Search

Objective: This study aims to characterize electrical signals to establish a diagnosis of cognitive-emotional dysfunction and guide a successful therapeutic intervention. Therefore, the present study aimed to observe these frequency bands in a sample of dysfunctional neurological behaviors to establish a neural marker of neural dysfunction that helps diagnose and monitor treatment. Methods: A descriptive retrospective (extracted from the database) observational study design based on real-world historical data from routine clinical practice. According to DSM-5, low academic achievement (n =70), disruptive behavior (externalizing behavior problems) (n=70), and somatic syndrome disorder (n=70) were the subjects. The mean age of the sample was 14.13 (SD = 1.46; range 12-18), 31.5% women. The measuring instrument was the NeXus-10, which is suitable for acquiring a wide range of physiological signals. Brain electrical activity was recorded by using the quantitative electroencephalograph (qEEG) in accordance with the 10-20 International Electrode Placement System. In particular, the specific form of miniQ (mini-qEEG) was used. Results: A pattern record present in all cases were identified. The record refers to (a) activity along the midline, namely, Fz-Cz-Pz, (b) activity from the center (Cz) to back, namely, Pz-O1 and O2, (c) activity from the center (Cz) forward (Fz), and (d) comparison between hemispheres. The characteristics of theta, alpha, and beta waves define the characteristic pattern of neurological dysfunction. The reversal of the dysfunctional pattern coincided with the remission of the clinical symptoms after treatment, which occurred in 87,6% of the subjects. We define remission as not meeting DSM-5 criteria. Conclusion: This study suggests that miniQ register could be considered a simple and objective tool for studying neurological dysfunction. This dysfunction is explained according to current neurological knowledge of interactive cognition-emotion processing. MiniQ may be a cheap and reliable method and a promising tool for the investigation in the field.

Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2022-2023. Tutor/Director: Rodríguez Allué, Manuel José, Neurodegenerative movement-related disorders are characterized by a progressive degeneration and loss of neurons, which lead to motor control impairment. Although the precise mechanisms underlying these conditions are still unknown, an increasing number of studies point towards the analysis of neural networks and functional connectivity to unravel novel insights. The main objective of this work is to understand cellular mechanisms related to dysregulated motor control symptoms in movement disorders, such as Chorea-Acanthocytosis (ChAc), by employing multielectrode arrays to analyze the electrical activity of neuronal networks in mouse models. We found no notable differences in cell viability between neurons with and without VPS13A knockdown, that is the only gene known to be implicated in the disease, suggesting that the absence of VPS13A in neurons may be partially compensated by other proteins. The MEA setup used to capture the electrical activity from neuron primary cultures is described in detail, pointing out its specific characteristics. At last, we present the alternative backup approach implemented to overcome the challenges faced during the research process and to explore the advanced algorithms for signal processing and analysis. In this report, we present a thorough account of the conception and implementation of our research, outlining the multiple limitations that have been encountered all along the course of the project. We provide a detailed analysis on the project’s economical and technical feasibility, as well as a comprehensive overview of the ethical and legal aspects considered during the execution.

31p.-7 fig. 1 graph. abst., Frontotemporal dementia is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is CHMP2B, which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a CHMP2B-mutated human embryonic stem cell line using genome editing with the purpose to create a human in vitro Frontotemporal dementia disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in co-cultures. With this approach, we have identified alterations in the endolysosomal system of Frontotemporal dementia astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and a neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development., This study was supported by funding from the Swedish Society for Medical Research (SSMF, S20-0003), Kockska, Segerfalk and Hardebo foundations to IC; the Swedish Research Council (VR:2018-02695), Swedish Alzheimer and Åhlen foundations to HA; the Swedish Research Council (VR:2016-01789) to AH; and the Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación (RTI2018-097624-BI00) and European Regional Development Fund to DPS.

