Vitamin D Deficiency and Depressive Symptomatology in Psychiatric Patients Hospitalized with a Current Depressive Episode: A Factor Analytic Study.

BACKGROUND Low vitamin D levels have been associated with depressive symptoms in population-based studies and non-clinical samples as well as with clinical depression. This study aimed to examine the association of vitamin D levels with the severity and dimensions of depressive symptoms in hospitalized patients with a current episode of depression taking into account confounding variables. METHODS We investigated 380 patients (mean age 47 ± 12 years, 70% women) who were consecutively hospitalized with a main diagnosis of an ICD-10 depressive episode. All patients self-rated depressive symptom severity with the Hospital Anxiety and Depression Scale (HADS-D), the Beck Depression Inventory-II (BDI-II), and the Brief Symptom Inventory. A principal component analysis was performed with all 34 items of these questionnaires and serum levels of 25-hydroxyvitamin D3 (25-OH D) were measured. RESULTS Vitamin D deficiency (< 50 nmol/l), insufficiency (50-75 nmol/l), and sufficiency (> 75 nmol/l) were present in 55.5%, 31.8% and 12.6%, respectively, of patients. Patients with vitamin D deficiency scored higher on the HADS-D scale and on an anhedonia symptom factor than those with insufficient (p-values ≤ 0.023) or sufficient (p-values ≤ 0.008) vitamin D. Vitamin D deficient patients also scored higher on the BDI-II scale than those with sufficient vitamin D (p = 0.007); BDI-II cognitive/affective symptoms, but not somatic/affective symptoms, were higher in patients with vitamin D deficiency (p = 0.005) and insufficiency (p = 0.041) relative to those with sufficient vitamin D. Effect sizes suggested clinically relevant findings. CONCLUSIONS Low vitamin D levels are frequent in hospitalized patients with a current episode of depression. Especially 25-OH D levels < 50 nmol/l were associated with cognitive/affective depressive symptoms, and anhedonia symptoms in particular.

Internal and external effects on cognition: Evidence from memory training in very preterm-born children and cognition in patients with carotid artery stenosis before and after treatment

The present synopsis aims to integrate one study about memory training in very preterm-born children and two studies about cognition in patients with carotid artery stenosis before and after treatments. Preterm-born children are at increased risk of cognitive deficits and behavioural problems compared with peers born at term. This thesis determined whether memory training would improve cognitive functions in school-age very preterm-born children. Memory strategy training produced significant improvements in trained and non-trained cognitive functions; a core working memory training revealed significant effects on short-term memory and working memory tasks. Six months after training, children in both training groups showed better working memory performance than children in the waiting control group. This is evidence that memory training – an external influence on cognition – induces plastic changes in very preterm-born children. Patients with carotid artery stenosis are known to be at increased risk of cognitive impairment. We showed that patients with symptomatic or asymptomatic carotid artery stenosis were at higher risk for cognitive deficits than expected in a normative sample. This thesis seeks to link cognitive plasticity to internal factors like carotid stenosis. An external factor, which influences blood flow to the brain is the nature of the carotid artery stenosis treatment. Research on the effects of carotid artery stenosis treatment on cognition has produced inconsistent results. We found significant improvement in frontal lobe functions, visual memory and motor speed one year after treatment independent of the treatment type (best medical treatment, carotid artery stenting, carotid artery endarterectomy); providing evidence for ‘treatment-induced’ cognitive plasticity. Baseline performance was negatively associated with improvement in various cognitive functions after training in very preterm-born children and after treatment in patients with carotid artery stenosis. The present synopsis aims to integrate these findings into the current and relevant literature, and discuss consequences as well as methodological considerations resulting from the studies constituting the thesis at hand.

The muscarinic antagonists scopolamine and atropine are competitive antagonists at 5-HT3 receptors

Scopolamine is a high affinity muscarinic antagonist that is used for the prevention of post-operative nausea and vomiting. 5-HT3 receptor antagonists are used for the same purpose and are structurally related to scopolamine. To examine whether 5-HT3 receptors are affected by scopolamine we examined the effects of this drug on the electrophysiological and ligand binding properties of 5-HT3A receptors expressed in Xenopus oocytes and HEK293 cells, respectively. 5-HT3 receptor-responses were reversibly inhibited by scopolamine with an IC50 of 2.09 μM. Competitive antagonism was shown by Schild plot (pA2 = 5.02) and by competition with the 5-HT3 receptor antagonists [3H]granisetron (Ki = 6.76 µM) and G-FL (Ki = 4.90 µM). The related molecule, atropine, similarly inhibited 5-HT evoked responses in oocytes with an IC50 of 1.74 µM, and competed with G-FL with a Ki of 7.94 µM. The reverse experiment revealed that granisetron also competitively bound to muscarinic receptors (Ki = 6.5 µM). In behavioural studies scopolamine is used to block muscarinic receptors and induce a cognitive deficit, and centrally administered concentrations can exceed the IC50 values found here. It is therefore possible that 5-HT3 receptors are also inhibited. Studies that utilise higher concentrations of scopolamine should be mindful of these potential off-target effects.

