Extensive serotonin (5-HT) fiber innervation throughout the brain corroborates 5-HT’s modulatory role in numerous behaviors including social behavior, emotion regulation, and learning and memory. Abnormal brain 5-HT levels and function are implicated in Autism Spectrum Disorder (ASD) which often co-occurs with other neuropsychiatric conditions. While 5-HT therapeutics are used to treat ASD, variable improvements in symptomatology require further investigation of 5-HT-mediated pathology. Neurexins (Nrxns) are presynaptic cell adhesion molecules that maintain synapse function for proper neural circuit assembly. Given that aberrant Nrxn and 5-HT function independently contribute to signaling pathology and behavioral impairments, it is critical to understand how Nrxn-mediated 5-HT neurotransmission participates in pathological mechanisms underlying ASD. Using fluorescence in situ hybridization, I found that the three Nrxn genes (Nrxn1, Nrxn2, and Nrxn3) are differentially expressed in 5-HT neurons in the dorsal raphe nucleus (DRN) and median raphe nucleus which contain the primary source of 5-HT neurons in the brain. Our lab generated a mouse model with selective deletion of Nrxns in 5-HT neurons to investigate the function of Nrxns in 5-HT signaling. The loss of Nrxns at 5-HT release sites reduced 5-HT release in the DRN and hippocampus and altered 5-HT innervation in specific brain regions. The lack of 5-HTergic Nrxns also reduced sociability and increased depressive-like behavior in males. This mouse model provides mechanisms to shed new light on 5-HT neurotransmission in the generation of complex behaviors.

Introduction: (Experimental part). Hypothesis evaluates the quasi-static risk of transpedicular fixation failure in the spinal cadaver with anterior column defect due to the fixation extension and defines the risk of transpedicular fixation failure due to screw convergence in cyclic loading. (Clinical part). Hypothesis evaluates the risk of isolated dorsal approach to ventral lumbar spondylodiscitis due to clinic and radiopraphic results and the risk of anterior radical debridement due to using titanium implant in the site of bone infection. Methods: (Experimental part). Four anatomically preparated spinal cadavers with anterior spinal column defect transpediculary instrumented were quasi-statically tested on MTS 858,2 Mini-Bionix. Concept of cyclic loading part were based on ASTM standard F1717. (Clinical part). The group A consisting of 23 patients was treated only by dorsal transmuscular approach and the second group B consisting of 8 patients was treated by two-stage postero- anterior surgery in lumbar spondylodiscitis. Results: (Experimental part). There were progress in all assessed parametres with considerable asymmetry direction in extension to flexion and duction in spinal column loading with anterior defect during quasi-static loading. The rod deformation decrease with extent of...

Microtubule targeting agents (MTAs) are chemotherapeutics commonly used in the treatment of breast, ovarian, lung, and lymphoma cancers. There are two main classes of MTAs based upon their effects on microtubule stability. The two classes are the destabilizing agents, which include the drug vincristine, and the stabilizing agents, which include paclitaxel and epothilone B. These drugs are highly effective antineoplastics, but their use is often accompanied by several side effects, one of which is peripheral neuropathy. Peripheral neuropathy can be characterized by burning pain, tingling, loss of proprioception, or numbness in the hands and feet. In some patients, the MTA-induced peripheral neuropathy is debilitating and dose-limiting; however, there are no effective prevention strategies or treatment options for peripheral neuropathy as the mechanisms mediating this side effect are unknown. The goal of this work was to investigate MTA-induced effects on neuronal activity and morphology in order to elucidate the underlying mechanisms involved in the development of MTA-induced peripheral neuropathy. As an indicator of sensory neuronal activity, the basal and stimulated release of the putative nociceptive peptide, calcitonin gene-related peptide (CGRP), was measured from sensory neurons in culture after exposure to the MTAs paclitaxel, epothilone B, and vincristine. Neurite length and branching were also measured in sensory neuronal cultures after treatment with these MTAs. The results described in this thesis demonstrate that MTAs alter the stimulated release of CGRP from sensory neurons in differential ways depending on the MTA agent employed, the CGRP evoking-stimulus used, the concentration of the MTA agent, the duration of exposure to the MTA agent, and the presence of NGF. It was also observed that MTA agents decrease neurite length and branching, independent of the concentration of NGF in the culture media. Thus, this thesis describes MTA-induced alterations of sensory neuronal sensitivity and neurite morphology and begins to elucidate the underlying mechanisms involved in MTA-induced alterations of sensory neurons. These findings will undoubtedly be used to help elucidate the mechanisms underlying MTA-induced peripheral neuropathy.