L'envelliment és un procés natural que es caracteritza per l'acumulació progressiva de canvis fisiològics i per enlentir alguns dominis cognitius. Tot i això, alguns aspectes d'aquests canvis cognitius també s'associen a estats patològics, com la malaltia d'Alzheimer (MA). La MA és un trastorn neurodegeneratiu progressiu, resultat d'una interacció complexa entre la genètica i els factors ambientals experimentats al llarg de la vida. Una aproximació per definir el patró del mecanisme biològic subjacent a l'aparició i el desenvolupament de la MA és l'ús d'eines no invasives que permetin caracteritzar i seguir el desenvolupament de la patologia de la MA des d'estadis preclínics. En aquest sentit, l'electroencefalografia (EEG) i la magnetoencefalografia (MEG) són eines útils ja que permeten estudiar l'evolució dels marcadors electrofisiològics al cervell de manera totalment no invasiva. L'objectiu principal d'aquesta Tesi Doctoral és identificar marcadors electrofisiològics i cognitius robusts que permetin distingir els subjectes sans dels pacients amb deteriorament cognitiu lleu (DCL), considerant com a fonts d'informació les dades sociodemogràfiques, l'avaluació neuropsicològica, els biomarcadors del líquid cefaloraquidi (LCR) i les mesures EEG/MEG extretes de l'activitat en repòs de mostres multiculturals. Per això, la tesi s'organitza en dues parts. Pel que fa a l'envelliment saludable, els dos primers estudis inclouen (i) l'anàlisi de l'impacte de les característiques sociodemogràfiques i d'estil de vida sobre el rendiment cognitiu en adults peruans i (ii) una revisió sistemàtica de les troballes prèvies sobre l'associació entre els perfils electrofisiològics en estat de repòs i el rendiment cognitiu. Pel que fa a l'envelliment patològic, la tesi inclou (iii) l'exploració de l'associació entre el record retardat i la connectivitat funcional en estat de repòs en subjectes cognitivament intactes i DCL; (iv) un estudi multicèntric dels marcadors del LCR i la seva associació amb el deteriorament de la memòria episòdica i les funcions executives en DCL; i (v) la relació dels patrons electrofisiològics del DCL amb els biomarcadors del LCR segons el sexe. Els nostres resultats corroboren la rellevància dels factors no modificables i modificables relacionats amb el deteriorament cognitiu en l'envelliment saludable. A més, des del punt de vista electrofisiològic, la mesura de la freqüència del pic alfa s'associa amb el rendiment cognitiu i es podria considerar com un marcador de l'envelliment saludable. D'altra banda, pel que fa al DCL, (i) els valors més alts a la connectivitat funcional de la banda beta a la regió occipital dreta es van associar amb puntuacions més baixes de record retardat en subjectes cognitivament intactes i amb DCL. El cervell sembla perdre progressivament la capacitat de desincronitzar les oscil·lacions beta, i aquest procés comença a ser significatiu a les etapes preclíniques, almenys en els participants amb vulnerabilitat a la MA, com la presència de l'al·lel APOE ε4; (ii) un deteriorament primerenc del funcionament executiu, que podria afectar en última instància el seu rendiment a la prova de memòria episòdica, podria ajudar a discriminar entre dos patrons diferents de DCL; i (iii) hi ha una possible associació diferencial entre els perfils EEG i els marcadors del LCR en els homes i les dones. Aquesta troballa podria ser la base per donar suport a la implementació d'iniciatives que fomentin un estil de vida saludable i promoguin activitats de salut cerebral que afavoreixin la reducció del deteriorament cognitiu a l'envelliment i reforcen la necessitat de realitzar assajos clínics més personalitzats per millorar la detecció primerenca de la MA fent ús de les tècniques de neuroimatge. El envejecimiento es un proceso natural que se caracteriza por la acumulación progresiva de cambios fisiológicos y la ralentización de algunos dominios cognitivos. Sin embargo, algunos aspectos de estos cambios cognitivos también se asocian a estados patológicos, como la enfermedad de Alzheimer (EA). La EA es un trastorno neurodegenerativo progresivo, resultado de una compleja interacción entre la genética y los factores ambientales experimentados a lo largo de la vida. Una aproximación para definir el patrón del mecanismo biológico que subyace a la aparición y desarrollo de la EA es el uso de herramientas no invasivas que permitan caracterizar y seguir el desarrollo de la patología de la EA desde estadios preclínicos. En este sentido, la electroencefalografía (EEG), y la magnetoencefalografía (MEG) son herramientas útiles ya que permiten estudiar la evolución de los marcadores electrofisiológicos en el cerebro de forma totalmente no invasiva. El objetivo principal de esta Tesis Doctoral es identificar marcadores electrofisiológicos y cognitivos robustos que permitan distinguir a los sujetos sanos de los pacientes con deterioro cognitivo leve (DCL), considerando como fuentes de información los datos sociodemográficos, la evaluación neuropsicológica, los biomarcadores del líquido cefalorraquídeo (LCR) y las medidas EEG/MEG extraídas de la actividad en reposo de muestras multiculturales. Para ello, la tesis se organiza en dos partes. En cuanto al envejecimiento saludable, los dos primeros estudios incluyen (i) el análisis del impacto de las características sociodemográficas y de estilo de vida sobre el rendimiento cognitivo en adultos peruanos y (ii) una revisión sistemática de los hallazgos previos sobre la asociación entre los perfiles electrofisiológicos en estado de reposo y el rendimiento cognitivo. En relación con el envejecimiento patológico, la tesis incluye (iii) la exploración de la asociación entre el recuerdo retardado y la conectividad funcional en estado de reposo en sujetos cognitivamente intactos y DCL; (iv) un estudio multicéntrico de los marcadores del LCR y su asociación con el deterioro de la memoria episódica y las funciones ejecutivas en DCL; y (v) la relación de los patrones electrofisiológicos del DCL con los biomarcadores del LCR según el sexo. Nuestros resultados corroboran la relevancia de los factores no modificables y modificables relacionados con el deterioro cognitivo en el envejecimiento saludable. Además, desde el punto de vista electrofisiológico, la medida de la frecuencia del pico alfa se asocia con el rendimiento cognitivo y podría considerarse como un marcador del envejecimiento saludable. Por otro lado, en lo que respecta al DCL, (i) los valores más altos en la conectividad funcional de la banda beta en la región occipital derecha se asociaron con puntuaciones más bajas de recuerdo retardado en sujetos cognitivamente intactos y con DCL. El cerebro parece perder progresivamente la capacidad de desincronizar las oscilaciones beta, y este proceso empieza a ser significativo en las etapas preclínicas, al menos en los participantes con vulnerabilidad a la EA, como la presencia del alelo APOE ε4; (ii) un deterioro temprano del funcionamiento ejecutivo, que podría afectar en última instancia a su rendimiento en la prueba de memoria episódica, podría ayudar a discriminar entre dos patrones diferentes de DCL; y (iii) existe una posible asociación diferencial entre los perfiles EEG y los marcadores del LCR en los hombres y mujeres. Este hallazgo podría ser la base para apoyar la implementación de iniciativas que fomenten un estilo de vida saludable y promuevan actividades de salud cerebral que favorezcan la reducción del deterioro cognitivo en el envejecimiento y refuerzan la necesidad de realizar ensayos clínicos más personalizados para mejorar la detección temprana de la EA haciendo uso de las técnicas de neuroimagen. Aging is a natural process characterized by the progressive accumulation of physiological changes and a slowdown of some cognitive domains. However, some aspects of these cognitive changes are also associated with pathological states, such as the Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder, results of a complex interaction between genetics and environmental factors experienced throughout life. One approach to defining the pattern of the biological mechanism underlying the onset and development of AD is the use of non-invasive tools able to detect changes in the structure and function of the nervous system in humans, which allows characterizing and following the development of AD pathology from preclinical stages. In this sense, electroencephalography (EEG), and magnetoencephalography (MEG) are useful tools since they allow studying the evolution of electrophysiological markers in the brain in a completely non-invasive way. The combined use of these techniques, evaluation brain activity in resting-state, with neuropathological markers of AD and cognitive performance, could help to improve the distinguish pattern of early AD. The main objective of this Doctoral Thesis is to identify robust electrophysiological and cognitive markers that allow to distinguish healthy subjects from patients with mild cognitive impairment (MCI), considering as sources of information sociodemographic data, neuropsychological assessment, cerebrospinal fluid (CSF) biomarkers, and EEG/MEG measures extracted from resting activity of multicultural samples. For this purpose, the thesis is organized into two parts focusing on the study of healthy and pathological aging. Regarding healthy aging, the first two studies include (i) the analysis of the impact of sociodemographic and lifestyle characteristics on cognitive performance in Peruvian adults and (ii) a systematic review of previous findings on the association between resting-state electrophysiological profiles and cognitive performance in healthy aging. Concerning pathological aging, the thesis includes (iii) the exploration of the potential association between delayed recall performance and resting-state functional connectivity in cognitively intact subjects and MCI patients; (iv) a multicenter study of CSF markers and their association with episodic memory impairment and executive functions in patients with MCI; and (v) the relationship of electrophysiological signs of MCI with CSF biomarkers and the assessment of this relationship according to sex. Our findings corroborate the relevance of non-modifiable and modifiable factors related with cognitive decline in healthy aging. Although nonmodifiable factors impact older adults' cognition, their influence is mediated by other factors that are indeed modifiable (i.e., time spend reading, engagement in physical activity). Furthermore, since electrophysiological point of view, the measure of alpha peak frequency is associated with the cognitive performance and could be considered as an electrophysiological marker of healthy aging. On the other hand, regarding the electrophysiological profile of MCI, (i) higher values in functional connectivity of the beta band in the right occipital region were associated with lower delayed recall scores in cognitively intact and MCI subjects. The brain seems to progressively lose the ability to desynchronize beta oscillations, and this process starts to become significant in preclinical stages, at least in participants with AD vulnerability such as the presence of the APOE ε4 allele; (ii) an early executive functioning impairment, which could ultimately affect their performance on episodic memory test could help to discriminate between two different patterns of MCI; and (iii) there is a potential differential association between EEG profiles and CSF markers in male and female participants. This finding could be the base to support the implementation of initiatives encouraging a healthy lifestyle and promoting brain health activities which could favor reducing cognitive decline in aging and reinforce the need for clinical trials focused on a more personalized approach to improve the early detection of AD taking account the neuroimaging techniques.

