Ecological validity of virtual reality daily living activities screening for early dementia: longitudinal study

Background: Dementia is a multifaceted disorder that impairs cognitive functions, such as memory, language, and executive functions necessary to plan, organize, and prioritize tasks required for goal-directed behaviors. In most cases, individuals with dementia experience difficulties interacting with physical and social environments. The purpose of this study was to establish ecological validity and initial construct validity of a fire evacuation Virtual Reality Day-Out Task (VR-DOT) environment based on performance profiles as a screening tool for early dementia. Objective: The objectives were (1) to examine the relationships among the performances of 3 groups of participants in the VR-DOT and traditional neuropsychological tests employed to assess executive functions, and (2) to compare the performance of participants with mild Alzheimer’s-type dementia (AD) to those with amnestic single-domain mild cognitive impairment (MCI) and healthy controls in the VR-DOT and traditional neuropsychological tests used to assess executive functions. We hypothesized that the 2 cognitively impaired groups would have distinct performance profiles and show significantly impaired independent functioning in ADL compared to the healthy controls. Methods: The study population included 3 groups: 72 healthy control elderly participants, 65 amnestic MCI participants, and 68 mild AD participants. A natural user interface framework based on a fire evacuation VR-DOT environment was used for assessing physical and cognitive abilities of seniors over 3 years. VR-DOT focuses on the subtle errors and patterns in performing everyday activities and has the advantage of not depending on a subjective rating of an individual person. We further assessed functional capacity by both neuropsychological tests (including measures of attention, memory, working memory, executive functions, language, and depression). We also evaluated performance in finger tapping, grip strength, stride length, gait speed, and chair stands separately and while performing VR-DOTs in order to correlate performance in these measures with VR-DOTs because performance while navigating a virtual environment is a valid and reliable indicator of cognitive decline in elderly persons. Results: The mild AD group was more impaired than the amnestic MCI group, and both were more impaired than healthy controls. The novel VR-DOT functional index correlated strongly with standard cognitive and functional measurements, such as mini-mental state examination (MMSE; rho=0.26, P=.01) and Bristol Activities of Daily Living (ADL) scale scores (rho=0.32, P=.001). Conclusions: Functional impairment is a defining characteristic of predementia and is partly dependent on the degree of cognitive impairment. The novel virtual reality measures of functional ability seem more sensitive to functional impairment than qualitative measures in predementia, thus accurately differentiating from healthy controls. We conclude that VR-DOT is an effective tool for discriminating predementia and mild AD from controls by detecting differences in terms of errors, omissions, and perseverations while measuring ADL functional ability.

Adult Neurogenesis in Drosophila

Adult neurogenesis has been linked to several cognitive functions and neurological disorders. Description of adult neurogenesis in a model organism like Drosophila could facilitate the genetic study of normal and abnormal neurogenesis in the adult brain. So far, formation of new neurons has not been detected in adult fly brains and hence has been thought to be absent in Drosophila. Here, we used an improved lineage-labeling method to show that, surprisingly, adult neurogenesis occurs in the medulla cortex of the Drosophila optic lobes. We also find that acute brain damage to this region stimulates adult neurogenesis. Finally, we identify a factor induced by acute damage, which is sufficient to specifically activate the proliferation of a cell type with adult neuroblast characteristics. Our results reveal unexpected plasticity in the adult Drosophila brain and describe a unique model for the genetic analysis of adult neurogenesis, plasticity, and brain regeneration.

Subacute neural stem cell therapy for traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) frequently results in devastating and prolonged morbidity. Cellular therapy is a burgeoning field of experimental treatment that has shown promise in the management of many diseases, including TBI. Previous work suggests that certain stem and progenitor cell populations migrate to sites of inflammation and improve functional outcome in rodents after neural injury. Unfortunately, recent study has revealed potential limitations of acute and intravenous stem cell therapy. We studied subacute, direct intracerebral neural stem and progenitor cell (NSC) therapy for TBI. MATERIALS AND METHODS: The NSCs were characterized by flow cytometry and placed (400,000 cells in 50 muL 1x phosphate-buffered saline) into and around the direct injury area, using stereotactic guidance, of female Sprague Dawley rats 1 wk after undergoing a controlled cortical impact injury. Immunohistochemistry was used to identify cells located in the brain at 48 h and 2 wk after administration. Motor function was assessed using the neurological severity score, foot fault, rotarod, and beam balance. Cognitive function was assessed using the Morris water maze learning paradigm. Repeated measures analysis of variance with post-hoc analysis were used to determine significance at P < 0.05. RESULTS: Immunohistochemistry analysis revealed that 1.4-1.9% of infused cells remained in the neural tissue at 48 h and 2 wk post placement. Nearly all cells were located along injection tracks at 48 h. At 2 wk some cell dispersion was apparent. Rotarod motor testing revealed significant increases in maximal speed among NSC-treated rats compared with saline controls at d 4 (36.4 versus 27.1 rpm, P < 0.05) and 5 (35.8 versus 28.9 rpm, P < 0.05). All other motor and cognitive evaluations were not significantly different compared to controls. CONCLUSIONS: Placement of NSCs led to the cells incorporating and remaining in the tissues 2 wk after placement. Motor function tests revealed improvements in the ability to run on a rotating rod; however, other motor and cognitive functions were not significantly improved by NSC therapy. Further examination of a dose response and optimization of placement strategy may improve long-term cell survival and maximize functional recovery.

