement and rotation of the LV wall based on tracking the geometric features of the inner, mid-, and outer walls of the LV. This overcomes noise sources that come from scanner and heart motion. To identify the abnormalities in the CC from brain MRI, the CCs are aligned using a rigid registration model and are segmented using a shape-appearance model. Then, they are mapped to a simple unified space for analysis. This work introduces a novel cylindrical mapping model, which is conformal (i.e., one to one transformation and bijective), that enables accurate 3D shape analysis of the CC in the cylindrical domain. The framework can detect abnormalities in all divisions of the CC (i.e., splenium, rostrum, genu and body). In addition, it offers a whole 3D analysis of the CC abnormalities instead of only area-based analysis as done by previous groups. The initial classification results based on the centerline length and CC thickness suggest that the proposed CC shape analysis is a promising supplement to the current techniques for diagnosing dyslexia. The proposed techniques in this dissertation have been successfully tested on complex synthetic and MR images and can be used to advantage in many of today’s clinical applications of computer-assisted medical diagnostics and intervention

Machine learning for efficient recognition of anatomical structures and abnormalities in biomedical images

Three studies have been carried out to investigate new approaches to efficient image segmentation and anomaly detection. The first study investigates the use of deep learning in patch based segmentation. Current approaches to patch based segmentation use low level features such as the sum of squared differences between patches. We argue that better segmentation can be achieved by harnessing the power of deep neural networks. Currently these networks make extensive use of convolutional layers. However, we argue that in the context of patch based segmentation, convolutional layers have little advantage over the canonical artificial neural network architecture. This is because a patch is small, and does not need decomposition and thus will not benefit from convolution. Instead, we make use of the canonical architecture in which neurons only compute dot products, but also incorporate modern techniques of deep learning. The resulting classifier is much faster and less memory-hungry than convolution based networks. In a test application to the segmentation of hippocampus in human brain MR images, we significantly outperformed prior art with a median Dice score up to 90.98% at a near real-time speed (<1s). The second study is an investigation into mouse phenotyping, and develops a high-throughput framework to detect morphological abnormality in mouse embryo micro-CT images. Existing work in this line is centred on, either the detection of phenotype-specific features or comparative analytics. The former approach lacks generality and the latter can often fail, for example, when the abnormality is not associated with severe volume variation. Both these approaches often require image segmentation as a pre-requisite, which is very challenging when applied to embryo phenotyping. A new approach to this problem in which non-rigid registration is combined with robust principal component analysis (RPCA), is proposed. The new framework is able to efficiently perform abnormality detection in a batch of images. It is sensitive to both volumetric and non-volumetric variations, and does not require image segmentation. In a validation study, it successfully distinguished the abnormal VSD and polydactyly phenotypes from the normal, respectively, at 85.19% and 88.89% specificities, with 100% sensitivity in both cases. The third study investigates the RPCA technique in more depth. RPCA is an extension of PCA that tolerates certain levels of data distortion during feature extraction, and is able to decompose images into regular and singular components. It has previously been applied to many computer vision problems (e.g. video surveillance), attaining excellent performance. However these applications commonly rest on a critical condition: in the majority of images being processed, there is a background with very little variation. By contrast in biomedical imaging there is significant natural variation across different images, resulting from inter-subject variability and physiological movements. Non-rigid registration can go some way towards reducing this variance, but cannot eliminate it entirely. To address this problem we propose a modified framework (RPCA-P) that is able to incorporate natural variation priors and adjust outlier tolerance locally, so that voxels associated with structures of higher variability are compensated with a higher tolerance in regularity estimation. An experimental study was applied to the same mouse embryo micro-CT data, and notably improved the detection specificity to 94.12% for the VSD and 90.97% for the polydactyly, while maintaining the sensitivity at 100%.Open Acces

Classification of patients with parkinsonian syndromes using medical imaging and artificial intelligence algorithms