INTRODUCTION AND OBJECTIVES: This article reports the results of the 2020 Spanish Catheter Ablation Registry, a year marked by the SARS-CoV-2 pandemic. METHODS: Data were collected retrospectively through completion and return of a specific form by the participating centers. RESULTS: Data from 97 centers (67 public, 30 private) were analyzed. A total of 15 169 ablation procedures were reported with a mean of 155 ± 117 and a median [interquartile range] of 115 [62-227]. Because of the SARS-CoV-2 pandemic, both procedures and participating centers markedly decreased (-3380 procedures, -18%) and there were 5 centers less than in 2019. The most common procedure continued to be atrial fibrillation ablation (4513; 30%), well ahead of the remaining substrates, followed by ablation of the cavotricuspid isthmus (3188; 21%), and intranodal re-entry tachycardia (2808; 18%). Ablation of these 3 substrates continued to form the bulk of the procedures. The total success rate was slightly lower than in previous years (88%) with a similar complication rate (n = 309; 2%) and mortality (n = 7; 0.04%). A total of 243 procedures were performed in pediatric patients (1.6%). CONCLUSIONS: The Spanish Catheter Ablation Registry systematically and continuously reflects the national trajectory, which, in 2020, was markedly affected by the SARS-CoV-2 pandemic. Although slightly lower than in previous years, the success rate remained high, with a low complication rate.

Introduction and objectives: This article reports the results of the 2020 Spanish Catheter Ablation Registry, a year marked by the SARS-CoV-2 pandemic. Methods: Data were collected retrospectively through completion and return of a specific form by the participating centers. Results: Data from 97 centers (67 public, 30 private) were analyzed. A total of 15 169 ablation procedures were reported with a mean of 155 117 and a median [interquartile range] of 115 [62-227]. Because of the SARS-CoV-2 pandemic, both procedures and participating centers markedly decreased ( 3380 procedures, 18%) and there were 5 centers less than in 2019. The most common procedure continued to be atrial fibrillation ablation (4513; 30%), well ahead of the remaining substrates, followed by ablation of the cavotricuspid isthmus (3188; 21%), and intranodal re-entry tachycardia (2808; 18%). Ablation of these 3 substrates continued to form the bulk of the procedures. The total success rate was slightly lower than in previous years (88%) with a similar complication rate (n = 309; 2%) and mortality (n = 7; 0.04%). A total of 243 procedures were performed in pediatric patients (1.6%).Conclusions: The Spanish Catheter Ablation Registry systematically and continuously reflects the national trajectory, which, in 2020, was markedly affected by the SARS-CoV-2 pandemic. Although slightly lower than in previous years, the success rate remained high, with a low complication rate. C 2021 Sociedad Espan ̃ola de Cardiologı ́a. Published by Elsevier Espan ̃a, S.L.U. All rights reserved. Introducción y objetivos Se describen los resultados del Registro Español de Ablación con Catéter de 2020, año marcado por la pandemia por SARS-CoV-2. Métodos La recogida de datos fue restrospectiva mediante la cumplimentación y envío de un formulario específico por los centros participantes. Resultados Se analizaron los datos de 97 centros (67 públicos, 30 privados). Se comunicaron 15.169 procedimientos de ablación (media, 155 ± 117; mediana, 115 [62-227]). La pandemia de SARS-CoV-2 ha condicionado una disminución notable tanto de los procedimientos (–3.380 casos, –18%) como de los centros participantes (5 menos que en 2019). La ablación de FA sigue siendo el procedimiento más frecuente (4.513; 30%), a distancia de los demás sustratos; junto con la ablación del ICT (3.188; 21%) y la taquicardia por reentrada intranodular (2.808; 18%), son los 3 sustratos más abordados. La tasa total de éxito reportada es discretamente inferior a las de años previos (88%), con similares tasas de complicaciones (309; 2%) y mortalidad (7; 0,04%). Se realizaron 243 procedimientos en pacientes pediátricos (1,6%). Conclusiones El Registro Español de Ablación con Catéter recoge de manera sistemática e ininterrumpida la trayectoria nacional, que este año se ha visto notablemente marcada por la pandemia por SARS-CoV-2. Aunque discretamente inferior a las años previos, la tasa de éxito sigue siendo alta, con una baja tasa de complicaciones.

Human beings continuously make use of learned associations to generate predictions about future occurrences in the environment. Such memory-related predictive processes provide a scaffold for learning in that mental rep-resentations of foreseeable events can be adjusted or strengthened based on a specific outcome. Learning the meaning of novel words through picture-word associations constitutes a prime example of associative learning because pictures preceding words can trigger word prediction through the pre-activation of the related mne-monic representations. In the present electroencephalography (EEG) study, we used event-related potentials (ERPs) to compare neural indices of word pre-activation between a word learning condition with maximal prediction likelihood and a non-learning control condition with low prediction. Results revealed that prediction -related N400 amplitudes in response to pictures decreased over time at central electrodes as a function of word learning, whereas late positive component (LPC) amplitudes increased. Notably, N400 but not LPC changes were also predictive of word learning performance, suggesting that the N400 component constitutes a sensitive marker of word pre-activation during associative word learning.

[ES] Las enfermedades cardiovasculares comprenden la gran mayoría de afecciones a los seres humanos, siendo así la principal causa de defunción a nivel global. Dentro de las enfermedades que más afectan a la población se encuentra la fibrilación auricular, la cual, es una arritmia que desarrolla en el paciente la remodelación de la aurícula con tejido fibrótico, afectando así la fisiología eléctrica y anatómica del órgano. Por esta razón, las simulaciones de la fisiología eléctrica empleando modelos cardiacos están cada vez en demanda para el estudio de las afecciones del corazón. En consecuencia, este trabajo pretende estudiar el comportamiento de la actividad eléctrica a través de estímulos en tejidos fibróticos generados a partir imágenes reales de fibrosis. Inicialmente, se cuenta con nueve imágenes de tejido fibrótico y se desarrolla un código de programación que genere las mallas de tejido a partir de ellas. En segundo lugar, las mallas generadas se emplean para realizar simulaciones eléctricas, para posteriormente medir registros de electrogramas en diferentes puntos de los tejidos, los cuales se comparan con registros obtenidos en otras investigaciones con el objetivo de explicarlos. Finalmente, se concluye que las mallas de tejido generadas poseen similaridad con las imágenes reales y, los registros muestran la influencia de la fibrosis en la conducción del potencial a través de las mallas de tejido generadas, pudiendo ser comparados con registros patológicos., [EN] Cardiovascular diseases comprise the vast majority of diseases affecting human beings, being the leading cause of death worldwide. Among the diseases that most affect the population is atrial fibrillation, which is an arrhythmia that develops in the patient the remodeling of the atrium with fibrotic tissue, thus affecting the electrical and anatomical physiology of the organ. For this reason, simulations of electrical physiology using cardiac models are increasingly in demand for the study of heart conditions. Consequently, this work aims to study the behavior of electrical activity through stimuli in fibrotic tissues generated from real images. Initially, nine images of fibrotic tissue are presented, and a programming code is developed to generate the tissue meshes from them. Secondly, the generated meshes are used to perform electrical simulations, to subsequently measure electrogram records at different points of the tissues, which are compared with records obtained in other investigations in order to explain them. Finally, it is concluded that the generated tissue meshes have similarity with real images and, the recordings show the influence of fibrosis in the conduction of the potential through the generated tissue meshes, being able to be compared with pathological recordings.