THE DESIGN AND DEVELOPMENT OF A SURVEY INSTRUMENT FOR THE ASSESSMENT OF OCCUPATIONAL STRESS

Using stress and coping as a unifying theoretical concept, a series of five models was developed in order to synthesize the survey questions and to classify information. These models identified the question, listed the research study, described measurements, listed workplace data, and listed industry and national reference data.^ A set of 38 instrument questions was developed within the five coping correlate categories. In addition, a set of 22 stress symptoms was also developed. The study was conducted within two groups, police and professors, on a large university campus. The groups were selected because their occupations were diverse, but they were a part of the same macroenvironment. The premise was that police officers would be more highly stressed than professors.^ Of a total study group of 80, there were 37 respondents. The difference in the mean stress responses was observable between the two groups. Not only were the responses similar within each group, but the stress level of response was also similar within each group. While the response to the survey instrument was good, only 3 respondents answered the stress symptom survey properly. It was determined that none of the 37 respondents believed that they were ill. This perception of being well was also evidenced by the grand mean of the stress scores of 2.76 (3.0 = moderate stress). This also caused fewer independent variables to be entered in the multiple regression model.^ The survey instrument was carefully designed to be universal. Universality is the ability to transcend occupational or regional definitions as applied to stress. It is the ability to measure responses within broad categories such as physiological, emotional, behavioral, social, and cognitive functions without losing the ability to measure the detail within the individual questions, or the relationships between questions and categories.^ Replication is much easier to achieve with standardized categories, questions, and measurement procedures such as those developed for the universal survey instrument. Because the survey instrument is universal it can be used as an analytical device, an assessment device, a basic tool for planning and a follow-up instrument to measure individual response to planned reductions in occupational stress. (Abstract shortened with permission of author.) ^

Neuropsychological long-term sequelae after posterior fossa tumour resection during childhood

The importance of the cerebellum for non‐motor functions is becoming more and more evident. The influence on cognitive functions from acquired cerebellar lesions during childhood, however, is not well known. We present follow‐up data from 24 patients, who were operated upon during childhood for benign cerebellar tumours. The benign histology of these tumours required neither radiotherapy nor chemotherapy. Post‐operatively, these children were of normal intelligence with a mean IQ of 99.1, performance intelligence quotient (PIQ) of 101.3 and verbal intelligence quotient (VIQ) of 96.8. However, 57% of patients showed abnormalities in subtesting. In addition, more extensive neuropsychological testing revealed significant problems for attention, memory, processing speed and interference. Visuo‐constructive problems were marked for copying the Rey figure, but less pronounced for recall of the figure. Verbal fluency was more affected than design fluency. Behavioural deficits could be detected in 33% of patients. Attention deficit problems were marked in 12.5%, whereas others demonstrated psychiatric symptoms such as mutism, addiction problems, anorexia, uncontrolled temper tantrums and phobia. Age at tumour operation and size of tumour had no influence on outcome. Vermis involvement was related to an increase in neuropsychological and psychiatric problems. The observation that patients with left‐sided cerebellar tumours were more affected than patients with right‐sided tumours is probably also influenced by a more pronounced vermian involvement in the former group. In summary, this study confirms the importance of the cerebellum for cognitive development and points to the necessity of careful follow‐up for these children to provide them with the necessary help to achieve full integration into professional life.

The human vestibular cortex revealed by coordinate-based activation likelihood estimation meta-analysis.

