Behavioural disinhibition in the syndromes associated with frontotemporal lobar degeneration

The different clinical syndromes caused by frontotemporal lobar degeneration (FTLD) have highly heterogenous and overlapping features which complicate clinical and research practice. Behavioural impairments are associated with all FTLD syndromes, cause high morbidity and lack proven symptomatic treatments. Treatments for cognitive and behavioural impairment in other neurodegenerative diseases include restoration of neurotransmitter deficits. Deficits in the neurotransmitters glutamate and GABA occur in FTLD syndromes and are associated with behavioural disinhibition in other diseases. I propose that these neurotransmitter deficits contribute to behavioural change in FTLD syndromes. This thesis has two main aims. First, to develop a transdiagnostic approach to FTLD syndromes to facilitate a better understanding of aetiology, pathophysiology and in due course their symptomatic treatment. Second, to use this approach to test the hypothesis that glutamate and GABA deficits are associated with behavioural disinhibition in FTLD syndromes. In a cross-sectional epidemiological study, I examined 310 of 365 regional patients with a FTLD-associated syndrome, including behavioural variant frontotemporal dementia, the nonfluent and semantic variants of primary progressive aphasia, progressive supranuclear palsy and corticobasal syndrome. Multivariate analyses of clinical features and brain morphometry identified components that showed considerable overlap across the diagnostic groups. The transdiagnostic components of clinical features predicted neuropathology better than the current FTLD diagnostic labels. Behavioural disturbance, including disinhibition, was associated with reduced functionally independent survival, irrespective of diagnosis. Next, I investigated the role of glutamate and GABA in behavioural disinhibition. Ultrahigh-field magnetic resonance spectroscopy was used to measure glutamate and GABA in the frontal cortex of 44 patients with a FTLD syndrome and 20 healthy controls. Bayesian modelling of a response inhibition task was used to quantify behavioural disinhibition. Both neurotransmitters were reduced in the frontal cortex, but not occipital cortex, of patients compared to controls. Glutamate and GABA concentrations in the frontal cortex were inversely associated with behavioural disinhibition. In summary, the transdiagnostic approach provided new insights into the phenotypic heterogeneity in FTLD syndromes. Behavioural disinhibition, which can occur to a variable degree in all FTLD syndromes, was associated with reduced functionally independent survival. GABA and glutamate deficits in the frontal cortex are associated with behavioural disinhibition and are a potential target for future treatments.Holt Fellowshi