[ES] La irrupción de los navegadores electroanatómicos cardiacos en la electrofisiología ha supuesto un desarrollo tecnológico sustancial en los últimos años. Aún así, el conocimiento sobre los mecanismos desencadenantes y de perpetuación de arritmias complejas sigue siendo un reto sin resolver. Los últimos avances indican la necesidad de mejorar la exploración local de las propiedades electrofisiológicas a partir del procesado adecuado de las señales registradas por la nueva generación de catéters basado en multielectrodos de alta densidad (HD). En ese sentido, el presente TFM pretende desarrollar una nueva metodología basada en conceptos vectoriales que permita un mejor aprovechamiento de la información proporcionada por los catéteres de nueva generación para la determinación de biomarcadores relevantes como los LATs (tiempos de activación local) y la velocidad de conducción. Los algoritmos implementados se validarán sobre un modelo de propagación de señales intracavitarias y se realizarán test sobre un conjunto de registros clínicos. Todo ello con el objetivo de mejorar la identificación de regiones de tejido con fibrosis susceptibles de ser ablacionadas.. El TFM se desarrolla en el marco de un proyecto de I+D+i competitiva. En concreto el proyecto Q-Substrate de referencia PID2019-109547RB-I00., [EN] The irruption of cardiac electroanatomic navigators in electrophysiology has led to substantial technological developments in recent years. Even so, knowledge of the triggering and perpetuating mechanisms of complex arrhythmias remains an unresolved challenge. Recent advances indicate the need to improve the local exploration of electrophysiological properties based on the appropriate processing of the signals recorded by the new generation of catheters based on high-density (HD) multielectrodes. In this sense, the present TFM aims to develop a new methodology based on vector concepts that allows a better use of the information provided by the new generation catheters for the determination of relevant biomarkers such as LATs (local activation times) and conduction velocity. The implemented algorithms will be validated on an intracavitary signal propagation model and tested on a set of clinical records. All this with the aim of improving the identification of tissue regions with fibrosis susceptible to ablation. The TFM will be developed within the framework of a competitive R+D+i project. Specifically the Q-Substrate project reference PID2019-109547RB-I00.

En els darrers anys, a través de diferents estudis s'ha demostrat que l'electrofisiologia de les plantes proporciona informació significativa sobre l'estat d'una planta, però encara queden coneixements substancials per obtenir que es traduiran en pràctiques agrícoles millorades. En aquest Treball de Fi de Grau, que forma part d'un projecte realitzat en col·laboració amb un soci industrial, s'ha utilitzat un conjunt de dades de senyals elèctrics de plantes sota estrès, recopilades amb un biosensor d'electrofisiologia vegetal multicanal. En enfocaments anteriors, es van aplicar tècniques de processament de senyals en aquests conjunts de dades per extreure característiques i després fer servir algoritmes d'anàlisi de dades intel·ligents en aquestes característiques per predir si les plantes estan estressades. L'objectiu principal d'aquest treball és fer la mateixa tasca fent servir tècniques d'aprenentatge profund d'última generació per avaluar l'ús de plantes com a dispositius de detecció d'estímuls biològics. In the recent years it has been shown through different studies that plant electrophysiology provides meaningful information about the state of a plant, but there are still substantial insights to be gained which will flow through to improved agriculture practices. In this Bachelor's Thesis, being part of a project realized in collaboration with an industrial partner, it has been used a dataset of under-stress plants' electrical signals, collected with a multi-channel plant electrophysiology biosensor. In previous approaches, signal-processing techniques were applied on these datasets to extract features, and then use intelligent data analysis algorithms on these features in order to predict if the plants are stressed. The main objective of this work is to realize the same task by employing state-of-the-art Deep Learning techniques, in order to evaluate the use of plants as biological stimuli-sensing devices.

Cardiac amyloidosis (CA) is a form of cardiomyopathy characterized by the extracellular deposit of protein fibers in the myocardium, leading to the development of heart failure, arrhythmias, and electrical conduction system alterations. It is known that most cardiomyopathies have a close relationship with heart rhythm abnormalities, however, CA is specially related to different kinds of arrhythmias even in pre-diagnosis stages. Arrhythmias like atrial fibrillation are present in up to 70% of patients with CA associated with a high risk of cardioembolic complications independent of the risk stratification. Ventricular arrhythmias are frequent, but the use of implantable cardioverter defibrillator has not been demonstrated to improve survival. The Atrial-Ventricular node disease is also common, and is frequently associated with the implantation of a pacemaker, even in asymptomatic patients. In this review, we clarify the recommendations of the most current guidelines, summarize historical and contemporaneous data and describe evidence-based strategies for the management of arrhythmias and their complications in CA. La amiloidosis cardíaca (AC) es una forma de cardiomiopatía caracterizada por el depósito extracelular de fibrillas de proteínas en el miocardio, lo que produce insuficiencia cardíaca, arritmias y alteraciones en el sistema de conducción eléctrica. La mayoría de las cardiomiopatías tienen una estrecha relación con las alteraciones del ritmo cardiaco, en especial la AC que está asociada a diferentes formas de arritmias, incluso en fases previas al diagnóstico. Arritmias como la fibrilación auricular se observan hasta en el 70% de los pacientes con AC asociadas a un especial riesgo de complicaciones cardioembólicas independiente de la estratificación de riesgo. Las arritmias ventriculares son frecuentes; sin embargo, la colocación del cardiodesfibrilador implantable no ha demostrado mejorar la sobrevida. La enfermedad del sistema de conducción eléctrica también es común, y con frecuencia es necesario implantar un marcapaso definitivo, incluso en pacientes asintomáticos. En esta revisión delimitamos las recomendaciones de las guías más recientes, resumimos datos históricos y contemporáneos, y describimos estrategias basadas en evidencia para el manejo de arritmias y sus secuelas en la AC.

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes. This research was funded by EU Horizon 2020 Framework Programme for Research and Innovation: Human Brain Project WaveScalES, Specific Grant Agreement 2 No. 785907 and Specific Grant Agreement 3 No. 945539; NEUROPA project, Grant Agreement No. 863214; DEEPER project ICT-36-2020-101016787; European Union Regional Development Fund within the framework of the ERDF Operational Program of Catalonia 2014-2020: CECH project; Ministry of Science and Innovation DEEP RED grant PID2019-111493RB-I00 funded by MCIN/AEI/10.13039/501100011033; Ministerio de Economía y Competitividad and European Regional Development Funds: Grant no. SAF2017-87629-R to V.C., SAF2016-80726-R to M.V.P., SAF2017-88076-R to M.M.; AGAUR/Generalitat de Catalunya: CERCA Programme; Generalitat de Catalunya: Grant no. 2017-SGR-1442 to P.G., 2017-SGR-1497 to V.C., 2017-SGR-210 to M.V.P., and 2017-SGR-00465 to J.H.; Fundaluce and “la Caixa” foundations: ID 100010434, grant agreement LCF/PR/HR19/52160010.