The vestibular system contributes to the control of posture and eye movements and is also involved in various cognitive functions including spatial navigation and memory. These functions are subtended by projections to a vestibular cortex, whose exact location in the human brain is still a matter of debate (Lopez and Blanke, 2011). The vestibular cortex can be defined as the network of all cortical areas receiving inputs from the vestibular system, including areas where vestibular signals influence the processing of other sensory (e.g. somatosensory and visual) and motor signals. Previous neuroimaging studies used caloric vestibular stimulation (CVS), galvanic vestibular stimulation (GVS), and auditory stimulation (clicks and short-tone bursts) to activate the vestibular receptors and localize the vestibular cortex. However, these three methods differ regarding the receptors stimulated (otoliths, semicircular canals) and the concurrent activation of the tactile, thermal, nociceptive and auditory systems. To evaluate the convergence between these methods and provide a statistical analysis of the localization of the human vestibular cortex, we performed an activation likelihood estimation (ALE) meta-analysis of neuroimaging studies using CVS, GVS, and auditory stimuli. We analyzed a total of 352 activation foci reported in 16 studies carried out in a total of 192 healthy participants. The results reveal that the main regions activated by CVS, GVS, or auditory stimuli were located in the Sylvian fissure, insula, retroinsular cortex, fronto-parietal operculum, superior temporal gyrus, and cingulate cortex. Conjunction analysis indicated that regions showing convergence between two stimulation methods were located in the median (short gyrus III) and posterior (long gyrus IV) insula, parietal operculum and retroinsular cortex (Ri). The only area of convergence between all three methods of stimulation was located in Ri. The data indicate that Ri, parietal operculum and posterior insula are vestibular regions where afferents converge from otoliths and semicircular canals, and may thus be involved in the processing of signals informing about body rotations, translations and tilts. Results from the meta-analysis are in agreement with electrophysiological recordings in monkeys showing main vestibular projections in the transitional zone between Ri, the insular granular field (Ig), and SII.

Memory and attention problems in children with brain tumors at diagnosis

Purpose: Results from previous studies indicate that children with brain tumors (BT) might present with cognitive problems at diagnosis and thus before the start of any medical treatment. The question remains whether these problems are due to the underlying tumor itself or due to the high level of emotional and physical stress which is involved at diagnosis of a malignant disorder. All children with a de novo oncological diagnosis not involving the central nervous systems (CNS) are usually exposed to a comparable level of distress. However, patients with cancer not involving the CNS are not expected to show disease-related cognitive problems. Thus they serve as a well-balanced control group (CG) to help distinguish between the probable causes of the effect. Method: In a pilot study we analyzed an array of cognitive functions in 16 children with BT and 17 control patients. In both groups, tests were administered in-patient at diagnosis before any therapeutic intervention such as surgery, chemotherapy od irradiation. Results: Performance of children with BT was comparable to that of CG patients in the areas of intelligence, perceptual reasoning, verbal comprehension, working memory, and processing speed. In contrast, however, BT patients performded significantly worse in verbal memory and attention. Conclusion: Memory and attention seem to be the most vulnerable funstions affected by BT, with other functions being preserved at the time of diagnosis. It ist to be expected that this vulnerability might exacerbate the cognitive decline after chemotherapy and radiation treatment - known to impair intellectual performance. The findings highlight the need of early cognitive assessments in children with BT in order to introduce cognitive training as early as possible to minimize or even prevent cognitive long-term sequelae. This might improve long-term academic and professional outcome of these children, but especially helps their return to school after hospitalization.

Gamma-hydroxybutyrate enhances mood and prosocial behavior without affecting plasma oxytocin and testosterone.

Gamma-hydroxybutyrate (GHB) is a GHB-/GABAB-receptor agonist. Reports from GHB abusers indicate euphoric, prosocial, and empathogenic effects of the drug. We measured the effects of GHB on mood, prosocial behavior, social and non-social cognition and assessed potential underlying neuroendocrine mechanisms. GHB (20mg/kg) was tested in 16 healthy males, using a randomized, placebo-controlled, cross-over design. Subjective effects on mood were assessed by visual-analogue-scales and the GHB-Specific-Questionnaire. Prosocial behavior was examined by the Charity Donation Task, the Social Value Orientation test, and the Reciprocity Task. Reaction time, memory, empathy, and theory-of-mind were also tested. Blood plasma levels of GHB, oxytocin, testosterone, progesterone, dehydroepiandrosterone (DHEA), cortisol, aldosterone, and adrenocorticotropic-hormone (ACTH) were determined. GHB showed stimulating and sedating effects, and elicited euphoria, disinhibition, and enhanced vitality. In participants with low prosociality, the drug increased donations and prosocial money distributions. In contrast, social cognitive abilities such as emotion recognition, empathy, and theory-of-mind, and basal cognitive functions were not affected. GHB increased plasma progesterone, while oxytocin and testosterone, cortisol, aldosterone, DHEA, and ACTH levels remained unaffected. GHB has mood-enhancing and prosocial effects without affecting social hormones such as oxytocin and testosterone. These data suggest a potential involvement of GHB-/GABAB-receptors and progesterone in mood and prosocial behavior.