Automated Characterisation and Classification of Liver Lesions From CT Scans

Cancer is a general term for a wide range of diseases that can affect any part of the body due to the rapid creation of abnormal cells that grow outside their normal boundaries. Liver cancer is one of the common diseases that cause the death of more than 600,000 each year. Early detection is important to diagnose and reduce the incidence of death. Examination of liver lesions is performed with various medical imaging modalities such as Ultrasound (US), Computer tomography (CT), and Magnetic resonance imaging (MRI). The improvements in medical imaging and image processing techniques have significantly enhanced the interpretation of medical images. Computer-Aided Diagnosis (CAD) systems based on these techniques play a vital role in the early detection of liver disease and hence reduce liver cancer death rate. Moreover, CAD systems can help physician, as a second opinion, in characterising lesions and making the diagnostic decision. Thus, CAD systems have become an important research area. Particularly, these systems can provide diagnostic assistance to doctors to improve overall diagnostic accuracy. The traditional methods to characterise liver lesions and differentiate normal liver tissues from abnormal ones are largely dependent on the radiologists experience. Thus, CAD systems based on the image processing and artificial intelligence techniques gained a lot of attention, since they could provide constructive diagnosis suggestions to clinicians for decision making. The liver lesions are characterised through two ways: (1) Using a content-based image retrieval (CBIR) approach to assist the radiologist in liver lesions characterisation. (2) Calculating the high-level features that describe/ characterise the liver lesion in a way that is interpreted by humans, particularly Radiologists/Clinicians, based on the hand-crafted/engineered computational features (low-level features) and learning process. However, the research gap is related to the high-level understanding and interpretation of the medical image contents from the low-level pixel analysis, based on mathematical processing and artificial intelligence methods. In our work, the research gap is bridged if a relation of image contents to medical meaning in analogy to radiologist understanding is established. This thesis explores an automated system for the classification and characterisation of liver lesions in CT scans. Firstly, the liver is segmented automatically by using anatomic medical knowledge, histogram-based adaptive threshold and morphological operations. The lesions and vessels are then extracted from the segmented liver by applying AFCM and Gaussian mixture model through a region growing process respectively. Secondly, the proposed framework categorises the high-level features into two groups; the first group is the high-level features that are extracted from the image contents such as (Lesion location, Lesion focality, Calcified, Scar, ...); the second group is the high-level features that are inferred from the low-level features through machine learning process to characterise the lesion such as (Lesion density, Lesion rim, Lesion composition, Lesion shape,...). The novel Multiple ROIs selection approach is proposed, in which regions are derived from generating abnormality level map based on intensity difference and the proximity distance for each voxel with respect to the normal liver tissue. Then, the association between low-level, high-level features and the appropriate ROI are derived by assigning the ability of each ROI to represents a set of lesion characteristics. Finally, a novel feature vector is built, based on high-level features, and fed into SVM for lesion classification. In contrast with most existing research, which uses low-level features only, the use of high-level features and characterisation helps in interpreting and explaining the diagnostic decision. The methods are evaluated on a dataset containing 174 CT scans. The experimental results demonstrated that the efficacy of the proposed framework in the successful characterisation and classification of the liver lesions in CT scans. The achieved average accuracy was 95:56% for liver lesion characterisation. While the lesion’s classification accuracy was 97:1% for the entire dataset. The proposed framework is developed to provide a more robust and efficient lesion characterisation framework through comprehensions of the low-level features to generate semantic features. The use of high-level features (characterisation) helps in better interpretation of CT liver images. In addition, the difference-of-features using multiple ROIs were developed for robust capturing of lesion characteristics in a reliable way. This is in contrast to the current research trend of extracting the features from the lesion only and not paying much attention to the relation between lesion and surrounding area. The design of the liver lesion characterisation framework is based on the prior knowledge of the medical background to get a better and clear understanding of the liver lesion characteristics in medical CT images

Morphological quantitation software in breast MRI: application to neoadjuvant chemotherapy patients

The work in this thesis examines the use of texture analysis techniques and shape descriptors to analyse MR images of the breast and their application as a potential quantitative tool for prognostic indication.Textural information is undoubtedly very heavily used in a radiologist’s decision making process. However, subtle variations in texture are often missed, thus by quantitatively analysing MR images the textural properties that would otherwise be impossible to discern by simply visually inspecting the image can be obtained. Texture analysis is commonly used in image classification of aerial and satellite photography, studies have also focussed on utilising texture in MRI especially in the brain. Recent research has focussed on other organs such as the breast wherein lesion morphology is known to be an important diagnostic and prognostic indicator. Recent work suggests benefits in assessing lesion texture in dynamic contrast-enhanced (DCE) images, especially with regards to changes during the initial enhancement and subsequent washout phases. The commonest form of analysis is the spatial grey-level dependence matrix method, but there is no direct evidence concerning the most appropriate pixel separation and number of grey levels to utilise in the required co-occurrence matrix calculations. The aim of this work is to systematically assess the efficacy of DCE-MRI based textural analysis in predicting response to chemotherapy in a cohort of breast cancer patients. In addition an attempt was made to use shape parameters in order to assess tumour surface irregularity, and as a predictor of response to chemotherapy.In further work this study aimed to texture map DCE MR images of breast patients utilising the co-occurrence method but on a pixel by pixel basis in order to determine threshold values for normal, benign and malignant tissue and ultimately creating functionality within the in house developed software to highlight hotspots outlining areas of interest (possible lesions). Benign and normal data was taken from MRI screening data and malignant data from patients referred with known malignancies.This work has highlighted that textural differences between groups (based on response, nodal status, triple negative and biopsy grade groupings) are apparent and appear to be most evident 1-3 minutes post-contrast administration. Whilst the large number of statistical tests undertaken necessitates a degree of caution in interpreting the results, the fact that significant differences for certain texture parameters and groupings are consistently observed is encouraging.With regards to shape analysis this thesis has highlighted that some differences between groups were seen in shape descriptors but that shape may be limited as a prognostic indicator. Using textural analysis gave a higher proportion of significant differences whilst shape analysis results showed inconsistency across time points.With regards to the mapping this work successfully analysed the texture maps for each case and established lesion detection is possible. The study successfully highlighted hotspots in the breast patients data post texture mapping, and has demonstrated the relationship between sensitivity and false positive rate via hotspot thresholding