Theoretical and experimental studies of linkage disequilibrium in human populations

Linkage disequilibrium (LD) is defined as the nonrandom association of alleles at two or more loci in a population and may be a useful tool in a diverse array of applications including disease gene mapping, elucidating the demographic history of populations, and testing hypotheses of human evolution. However, the successful application of LD-based approaches to pertinent genetic questions is hampered by a lack of understanding about the forces that mediate the genome-wide distribution of LD within and between human populations. Delineating the genomic patterns of LD is a complex task that will require interdisciplinary research that transcends traditional scientific boundaries. The research presented in this dissertation is predicated upon the need for interdisciplinary studies and both theoretical and experimental projects were pursued. In the theoretical studies, I have investigated the effect of genotyping errors and SNP identification strategies on estimates of LD. The primary importance of these two chapters is that they provide important insights and guidance for the design of future empirical LD studies. Furthermore, I analyzed the allele frequency distribution of 26,530 single nucleotide polymorphisms (SNPs) in three populations and generated the first-generation natural selection map of the human genome, which will be an important resource for explaining and understanding genomic patterns of LD. Finally, in the experimental study, I describe a novel and simple, low-cost, and high-throughput SNP genotyping method. The theoretical analyses and experimental tools developed in this dissertation will facilitate a more complete understanding of patterns of LD in human populations. ^

Delineating the molecular basis of human genetic diseases: Epigenetic and functional studies

Identifying and characterizing the genes responsible for inherited human diseases will ultimately lead to a more holistic understanding of disease pathogenesis, catalyze new diagnostic and treatment modalities, and provide insights into basic biological processes. This dissertation presents research aimed at delineating the genetic and molecular basis of human diseases through epigenetic and functional studies and can be divided into two independent areas of research. The first area of research describes the development of two high-throughput melting curve based methods to assay DNA methylation, referred to as McMSP and McCOBRA. The goal of this project was to develop DNA methylation methods that can be used to rapidly determine the DNA methylation status at a specific locus in a large number of samples. McMSP and McCOBRA provide several advantages over existing methods, as they are simple, accurate, robust, and high-throughput making them applicable to large-scale DNA methylation studies. McMSP and McCOBRA were then used in an epigenetic study of the complex disease Ankylosing spondylitis (AS). Specifically, I tested the hypothesis that aberrant patterns of DNA methylation in five AS candidate genes contribute to disease susceptibility. While no statistically significant methylation differences were observed between cases and controls, this is the first study to investigate the hypothesis that epigenetic variation contributes to AS susceptibility and therefore provides the conceptual framework for future studies. ^ In the second area of research, I performed experiments to better delimit the function of aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), which when mutated causes various forms of inherited blindness such as Leber congenital amaurosis. A yeast two-hybrid screen was performed to identify putative AIPL1-interacting proteins. After screening 2 × 106 bovine retinal cDNA library clones, 6 unique putative AIPL1-interacting proteins were identified. While these 6 AIPL1 protein-protein interactions must be confirmed, their identification is an important step in understanding the functional role of AIPL1 within the retina and will provide insight into the molecular mechanisms underlying inherited blindness. ^

Hypertension and cognitive decline among patients of Alzheimer's disease

Objective. The main aim of our study is to assess the effect of hypertension on the decline in cognitive impairment among Alzheimer’s patients. Methods. We analyzed the data of AD patients enrolled in Baylor ADMDC in a prospective study design. We divided AD patients into two groups based on the definition of hypertension. We described a decline in cognitive impairment as a change of 5 points in mini-mental state examination score (MMSE) from the baseline visit. Results. Independent of covariates, AD patients with hypertension did not exhibit a significant decline in cognitive impairment after adjustment of covariates, age, race and education (Hazard Ratio (HR) = 1.07, p value 0.58, 95% confidence interval 0.84-1.39) than AD patients without hypertension. In addition, AD patients with hypertension did not experience decline in cognitive impairment sooner than AD patients without hypertension. (P value 0.83). Conclusions . Hypertension is not associated with cognitive impairment over time among patients with Alzheimer’s disease enrolled in Baylor ADMDC after other potential confounders were taken into account. These findings should not be interpreted as a basis for discouraging appropriate medical treatment of hypertension in AD patients. Greater efforts should be made to improve the recognition of hypertension as a modifiable risk factor for decline in cognitive impairment in AD population. ^

Effects of a health advocacy program to promote physical activity and nutrition behaviors among adolescents: An evaluation of the Young Leaders for Healthy Change program