The distinction of Parkinsonian Syndromes (PS) is challenging due to similarities of symptoms and signs at early stages of disease. Thus, the need of accurate methods for differential diagnosis at those early stages has emerged. To improve the evaluation of medical images, artificial intelligence turns out to be a useful tool. Parkinson’s Disease, the commonest PS, is characterized by the degeneration of dopamine neurons in the substantia nigra which is detected by the dopamine transporter scan (DaTscanTM), a single photon-emission tomography (SPECT) exam that uses of a radiotracer that binds dopamine receptors. In fact, by using such exam it was possible to identify a sub-group of PD patients known as “Scans without evidence of dopaminergic deficit” (SWEDD) that present a normal exam, unlike PD patients. In this study, an approach based on Convolutional Neural Networks (CNNs) was proposed for classifying PD patients, SWEDD patients and healthy subjects using SPECT and Magnetic Resonance Imaging (MRI) images. Then, these images were divided into subsets of slices in the axial view that contains particular regions of interest since 2D images are the norm in clinical practice. The classifier evaluation was performed with Cohen’s Kappa and Receiver Operating Characteristic (ROC) curve. The results obtained allow to conclude that the CNN using imaging information of the Basal Ganglia and the mesencephalon was able to distinguish PD patients from healthy subjects since achieved 97.4% accuracy using MRI and 92.4% accuracy using SPECT, and PD from SWEDD with 97.3% accuracy using MRI and 93.3% accuracy using SPECT. Nonetheless, using the same approach, it was not possible to discriminate SWEDD patients from healthy subjects (60% accuracy) using DaTscanTM and MRI. These results allow to conclude that this approach may be a useful tool to aid in PD diagnosis in the future

Methodological aspects for improving clinical value of SPECT and MRI

Image processing methods were developed for SPECT and MR images. The methods were validated in clinical environment. Segmentation of SPECT images for region of interest (ROI) analysis was found to be unreliable without accurate attenuation and scatter correction for the original images. The reliability of ROI analysis of brain SPECT images was enhanced using registration with MRI. The method was based on external markers. The registration error was studied using phantom tests and simulations. It was concluded that the registration accuracy was not the limiting factor in ROI analysis of the registered images provided that the external marker system was properly designed and attached. Quality requirements for MRI data from patients with cerebral infarctions were evaluated in order to make segmentation as automatic as possible. Quantitative information from these images could be extracted with e.g. statistical and neural network classifiers, but required more manual work than expected due to the visible intensity nonuniformity in the images. The third application consisted of developing a registration methodology for ictal and interictal SPECT, MRI and EEG for improved localization of the epileptogenic foci. The methodology was based on SPECT transmission imaging. The accuracy of registration was about 3-5 mm. As a conclusion, improved analysis of SPECT and MR images was obtained with the carefully evaluated methodology presented in the thesis. The registration procedure for brain SPECT and MRI as well as the registration procedure for epilepsy surgery candidates are in clinical use for selected patients in Helsinki University Central Hospital (currently Health Care Region of Helsinki and Uusimaa).reviewe

Classification of Alzheimer's Disease and Mild Cognitive Impairment Using Longitudinal FDG-PET Images

