Multimodal and multiscale brain networks : understanding aging, Alzheimer’s disease, and other neurodegenerative disorders

The human brain can be modeled as a complex network, often referred to as the connectome, where structural and functional connections govern its organization. Several neuroimaging studies have focused on understanding the architecture of healthy brain networks and have shed light on how these networks evolve with age and in the presence of neurodegenerative disorders. Many studies have explored the brain networks in Alzheimer’s disease (AD), the most common type of dementia, using various neuroimaging modalities independently. However, most of these studies ignored the complex and multifactorial nature of AD. The aim of this thesis was to investigate and analyze the brain’s multimodal and multiscale network organization in aging and in AD by using different multilayer brain network analyses and different types of data. Additionally, this research extended its scope to incorporate other dementias, such as Lewy body dementias, allowing for a comparison of these disorders with AD and normal aging. These comparisons were made possible through the application of protein co-expression networks. In Study I, we investigated sex differences in healthy individuals using multimodal brain networks. To do this we used resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion-weighted imaging (DWI) data from the Human Connectome Project (HCP) to perform multilayer and deep learning analyses. These analyses identified differences between men's and women's underlying brain network organization, showing that the deep-learning analysis with multilayer network metrics (area under the curve, AUC, of 0.81) outperforms the classification using single-layer network measures (AUC of 0.72 for functional networks and 0.70 for anatomical networks). Furthermore, we integrated the multilayer brain networks methodology and neural network models into a software package that is easy to use by researchers with different backgrounds and is also easily expandable for researchers with different levels of programming experience. Then, we used the multilayer brain networks methodology to study the interaction between sex and age on the functional network topology using a large group of people from the UK Biobank (Study II). By incorporating multilayer brain network analyses, we analyzed both positive and negative connections derived from functional correlations, and we obtained important insights into how cognitive abilities, physical health, and even genetic factors differ between men and women as they age. Age and sex were strongly associated with multiplex and multilayer measures such as the multiplex participation coefficient, multilayer clustering, and multilayer global efficiency, accounting for up to 89.1%, 79.9%, and 79.5% of the variance related to age, respectively. These results indicate that incorporating separate layers for positive and negative connections within a complex network framework reveals sensitive insights into age- and sex-related variations that are not detected by traditional metrics. Furthermore, our functional metrics exhibited associations with genes that have previously been linked to processes related to aging. In Study III, we assessed whether multilayer connectome analyses could offer new perspectives on the relationship between amyloid pathology and gray matter atrophy across the AD continuum. Subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were divided into four groups based on cerebrospinal fluid (CSF) amyloid-β (Aβ) biomarker levels and clinical diagnosis. We compared the different groups using weighted and binary multilayer measures that assess the strength of the connections, the modularity, as well as the multiplex segregation and integration of the brain connectomes. Across Aβ-positive (Aβ+) groups, we found widespread increases in the overlapping connectivity strength and decreases in the number of identical connections in both layers. Moreover, the brain modules were reorganized in the mild cognitive impairment (MCI) Aβ+ group and an imbalance in the quantity of couplings between the two layers was found in patients with MCI Aβ+ and AD Aβ+. Using a subsample from the same database, ADNI, we analyzed rs-fMRI data from individuals at preclinical and clinical stages of AD (Study IV). By dividing the time series into different time windows, we built temporal multilayer networks and studied the modular organization across time. We were able to capture the dynamic changes across different AD stages using this temporal multilayer network approach, obtaining outstanding areas under the curve of 0.90, 0.92 and 0.99 in the distinction of controls from preclinical, prodromal, and clinical AD stages, respectively, on top and beyond common risk factors. Our results not only improved the discrimination between various disease stages but, importantly, they also showed that dynamic multilayer functional measures are associated with memory and global cognition in addition to amyloid and tau load derived from positron emission tomography. These results highlight the potential of dynamic multilayer functional connectivity measures as functional biomarkers of AD progression. In Study V, we used in-depth quantitative proteomics to compare post-mortem brains from three key brain regions (prefrontal cortex, cingulate cortex, and the parietal cortex) directly related to the disease mechanisms of AD, Parkinson’s disease with dementia (PDD), dementia with Lewy bodies (DLB) in prospectively followed patients and older adults without dementia. We used covariance weighted networks to find modules of protein sets to further understand altered pathways in these dementias and their implications for prognostic and diagnostic purposes. In conclusion, this thesis explored the complex world of brain networks and offered insightful information about how age, sex, and AD influence these networks. We have improved our understanding of how the brain is organized in different imaging modalities and different time scales, as well as developing software tools to make this methodology available to more researchers. Additionally, we assessed the connections among various proteins in different areas of the brain in relation to health, Alzheimer's disease, and Lewy body dementias. This work contributes to the collective effort of unraveling the mysteries of the human brain organization and offers a foundation for future research to understand brain networks in health and disease

A Model of the Network Architecture of the Brain that Supports Natural Language Processing

