Deep Interpretability Methods for Neuroimaging

Brain dynamics are highly complex and yet hold the key to understanding brain function and dysfunction. The dynamics captured by resting-state functional magnetic resonance imaging data are noisy, high-dimensional, and not readily interpretable. The typical approach of reducing this data to low-dimensional features and focusing on the most predictive features comes with strong assumptions and can miss essential aspects of the underlying dynamics. In contrast, introspection of discriminatively trained deep learning models may uncover disorder-relevant elements of the signal at the level of individual time points and spatial locations. Nevertheless, the difficulty of reliable training on high-dimensional but small-sample datasets and the unclear relevance of the resulting predictive markers prevent the widespread use of deep learning in functional neuroimaging. In this dissertation, we address these challenges by proposing a deep learning framework to learn from high-dimensional dynamical data while maintaining stable, ecologically valid interpretations. The developed model is pre-trainable and alleviates the need to collect an enormous amount of neuroimaging samples to achieve optimal training. We also provide a quantitative validation module, Retain and Retrain (RAR), that can objectively verify the higher predictability of the dynamics learned by the model. Results successfully demonstrate that the proposed framework enables learning the fMRI dynamics directly from small data and capturing compact, stable interpretations of features predictive of function and dysfunction. We also comprehensively reviewed deep interpretability literature in the neuroimaging domain. Our analysis reveals the ongoing trend of interpretability practices in neuroimaging studies and identifies the gaps that should be addressed for effective human-machine collaboration in this domain. This dissertation also proposed a post hoc interpretability method, Geometrically Guided Integrated Gradients (GGIG), that leverages geometric properties of the functional space as learned by a deep learning model. With extensive experiments and quantitative validation on MNIST and ImageNet datasets, we demonstrate that GGIG outperforms integrated gradients (IG), which is considered to be a popular interpretability method in the literature. As GGIG is able to identify the contours of the discriminative regions in the input space, GGIG may be useful in various medical imaging tasks where fine-grained localization as an explanation is beneficial

Development and characterization of deep learning techniques for neuroimaging data

Deep learning methods are extremely promising machine learning tools to analyze neuroimaging data. However, their potential use in clinical settings is limited because of the existing challenges of applying these methods to neuroimaging data. In this study, first a data leakage type caused by slice-level data split that is introduced during training and validation of a 2D CNN is surveyed and a quantitative assessment of the model’s performance overestimation is presented. Second, an interpretable, leakage-fee deep learning software written in a python language with a wide range of options has been developed to conduct both classification and regression analysis. The software was applied to the study of mild cognitive impairment (MCI) in patients with small vessel disease (SVD) using multi-parametric MRI data where the cognitive performance of 58 patients measured by five neuropsychological tests is predicted using a multi-input CNN model taking brain image and demographic data. Each of the cognitive test scores was predicted using different MRI-derived features. As MCI due to SVD has been hypothesized to be the effect of white matter damage, DTI-derived features MD and FA produced the best prediction outcome of the TMT-A score which is consistent with the existing literature. In a second study, an interpretable deep learning system aimed at 1) classifying Alzheimer disease and healthy subjects 2) examining the neural correlates of the disease that causes a cognitive decline in AD patients using CNN visualization tools and 3) highlighting the potential of interpretability techniques to capture a biased deep learning model is developed. Structural magnetic resonance imaging (MRI) data of 200 subjects was used by the proposed CNN model which was trained using a transfer learning-based approach producing a balanced accuracy of 71.6%. Brain regions in the frontal and parietal lobe showing the cerebral cortex atrophy were highlighted by the visualization tools

Quantitative texture analysis in MR imaging in the assessment of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease which is clinically characterized by cognitive impairment and memory loss. Anatomically, AD initially affects specific structures within the Medial Temporal Lobe (MTL), which are essential for declarative memory. A definitive diagnosis of AD relies on post-mortem biopsy therefore, clinical assessment and cognitive tests are currently used. However, these tests are not sensitive to detect AD in an early stage. The aim of this research was to investigate the usefulness of quantitative Magnetic Resonance Imaging (MRI) and specifically of texture features in the assessment of Mild Cognitive Impairment (MCI) which is the pre-dementia stage and AD. Firstly, two types of magnetic fields where investigated in order to examine whether, a stronger MR magnetic field would benefit quantitative imaging analysis derived from texture features. Secondly, texture features were extracted from the entorhinal cortex and evaluated in the diagnosis and prediction of MCI and AD. To the best of our knowledge this is the first research that investigated how the MR field strength affects texture features and used entorhinal cortex texture features on the assessment of AD. The main results of this PhD showed that (1) texture features could provide more sensitive measures when they are extracted from stronger MRI magnetic field, such as 3T, compared to 1.5T. From a disease classification and prediction perspective, (2) entorhinal cortex texture features provide better classification between Normal Controls (NC), MCI and AD subjects, and (3) better prediction of the conversion from MCI to AD. In conclusion, this research has shown for the first time in the literature that entorhinal cortex texture features from MRI could contribute towards the early classification of AD

Large-scale inference in the focally damaged human brain

Clinical outcomes in focal brain injury reflect the interactions between two distinct anatomically distributed patterns: the functional organisation of the brain and the structural distribution of injury. The challenge of understanding the functional architecture of the brain is familiar; that of understanding the lesion architecture is barely acknowledged. Yet, models of the functional consequences of focal injury are critically dependent on our knowledge of both. The studies described in this thesis seek to show how machine learning-enabled high-dimensional multivariate analysis powered by large-scale data can enhance our ability to model the relation between focal brain injury and clinical outcomes across an array of modelling applications. All studies are conducted on internationally the largest available set of MR imaging data of focal brain injury in the context of acute stroke (N=1333) and employ kernel machines at the principal modelling architecture. First, I examine lesion-deficit prediction, quantifying the ceiling on achievable predictive fidelity for high-dimensional and low-dimensional models, demonstrating the former to be substantially higher than the latter. Second, I determine the marginal value of adding unlabelled imaging data to predictive models within a semi-supervised framework, quantifying the benefit of assembling unlabelled collections of clinical imaging. Third, I compare high- and low-dimensional approaches to modelling response to therapy in two contexts: quantifying the effect of treatment at the population level (therapeutic inference) and predicting the optimal treatment in an individual patient (prescriptive inference). I demonstrate the superiority of the high-dimensional approach in both settings