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería., [CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria., [EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.

Resumen La resonancia magnética cardiaca permite una evaluación integral del corazón, provee información de funcionalidad, anatómica y de caracterización tisular, y permite la valoración de la perfusión miocárdica. Entre las secuencias de caracterización tisular se encuentra el realce tardío, el cual ocurre en corazones con fibrosis, trastornos infiltrativos o procesos agudos como miocarditis o infarto agudo de miocardio. Para el área de la electrofisiología, la resonancia magnética cardiaca aporta una gran ayuda en el abordaje diagnóstico de las miocardiopatías isquémicas y no isquémicas, y apoyo para definir el pronóstico de los pacientes con miocardiopatías de acuerdo con la presencia o no de fibrosis miocárdica; además, como parámetro adicional ha demostrado utilidad para la adecuada toma de decisiones en el implante de cardiodesfibriladores en prevención primaria y el implante de terapia de resincronización cardiaca. También ha probado ser de utilidad como guía en la terapia de ablación de la aurícula y el ventrículo izquierdos, y el seguimiento posablación de venas pulmonares para detectar líneas discontinuas de ablación. Abstract Cardiac magnetic resonance imaging allows a comprehensive evaluation of the heart, provides information on functionality, anatomy, tissue characterization and allows the evaluation of myocardial perfusion. Tissue characterization sequences include late enhancement, which occurs in hearts with fibrosis, infiltrative disorders, or in acute processes such as myocarditis or acute myocardial infarction. In the area of electrophysiology, cardiac magnetic resonance imaging is of great assistance in the diagnostic approach of ischemic and non-ischemic cardiomyopathies, supports in defining the prognosis of patients with cardiomyopathies according to the presence or absence of myocardial fibrosis, and also as an additional parameter that has been shown to be useful for taking adequate decisions in the implantation of cardioverter defibrillators in primary prevention and the implantation of cardiac resynchronization therapy. It has also proven to be useful as a guide in ablation therapy for the left atrium and left ventricle and its post-ablation monitoring of pulmonary veins to detect discontinuous lines of ablation.

[ES] El síndrome de Dravet es una epilepsia severa rara causada por mutaciones en el gen SCN1A, el cual codifica para la proteína Nav1.1, subunidad α de los canales de sodio regulados por voltaje. En esta tesis se ha generado mediante recombinación homóloga, una nueva mutación en el gen para que hemos denominado paraKO, el cual cumple la misma función en Drosophila melanogaster. Estas moscas han mostrado un fenotipo epiléptico inducido por altas temperaturas, y muerte súbita en el caso de las crisis de larga duración. También se han observado alteraciones musculares en ensayos de geotaxis negativa, vuelo y locomoción. Del mismo modo, han presentado problemas cognitivos como la ansiedad y dificultades en el aprendizaje. El uso de imanes como terapia contra el fenotipo epiléptico ha tenido buenos resultados retrasando la aparición de las crisis y disminuyendo su duración y la cantidad de moscas que las padecen. El perfil metabolómico de las cabezas de estas moscas mostró un incremento en la concentración de aminoácidos, succinato y lactato, alteraciones que se pueden relacionar con la epilepsia y la disfunción mitocondrial. El neurotransmisor GABA, principal implicado en el síndrome de Dravet, mostró niveles superiores en el modelo generado. El análisis electrofisiológico de las corrientes de sodio de las motoneuronas aCC en estadío de larva señaló aumentos en las corrientes persistentes de sodio y su ratio con las transitorias, lo cual podría justificar las crisis epilépticas. Además, la excitabilidad y el tamaño de estas células fueron menores. Todos estos cambios presentes en los mutantes KO generados hacen de estas moscas un buen modelo para estudio de la epilepsia en general, y del síndrome de Dravet en particular. Este modelo ofrece nuevas herramientas para entender la patofisiología de la enfermedad y la búsqueda de biomarcadores y tratamientos. Finalmente la búsqueda de modificadores genéticos a través de ensayos de supervivencia, tiempo de recuperación a crisis y vuelo empleando el modelo parabss1 obtuvo buenos resultados con los genes nAchRα4 y KCNQ. El gen toy por el contrario resultó ser intensificador. La variabilidad en los resultados obtenidos en este apartado cuestiona la manera de llevar a cabo este tipo de estudios en modelos animales y pacientes del síndrome de Dravet., [CA] La síndrome de Dravet és una epilèpsia severa rara causada por mutacions en el gen SCN1A, el qual codifica para la proteïna Nav1.1, subunitat α dels canals de sodi regulats por voltatge. En aquesta tesis s'ha generat, mitjançant recombinació homòloga, una nova mutació en el gen para, anomenada paraKO, el qual té la mateixa funció en Drosophila melanogaster. Aquestes mosques han mostrat un fenotip epilèptic induït por altes temperatures, y mort súbdita en el cas de les crisis de llarga duració. També s'han observat alteracions musculars en assajos de geotaxis negativa, vol y locomoció. De la mateixa manera, han presentat problemes cognitius como l'ansietat i dificultats en l'aprenentatge. L'ús d'imants com teràpia contra el fenotip epilèptic ha tingut bons resultats endarrerint l'aparició de les crisis i disminuint la seua durada i la quantitat de mosques que les pateixen. El perfil metabolòmic dels caps d'aquestes mosques mostrà increments en la concentració d'aminoàcids, succinat i lactat, alteracions les quals es poden relacionar amb l'epilèpsia y la disfunció mitocondrial. El neurotransmissor GABA, principal implicat en la síndrome de Dravet, mostrà nivells superiores en el model generat. L'anàlisi electrofisiològic de las corrents de sodi de les motoneurones aCC en estadi de larva assenyalà augments en les corrents persistents de sodi y el seu ràtio amb las transitòries, lo qual podria justificar las crisis epilèptiques. A més a més, l'excitabilitat y el tamany d'aquestes cèl·lules va ser menor. Todos aquests canvis presents en els mutants KO generats fan d'aquestes mosques un model per a l'estudi de l'epilèpsia en general, i de la síndrome de Dravet en particular. Aquest model ofereix noves ferramentes per a entendre la patofisiología de la malaltia i la recerca de biomarcadors y tractaments. Finalment la recerca de modificadors genètics a través d'assajos de supervivència, temps de recuperació a crisis y vol mitjançant el model parabss1 va obtindre bons resultats amb els gens nAchRα4 y KCNQ. El gen toy pel contrari resultà ser intensificador. La variabilitat en els resultats obtinguts en aquest apartat qüestiona la manera de fer aquest tipus d'estudis en models animals i pacients de la síndrome de Dravet., [EN] Dravet syndrome is a severe rare epileptic disease caused by mutations in the SCN1A gene coding for the Nav1.1 protein, a voltage-gated sodium channel alpha subunit. In this thesis we have made a new mutation in a gene called paraKO through homologous recombination, the single Drosophila melanogaster gene encoding this type of protein. These flies showed a heat-induced seizing phenotype, and sudden death in long term seizures. In addition to seizures, neuromuscular alterations were observed in climbing, flight and locomotion tests. Moreover, they also manifested some cognitive alterations such as anxiety and difficulties in learning. Using magnets as a therapy for epileptic phenotype, seizures start was delayed, and its duration and the quantity of flies affected was lower. Metabolomic profile of these flies' brains showed an increase in the amount of aminoacids, succinate and lactate, alterations that could be related with epilepsy and mitochondrial dysfunction. GABA, the main neurotransmitter involved in Dravet syndrome, was higher in the paraKO model. Electrophysiological sodium current analysis from aCC motoneurons in larvae stage revealed an increase in persistent currents and their ratio with transients, which is a symptom for epileptic seizures. Cell size and excitability were lower in these cells too. All these changes in the paralytic knock-out flies indicate that this is a good model for epilepsy and specifically for Dravet syndrome. This model could be a new tool to understand the pathophysiology of the disease and to find biomarkers, genetic modifiers and new treatments. Finally, a search for genetic modifiers through survival, recuperation time and flight using parabss1 flies obtained good results with nAchR¿4 y KCNQ. Otherwise, toy gene was an enhancer. However, variability observed in these type of assays dispute how modifiers search is made with model animals and Dravet syndrome patients.

