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This dissertation introduces a novel approach at gauging patterns of informa- tion flow using brain connectivity analysis and partial directed coherence (PDC) in epilepsy. The main objective of this dissertation is to assess the key characteristics that delineate neural activities obtained from patients with epilepsy, considering both focal and generalized seizures. The use of PDC analysis is noteworthy as it es- timates the intensity and direction of propagation from neural activities generated in the cerebral cortex, and it ascertains the coefficients as weighted measures in formulating the multivariate autoregressive model (MVAR). The PDC is used here as a feature extraction method for recorded scalp electroencephalograms (EEG) as means to examine the interictal epileptiform discharges (IEDs) and reflect the phys- iological changes of brain activity during interictal periods. Two experiments were set up to investigate the epileptic data by using the PDC concept. For the investigation of IEDs data (interictal spike (IS), spike and slow wave com- plex (SSC), and repetitive spikes and slow wave complex (RSS)), the PDC analysis estimates the intensity and direction of propagation from neural activities gener- ated in the cerebral cortex, and analyzes the coefficients obtained from employing MVAR. Features extracted by using PDC were transformed into adjacency matrices using surrogate data analysis and were classified by using the multilayer Perceptron (MLP) neural network. The classification results yielded a high accuracy and pre- cision number. The second experiment introduces the investigation of intensity (or strength) of information flow. The inflow activity deemed significant and flowing from other regions into a specific region together with the outflow activity emanating from one region and spreading into other regions were calculated based on the PDC results and were quantified by the defined regions of interest. Three groups were considered for this study, the control population, patients with focal epilepsy, and patients with generalized epilepsy. A significant difference in inflow and outflow validated by the nonparametric Kruskal-Wallis test was observed for these groups. By taking advantage of directionality of brain connectivity and by extracting the intensity of information flow, specific patterns in different brain regions of interest between each data group can be revealed. This is rather important as researchers could then associate such patterns in context to the 3D source localization where seizures are thought to emanate in focal epilepsy. This research endeavor, given its generalized construct, can extend for the study of other neurological and neurode- generative disorders such as Parkinson, depression, Alzheimers disease, and mental illness.

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This thesis is concerned with convex optimization problems over matrix polynomials that are constrained to be positive semidefinite on the unit circle. Problems of this form appear in signal processing and can often be solved as semidefinite programs (SDPs). Interior-point solvers for these SDPs scale poorly, and this thesis aims to design first-order methods that are more efficient. We propose methods based on a generalized proximal operator defined in terms of a Bregman divergence. Empirical results on three applications in signal processing demonstrate that the proposed methods scale much better than interior-point solvers. As an example, for sparse estimation of spectral density matrices, Douglas--Rachford splitting with the generalized proximal operator is about 1000 times faster and scales to much larger problems. The ability to solve larger problems allows us to perform functional connectivity analysis of the brain by constructing a sparse estimate of the inverse spectral density matrix.

Young football players are hypothesized to experience damage to the brain and brain function from repeated subconcussive head acceleration events (HAEs) during practices and games. Such damage may cause delayed cognitive and mental problems. Resting state fMRI (rs-fMRI) is an effective non-invasive method to detect alterations in brain functional connectivity. Seed-based rsfMRI analysis using the central node of the default mode network (DMN) as the seed is a common approach to measuring intrinsic changes of the DMN, accepted as a key network in brain function. Seed-based rs-fMRI analysis of the DMN was used to explore how age, HAE intensity, and HAE counts influence brain connectivity in youth athletes (ages 12-18). Middle school and high school football players and peer controls were studied using rs-fMRI before and after one season of competition. An identifiability matrix was generated from the seed-based connectivity matrix, allowing measurement of similarity between pre-season and post-season functional connectivity. The consistency of seed-based brain functional connectivity we observed across the season of play for players has no statistically significant difference from controls. The identifiability matrix exhibited no relation to the number and magnitude of any subset of HAEs experienced which rejected our hypothesis. Another finding is that high school football players exhibited the largest percentage increase in identification from middle school football players in the somatomotor network over other resting-state networks.