Background. This study was designed to evaluate the effects of the Young Leaders for Healthy Change program, an internet-delivered program in the school setting that emphasized health advocacy skills-development, on nutrition and physical activity behaviors among older adolescents (13–18 years). The program consisted of online curricular modules, training modules, social media, peer and parental support, and a community service project. Module content was developed based on Social Cognitive Theory and known determinants of behavior for older adolescents. ^ Methods. Of the 283 students who participated in the fall 2011 YL program, 38 students participated in at least ten of the 12 weeks and were eligible for this study. This study used a single group-only pretest/posttest evaluation design. Participants were 68% female, 58% white/Caucasian, 74% 10th or 11th graders, and 89% mostly A and/or B students. The primary behavioral outcomes for this analysis were participation in 60-minutes of physical activity per day, 20-minutes of vigorous- or moderate- intensity physical activity (MVPA) participation per day, television and computer time, fruit and vegetable (FV) intake, sugar-sweetened beverage intake, and consumption of breakfast, home-cooked meals, and fast food. Other outcomes included knowledge, beliefs, and attitudes related to healthy eating, physical activity, and advocacy skills. ^ Findings. Among the 38 participants, no significant changes in any variables were observed. However, among those who did not previously meet behavioral goals there was an 89% increase in students who participated in more than 20 minutes of MVPA per day and a 58% increase in students who ate home-cooked meals 5–7 days per week. The majority of participants met program goals related to knowledge, beliefs, and attitudes prior to the start of the program. Participants reported either maintaining or improving to the goal at posttest for all items except FV intake knowledge, taste and affordability of healthy foods, interest in teaching others about being healthy, and ease of finding ways to advocate in the community. ^ Conclusions. The results of this evaluation indicated that promoting healthy behaviors requires different strategies than maintaining healthy behaviors among high school students. In the school setting, programs need to target the promotion and maintenance of health behaviors to engage all students who participate in the program as part of a class or club activity. Tailoring the program using screening and modifying strategies to meet the needs of all students may increase the potential reach of the program. The Transtheoretical Model may provide information on how to develop a tailored program. Additional research on how to utilize the constructs of TTM effectively among high school students needs to be conducted. Further evaluation studies should employ a more expansive evaluation to assess the long-term effectiveness of health advocacy programming.^

BAYESIAN STATISTICAL METHODS IN GENE-ENVIRONMENT AND GENE-GENE INTERACTION STUDIES

Complex diseases such as cancer result from multiple genetic changes and environmental exposures. Due to the rapid development of genotyping and sequencing technologies, we are now able to more accurately assess causal effects of many genetic and environmental factors. Genome-wide association studies have been able to localize many causal genetic variants predisposing to certain diseases. However, these studies only explain a small portion of variations in the heritability of diseases. More advanced statistical models are urgently needed to identify and characterize some additional genetic and environmental factors and their interactions, which will enable us to better understand the causes of complex diseases. In the past decade, thanks to the increasing computational capabilities and novel statistical developments, Bayesian methods have been widely applied in the genetics/genomics researches and demonstrating superiority over some regular approaches in certain research areas. Gene-environment and gene-gene interaction studies are among the areas where Bayesian methods may fully exert its functionalities and advantages. This dissertation focuses on developing new Bayesian statistical methods for data analysis with complex gene-environment and gene-gene interactions, as well as extending some existing methods for gene-environment interactions to other related areas. It includes three sections: (1) Deriving the Bayesian variable selection framework for the hierarchical gene-environment and gene-gene interactions; (2) Developing the Bayesian Natural and Orthogonal Interaction (NOIA) models for gene-environment interactions; and (3) extending the applications of two Bayesian statistical methods which were developed for gene-environment interaction studies, to other related types of studies such as adaptive borrowing historical data. We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions (epistasis) and gene by environment interactions in the same model. It is well known that, in many practical situations, there exists a natural hierarchical structure between the main effects and interactions in the linear model. Here we propose a model that incorporates this hierarchical structure into the Bayesian mixture model, such that the irrelevant interaction effects can be removed more efficiently, resulting in more robust, parsimonious and powerful models. We evaluate both of the 'strong hierarchical' and 'weak hierarchical' models, which specify that both or one of the main effects between interacting factors must be present for the interactions to be included in the model. The extensive simulation results show that the proposed strong and weak hierarchical mixture models control the proportion of false positive discoveries and yield a powerful approach to identify the predisposing main effects and interactions in the studies with complex gene-environment and gene-gene interactions. We also compare these two models with the 'independent' model that does not impose this hierarchical constraint and observe their superior performances in most of the considered situations. The proposed models are implemented in the real data analysis of gene and environment interactions in the cases of lung cancer and cutaneous melanoma case-control studies. The Bayesian statistical models enjoy the properties of being allowed to incorporate useful prior information in the modeling process. Moreover, the Bayesian mixture model outperforms the multivariate logistic model in terms of the performances on the parameter estimation and variable selection in most cases. Our proposed models hold the hierarchical constraints, that further improve the Bayesian mixture model by reducing the proportion of false positive findings among the identified interactions and successfully identifying the reported associations. This is practically appealing for the study of investigating the causal factors from a moderate number of candidate genetic and environmental factors along with a relatively large number of interactions. The natural and orthogonal interaction (NOIA) models of genetic effects have previously been developed to provide an analysis framework, by which the estimates of effects for a quantitative trait are statistically orthogonal regardless of the existence of Hardy-Weinberg Equilibrium (HWE) within loci. Ma et al. (2012) recently developed a NOIA model for the gene-environment interaction studies and have shown the advantages of using the model for detecting the true main effects and interactions, compared with the usual functional model. In this project, we propose a novel Bayesian statistical model that combines the Bayesian hierarchical mixture model with the NOIA statistical model and the usual functional model. The proposed Bayesian NOIA model demonstrates more power at detecting the non-null effects with higher marginal posterior probabilities. Also, we review two Bayesian statistical models (Bayesian empirical shrinkage-type estimator and Bayesian model averaging), which were developed for the gene-environment interaction studies. Inspired by these Bayesian models, we develop two novel statistical methods that are able to handle the related problems such as borrowing data from historical studies. The proposed methods are analogous to the methods for the gene-environment interactions on behalf of the success on balancing the statistical efficiency and bias in a unified model. By extensive simulation studies, we compare the operating characteristics of the proposed models with the existing models including the hierarchical meta-analysis model. The results show that the proposed approaches adaptively borrow the historical data in a data-driven way. These novel models may have a broad range of statistical applications in both of genetic/genomic and clinical studies.