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.

Effects of treatment on orienting in Parkinson disease

Parkinson disease (PD) is a movement disorder affecting over one million Americans, and 1% of our population over 60 years of age. Currently, PD has an unknown cause, no predictive biomarker, and no cure, yet there are effective treatments (medicine and surgery) to chronically manage the motor symptoms. But, PD patients also develop cognitive symptoms (e.g., distractibility, executive dysfunction) that remain untreated or may decline as a result of treating the motor symptoms. To address this important issue, I measured covert orienting of attention and overt eye movements in PD patients to assess the patients' ability to automatically detect stimuli in their visual field, to predict and attend to where the stimuli would appear, and to volitionally look somewhere else. ^ PD patients completed the cognitive tasks under multiple treatment conditions, and their performance was compared to healthy adults. PD patients first completed the tasks after they had withdrawn from medication. Their unmedicated performance revealed exaggerated automatic orienting, poor predictability, and weak volitional orienting. PD patients then repeated the tasks while medication was giving its peak benefit. The medication returned automatic covert orienting toward normal but did not improve volitional covert orienting. Several PD patients completed the tasks a third time after receiving surgery (specifically, implantation of stimulating electrodes in a subcortical brain region to alleviate motor symptoms). The stimulation (without medication) returned automatic orienting toward normal, did not change predictability, and further impaired volitional orienting. Taken together, treatments prescribed to alleviate the motor symptoms (a patient's primary concern) only improve some cognitive functions. Future studies may establish criteria to predict which patients are more likely to have cognitive benefit from medication over surgery, or vice versa. ^ I have also hypothesized an anatomical model relating orienting circuitry to abnormal PD circuitry and the therapeutic targets. My results suggest medication is more effective restoring the orienting circuitry than stimulation. Further, automatic and volitional orienting abilities seem to be modulated independently, which differs from an earlier model proposing a dependent, inverse relationship. My results are further discussed in terms of response inhibition, response selection, and the location of the selection. ^

Changes in resting-state functionally connected parieto-frontal networks after videogame practice

Neuroimaging studies provide evidence for organized intrinsic activity under task-free conditions. This activity serves functionally relevant brain systems supporting cognition. Here, we analyze changes in resting-state functional connectivity after videogame practice applying a test–retest design. Twenty young females were selected from a group of 100 participants tested on four standardized cognitive ability tests. The practice and control groups were carefully matched on their ability scores. The practice group played during two sessions per week across 4 weeks (16 h total) under strict supervision in the laboratory, showing systematic performance improvements in the game. A group independent component analysis (GICA) applying multisession temporal concatenation on test–retest resting-state fMRI, jointly with a dual-regression approach, was computed. Supporting the main hypothesis, the key finding reveals an increased correlated activity during rest in certain predefined resting state networks (albeit using uncorrected statistics) attributable to practice with the cognitively demanding tasks of the videogame. Observed changes were mainly concentrated on parietofrontal networks involved in heterogeneous cognitive functions.

Functional and effective connectivity in MEG. Application to the study of epilepsy