For most of the naturally occurring signals, especially biomedical signals, the underlying physical process generating the signal is often not fully known, making it difficult to obtain a parametric model. Therefore, signal processing techniques are used to analyze the signal for non-parametrically characterizing the underlying system from which the signals are produced. Most of the real life systems are nonlinear and time varying, which poses a challenge while characterizing them. Additionally, multiple sensors are used to extract signals from such systems, resulting in multichannel signals which are inherently coupled. In this thesis, we counter this challenge by using Recurrence Plot based techniques for characterizing biomedical systems such as heart or brain, using signals such as heart rate variability (HRV), electroencephalogram(EEG) or functional magnetic resonance imaging (fMRI), respectively, extracted from them. In time series analysis, it is well known that a system can be represented by a trajectory in an N-dimensional state space, which completely represents an instance of the system behavior. Such a system characterization has been done using dynamical invariants such as correlation dimension, Lyapunov exponent etc. Takens has shown that when the state variables of the underlying system are not known, one can obtain a trajectory in ‘phase space’ using only the signals obtained from such a system. The phase space trajectory is topologically equivalent to the state space trajectory. This enables us to characterize the system behavior from only the signals sensed from them. However, estimation of correlation dimension, Lyapunov exponent, etc, are vulnerable to non-stationarities in the signal and require large number of sample points for accurate computation, both of which are important in the case of biomedical signals. Alternatively, a technique called Recurrence Plots (RP) has been proposed, which addresses these concerns, apart from providing additional insights. Measures to characterize RPs of single and two channel data are called Recurrence Quantification Analysis (RQA) and cross RQA (CRQA), respectively. These methods have been applied with a good measure of success in diverse areas. However, they have not been studied extensively in the context of experimental biomedical signals, especially multichannel data. In this thesis, the RP technique and its associated measures are briefly reviewed. Using the computational tools developed for this thesis, RP technique has been applied on select single channel, multichannel and multimodal (i.e. multiple channels derived from different modalities) biomedical signals. Connectivity analysis is demonstrated as post-processing of RP analysis on multichannel signals such as EEG and fMRI. Finally, a novel metric, based on the modification of a CRQA measure is proposed, which shows improved results. For the case of single channel signal, we have considered a large database of HRV signals of 112 subjects recorded for both normal and abnormal (anxiety disorder and depression disorder) subjects, in both supine and standing positions. Existing RQA measures, Recurrence Rate and Determinism, were used to distinguish between normal and abnormal subjects with an accuracy of 58.93%. A new measure, MLV has been introduced, using which a classification accuracy of 98.2% is obtained. Correlation between probabilities of recurrence (CPR) is a CRQA measure used to characterize phase synchronization between two signals. In this work, we demonstrate its utility with application to multimodal and multichannel biomedical signals. First, for the multimodal case, we have computed running CPR (rCPR), a modification proposed by us, which allows dynamic estimation of CPR as a function of time, on multimodal cardiac signals (electrocardiogram and arterial blood pressure) and demonstrated that the method can clearly detect abnormalities (premature ventricular contractions); this has potential applications in cardiac care such as assisted automated diagnosis. Second, for the multichannel case, we have used 16 channel EEG signals recorded under various physiological states such as (i) global epileptic seizure and pre-seizure and (ii) focal epilepsy. CPR was computed pair-wise between the channels and a CPR matrix of all pairs was formed. Contour plot of the CPR matrix was obtained to illustrate synchronization. Statistical analysis of CPR matrix for 16 subjects of global epilepsy showed clear differences between pre-seizure and seizure conditions, and a linear discriminant classifier was used in distinguishing between the two conditions with 100% accuracy. Connectivity analysis of multichannel EEG signals was performed by post-processing of the CPR matrix to understand global network-level characterization of the brain. Brain connectivity using thresholded CPR matrix of multichannel EEG signals showed clear differences in the number and pattern of connections in brain connectivity graph between epileptic seizure and pre-seizure. Corresponding brain headmaps provide meaningful insights about synchronization in the brain