Effects of binaural stimulation in attention and EEG

When two pure tones of slightly different frequency are presented separately to each ear, the listener perceives a third single tone with amplitude variations at a frequency that equals the difference between the two tones, this perceptual illusion is known as binaural auditory beat. There are anecdotal reports that suggest that the binaural beat can entrain EEG activity and may affect the arousal levels, although few studies have been published. There is a need for double-blind, well-designed studies in order to establish a solid foundation for these sounds, as most of the documented benefits come from self-reported cases that could be affected by placebo effect. As BB’s are a cheap technology (it even exists a free open source programmable bin aural-beat generator on the internet named Gnaural), any achievement in this area could be of public interest. The aim in our research was to explore the potential of BB’s in a particular field: tasks that require focus and concentration. In order to detect changes in the brain waves that could relate to any particular improvement, EEG recordings of a small sample of individuals were also obtained. In this study we compare the effect of different binaural stimulation in 7 EEG frequency ranges, 78 participants were exposed to 20 min binaural beat stimulation. The effects were obtained both qualitative with cognitive test and quantitative with EEG analysis. Results suggest no significant statistical improvement in 20 min stimulation.

Effect of binaural stimulation on attention and EEG

When two pure tones of slightly different frequency are presented separately to each ear, the listener perceives a third single tone with amplitude variations at a frequency that equals the difference between the two tones; this perceptual illusion is known as the binaural auditory beat (BB). There are anecdotal reports that suggest that the binaural beat can entrain EEG activity and may affect the arousal levels, although few studies have been published. There is a need for double-blind, well-designed studies in order to establish a solid foundation for these sounds, as most of the documented benefits come from self-reported cases that could be affected by placebo effect. As BBs are a cheap technology (it even exists a free open source programmable binaural- beat generator on the Internet named Gnaural), any achievement in this area could be of public interest. The aim in our research was to explore the potential of BBs in a particular field: tasks that require focus and concentration. In order to detect changes in the brain waves that could relate to any particular improvement, EEG recordings of a small sample of individuals were also obtained. In this study we compare the effect of different binaural stimulation in 7 EEG frequency ranges. 78 participants were exposed to 20-min binaural beat stimulation. The effects were obtained both quali- tative with cognitive test and quantitative with EEG analysis. Results suggest no significant statistical improvement in 20-min stimulation.

Multimodal integration of functional and structural brain connectivity. An application to the characterization of Mild Cognitive Impairment