RÉSUMÉ La maladie d’Alzheimer (MA) est la principale cause de maladies dégénératives et se caractérise par un début insidieux, une perte de mémoire précoce, des déficits verbaux et visuo-spatiaux (associés à la destruction des lobes temporal et pariétal), un développement progressif et une absence de signes neurologiques tôt dans l’apparition de la maladie. Aucun traitement n’est disponible en ce moment pour guérir la MA. Les traitements actuels peuvent souvent ralentir de façon significative la progression de la maladie. La capacité de diagnostiquer la MA à son stade initial a un impact majeur sur l’intervention clinique et la planification thérapeutique, réduisant ainsi les coûts associés aux soins de longue durée. La distinction entre les différents stades de la démence est essentielle afin de ralentir la progression de la MA. La différenciation entre les patients ayant la MA, une déficience cognitive légère précoce (DCLP), une déficience cognitive légère tardive (DCLT) ou un état cognitif normal (CN) est un domaine de recherche qui a suscité beaucoup d’intérêt durant la dernière décennie. Les images obtenues par tomographie par émission de positrons (TEP) font partie des meilleures méthodes accessibles pour faciliter la distinction entre ces différentes classes. Du point de vue de la neuro-imagerie, les images TEP par fluorodésoxyglucose (FDG) pour le métabolisme cérébral du glucose et pour les plaques amyloïdes (AV45) sont considérées comme des biomarqueurs ayant une puissance diagnostique élevée. Cependant, seules quelques approches ont étudié l’efficacité de considérer uniquement les zones actives localisées par la TEP à des fins de classification. La question de recherche principale de ce travail est de démontrer la capacité des images TEP à classer les résultats de façon précise et de comparer les résultats de deux méthodes d’imagerie TEP (FDG et AV45). Afin de déterminer la meilleure façon de classer les sujets dans les catégories MA, DCLP, DCLT ou CN en utilisant exclusivement les images TEP, nous proposons une procédure qui utilise les caractéristiques apprises à partir d’images TEP identifiées sémantiquement. Les machines à vecteurs de support (MVS) sont déjà utilisées pour faire de nombreuses classifications et font partie des techniques les plus utilisées pour la classification basée sur la neuro-imagerie, comme pour la MA. Les MVS linéaires et la fonction de base radiale (FBR)-MVS sont deux noyaux populaires utilisés dans notre classification. L’analyse en composante principale (ACP) est utilisée pour diminuer la taille des données suivie par les MVS linéaires qui sont une autre méthode de classification. Les forêts d’arbres décisionnels (FAD) sont aussi exécutées pour rendre les résultats obtenus par MVS comparables. L’objectif général de ce travail est de concevoir un ensemble d’outils déjà existants pour classer la MA et les différents stades de DCL. Suivant les étapes de normalisation et de prétraitement, une méthode d’enregistrement TEP-IRM ultimodale et déformable est proposée afin de fusionner l’atlas du MNI au scan TEP de chaque patient et de développer une méthode simple de segmentation basée sur l’atlas du cerveau dans le but de générer un volume étiqueté avec 10 régions d’intérêt communes. La procédure a deux approches : la première utilise l’intensité des voxels des régions d’intérêt, et la seconde, l’intensité des voxels du cerveau en entier. La méthode a été testée sur 660 sujets provenant de la base de données de l’(Alzheimer’s Disease Neuroimaging Initiative) et a été comparée à une approche qui incluait le cerveau en entier. La précision de la classification entre la MA et les CN a été mesurée à 91,7% et à 91,2% en utilisant la FBR et les FAD, respectivement, sur des données combinant les caractéristiques multirégionales des FDG-TEP des examens transversal et de suivi. Une amélioration considérable a été notée pour la précision de classification entre les DCLP et DCLT avec un taux de 72,5%. La précision de classification entre la MA et les CN en utilisant AV45-TEP avec les données combinées a été mesurée à 90,8% et à 87,9% pour la FBR et les FAD, respectivement. Cette procédure démontre le potentiel des caractéristiques multirégionales de la TEP pour améliorer l’évaluation cognitive. Les résultats observés confirment qu’il est possible de se fier uniquement aux images TEP sans ajout d’autres bio-marqueurs pour obtenir une précision de classification élevée.----------ABSTRACT Alzheimer’s disease (AD) is the most general cause of degenerative dementia, characterized by insidious onset early memory loss, language and visuospatial deficits (associated with the destruction of the temporal and parietal lobes), a progressive course, and lack of early neurological signs early in the course of disease. There is currently no absolute cure for AD but some treatments can slow down the progression of the disease in early stages of AD. The ability to diagnose AD at an early stage has a great impact on the clinical intervention and treatment planning, and hence reduces costs associated with long-term care. In addition, discrimination of different stages of dementia is crucial to slow down the progression of AD. Distinguishing patients with AD, early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and normal controls (NC) is an extremely active research area, which has garnered significant attention in the past decade. Positron emission tomography (PET) images are one of the best accessible ways to discriminate between different classes. From a neuroimaging point of view, PET images of fluorodeoxyglucose (FDG) for cerebral glucose metabolism and amyloid plaque images (AV45) are considered a highly powerful diagnostic biomarker, but few approaches have investigated the efficacy of focusing on localized PETactive areas for classification purposes. The main research question of this work is to show the ability of using PET images to achieve accurate classification results and to compare the results of two imaging methods of PET (FDG and AV45). To find the best scenario to classify our subjects into AD, EMCI, LMCI, and NC using PET images exclusively, we proposed a pipeline using learned features from semantically labelled PET images to perform group classification using four classifiers. Support vector machines (SVMs) are already applied in a wide variety of classifications, and it is one of the most popular techniques in classification based on neuroimaging like AD. Linear SVMs and radial basis function (RBF) SVMs are two common kernels used in our classification. Principal component analysis (PCA) is used to reduce the dimension of our data followed by linear SVMs, which is another method of classification. Random forest (RF) is also applied to make our SVM results comparable. The general objective of this work is to design a set of existing tools for classifying AD and different stages of MCI. Following normalization and pre-processing steps, a multi-modal PET-MRI registration method is proposed to fuse the Montreal Neurological Institute (MNI) atlas to PET images of each patient which is registered to its corresponding MRI scan, developing a simple method of segmentation based on a brain atlas generated from a fully labelled volume with 10 common regions of interest (ROIs). This pipeline can be used in two ways: (1) using voxel intensities from specific regions of interest (multi-region approach), and (2) using voxel intensities from the entire brain (whole brain approach). The method was tested on 660 subjects from the Alzheimer’s Disease Neuroimaging Initiative database and compared to a whole-brain approach. The classification accuracy of AD vs NC was measured at 91.7 % and 91.2 % when using RBF-SVM and RF, respectively, on combining both multi-region features from FDG-PET on cross-sectional and follow-up exams. A considerable improvement compare to the similar works in the EMCI vs LMCI classification accuracy was achieved at 72.5 %. The classification accuracy of AD versus NC using AV45-PET on the combined data was measured at 90.8 % and 87.9 % using RBF-SVM and RF, respectively. The pipeline demonstrates the potential of exploiting longitudinal multi-region PET features to improve cognitive assessment. We can achieve high accuracy using only PET images. This suggests that PET images are a rich source of discriminative information for this task. We note that other methods rely on the combination of multiple sources