Nuestro cerebro contiene cerca de 1014 sinapsis neuronales. Esta enorme cantidad de conexiones proporciona un entorno ideal donde distintos grupos de neuronas se sincronizan transitoriamente para provocar la aparición de funciones cognitivas, como la percepción, el aprendizaje o el pensamiento. Comprender la organización de esta compleja red cerebral en base a datos neurofisiológicos, representa uno de los desafíos más importantes y emocionantes en el campo de la neurociencia. Se han propuesto recientemente varias medidas para evaluar cómo se comunican las diferentes partes del cerebro a diversas escalas (células individuales, columnas corticales, o áreas cerebrales). Podemos clasificarlos, según su simetría, en dos grupos: por una parte, la medidas simétricas, como la correlación, la coherencia o la sincronización de fase, que evalúan la conectividad funcional (FC); mientras que las medidas asimétricas, como la causalidad de Granger o transferencia de entropía, son capaces de detectar la dirección de la interacción, lo que denominamos conectividad efectiva (EC). En la neurociencia moderna ha aumentado el interés por el estudio de las redes funcionales cerebrales, en gran medida debido a la aparición de estos nuevos algoritmos que permiten analizar la interdependencia entre señales temporales, además de la emergente teoría de redes complejas y la introducción de técnicas novedosas, como la magnetoencefalografía (MEG), para registrar datos neurofisiológicos con gran resolución. Sin embargo, nos hallamos ante un campo novedoso que presenta aun varias cuestiones metodológicas sin resolver, algunas de las cuales trataran de abordarse en esta tesis. En primer lugar, el creciente número de aproximaciones para determinar la existencia de FC/EC entre dos o más señales temporales, junto con la complejidad matemática de las herramientas de análisis, hacen deseable organizarlas todas en un paquete software intuitivo y fácil de usar. Aquí presento HERMES (http://hermes.ctb.upm.es), una toolbox en MatlabR, diseñada precisamente con este fin. Creo que esta herramienta será de gran ayuda para todos aquellos investigadores que trabajen en el campo emergente del análisis de conectividad cerebral y supondrá un gran valor para la comunidad científica. La segunda cuestión practica que se aborda es el estudio de la sensibilidad a las fuentes cerebrales profundas a través de dos tipos de sensores MEG: gradiómetros planares y magnetómetros, esta aproximación además se combina con un enfoque metodológico, utilizando dos índices de sincronización de fase: phase locking value (PLV) y phase lag index (PLI), este ultimo menos sensible a efecto la conducción volumen. Por lo tanto, se compara su comportamiento al estudiar las redes cerebrales, obteniendo que magnetómetros y PLV presentan, respectivamente, redes más densamente conectadas que gradiómetros planares y PLI, por los valores artificiales que crea el problema de la conducción de volumen. Sin embargo, cuando se trata de caracterizar redes epilépticas, el PLV ofrece mejores resultados, debido a la gran dispersión de las redes obtenidas con PLI. El análisis de redes complejas ha proporcionado nuevos conceptos que mejoran caracterización de la interacción de sistemas dinámicos. Se considera que una red está compuesta por nodos, que simbolizan sistemas, cuyas interacciones se representan por enlaces, y su comportamiento y topología puede caracterizarse por un elevado número de medidas. Existe evidencia teórica y empírica de que muchas de ellas están fuertemente correlacionadas entre sí. Por lo tanto, se ha conseguido seleccionar un pequeño grupo que caracteriza eficazmente estas redes, y condensa la información redundante. Para el análisis de redes funcionales, la selección de un umbral adecuado para decidir si un determinado valor de conectividad de la matriz de FC es significativo y debe ser incluido para un análisis posterior, se convierte en un paso crucial. En esta tesis, se han obtenido resultados más precisos al utilizar un test de subrogadas, basado en los datos, para evaluar individualmente cada uno de los enlaces, que al establecer a priori un umbral fijo para la densidad de conexiones. Finalmente, todas estas cuestiones se han aplicado al estudio de la epilepsia, caso práctico en el que se analizan las redes funcionales MEG, en estado de reposo, de dos grupos de pacientes epilépticos (generalizada idiopática y focal frontal) en comparación con sujetos control sanos. La epilepsia es uno de los trastornos neurológicos más comunes, con más de 55 millones de afectados en el mundo. Esta enfermedad se caracteriza por la predisposición a generar ataques epilépticos de actividad neuronal anormal y excesiva o bien síncrona, y por tanto, es el escenario perfecto para este tipo de análisis al tiempo que presenta un gran interés tanto desde el punto de vista clínico como de investigación. Los resultados manifiestan alteraciones especificas en la conectividad y un cambio en la topología de las redes en cerebros epilépticos, desplazando la importancia del ‘foco’ a la ‘red’, enfoque que va adquiriendo relevancia en las investigaciones recientes sobre epilepsia. ABSTRACT There are about 1014 neuronal synapses in the human brain. This huge number of connections provides the substrate for neuronal ensembles to become transiently synchronized, producing the emergence of cognitive functions such as perception, learning or thinking. Understanding the complex brain network organization on the basis of neuroimaging data represents one of the most important and exciting challenges for systems neuroscience. Several measures have been recently proposed to evaluate at various scales (single cells, cortical columns, or brain areas) how the different parts of the brain communicate. We can classify them, according to their symmetry, into two groups: symmetric measures, such as correlation, coherence or phase synchronization indexes, evaluate functional connectivity (FC); and on the other hand, the asymmetric ones, such as Granger causality or transfer entropy, are able to detect effective connectivity (EC) revealing the direction of the interaction. In modern neurosciences, the interest in functional brain networks has increased strongly with the onset of new algorithms to study interdependence between time series, the advent of modern complex network theory and the introduction of powerful techniques to record neurophysiological data, such as magnetoencephalography (MEG). However, when analyzing neurophysiological data with this approach several questions arise. In this thesis, I intend to tackle some of the practical open problems in the field. First of all, the increase in the number of time series analysis algorithms to study brain FC/EC, along with their mathematical complexity, creates the necessity of arranging them into a single, unified toolbox that allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of them. I developed such a toolbox for this aim, it is named HERMES (http://hermes.ctb.upm.es), and encompasses several of the most common indexes for the assessment of FC and EC running for MatlabR environment. I believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis and will entail a great value for the scientific community. The second important practical issue tackled in this thesis is the evaluation of the sensitivity to deep brain sources of two different MEG sensors: planar gradiometers and magnetometers, in combination with the related methodological approach, using two phase synchronization indexes: phase locking value (PLV) y phase lag index (PLI), the latter one being less sensitive to volume conduction effect. Thus, I compared their performance when studying brain networks, obtaining that magnetometer sensors and PLV presented higher artificial values as compared with planar gradiometers and PLI respectively. However, when it came to characterize epileptic networks it was the PLV which gives better results, as PLI FC networks where very sparse. Complex network analysis has provided new concepts which improved characterization of interacting dynamical systems. With this background, networks could be considered composed of nodes, symbolizing systems, whose interactions with each other are represented by edges. A growing number of network measures is been applied in network analysis. However, there is theoretical and empirical evidence that many of these indexes are strongly correlated with each other. Therefore, in this thesis I reduced them to a small set, which could more efficiently characterize networks. Within this framework, selecting an appropriate threshold to decide whether a certain connectivity value of the FC matrix is significant and should be included in the network analysis becomes a crucial step, in this thesis, I used the surrogate data tests to make an individual data-driven evaluation of each of the edges significance and confirmed more accurate results than when just setting to a fixed value the density of connections. All these methodologies were applied to the study of epilepsy, analysing resting state MEG functional networks, in two groups of epileptic patients (generalized and focal epilepsy) that were compared to matching control subjects. Epilepsy is one of the most common neurological disorders, with more than 55 million people affected worldwide, characterized by its predisposition to generate epileptic seizures of abnormal excessive or synchronous neuronal activity, and thus, this scenario and analysis, present a great interest from both the clinical and the research perspective. Results revealed specific disruptions in connectivity and network topology and evidenced that networks’ topology is changed in epileptic brains, supporting the shift from ‘focus’ to ‘networks’ which is gaining importance in modern epilepsy research.