Les neurones nocicepteurs jouent un rôle clé dans la défense de l’organisme. Dans le cas des réactions inflammatoires, ils initient des réflexes protecteurs tels que la toux, les vomissements, où les démangeaisons, et participent à la régulation de plusieurs mécanismes physiologiques, notamment la réponse immunitaire. Ils jouent ainsi un rôle prépondérant dans l’inflammation de type 2, souvent associée aux allergies. Mais les mécanismes qui permettent l’activation de ces neurones dans ce contexte sont encore mal connus. Au cours de ce projet de recherche, nous avons exploré la capacité des neurones nocicepteurs à détecter les signaux immunitaires spécifiquement associés à l’asthme. Nous avons ainsi identifié les caractéristiques des nocicepteurs des voies aériennes. Nous avons également démontré leur sensibilité aux allergènes grâce à l’expression du récepteur aux immunoglobulines de type E, FcεR1, ainsi que leur capacité à modifier leur transcriptome en réponse aux cytokines IL-4 et IL-13. Ces travaux soutiennent l’importance de la communication entre systèmes nerveux et immunitaires, et mettent en évidence de nouvelles cibles pour limiter la contribution neuronale aux réactions allergiques. / Nociceptor neurons play a major role in organism defense. In the context of inflammation, they initiate protective reflexes such as cough, vomiting, or itch, and participate in the regulation of various physiological mechanisms, including the immune response. They notably participate in type 2 inflammation, often associated with allergies. But the mechanisms driving the activation of nociceptor neurons in this context are still elusive. During this research project, we investigated the ability of nociceptor neurons to sense immune signals specifically associated with asthma. We identified the characteristics of airway innervating nociceptors. We also demonstrated their sensitivity to allergens through the expression of the Immunoglobulin E receptor FcεR1, as well as their ability to change their transcriptome in response to IL-4 and IL-13. This work supports the importance of bidirectional communication between the nervous and immune systems and unravels new targets to regulate neuronal contribution to inflammation.

[ES] El dolor crónico constituye un problema social y económico de primer orden. Se estima que alrededor del 19% de la población sufre de esta patología y de ellos un 12% son pacientes afectados por dolor severo. El coste económico asociado a las consecuencias del dolor en España se calcula en torno al 2,5% del PIB. La neuroestimulación medular eléctrica tónica es una de las terapias de elección para pacientes aquejados de dolor crónico severo neuropático y vascular, refractario a tratamientos farmacológicos, desde hace más de cincuenta años. El éxito de la terapia, en términos de alivio del dolor, depende de muchos factores relativos al propio paciente (patología, características anatómicas y aspectos psicológicos), así como de aspectos técnicos asociados al dispositivo utilizado y a su programación. Una correcta programación del neuroestimulador, así como otros factores asociados a la elección de los electrodos y posición de éstos en el espacio epidural, constituye uno de los factores críticos para la eficacia de la terapia. Sin embargo, hay una enorme escasez de información respecto a estos aspectos, a pesar de la cantidad de información clínica que existe sobre la terapia. Esta tesis estudia, mediante un modelo de neuroestimulación medular basado en métodos matemáticos y simulación computacional, diversas configuraciones de electrodos, posición de éstos, y programación de polaridades, con la finalidad de extraer conclusiones de utilidad clínica en la terapia de neuroestimulación tónica. El modelo desarrollado está basado en dos submodelos: un modelo tridimensional que simula la distribución del campo eléctrico en la médula, en cualquier nivel metamérico, si bien el presente trabajo se centra en T8 y T10, denominado volumen conductor, y