A perceptual learning model to discover the hierarchical latent structure of image collections

Biology has been an unparalleled source of inspiration for the work of researchers in several scientific and engineering fields including computer vision. The starting point of this thesis is the neurophysiological properties of the human early visual system, in particular, the cortical mechanism that mediates learning by exploiting information about stimuli repetition. Repetition has long been considered a fundamental correlate of skill acquisition andmemory formation in biological aswell as computational learning models. However, recent studies have shown that biological neural networks have differentways of exploiting repetition in forming memory maps. The thesis focuses on a perceptual learning mechanism called repetition suppression, which exploits the temporal distribution of neural activations to drive an efficient neural allocation for a set of stimuli. This explores the neurophysiological hypothesis that repetition suppression serves as an unsupervised perceptual learning mechanism that can drive efficient memory formation by reducing the overall size of stimuli representation while strengthening the responses of the most selective neurons. This interpretation of repetition is different from its traditional role in computational learning models mainly to induce convergence and reach training stability, without using this information to provide focus for the neural representations of the data. The first part of the thesis introduces a novel computational model with repetition suppression, which forms an unsupervised competitive systemtermed CoRe, for Competitive Repetition-suppression learning. The model is applied to generalproblems in the fields of computational intelligence and machine learning. Particular emphasis is placed on validating the model as an effective tool for the unsupervised exploration of bio-medical data. In particular, it is shown that the repetition suppression mechanism efficiently addresses the issues of automatically estimating the number of clusters within the data, as well as filtering noise and irrelevant input components in highly dimensional data, e.g. gene expression levels from DNA Microarrays. The CoRe model produces relevance estimates for the each covariate which is useful, for instance, to discover the best discriminating bio-markers. The description of the model includes a theoretical analysis using Huber’s robust statistics to show that the model is robust to outliers and noise in the data. The convergence properties of themodel also studied. It is shown that, besides its biological underpinning, the CoRe model has useful properties in terms of asymptotic behavior. By exploiting a kernel-based formulation for the CoRe learning error, a theoretically sound motivation is provided for the model’s ability to avoid local minima of its loss function. To do this a necessary and sufficient condition for global error minimization in vector quantization is generalized by extending it to distance metrics in generic Hilbert spaces. This leads to the derivation of a family of kernel-based algorithms that address the local minima issue of unsupervised vector quantization in a principled way. The experimental results show that the algorithm can achieve a consistent performance gain compared with state-of-the-art learning vector quantizers, while retaining a lower computational complexity (linear with respect to the dataset size). Bridging the gap between the low level representation of the visual content and the underlying high-level semantics is a major research issue of current interest. The second part of the thesis focuses on this problem by introducing a hierarchical and multi-resolution approach to visual content understanding. On a spatial level, CoRe learning is used to pool together the local visual patches by organizing them into perceptually meaningful intermediate structures. On the semantical level, it provides an extension of the probabilistic Latent Semantic Analysis (pLSA) model that allows discovery and organization of the visual topics into a hierarchy of aspects. The proposed hierarchical pLSA model is shown to effectively address the unsupervised discovery of relevant visual classes from pictorial collections, at the same time learning to segment the image regions containing the discovered classes. Furthermore, by drawing on a recent pLSA-based image annotation system, the hierarchical pLSA model is extended to process and representmulti-modal collections comprising textual and visual data. The results of the experimental evaluation show that the proposed model learns to attach textual labels (available only at the level of the whole image) to the discovered image regions, while increasing the precision/ recall performance with respect to flat, pLSA annotation model

IX Malta Medical School Conference

Abstracts of papers presented at the 9th Malta Medical School Conference held at the Hilton Malta Hotel, Portomaso, St. Julians between 3rd and 5th December 2015.peer-reviewe