En diferentes pruebas neurofisiológicas diagnósticas y terapéuticas, se requiere el posicionamiento de electrodos de registro o de estimulación en el cuero cabelludo según el sistema internacional 10/20. En la práctica clínica, para localizar las posiciones craneales, se utiliza una cinta métrica y un rotulador con el que se realiza el proceso de marcaje, previo a la colocación de los electrodos. En este estudio se ha comparado el marcaje del método convencional y un nuevo método desarrollado en la URV, el dispositivo EPlacement para distintos tests electrofisiológicos. La comparación se ha realizado teniendo en cuenta el tiempo utilizado, la precisión en la localización de las posiciones y una encuesta realizada al personal sanitario. En el estudio han participado 10 sanitarios, se han realizado 90 marcajes en maniquís y 10 marcajes en voluntarios. Los resultados muestran que con EPlacement, se incrementa la exactitud en el marcaje, se reduce el tiempo empleado para dicho marcaje, y el personal sanitario es receptivo a adoptar esta tecnología.

Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is ultimately regulated at the cellular scale, by the interaction of spatially separated but diffusively coupled nanodomains with other sub-cellular and surface-membrane calcium transport channels with strong non-linear interactions; and cardiac electrophysiology and arrhythmia mechanisms are ultimately tissue-scale phenomena, regulated by the interaction of a heterogeneous population of coupled myocytes. Recent advances in imaging modalities and image-analysis are enabling the super-resolution reconstruction of the structures responsible for regulating calcium homeostasis, including the internal structure of nanodomains themselves. Extrapolating functional and imaging data from the nanodomain to the whole-heart is non-trivial, yet essential for translational insight into disease mechanisms. Computational modeling has important roles to play in relating structural and functional data at the sub-cellular scale and translating data across the scales. This review covers recent methodological advances that enable image-based modeling of the single nanodomain and whole cardiomyocyte, as well as the development of multi-scale simulation approaches to integrate data from nanometer to whole-heart. Firstly, methods to overcome the computational challenges of simulating spatial calcium dynamics in the nanodomain are discussed, including image-based modeling at this scale. Then, recent whole-cell models, capable of capturing a range of different structures (such as the T-system and mitochondria) and cellular heterogeneity/variability are discussed at two different levels of discretization. Novel methods to integrate the models and data across the scales and simulate stochastic dynamics in tissue-scale models are then discussed, enabling elucidation of the mechanisms by which nanodomain remodeling underlies arrhythmia and contractile dysfunction. Perspectives on model differences and future directions are provided throughout.

Neural entrainment, or the synchronization of endogenous oscillations to exogenous rhythmic events, has been postulated as a powerful mechanism underlying stimulus prediction. Nevertheless, studies that have explored the benefits of neural entrainment on attention, perception, and other cognitive functions have received criticism, which could compromise their theoretical and clinical value. Therefore, the aim of the present study was [1] to confirm the presence of entrainment using a set of pre-established criteria and [2] to establish whether the reported behavioral benefits of entrainment remain when temporal predictability related to target appearance is reduced. To address these points, we adapted a previous neural entrainment paradigm to include: a variable entrainer length and increased target-absent trials, and instructing participants to respond only if they had detected a target, to avoid guessing. Thirty-six right-handed women took part in this study. Our results indicated a significant alignment of neural activity to the external periodicity as well as a persistence of phase alignment beyond the offset of the driving signal. This would appear to indicate that neural entrainment triggers preexisting endogenous oscillations, which cannot simply be explained as a succession of event-related potentials associated with the stimuli, expectation and/or motor response. However, we found no behavioral benefit for targets in-phase with entrainers, which would suggest that the effect of neural entrainment on overt behavior may be more limited than expected. These results help to clarify the mechanistic processes underlying neural entrainment and provide new insights on its applications. The project leading to these results has received funding from “la Caixa” Foundation under the project code LCF/PR/PR16/51110005 and has been co- funded with 50% by the European Regional Development Fund under the framework of the ERFD Operative Programme for Catalunya 2014– 2020, with a grant of 1.527.637,88€. AVB is supported by the Spanish MICINN Juan de la Cierva postdoctoral grant (FJC2018- 036804- I), and AMM by a predoctoral grant from the “Fundació Institut de Recerca Hospital Universitari Vall d'Hebron” (VHIR/BEQUESPREDOC/2020/MARTI). AVB and AMM have received a postdoctoral and a predoctoral contract re-spectively, from the “La Caixa” Foundation. SS- F is supported by grants from the Ministerio de Ciencia e Innovación (PID2019-108531GB-I00 AEI/FEDER) and AGAUR Generalitat de Catalunya (2017 SGR 1545). PPR has received honoraria as a consultant and speaker for Allergan, Almirall, Biohaven, Chiesi, Eli Lilly, Medscape, Neurodiem, Novartis, and Teva. Her research group has received research grants from Allergan, AGAUR, la Caixa foundation, Migraine Research Foundation, Instituto Investigación Carlos III, MICINN, PERIS; and has received funding for clinical trials from Alder, Electrocore, Eli Lilly, Novartis, and Teva.