Knowledge representation tool for cognitiveprocesses modeling

In the last decades, neuropsychological theories tend to consider cognitive functions as a result of the whole brainwork and not as individual local areas of its cortex. Studies based on neuroimaging techniques have increased in the last years, promoting an exponential growth of the body of knowledge about relations between cognitive functions and brain structures [1]. However, so fast evolution make complicated to integrate them in verifiable theories and, even more, translated in to cognitive rehabilitation. The aim of this research work is to develop a cognitive process-modeling tool. The purpose of this system is, in the first term, to represent multidimensional data, from structural and functional connectivity, neuroimaging, data from lesion studies and derived data from clinical intervention [2][3]. This will allow to identify consolidated knowledge, hypothesis, experimental designs, new data from ongoing studies and emerging results from clinical interventions. In the second term, we pursuit to use Artificial Intelligence to assist in decision making allowing to advance towards evidence based and personalized treatments in cognitive rehabilitation. This work presents the knowledge base design of the knowledge representation tool. It is compound of two different taxonomies (structure and function) and a set of tags linking both taxonomies at different levels of structural and functional organization. The remainder of the abstract is organized as follows: Section 2 presents the web application used for gathering necessary information for generating the knowledge base, Section 3 describes knowledge base structure and finally Section 4 expounds reached conclusions.