La investigación para el conocimiento del cerebro es una ciencia joven, su inicio se remonta a Santiago Ramón y Cajal en 1888. Desde esta fecha a nuestro tiempo la neurociencia ha avanzado mucho en el desarrollo de técnicas que permiten su estudio. Desde la neurociencia cognitiva hoy se explican muchos modelos que nos permiten acercar a nuestro entendimiento a capacidades cognitivas complejas. Aun así hablamos de una ciencia casi en pañales que tiene un lago recorrido por delante. Una de las claves del éxito en los estudios de la función cerebral ha sido convertirse en una disciplina que combina conocimientos de diversas áreas: de la física, de las matemáticas, de la estadística y de la psicología. Esta es la razón por la que a lo largo de este trabajo se entremezclan conceptos de diferentes campos con el objetivo de avanzar en el conocimiento de un tema tan complejo como el que nos ocupa: el entendimiento de la mente humana. Concretamente, esta tesis ha estado dirigida a la integración multimodal de la magnetoencefalografía (MEG) y la resonancia magnética ponderada en difusión (dMRI). Estas técnicas son sensibles, respectivamente, a los campos magnéticos emitidos por las corrientes neuronales, y a la microestructura de la materia blanca cerebral. A lo largo de este trabajo hemos visto que la combinación de estas técnicas permiten descubrir sinergias estructurofuncionales en el procesamiento de la información en el cerebro sano y en el curso de patologías neurológicas. Más específicamente en este trabajo se ha estudiado la relación entre la conectividad funcional y estructural y en cómo fusionarlas. Para ello, se ha cuantificado la conectividad funcional mediante el estudio de la sincronización de fase o la correlación de amplitudes entre series temporales, de esta forma se ha conseguido un índice que mide la similitud entre grupos neuronales o regiones cerebrales. Adicionalmente, la cuantificación de la conectividad estructural a partir de imágenes de resonancia magnética ponderadas en difusión, ha permitido hallar índices de la integridad de materia blanca o de la fuerza de las conexiones estructurales entre regiones. Estas medidas fueron combinadas en los capítulos 3, 4 y 5 de este trabajo siguiendo tres aproximaciones que iban desde el nivel más bajo al más alto de integración. Finalmente se utilizó la información fusionada de MEG y dMRI para la caracterización de grupos de sujetos con deterioro cognitivo leve, la detección de esta patología resulta relevante en la identificación precoz de la enfermedad de Alzheimer. Esta tesis está dividida en seis capítulos. En el capítulos 1 se establece un contexto para la introducción de la connectómica dentro de los campos de la neuroimagen y la neurociencia. Posteriormente en este capítulo se describen los objetivos de la tesis, y los objetivos específicos de cada una de las publicaciones científicas que resultaron de este trabajo. En el capítulo 2 se describen los métodos para cada técnica que fue empleada: conectividad estructural, conectividad funcional en resting state, redes cerebrales complejas y teoría de grafos y finalmente se describe la condición de deterioro cognitivo leve y el estado actual en la búsqueda de nuevos biomarcadores diagnósticos. En los capítulos 3, 4 y 5 se han incluido los artículos científicos que fueron producidos a lo largo de esta tesis. Estos han sido incluidos en el formato de la revista en que fueron publicados, estando divididos en introducción, materiales y métodos, resultados y discusión. Todos los métodos que fueron empleados en los artículos están descritos en el capítulo 2 de la tesis. Finalmente, en el capítulo 6 se concluyen los resultados generales de la tesis y se discuten de forma específica los resultados de cada artículo. ABSTRACT In this thesis I apply concepts from mathematics, physics and statistics to the neurosciences. This field benefits from the collaborative work of multidisciplinary teams where physicians, psychologists, engineers and other specialists fight for a common well: the understanding of the brain. Research on this field is still in its early years, being its birth attributed to the neuronal theory of Santiago Ramo´n y Cajal in 1888. In more than one hundred years only a very little percentage of the brain functioning has been discovered, and still much more needs to be explored. Isolated techniques aim at unraveling the system that supports our cognition, nevertheless in order to provide solid evidence in such a field multimodal techniques have arisen, with them we will be able to improve current knowledge about human cognition. Here we focus on the multimodal integration of magnetoencephalography (MEG) and diffusion weighted magnetic resonance imaging. These techniques are sensitive to the magnetic fields emitted by the neuronal currents and to the white matter microstructure, respectively. The combination of such techniques could bring up evidences about structural-functional synergies in the brain information processing and which part of this synergy fails in specific neurological pathologies. In particular, we are interested in the relationship between functional and structural connectivity, and how two integrate this information. We quantify the functional connectivity by studying the phase synchronization or the amplitude correlation between time series obtained by MEG, and so we get an index indicating similarity between neuronal entities, i.e. brain regions. In addition we quantify structural connectivity by performing diffusion tensor estimation from the diffusion weighted images, thus obtaining an indicator of the integrity of the white matter or, if preferred, the strength of the structural connections between regions. These quantifications are then combined following three different approaches, from the lowest to the highest level of integration, in chapters 3, 4 and 5. We finally apply the fused information to the characterization or prediction of mild cognitive impairment, a clinical entity which is considered as an early step in the continuum pathological process of dementia. The dissertation is divided in six chapters. In chapter 1 I introduce connectomics within the fields of neuroimaging and neuroscience. Later in this chapter we describe the objectives of this thesis, and the specific objectives of each of the scientific publications that were produced as result of this work. In chapter 2 I describe the methods for each of the techniques that were employed, namely structural connectivity, resting state functional connectivity, complex brain networks and graph theory, and finally, I describe the clinical condition of mild cognitive impairment and the current state of the art in the search for early biomarkers. In chapters 3, 4 and 5 I have included the scientific publications that were generated along this work. They have been included in in their original format and they contain introduction, materials and methods, results and discussion. All methods that were employed in these papers have been described in chapter 2. Finally, in chapter 6 I summarize all the results from this thesis, both locally for each of the scientific publications and globally for the whole work.