El hipocampo es una estructura del cerebro mamífero que juega un rol clave en la formación de memorias nuevas y mapas cognitivos. Recibe aferencias provenientes de la corteza entorrinal que llegan al giro dentado, la región de entrada al hipocampo, y contactan con las neuronas principales, las células granulares (GCs, del inglés Granule Cells). El giro dentado es una de las dos áreas del cerebro en donde ocurre la neurogénesis adulta. Las GCs que nacen en el adulto atraviesan un proceso de maduración de alrededor de 8 semanas en donde gradualmente cambian sus propiedades eléctricas intrínsecas y de conectividad. De este modo, el agregado continuo de neuronas en el giro dentado incrementa y estructura la variabilidad en la población. Una de las funciones asociadas al giro dentado del hipocampo, en la cual las GCs inmaduras tienen un rol, es la de separación de patrones, un procesamiento que involucra incrementar las diferencias entre patrones de actividad aferente similares. Nuestra hipótesis es que la heterogeneidad en las propiedades intrínsecas de las GCs de distintas edades que introduce la neurogénesis, resulta beneficiosa para la codificación y discriminación de estímulos realizada por la población, contribuyendo de esta manera a la función del giro dentado. Para explorar esta hipótesis, en esta tesis nos planteamos los siguiente objetivos: Estudiar la influencia de las propiedades intrínsecas de las GCs de distintas edades madurativas en la codificación de estímulos. Caracterizar la transformación estímulo-respuesta que realizan las GCs de distintas edades mediante modelos estadísticos. Decodificar estímulos empleando estos modelos estadísticos para revelar el impacto de la edad de las GCs en la representación de los mismos. Determinar cómo la heterogeneidad en una población de GCs contribuye a una tarea de discriminacion de estímulos. Para esto, empleamos un abordaje multidisciplinario combinando experimentos de electrofisiología en rodajas de hipocampo, herramientas de análisis de series temporales, conceptos de teoría de la información y modelos estadísticos. Con el fin de estudiar diferencias en la codificación de estímulos, realizamos experimentos de patch-clamp en GCs de distintas edades marcadas fluorescentemente en ratones transgénicos. Inyectamos corrientes de estimulación fluctuantes, al mismo tiempo que registramos la respuesta de voltaje y potenciales de acción. Este tipo de estímulos fluctuantes que producen respuestas fiables y con una estructura temporal rica, permitieron un análisis profundo de la estructura de las respuestas y la influencia de las propiedades intrínsecas. Hallamos que las GCs inmaduras producen respuestas más variables que las maduras, exhibiendo tiempos de disparo imprecisos y menos alineados con los estímulos. Luego, ajustamos modelos estadísticos que capturan el potencial de membrana subumbral y las respuestas de disparos de las GCs, obteniendo parámetros que reflejan las diferencias madurativas y sugieren que las GCs inmaduras realizan una codificación de estímulos diferente. Nuestro análisis indica que las GCs inmaduras tienen constantes temporales más largas, que contribuyen a hacer su respuesta más variable, y efectos refractarios de menor magnitud. A continuación, utilizamos los modelos de las GCs obtenidos para realizar la decodificación de estímulos y evaluar la influencia de la edad en su codificación. Reconstruyendo estímulos a partir de un conjunto dado de respuestas de GCs, evaluamos la calidad de las representaciones estimando el error en la reconstrucción y la información mútua. Realizando la decodificación con GCs individuales, encontramos que tanto la reconstrucción del estímulo como la información mútua mejoran con la edad madurativa de la GC. Estudiamos también la codificación realizada por poblaciones de GCs y la influencia de la heterogeneidad en las edades de la población. Inesperadamente, a pesar de la calidad inferior de las representaciones de las GCs inmaduras estudiadas individualmente, encontramos que la presencia de GCs inmaduras en una población mejora la fidelidad de la señal codificada. Por último, dado el rol del giro dentado en la separación de patrones, nos preguntamos si esta mejora en la representación podría contribuir a la discriminacion de estímulos similares. Entonces, dise~namos una tarea que consistió en discriminar entre estímulos correlacionados fluctuantes en el tiempo y encontramos que la heterogeneidad de edades madurativas en las poblaciones ayudan a esta discriminación. Los resultados obtenidos en esta tesis aportan al entendimiento de posibles mecanismos por los cuales las GCs del giro dentado contribuyen al procesamiento de información. Encontramos que las GCs inmaduras introducen un grado de heterogeneidad en la población que puede ser aprovechado para realizar una mejor representación de los estímulos aferentes y, a la vez, discriminarlos mejor. En un contexto más general, los resultados de esta tesis muestran que la heterogeneidad en las propiedades intrínsecas de las neuronas de una población puede cumplir un rol importante en la plasticidad de la representación de estímulos asociados a la función cerebral. The hippocampus is a structure of the mammalian brain that plays a key role in the formation of new memories and cognitive maps. It receives afferents from the entorhinal cortex that reach the dentate gyrus, the entrance region to the hippocampus, and contact the principal neurons, the granule cells (GCs). The dentate gyrus is one of the two areas of the brain where adult neurogenesis occurs. The GCs that are born in the adult undergo a maturation process of about 8 weeks where they gradually change their electrical intrinsic and connectivity properties. Thus, the continuous aggregation of neurons in the dentate gyrus increases and structures the variability in the population. One of the functions associated with the hippocampal dentate gyrus, in which immature GCs play a role, is pattern separation, a processing that involves increasing the differences between similar patterns of afferent activity. We hypothesize that the heterogeneity in the intrinsic properties of GCs of different ages introduced by neurogenesis is beneficial to the coding and discrimination of stimuli performed by the population, thus contributing to dentate gyrus function. To explore this hypothesis, in this thesis we set the following objectives: Study the influence of the intrinsic properties of GCs of different maturational ages on stimulus encoding. Characterize the stimulus-response transformation performed by GCs of different ages by using statistical models. Decode stimuli using these statistical models to reveal the impact of GC age on stimulus representation. Determine how heterogeneity in a population of GCs contributes to a stimulus discrimination task. To do these, we employed a multidisciplinary approach combining electrophysiology experiments on hippocampal slices, time series analysis tools, information theory concepts and statistical models. In order to study differences in stimulus encoding, we performed patch-clamp experiments on fluorescently labeled GCs of different ages in transgenic mice. We injected fluctuating stimulation currents, while recording the voltage response and action potentials. Such fluctuating stimuli that produce reliable responses with a rich temporal structure allowed an in-depth analysis of the structure of the responses and the influence of intrinsic properties. We found that immature GCs produce more variable responses than mature GCs, exhibiting imprecise and less stimulus-aligned firing times. We then fitted statistical models that captured the subthreshold membrane potential and spiking responses of the GCs, obtaining parameters that reflect maturational differences and suggest that immature GCs perform different stimulus encoding. Our analysis indicates that immature GCs have weaker refractory effects and longer time constants, which contribute to making their responses more variable. We then used the obtained GC models to perform stimulus decoding and evaluate the influence of age on their representation. Reconstructing stimuli from a given set of GC responses, we evaluated the quality of the representations by estimating the reconstruction error and the mutual information. Performing decoding with individual GCs, we found that both stimulus reconstruction and mutual information improve with GC age. We also studied the encoding performed by populations of GCs and the influence of age heterogeneity in the population. Unexpectedly, despite the inferior quality of the representations of immature GCs when studied individually, we found that the presence of immature GCs in a population improves the fidelity of the encoded signal. Finally, given the role of the dentate gyrus in pattern separation, we wondered whether this improved representation might contribute to the discrimination of similar stimuli. We then designed a task that consisted in discriminating between time-fluctuating correlated stimuli and found that age heterogeneity in the populations aids this discrimination. The results obtained in this thesis contribute to the understanding of possible mechanisms by which the GCs of the dentate gyrus help information processing. We find that immature GCs introduce a degree of heterogeneity in the population that can be leveraged to perform a better representation of afferent stimuli and, at the same time, discriminate them better. In a more general context, the results of this thesis show that heterogeneity in the intrinsic properties of neurons in a population can play an important role in the plasticity of stimulus representation associated with brain function. Fil: Arribas, Diego Martín. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Background and ObjectivesTo demonstrate that an analog (SGE-301) of a brain-derived cholesterol metabolite, 24(S)-hydroxycholesterol, which is a selective positive allosteric modulator (PAM) of NMDA receptors (NMDARs), is able to reverse the memory and synaptic alterations caused by CSF from patients with anti-NMDAR encephalitis in an animal model of passive transfer of antibodies.MethodsFour groups of mice received (days 1–14) patients' or controls' CSF via osmotic pumps connected to the cerebroventricular system and from day 11 were treated with daily subcutaneous injections of SGE-301 or vehicle (no drug). Visuospatial memory, locomotor activity (LA), synaptic NMDAR cluster density, hippocampal long-term potentiation (LTP), and paired-pulse facilitation (PPF) were assessed on days 10, 13, 18, and 26 using reported techniques.ResultsOn day 10, mice infused with patients' CSF, but not controls' CSF, presented a significant visuospatial memory deficit, reduction of NMDAR clusters, and impairment of LTP, whereas LA and PPF were unaffected. These alterations persisted until day 18, the time of maximal deficits in this model. In contrast, mice that received patients' CSF but from day 11 were treated with SGE-301 showed memory recovery (day 13), and on day 18, all paradigms (memory, NMDAR clusters, and LTP) had reversed to values similar to those of controls. On day 26, no differences were observed among experimental groups.DiscussionAn oxysterol biology-based PAM of NMDARs is able to reverse the synaptic and memory deficits caused by CSF from patients with anti-NMDAR encephalitis. These findings suggest a novel adjuvant treatment approach that deserves future clinical evaluation.