Video-based tasks for emotional processing rehabilitation in schizophrenia

Schizophrenia is a mental disorder characterized by a breakdown of cognitive processes and by a deficit of typi-cal emotional responses. Effectiveness of computerized task has been demonstrated in the field of cognitive rehabilitation. However, current rehabilitation programs based on virtual environments normally focus on higher cognitive functions, not covering social cognition training. This paper presents a set of video-based tasks specifically designed for the rehabilita-tion of emotional processing deficits in patients in early stages of schizophrenia or schizoaffective disorders. These tasks are part of the Mental Health program of Guttmann NeuroPer-sonalTrainer® cognitive tele-rehabilitation platform, and entail innovation both from a clinical and technological per-spective in relation with former traditional therapeutic con-tents.

Monitorización y optimización de terapias de tele-neurorrehabilitación cognitiva

El Daño Cerebral Adquirido (DCA) se define como una lesión cerebral que ocurre después del nacimiento y que no guarda relación con defectos congénitos o enfermedades degenerativas. En el cerebro, se llevan a cabo las funciones mentales superiores como la atención, la memoria, las funciones ejecutivas y el lenguaje, consideradas pre-requisitos básicos de la inteligencia. Sea cual sea su causa, todo daño cerebral puede afectar a una o varias de estas funciones, de ahí la gravedad del problema. A pesar de los avances en nuevas técnicas de intervención precoz y el desarrollo de los cuidados intensivos, las afectaciones cerebrales aún no tienen tratamiento ni quirúrgico ni farmacológico que permita una restitución de las funciones perdidas. Los tratamientos de neurorrehabilitación cognitiva y funcional pretenden, por tanto, la minimización o compensación de las alteraciones ocasionadas por una lesión en el sistema nervioso. En concreto, la rehabilitación cognitiva se define como el proceso en el que personas que han sufrido un daño cerebral trabajan de manera conjunta con profesionales de la salud para remediar o aliviar los déficits cognitivos surgidos como consecuencia de un episodio neurológico. Esto se consigue gracias a la naturaleza plástica del sistema nervioso, donde el cerebro es capaz de reconfigurar sus conexiones neuronales, tanto creando nuevas como modificando las ya existentes. Durante los últimos años hemos visto una transformación de la sociedad, en lo que se ha denominado "sociedad de la información", cuyo pilar básico son las Tecnologías de la Información y las Comunicaciones (TIC). La aplicación de estas tecnologías en medicina ha revolucionado la manera en que se proveen los servicios sanitarios. Así, donde tecnología y medicina se mezclan, la telerrehabilitación se define como la rehabilitación a distancia, ayudando a extender los servicios de rehabilitación más allá de los centros hospitalarios, rompiendo las barreras geográficas, mejorando la eficiencia de los procesos y monitorizando en todo momento el estado y evolución del paciente. En este contexto, el objetivo general de la presente tesis es mejorar la rehabilitación neuropsicológica de pacientes que sufren alteraciones cognitivas, mediante el diseño, desarrollo y validación de un sistema de telemedicina que incorpora las TIC para avanzar hacia un nuevo paradigma personalizado, ubicuo y ecológico. Para conseguirlo, se han definido los siguientes objetivos específicos: • Analizar y modelar un sistema de telerrehabilitación, mediante la definición de objetivos y requisitos de usuario para diseñar las diferentes funcionalidades necesarias. • Definir una arquitectura de telerrehabilitación escalable para la prestación de diferentes servicios que agrupe las funcionalidades necesarias en módulos. • Diseñar y desarrollar la plataforma de telerrehabilitación, incluida la interfaz de usuario, creando diferentes roles de usuario con sus propias funcionalidades. • Desarrollar de un módulo de análisis de datos para extraer conocimiento basado en los resultados históricos de las sesiones de rehabilitación almacenadas en el sistema. • Evaluación de los resultados obtenidos por los pacientes después del programa de rehabilitación, obteniendo conclusiones sobre los beneficios del servicio implementado. • Evaluación técnica de la plataforma de telerrehabilitación, así como su usabilidad y la relación coste/beneficio. • Integración de un dispositivo de eye-tracking que permita la monitorización de la atención visual mientras los pacientes ejecutan tareas de neurorrehabilitación. •Diseño y desarrollo de un entorno de monitorización que permita obtener patrones de atención visual. Como resumen de los resultados obtenidos, se ha desarrollado y validado técnicamente la plataforma de telerrehabilitación cognitiva, demostrando la mejora en la eficiencia de los procesos, sin que esto resulte en una reducción de la eficacia del tratamiento. Además, se ha llevado a cabo una evaluación de la usabilidad del sistema, con muy buenos resultados. Respecto al módulo de análisis de datos, se ha diseñado y desarrollado un algoritmo que configura y planifica sesiones de rehabilitación para los pacientes, de manera automática, teniendo en cuenta las características específicas de cada paciente. Este algoritmo se ha denominado