User experience with immersive and interactive media = Experiencia de usuario en entornos 3D inmersivos e interactivos

Estudios recientes promueven la integración de estímulos multisensoriales en activos multimedia con el fin de mejorar la experiencia de usuario mediante la estimulación de nuevos sentidos, más allá de la tradicional experiencia audiovisual. Del mismo modo, varios trabajos proponen la introducción de componentes de interacción capaces de complementar con nuevas características, funcionalidades y/o información la experiencia multimedia. Efectos sensoriales basados en el uso de nuevas técnicas de audio, olores, viento, vibraciones y control de la iluminación, han demostrado tener un impacto favorable en la sensación de Presencia, en el disfrute de la experiencia multimedia y en la calidad, relevancia y realismo de la misma percibidos por el usuario. Asimismo, los servicios basados en dos pantallas y la manipulación directa de (elementos en) la escena de video tienen el potencial de mejorar la comprensión, la concentración y la implicación proactiva del usuario en la experiencia multimedia. El deporte se encuentra entre los géneros con mayor potencial para integrar y explotar éstas soluciones tecnológicas. Trabajos previos han demostrado asimismo la viabilidad técnica de integrar éstas tecnologías con los estándares actualmente adoptados a lo largo de toda la cadena de transmisión de televisión. De este modo, los sistemas multimedia enriquecidos con efectos sensoriales, los servicios interactivos multiplataforma y un mayor control del usuario sobre la escena de vídeo emergen como nuevas formas de llevar la multimedia immersiva e interactiva al mercado de consumo de forma no disruptiva. Sin embargo, existen numerosas interrogantes relativas a los efectos sensoriales y/o soluciones interactivas más adecuadas para complementar un contenido audiovisual determinado o a la mejor manera de de integrar y combinar dichos componentes para mejorar la experiencia de usuario de un segmento de audiencia objetivo. Además, la evidencia científica sobre el impacto de factores humanos en la experiencia de usuario con estas nuevas formas de immersión e interacción en el contexto multimedia es aún insuficiente y en ocasiones, contradictoria. Así, el papel de éstos factores en el potencial de adopción de éstas tecnologías ha sido amplia-mente ignorado. La presente tesis analiza el impacto del audio binaural, efectos sensoriales (de iluminación y olfativos), interacción con objetos 3D integrados en la escena de vídeo e interacción con contenido adicional utilizando una segunda pantalla en la experiencia de usuario con contenidos de deporte. La posible influencia de dichos componentes en las variables dependientes se explora tanto a nivel global (efecto promedio) como en función de las características de los usuarios (efectos heterogéneos). Para ello, se ha llevado a cabo un experimento con usuarios orientado a explorar la influencia de éstos componentes immersivos e interactivos en dos grandes dimensiones de la experiencia multimedia: calidad y Presencia. La calidad de la experiencia multimedia se analiza en términos de las posibles variaciones asociadas a la calidad global y a la calidad del contenido, la imagen, el audio, los efectos sensoriales, la interacción con objetos 3D y la interacción con la segunda pantalla. El posible impacto en la Presencia considera dos de las dimensiones definidas por el cuestionario ITC-SOPI: Presencia Espacial (Spatial Presence) e Implicación (Engagement). Por último, los individuos son caracterizados teniendo en cuenta los siguientes atributos afectivos, cognitivos y conductuales: preferencias y hábitos en relación con el contenido, grado de conocimiento de las tecnologías integradas en el sistema, tendencia a involucrarse emocionalmente, tendencia a concentrarse en una actividad bloqueando estímulos externos y los cinco grandes rasgos de la personalidad: extroversión, amabilidad, responsabilidad, inestabilidad emocional y apertura a nuevas experiencias. A nivel global, nuestro estudio revela que los participantes prefieren el audio binaural frente al sistema estéreo y que los efectos sensoriales generan un aumento significativo del nivel de Presencia Espacial percibido por los usuarios. Además, las manipulaciones experimentales realizadas permitieron identificar una gran variedad de efectos heterogéneos. Un resultado interesante es que dichos efectos no se encuentran distribuidos de forma equitativa entre las medidas de calidad y Presencia. Nuestros datos revelan un impacto generalizado del audio binaural en la mayoría de las medidas de calidad y Presencia analizadas. En cambio, la influencia de los efectos sensoriales y de la interacción con la segunda pantalla se concentran en las medidas de Presencia y calidad, respectivamente. La magnitud de los efectos heterogéneos identificados está modulada por las siguientes características personales: preferencias en relación con el contenido, frecuencia con la que el usuario suele ver contenido similar, conocimiento de las tecnologías integradas en el demostrador, sexo, tendencia a involucrarse emocionalmente, tendencia a a concentrarse en una actividad bloqueando estímulos externos y niveles de amabilidad, responsabilidad y apertura a nuevas experiencias. Las características personales consideradas en nuestro experimento explicaron la mayor parte de la variación en las variables dependientes, confirmando así el importante (y frecuentemente ignorado) papel de las diferencias individuales en la experiencia multimedia. Entre las características de los usuarios con un impacto más generalizado se encuentran las preferencias en relación con el contenido, el grado