The aim of this work is to investigate the human nociceptive system at the peripheral level. Researchers are still debating how the pain perception arises from this very intricate network. The human perception is the most elusive part of our knowledge since different subsystems are involved. The external information such as noxious stimuli must be processed at the peripheral level and through signal cascades and transduction this signal must reach the brain. At the brain level the information is processed and some decisions are taken, such as the well-known fight-or-flight response. In the introduction, the author describes how the human nociceptive system works and in which way the noxious stimulus is converted into a signal understandable by the brain. Several cortical and subcortical areas are involved in this signal processing and going deeper in this assembly line the information becomes more abstracted. The whole pathway is fundamental for pain perception, however some diseases start at the peripheral level. This in turn makes wrong signals reaching the brain. The brain is then processing information that are not real and the responses do not suit with the needs. Therefore, the peripheral system must be investigated and understood firstly, since some central diseases may have a peripheral component as well. With this purpose in mind the microneurography technique has been used. This technique has got some complexity and a computer-aided system must be implemented. The hardware aims to filter out the noisy signal and perform recording and stimulation of the neural fibers. The software is instead used to make the stimulation and recording as automatic as possible in a way that researchers do not have to deal with a lot of parameters and steps to carry out this powerful but also time consuming technique. Some software are already available in the market however even if they work fine with slow conduction fibers such as C-fibers they cannot cope with faster neurons (e.g. Aδ fibers). The aim of this work is to create a software (i.e. SPiike) able to stimulate and record every type of fibers implementing advanced analysis technique as well. Furthermore, considering that some in vivo experiments have been pursued within the project to check the functionality of the software, more specifically in rats and mice, the comparison between human nociceptors and mouse nociceptors is depicted in this section. In the method section, the experimental approach is described step by step. This is composed by several systems that work together for the stimulation, recording and analysis of the neural fibers. The control and acquisition module is composed by the software and a data acquisition board that trigger the stimulator and record the filtered signal. The stimulation module is composed by a stimulator that can be tuned as wish through dedicated knobs. Then the stimulus is delivered to the animal model (or the human patient) and the signal is recorded though a microelectrode inserted into the sciatic nerve. The amplification module is filtering out the noisy signal and is feeding a audio monitor for helping the researcher during the insertion of the electrode inside the nerve and it provides support during the whole experiment giving insights on fiber discharges. In this section the whole setup is described in details as well as the devices needed for the recording. Furthermore, the software development that is the core of this project is described as well, with all the considerations that must be considered during coding. Indeed, the flow chart must be followed methodically in order to minimize bugs and errors that may arise in the final product. Thus a description of the compiler and the Matlab IDE is given along with system and software requirements for the making of the SPiike software. Eventually the explanation of embedded functionalities and capabilities of SPiike is depicted in the final part of this section. This software is indeed able to stimulate slow conducting fibers as well as faster ones, and enhanced analysis techniques such as supervised machine learning are implemented. In the results section, the graphical user interface of the Spiike software is reveled. It resembles the one of another software already available in the market, with a filtered signal and a raster plot embedded on it. However, this software is more user-friendly and it accounts with icons and drop-down menus that enhance the experience of the users during the use of the tool, making their interactions smooth and intuitive. The SPiike software is subdivide into two different tools, a recording module and a analysis module. The former allows the stimulation and recording of neural fibers with a stimulation frequency up to 1000Hz and some online analysis can be conducted to have insights on fibers type and behavior. The analysis module is instead a more powerful analysis environment that can retrieve the dataset recorded with the other module or with the LabChart software. Advanced analysis techniques are implemented in this module, this is meant to speed up fiber classification and analysis. Conclusion and discussion provide a overview on some results. These will be compared to those obtainable through other software available in the market. In this section, pros and cons of the new implemented software, SPiike, will be described as well.

This study reports a method for the detection of mechanical signaling anomalies in cardiac tissue through the use of deep learning and the design of two anomaly detectors. In contrast to anomaly classifiers, anomaly detectors allow accurate identification of the time position of the anomaly. The first detector used a recurrent neural network (RNN) of long short-term memory (LSTM) type, while the second used an autoencoder. Mechanical contraction data present several challanges, including high presence of noise due to the biological variability in the contraction response, noise introduced by the data acquisition chain and a wide variety of anomalies. Therefore, we present a robust deep-learning-based anomaly detection framework that addresses these main issues, which are difficult to address with standard unsupervised learning techniques. For the time series recording, an experimental model was designed in which signals of cardiac mechanical contraction (right and left atria) of a CD-1 mouse could be acquired in an automatic organ bath, reproducing the physiological conditions. In order to train the anomaly detection models and validate their performance, a database of synthetic signals was designed (n = 800 signals), including a wide range of anomalous events observed in the experimental recordings. The detector based on the LSTM neural network was the most accurate. The performance of this detector was assessed by means of experimental mechanical recordings of cardiac tissue of the right and left atria. info:eu-repo/semantics/publishedVersion