in those states. K-means clustering of connectivity parameters of CPR and linear correlation obtained from global epileptic seizure and pre-seizure showed significantly larger cluster centroid distances for CPR as opposed to linear correlation, thereby demonstrating the efficacy of CPR. The headmap in the case of focal epilepsy clearly enables us to identify the focus of the epilepsy which provides certain diagnostic value. Connectivity analysis on multichannel fMRI signals was performed using CPR matrix and graph theoretic analysis. Adjacency matrix was obtained from CPR matrices after thresholding it using statistical significance tests. Graph theoretic analysis based on communicability was performed to obtain community structures for awake resting and anesthetic sedation states. Concurrent behavioral data showed memory impairment due to anesthesia. Given the fact that previous studies have implicated the hippocampus in memory function, the CPR results showing the hippocampus within the community in awake state and out of it in anesthesia state, demonstrated the biological plausibility of the CPR results. On the other hand, results from linear correlation were less biologically plausible. In biological systems, highly synchronized and desynchronized systems are of interest rather than moderately synchronized ones. However, CPR is approximately a monotonic function of synchronization and hence can assume values which indicate moderate synchronization. In order to emphasize high synchronization/ desynchronization and de-emphasize moderate synchronization, a new method of Correlation Synchronization Convergence Time (CSCT) is proposed. It is obtained using an iterative procedure involving the evaluation of CPR for successive autocorrelations until CPR converges to a chosen threshold. CSCT was evaluated for 16 channel EEG data and corresponding contour plots and histograms were obtained, which shows better discrimination between synchronized and asynchronized states compared to the conventional CPR. This thesis has demonstrated the efficacy of RP technique and associated measures in characterizing various classes of biomedical signals. The results obtained are corroborated by well known physiological facts, and they provide physiologically meaningful insights into the functioning of the underlying biological systems, with potential diagnostic value in healthcare.

Esta tesis se centra en la construcción y usos de los modelos metabólicos a escala genómica para obtener biocombustibles de manera eficiente, como etanol e hidrógeno. Como organismo objetivo, se ha elegido a la cianobacteria Synechocystis sp. PCC6803. Este organismo ha sido estudiado como una potencial plataforma de producción alimentada por fotones, dada su capacidad de crecer solamente a partir de dióxido de carbono y fotones. Esta tesis versa acerca de los métodos para modelar, analizar, estimar y predecir el comportamiento del metabolismo de las células. La principal meta es extraer conocimiento de los diferentes aspectos biológicos de un organismo con el fin de utilizarlo para un objetivo industrial pertinente. Esta tesis ha sido estructurada en capítulos organizados de acuerdo con las sucesivas tareas que terminan con la construcción de una célula in silico que se comporta, idealmente, como la que está basada en el carbono. Este proceso suele comenzar con los archivos de anotación del genoma y termina con un modelo metabólico a escala genómica capaz de integrar datos -ómicos. El primer objetivo de la presente tesis es la reconstrucción de un modelo del metabolismo de esta cianobacteria que tenga en cuenta todas las reacciones presentes en la misma. Esta reconstrucción tenía que ser lo suficientemente flexible como para permitir el crecimiento en las distintas condiciones ambientales bajo las cuales este organismo crece en la naturaleza, así como permitir la integración de diferentes niveles de información biológica. Una vez que se cumplió este requisito, se pudieron simular variaciones ambientales y estudiar sus efectos desde una perspectiva de sistema. Se han estudiado hasta cinco diferentes condiciones de crecimiento en este modelo metabólico y sus diferencias han sido evaluadas. La siguiente tarea fue definir estrategias de producción para sopesar la viabilidad de este organismo como una plataforma de producción. Se simularon perturbaciones genéticas para e / This thesis is focused on the construction and uses of genome-scale metabolic models to efficiently obtain biofuels, such as ethanol and hydrogen. As a target organism, cyanobacterium Synechocystis sp. PCC6803 was chosen. This organism has been studied as a potential photon-fuelled production platform, for its ability to grow only from carbon dioxide, water and photons. This dissertation verses about methods to model, analyse, estimate and predict the metabolic behaviour of cells. Principal goal is to extract knowledge from the different biological aspects of an organism in order to use it for an industrial relevant objective. This dissertation has been structured in chapters accordingly organized as the successive tasks that