de conocimiento de las tecnologías integradas en el sistema y la tendencia a involucrarse emocionalmente. En particular, los primeros dos factores parecen generar un conflicto de atención hacia el contenido versus las características/elementos técnicos del sistema, respectivamente. Asimismo, la experiencia multimedia de los fans del fútbol parece estar modulada por procesos emociona-les, mientras que para los no-fans predominan los procesos cognitivos, en particular aquellos directamente relacionados con la percepción de calidad. Abstract Recent studies encourage the integration of multi-sensorial stimuli into multimedia assets to enhance the user experience by stimulating other senses beyond sight and hearing. Similarly, the introduction of multi-modal interaction components complementing with new features, functionalities and/or information the multimedia experience is promoted. Sensory effects as odor, wind, vibration and light effects, as well as an enhanced audio quality, have been found to favour media enjoyment and to have a positive influence on the sense of Presence and on the perceived quality, relevance and reality of a multimedia experience. Two-screen services and a direct manipulation of (elements in) the video scene have the potential to enhance user comprehension, engagement and proactive involvement of/in the media experience. Sports is among the genres that could benefit the most from these solutions. Previous works have demonstrated the technical feasibility of implementing and deploying end-to-end solutions integrating these technologies into legacy systems. Thus, sensorially-enhanced media, two-screen services and an increased user control over the displayed scene emerge as means to deliver a new form of immersive and interactive media experiences to the mass market in a non-disruptive manner. However, many questions remain concerning issues as the specific interactive solutions or sensory effects that can better complement a given audiovisual content or the best way in which to integrate and combine them to enhance the user experience of a target audience segment. Furthermore, scientific evidence on the impact of human factors on the user experience with these new forms of immersive and interactive media is still insufficient and sometimes, contradictory. Thus, the role of these factors on the potential adoption of these technologies has been widely ignored. This thesis analyzes the impact of binaural audio, sensory (light and olfactory) effects, interaction with 3D objects integrated into the video scene and interaction with additional content using a second screen on the sports media experience. The potential influence of these components on the dependent variables is explored both at the overall level (average effect) and as a function of users’ characteristics (heterogeneous effects). To these aims, we conducted an experimental study exploring the influence of these immersive and interactive elements on the quality and Presence dimensions of the media experience. Along the quality dimension, we look for possible variations on the quality scores as-signed to the overall media experience and to the media components content, image, audio, sensory effects, interaction with 3D objects and interaction using the tablet device. The potential impact on Presence is analyzed by looking at two of the four dimensions defined by the ITC-SOPI questionnaire, namely Spatial Presence and Engagement. The users’ characteristics considered encompass the following personal affective, cognitive and behavioral attributes: preferences and habits in relation to the content, knowledge of the involved technologies, tendency to get emotionally involved and tendency to get absorbed in an activity and block out external distractors and the big five personality traits extraversion, agreeableness, conscientiousness, neuroticism and openness to experience. At the overall level, we found that participants preferred binaural audio than standard stereo audio and that sensory effects increase significantly the level of Spatial Presence. Several heterogeneous effects were also revealed as a result of our experimental manipulations. Interestingly, these effects were not equally distributed across the quality and Presence measures analyzed. Whereas binaural audio was foud to have an influence on the majority of the quality and Presence measures considered, the effects of sensory effects and of interaction with additional content through the tablet device concentrate mainly on the dimensions of Presence and on quality measures, respectively. The magnitude of these effects was modulated by individual’s characteristics, such as: preferences in relation to the content, frequency of viewing similar content, knowledge of involved technologies, gender, tendency to get emotionally involved, tendency to absorption and levels of agreeableness, conscientiousness and openness to experience. The personal characteristics collected in our experiment explained most of the variation in the dependent variables, confirming the frequently neglected role of individual differences on the media experience. Preferences in relation to the content, knowledge of involved technologies and tendency to get emotionally involved were among the user variables with the most generalized influence. In particular, the former two features seem to present a conflict in the allocation of attentional resources towards the media content versus the technical features of the system, respectively. Additionally, football fans’ experience seems to be modulated by emotional processes whereas for not fans, cognitive processes (and in particular those related to quality judgment) prevail.