Quantitative MRI correlates of hippocampal and neocortical pathology in intractable temporal lobe epilepsy

Intractable or drug-resistant epilepsy occurs in over 30% of epilepsy patients, with many of these patients undergoing surgical excision of the affected brain region to achieve seizure control. Advances in MRI have the potential to improve surgical treatment of epilepsy through improved identification and delineation of lesions. However, validation is currently needed to investigate histopathological correlates of these new imaging techniques. The purpose of this work is to investigate histopathological correlates of quantitative relaxometry and DTI from hippocampal and neocortical specimens of intractable TLE patients. To achieve this goal I developed and evaluated a pipeline for histology to in-vivo MRI image registration, which finds dense spatial correspondence between both modalities. This protocol was divided in two steps whereby sparsely sectioned histology from temporal lobe specimens was first registered to the intermediate ex-vivo MRI which is then registered to the in-vivo MRI, completing a pipeline for histology to in-vivo MRI registration. When correlating relaxometry and DTI with neuronal density and morphology in the temporal lobe neocortex, I found T1 to be a predictor of neuronal density in the neocortical GM and demonstrated that employing multi-parametric MRI (combining T1 and FA together) provided a significantly better fit than each parameter alone in predicting density of neurons. This work was the first to relate in-vivo T1 and FA values to the proportion of neurons in GM. When investigating these quantitative multimodal parameters with histological features within the hippocampal subfields, I demonstrated that MD correlates with neuronal density and size, and can act as a marker for neuron integrity within the hippocampus. More importantly, this work was the first to highlight the potential of subfield relaxometry and diffusion parameters (mainly T2 and MD) as well as volumetry in predicting the extent of cell loss per subfield pre-operatively, with a precision so far unachievable. These results suggest that high-resolution quantitative MRI sequences could impact clinical practice for pre-operative evaluation and prediction of surgical outcomes of intractable epilepsy