end up building an in silico cell that behaves as the carbon-based one. This process usually starts with the genome annotation files and ends up with a genome-scale metabolic model able to integrate ¿omics data. First objective of present thesis is to reconstruct a model of this cyanobacteria¿s metabolism that accounts for all the reactions present in it. This reconstruction had to be flexible enough as to allow growth under the different environmental conditions under which this organism grows in nature as well as to allow the integration of different levels of biological information. Once this requisite was met, environmental variations could be simulated and their effect studied under a system-wide perspective. Up to five different growth conditions were simulated on this metabolic model and differences were evaluated. Following assignment was to define production strategies to weigh this organism¿s viability as a production platform. Genetic perturbations were simulated to design strains with an enhanced production of three industrially-relevant metabolites: succinate, ethanol and hydrogen. Resulting sets of genetic modifications for the overproduction of those metabolites are, thus, proposed. Moreover, functional reactions couplings were studied and weighted to their metabolite production importance. Finally, genome-scale metabolic models allow establishing integrative approaches to include different types of data that help to find regulatory hotspots that can be targets of genetic modification. Such regulatory hubs were identified upon light/dark shifts and general metabolism operational principles inferred. All along this process, blind spots in Synechocystis sp. PCC6803 metabolism, and more importantly, blind spots in our understanding of it, are revealed. Overall, the work presented in this thesis unveils the industrial capabilities of cyanobacterium Synechocystis sp. PCC6803 to evolve interesting metabolites as a clean production platform. / Esta tesis es centra en la construcció i els usos del models metabòlics a escala genòmica per a obtenir eficientment biocombustibles, com etanol i hidrogen. Com a organisme diana, s¿elegí el cianobacteri Synechocystis sp. PCC6803. Aquest organisme ha segut estudiat com una plataforma de producció nodrida per fotons, per la seva habilitat per créixer a partir únicament de diòxid de carboni, aigua i fotons. Aquesta tesi versa sobre mètodes per a modelitzar, analitzar, estimar i predir el comportament metabòlic de cèl¿lules. La principal meta és extreure coneixement del diferents aspectes biològics d¿un organisme de manera que s¿usen per a un objectiu industrial rellevant. La tesi ha segut estructurada en capítols organitzats d¿acord a les successives tasques que acaben construint una cèl¿lula in silico que es comporta, idealment, com la que està basada en carboni. Aquest procés generalment comença amb els arxius de l¿anotació del genoma i acaba amb un model metabòlic a escala genòmica capaç d¿integrar dades ¿òmiques. El primer objectiu de la present tesi és la reconstrucció d¿un model del metabolisme d¿aquest cianobacteri que tinga en compte totes les reaccions que hi estan presents. Esta reconstrucció havia de ser prou flexible com per permetre la simulació del creixement en les diferents condicions ambientals en les quals aquest cianobacteri creix en la natura, així com permetre la integració de diferents nivells d¿informació biològica. Una vegada que aquest requisit fou assolit, es pogueren simular variacions ambientals i estudiar els seus efectes amb una perspectiva de sistema. S¿han simulat fins a cinc condicions de creixement en este model metabòlic i les seves diferències han segut avaluades. La següent tasca fou definir estratègies de producció per a valorar la viabilitat d¿aquest organisme com a plataforma de producció. Es simularen pertorbacions genètiques per al disseny de soques amb producció millorada de metabòlits de rellevància industrial: succinat, etanol i hidrogen. Així, es proposen conjunts de modificacions genètiques per a la sobreproducció d¿aquests metabòlits. També s'han estudiat reaccions acoblades funcionalment i s¿ha ponderat la seva importància en la producció de metabòlits. Finalment, els models metabòlics a escala genòmica permeten establir criteris per integrar diferents tipus de dades que ens ajuden a trobar punts importants de regulació. Eixos centres reguladors, que poden ser objecte de modificacions genètiques, han segut investigats baix canvis dràstics d¿il¿luminació i s¿han inferit principis operacionals del metabolisme. Al llarg d'aquest procés, s¿han revelat punts cecs al metabolisme de Synechocystis sp. PCC6803 i, el més important, punts cecs en la nostra comprensió d'aquest metabolisme. En general, el treball presentat en aquesta tesi dona a conèixer les capacitats industrials del cianobacteri Synechocystis sp. PCC6803 per a produir metabòlits d'interès, tot sent una plataforma de producció neta i sostenible. / Montagud Aquino, A. (2012). Modelling and analysis of biological systems to obtain biofuels [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/17319