For centuries, neuroscience has proposed models of the neurobiology of language processing that are static and localised to few temporal and inferior frontal regions. Although existing models have offered some insight into the processes underlying lower-level language features, they have largely overlooked how language operates in the real world. Here, we aimed at investigating the network organisation of the brain and how it supports language processing in a naturalistic setting. We hypothesised that the brain is organised in a multiple core-periphery and dynamic modular architecture, with canonical language regions forming high-connectivity hubs. Moreover, we predicted that language processing would be distributed to much of the rest of the brain, allowing it to perform more complex tasks and to share information with other cognitive domains. To test these hypotheses, we collected the Naturalistic Neuroimaging Database of people watching full length movies during functional magnetic resonance imaging. We computed network algorithms to capture the voxel-wise architecture of the brain in individual participants and inspected variations in activity distribution over different stimuli and over more complex language features. Our results confirmed the hypothesis that the brain is organised in a flexible multiple core-periphery architecture with large dynamic communities. Here, language processing was distributed to much of the rest of the brain, together forming multiple communities. Canonical language regions constituted hubs, explaining why they consistently appear in various other neurobiology of language models. Moreover, language processing was supported by other regions such as visual cortex and episodic memory regions, when processing more complex context-specific language features. Overall, our flexible and distributed model of language comprehension and the brain points to additional brain regions and pathways that could be exploited for novel and more individualised therapies for patients suffering from speech impairments

Exploring Neuromodulatory Systems for Dynamic Learning

In a continual learning system, the network has to dynamically learn new tasks from few samples throughout its lifetime. It is observed that neuromodulation acts as a key factor in continual and dynamic learning in the central nervous system. In this work, the neuromodulatory plasticity is embedded with dynamic learning architectures. The network has an inbuilt modulatory unit that regulates learning depending on the context and the internal state of the system, thus rendering the networks with the ability to self modify their weights. In one of the proposed architectures, ModNet, a modulatory layer is introduced in a random projection framework. This layer modulates the weights of the output layer neurons in tandem with hebbian learning. Moreover, to explore modulatory mechanisms in conjunction with backpropagation in deeper networks, a modulatory trace learning rule is introduced. The proposed learning rule, uses a time dependent trace to automatically modify the synaptic connections as a function of ongoing states and activations. The trace itself is updated via simple plasticity rules thus reducing the demand on resources. A digital architecture is proposed for ModNet, with on-device learning and resource sharing, to facilitate the efficacy of dynamic learning on the edge. The proposed modulatory learning architecture and learning rules demonstrate the ability to learn from few samples, train quickly, and perform one shot image classification in a computationally efficient manner. The ModNet architecture achieves an accuracy of ∼91% for image classification on the MNIST dataset while training for just 2 epochs. The deeper network with modulatory trace achieves an average accuracy of 98.8%±1.16 on the omniglot dataset for five-way one-shot image classification task. In general, incorporating neuromodulation in deep neural networks shows promise for energy and resource efficient lifelong learning systems

Spiking neural models & machine learning for systems neuroscience: Learning, Cognition and Behavior.

Learning, cognition and the ability to navigate, interact and manipulate the world around us by performing appropriate behavior are hallmarks of artificial as well as biological intelligence. In order to understand how intelligent behavior can emerge from computations of neural systems, this thesis suggests to consider and study learning, cognition and behavior simultaneously to obtain an integrative understanding. This involves building detailed functional computational models of nervous systems that can cope with sensory processing, learning, memory and motor control to drive appropriate behavior. The work further considers how the biological computational substrate of neurons, dendrites and action potentials can be successfully used as an alternative to current artificial systems to solve machine learning problems. It challenges the simplification of currently used rate-based artificial neurons, where computational power is sacrificed by mathematical convenience and statistical learning. To this end, the thesis explores single spiking neuron computations for cognition and machine learning problems as well as detailed functional networks thereof that can solve the biologically relevant foraging behavior in flying insects. The obtained results and insights are new and relevant for machine learning, neuroscience and computational systems neuroscience. The thesis concludes by providing an outlook how application of current machine learning methods can be used to obtain a statistical understanding of larger scale brain systems. In particular, by investigating the functional role of the cerebellar-thalamo-cortical system for motor control in primates

Development of a web application for processing Neuroimaging data in the Cloud. Application to Brain Connectivity

Neuropsychiatric disorders, or mental disorders, have long been known to be a major cause of burden to society and it is estimated that one in every four people worldwide will be affected by one of these conditions during their lifetime. The diagnosis of these conditions is based on a set of subjective criteria and on the experience of physicians and is therefore highly prone to error. Alcohol Use Disorder (AUD) is one such disorder with particularly devastating consequences to both individual and society, representing a total of 5.1% of the global burden of disease and injury. As image classification methods improve, reaching near-human capabilities, and research on brain physiology continues to advance and allow us to better understand brain structure and function through novel methods such as Brain Connectivity analysis, ingenious approaches to medical diagnosis can be envisioned. Furthermore, as new technologies allow the world to be more connected and less dependent on physical machinery, there is an interest in bringing this vision to both healthcare and biomedical research, through technologies such as Cloud computing. This work focuses on the creation of an intuitive Cloud-based application which uses the image classification algorithm Convolutional Neural Network (CNN). The application would then be used to classify Electroencephalography data to diagnose AUD, in particular using Brain Connectivity metrics. The created application was successfully developed according to the objectives, proving to be simple to operate but effective in the use of the CNN algorithm. However, due to the environment used, it showed high processing times which hamper the training of CNN classifiers. Classification results, while not conclusive, show indication that the employed metrics and methodology may be of use in the context of neuropsychiatric disorder diagnosis both in a research and clinical context in the future. Finally, discussion and analysis of these results were performed so as to drive forward the research into this methodology