Intelligent Therapy Assistant (ITA). Los resultados obtenidos por el asistente muestran una mejora tanto en la eficiencia como en la eficacia de los procesos, comparado los resultados obtenidos con los de la planificación manual llevada a cabo por los terapeutas. Por último, se ha integrado con éxito el dispositivo de eye-tracking en la plataforma de telerrehabilitación, llevando a cabo una prueba con pacientes y sujetos control que ha demostrado la viabilidad técnica de la solución, así como la existencia de diferencias en los patrones de atención visual en pacientes con daño cerebral. ABSTRACT Acquired Brain Injury (ABI) is defined as brain damage that suddenly and unexpectedly appears in people’s life, being the main cause of disability in developed countries. The brain is responsible of the higher cognitive functions such as attention, memory, executive functions or language, which are considered basic requirements of the intelligence. Whatever its cause is, every ABI may affects one or several functions, highlighting the severity of the problem. New techniques of early intervention and the development of intensive ABI care have noticeably improved the survival rate. However, despite these advances, brain injuries still have no surgical or pharmacological treatment to re-establish lost functions. Cognitive rehabilitation is defined as a process whereby people with brain injury work together with health service professionals and others to remediate or alleviate cognitive deficits arising from a neurological insult. This is achieved by taking advantage of the plastic nature of the nervous system, where the brain can reconfigure its connections, both creating new ones, and modifying the previously existing. Neuro-rehabilitation aims to optimize the plastic nature by inducing a reorganization of the neural network, based on specific experiences. Personalized interventions from individual impairment profile will be necessary to optimize the remaining resources by potentiating adaptive responses and inhibiting maladaptive changes. In the last years, some applications and software programs have been developed to train or stimulate cognitive functions of different neuropsychological disorders, such as ABI, Alzheimer, psychiatric disorders, attention deficit or hyperactivity disorder (ADHD). The application of technologies into medicine has changed the paradigm. Telemedicine allows improving the quality of clinical services, providing better access to them and helping to break geographical barriers. Moreover, one of the main advantages of telemedicine is the possibility to extend the therapeutic processes beyond the hospital (e.g. patient's home). As a consequence, a reduction of unnecessary costs and a better costs/benefits ratio are achieved, making possible a more efficient use of the available resources In this context, the main objective of this work is to improve neuro-rehabilitation of patients suffering cognitive deficits, by designing, developing and validating a telemedicine system that incorporates ICTs to change this paradigm, making it more personalized, ubiquitous and ecologic. The following specific objectives have been defined: • To analyse and model a tele-rehabilitation system, defining objectives and user requirements to design the different needed functionalities. • To define a scalable tele-rehabilitation architecture to offer different services grouping functionalities into modules. • To design and develop the tele-rehabilitation platform, including the graphic user interface, creating different user roles and permissions. • To develop a data analysis module to extract knowledge based on the historic results from the rehabilitation sessions stored in the system. • To evaluate the obtained results by patients after the rehabilitation program, arising conclusions about the benefits of the implemented service. • To technically evaluate the tele-rehabilitation platform, and its usability and the costs/benefit ratio. • To integrate an eye-tracking device allowing the monitoring of the visual attention while patients execute rehabilitation tasks. •To design and develop a monitoring environment that allows to obtain visual attention patterns. Summarizing the obtained results, the cognitive tele-rehabilitation platform has been developed and evaluated technically, demonstrating the improvements on the efficiency without worsening the efficacy of the process. Besides, a usability evaluation has been carried out, with very good results. Regarding the data analysis module, an algorithm has been designed and developed to automatically select and configure rehabilitation sessions, taking into account the specific characteristics of each patient. This algorithm is called Intelligent Therapy Assistant (ITA). The obtained results show an improvement both in the efficiency and the efficacy of the process, comparing the results obtained by patients when they receive treatments scheduled manually by therapists. Finally, an eye-tracking device has been integrated in the tele-rehabilitation platform, carrying out a study with patients and control subjects demonstrating the technical viability of the developed monitoring environment. First results also show that there are differences between the visual attention patterns between ABI patients and control subjects.