The Structural Basis for Brain Health

Cardiovascular disease (CVD) remains the leading cause of mortality in the United States. Stroke and dementia are the leading causes of adult disability worldwide, and the 5th and 6th leading causes of mortality respectively in the United States. Furthermore, CVD annually accounts for approximately $330 billion in direct and indirect costs in the United States: approximately one in seven health care dollars is spent on CVD. While these diseases have different etiologies, and present with different clinical manifestations and prognosis, converging evidence increasingly supports the idea of CVD as a common pathophysiological origin of cerebrovascular disease, potentially indicating a complex interplay between brain health and cardiovascular health. In this thesis, we leverage methodological advancements in systems and computational neurosciences related to the human brain connectome to assess individual topological network organization and integrity in acute and chronic stroke cohorts, and in a non-stroke cohort with varying CV risk factor burden, using graph theory and network analysis. We propose measures that underly neuroanatomical mechanisms that constitute efficient transfer of information and brain health. We demonstrate the impact of cardiovascular risk factors on brain health, even before overt clinical manifestation, and the resulting impact on cognitive performance, and further determine the underlying pathophysiology relating white matter disease and post-stroke outcomes

Modelling and inferring connections in complex networks

Network phenomena are of key importance in the majority of scientific disciplines. They motivate the desire to better understand the implications of interactions between connected entities. In the focus of this thesis are two of the most prominent tasks in the research of such phenomena: the modelling and the inference of connections within networks. In particular, I provide a systematic framework for using the topology and unifying characteristics of networks from fields as diverse as biology, sociology, and economics to predict and validate connections. I build on existing random graph models and node similarity measures, which I then employ in both unsupervised and supervised machine learning approaches. Furthermore, I present novel methods for identifying the statistically significant connections in network settings that involve multiple types of entities and connections — a crucial element of modelling, which most available methods fail to address. To demonstrate the potential of these new tools, I use them to filter networks that were constructed from large-scale noisy data generated by biological experiments as well as records of online social activity. Subsequently, I predict previously unobserved connections within these networks and evaluate the performance of the developed tools based on ground truth data. In further data sets without direct evidence for the connections in the network, a second, bipartite network serves as proxy for the analysis. Specifically, in an e-commerce setting I use connections between products and customers to deduce similarities between the products based on customer behaviour. In an analysis of high-throughput screening data on the other hand, I utilize relations between proteins and experimental conditions to identify potential functional affinities among the proteins. The findings presented here show that the computational prediction of connections can both help researchers gain a better understanding of costly large-scale data and guide further experimental design. The thesis demonstrates the potential of a network analytic approach to modelling and inference on multiple applications, such as the uncovering of possible privacy issues in the context of online social networking platforms and the optimization of drug development in cancer treatment

Structural and dynamical interdependencies in complex networks at meso- and macroscale: nestedness, modularity, and in-block nestedness

Many real systems like the brain are considered to be complex, i.e. they are made of several interacting components and display a collective behaviour that cannot be inferred from how the individual parts behave. They are usually described as networks, with the components represented as nodes and the interactions between them as links. Research into networks mainly focuses on exploring how a network's dynamic behaviour is constrained by the nature and topology of the interactions between its elements. Analyses of this sort are performed on three scales: the microscale, based on single nodes; the macroscale, which explores the whole network; and the mesoscale, which studies groups of nodes. Nonetheless, most studies so far have focused on only one scale, despite increasing evidence suggesting that networks exhibit structure on several scales. In our thesis, we apply structural analysis to a variety of synthetic and empirical networks on multiple scales. We focus on the examination of nested, modular, and in-block nested patterns, and the effects that they impose on each other. Finally, we introduce a theoretical model to help us to better understand some of the mechanisms that enable such patterns to emerge.Molts sistemes, com el cervell o internet, són considerats complexos: sistemes formats per una gran quantitat d'elements que interactuen entre si, que exhibeixen un comportament col·lectiu que no es pot inferir des de les propietats dels seus elements aïllats. Aquests sistemes s'estudien mitjançant xarxes, en les quals els elements constituents són els nodes, i les interaccions entre ells, els enllaços. La recerca en xarxes s'enfoca principalment a explorar com el comportament dinàmic d'una xarxa està definit per la naturalesa i la topologia de les interaccions entre els seus elements. Aquesta anàlisi sovint es fa en tres escales: la microescala, que estudia les propietats dels nodes individuals; la macroescala, que explora les propietats de tota la xarxa, i la mesoescala, basada en les propietats de grups de nodes. No obstant, la majoria dels estudis se centren només en una escala, tot i la creixent evidència que suggereix que les xarxes sovint exhibeixen estructura a múltiples escales. En aquesta tesi estudiarem les propietats estructurals de les xarxes a escala múltiple. Analitzarem les propietats estructurals dels patrons in-block nested i la seva relació amb els patrons niats i modulars. Finalment, introduirem un model teòric per explorar alguns dels mecanismes que permeten l'emergència d'aquests patrons.Muchos sistemas, como el cerebro o internet, son considerados complejos: sistemas formados por una gran cantidad de elementos que interactúan entre sí, que exhiben un comportamiento colectivo que no puede inferirse desde las propiedades de sus elementos aislados. Estos sistemas se estudian mediante redes, en las que los elementos constituyentes son los nodos, y las interacciones entre ellos, los enlaces. La investigación en redes se enfoca principalmente a explorar cómo el comportamiento dinámico de una red está definido por la naturaleza y la topología de las interacciones entre sus elementos. Este análisis a menudo se hace en tres escalas: la microescala, que estudia las propiedades de los nodos individuales; la macroescala, que explora las propiedades de toda la red, y la mesoescala, basada en las propiedades de grupos de nodos. No obstante, la mayoría de los estudios se centran solo en una escala, a pesar de la creciente evidencia que sugiere que las redes a menudo exhiben estructura a múltiples escalas. En esta tesis estudiaremos las propiedades estructurales de las redes a escala múltiple. Analizaremos las propiedades estructurales de los patrones in-block nested y su relación con los patrones anidados y modulares. Finalmente, introduciremos un modelo teórico para explorar algunos de los mecanismos que permiten la emergencia de estos patrones.Tecnologías de la información y de rede