Cognitive Surveillance Architecture for Scenario Understanding

Uno de los mayores retos para la comunidad científica es conseguir que las máquinas posean en un futuro la capacidad del sistema visual y cognitivo humanos, de forma que, por ejemplo, en entornos de video vigilancia, puedan llegar a proporcionar de manera automática una descripción fiable de lo que está ocurriendo en la escena. En la presente tesis, mediante la propuesta de un marco de trabajo de referencia, se discuten y plantean los pasos necesarios para el desarrollo de sistemas más inteligentes capaces de extraer y analizar, a diferentes niveles de abstracción y mediante distintos módulos de procesamiento independientes, la información necesaria para comprender qué está sucediendo en un conjunto amplio de escenarios de distinta naturaleza. Se parte de un análisis de requisitos y se identifican los retos para este tipo de sistemas en la actualidad, lo que constituye en sí mismo los objetivos de esta tesis, contribuyendo así a un modelo de datos basado en el conocimiento que permitirá analizar distintas situaciones en las que personas y vehículos son los actores principales, dejando no obstante la puerta abierta a la adaptación a otros dominios. Así mismo, se estudian los distintos procesos que se pueden lanzar a nivel interno así como la necesidad de integrar mecanismos de realimentación a distintos niveles que permitan al sistema adaptarse mejor a cambios en el entorno. Como resultado, se propone un marco de referencia jerárquico que integra las capacidades de percepción, interpretación y aprendizaje para superar los retos identificados en este ámbito; y así poder desarrollar sistemas de vigilancia más robustos, flexibles e inteligentes, capaces de operar en una variedad de entornos. Resultados experimentales ejecutados sobre distintas muestras de datos (secuencias de vídeo principalmente) demuestran la efectividad del marco de trabajo propuesto respecto a otros propuestos en el pasado. Un primer caso de estudio, permite demostrar la creación de un sistema de monitorización de entornos de parking en exteriores para la detección de vehículos y el análisis de plazas libres de aparcamiento. Un segundo caso de estudio, permite demostrar la flexibilidad del marco de referencia propuesto para adaptarse a los requisitos de un entorno de vigilancia completamente distinto, como es un hogar inteligente donde el análisis automático de actividades de la vida cotidiana centra la atención del estudio. ABSTRACT One of the most ambitious objectives for the Computer Vision and Pattern Recognition research community is that machines can achieve similar capacities to the human's visual and cognitive system, and thus provide a trustworthy description of what is happening in the scene under surveillance. Thus, a number of well-established scenario understanding architectural frameworks to develop applications working on a variety of environments can be found in the literature. In this Thesis, a highly descriptive methodology for the development of scene understanding applications is presented. It consists of a set of formal guidelines to let machines extract and analyse, at different levels of abstraction and by means of independent processing modules that interact with each other, the necessary information to understand a broad set of different real World surveillance scenarios. Taking into account the challenges that working at both low and high levels offer, we contribute with a highly descriptive knowledge-based data model for the analysis of different situations in which people and vehicles are the main actors, leaving the door open for the development of interesting applications in diverse smart domains. Recommendations to let systems achieve high-level behaviour understanding will be also provided. Furthermore, feedback mechanisms are proposed to be integrated in order to let any system to understand better the environment and the logical context around, reducing thus the uncertainty and noise, and increasing its robustness and precision in front of low-level or high-level errors. As a result, a hierarchical cognitive architecture of reference which integrates the necessary perception, interpretation, attention and learning capabilities to overcome main challenges identified in this area of research is proposed; thus allowing to develop more robust, flexible and smart surveillance systems to cope with the different requirements of a variety of environments. Once crucial issues that should be treated explicitly in the design of this kind of systems have been formulated and discussed, experimental results shows the effectiveness of the proposed framework compared with other proposed in the past. Two case studies were implemented to test the capabilities of the framework. The first case study presents how the proposed framework can be used to create intelligent parking monitoring systems. The second case study demonstrates the flexibility of the system to cope with the requirements of a completely different environment, a smart home where activities of daily living are performed. Finally, general conclusions and future work lines to further enhancing the capabilities of the proposed framework are presented.

Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry.

Patients suffering from schizophrenia display subtle cognitive abnormalities that may reflect a difficulty in rapidly coordinating the steps that occur in a variety of mental activities. Working interactively with the prefrontal cortex, the cerebellum may play a role in coordinating both motor and cognitive performance. This positron-emission tomography study suggests the presence of a prefrontal-thalamic-cerebellar network that is activated when normal subjects recall complex narrative material, but is dysfunctional in schizophrenic patients when they perform the same task. These results support a role for the cerebellum in cognitive functions and suggest that patients with schizophrenia may suffer from a "cognitive dysmetria" due to dysfunctional prefrontal-thalamic-cerebellar circuitry.

Androgen responsiveness to competition in humans: the role of cognitive variables

Although androgens are commonly seen as male sex hormones, it has been established over the years that in both sexes, androgens also respond to social challenges. To explain the socially driven changes in androgens, two theoretical models have been proposed: the biosocial model and the challenge hypothesis. These models are typically seen as partly overlapping; however, they generate different predictions that are clarified here. In humans, sports competition and nonmetabolic competitive tasks have been used in the laboratory setting, as a proxy for agonistic interactions in animals. The results reviewed here show that the testosterone (T) response to competition in humans is highly variable – the studies present postcompetition T levels and changes in T that depend on the contest outcome and that cannot be predicted by the current theoretical models. These conflicting results bring to the foreground the importance of considering cognitive factors that could moderate the androgen response to competition. Among these variables, we elect cognitive appraisal and its components as a key candidate modulating factor. It is known that T also modulates the cognitive processes that are relevant to performance in competition. In this article, we reviewed the evidence arising from studies investigating the effect of administering exogenous T and compare those results with the findings from studies that measured endogenous T levels. Finally, we summarized the importance of also considering the interaction between androgens and other hormones, such as cortisol, when investigating the social modulation of T, as proposed by the dual-hormone hypothesis.