un modelo de fibra que permite estudiar si una fibra mielinizada de un determinado diámetro desarrolla un potencial de acción bajo la acción de un campo eléctrico externo. Utilizando este modelo, se ha estudiado el efecto de diferentes factores de enorme influencia en la práctica clínica: - Elección del material pre-implante: efecto de la distancia entre polos del electrodo en la estimulación (elección del electrodo). - Técnica de implante: efecto de la distancia lateral entre electrodos paralelos implantados a la misma altura metamérica (posicionamiento de los electrodos en el espacio epidural). - Herramientas de programación: estudio del efecto de la polaridad en la estimulación (resultados para las distintas polaridades utilizadas habitualmente). - Técnica para desplazar la parestesia lateralmente: estudio del efecto de la estimulación transversa. Se ha procedido además a un registro de distintos umbrales de estimulación para varias programaciones en una muestra de 26 pacientes, mediante un estudio clínico observacional registrado en el CEIC (Comité Ético de Investigación Clínica) del Consorcio Hospital General Universitario de Valencia, para validar el modelo. Como resultado de la tesis, se ha desarrollado un modelo que permite estudiar el efecto de la estimulación tónica en cualquier nivel metamérico y determinar su eficacia en la creación de potenciales de acción, y se han sugerido unas pautas para la elección de los parámetros asociados a la terapia que puedan ser de utilidad clínica. / [CA] El dolor crònic constitueix un problema social i econòmic de primer ordre. S'estima que al voltant del 19% de la població pateix d'aquesta patologia i d'ells un 12% són pacients afectats per dolor sever. El cost econòmic associat a les conseqüències del dolor a Espanya es calcula entorn del 2,5% del PIB. La neuroestimulació medul·lar elèctrica tònica és una de les teràpies d'elecció per a pacients afligits de dolor crònic sever neuropàtic i vascular, refractari a tractaments farmacològics, des de fa més de cinquanta anys. L'èxit de la teràpia, en termes d'alleujament del dolor, depén de molts factors relatius al propi pacient (patologia, característiques anatòmiques i aspectes psicològics), així com d'aspectes tècnics associats al dispositiu utilitzat i a la seua programació. Una correcta programació del *neuroestimulador, així com altres factors associats a l'elecció dels elèctrodes i posició d'aquests en l'espai epidural, constitueix un dels factors crítics per a l'eficàcia de la teràpia. No obstant això, hi ha una enorme escassetat d'informació respecte a aquests aspectes, malgrat la quantitat d'informació clínica que existeix sobre la teràpia. Aquesta tesi estudia, mitjançant un model de neuroestimulació medul·lar basat en mètodes matemàtics i simulació computacional, diverses configuracions d'elèctrodes, posició d'aquests, i programació de polaritats, amb la finalitat d'extraure conclusions d'utilitat clínica en la teràpia de neuroestimulació tònica. El model desenvolupat està basat en dos submodels: un model tridimensional que simula la distribució del camp elèctric en la medul·la, en qualsevol nivell metamèric, si bé el present treball se centra en T8 i T10, denominat volum conductor, i un model de fibra que permet estudiar si una fibra mielinitzada d'un determinat diàmetre desenvolupa un potencial d'acció sota l'acció d'un camp elèctric extern. Utilitzant aquest model, s'ha estudiat l'efecte de diferents factors d'enorme influència en la pràctica clínica: - Elecció del material pre-implant: efecte de la distància entre pols de l'elèctrode en l'estimulació (elecció de l'elèctrode). - Tècnica d'implant: efecte de la distància lateral entre elèctrodes paral·lels implantats a la mateixa altura metamèrica (posicionament dels elèctrodes en l'espai epidural). - Eines de programació: estudi de l'efecte de la polaritat en l'estimulació (resultats per a les diferents polaritats utilitzades habitualment). - Tècnica per a desplaçar la parestèsia lateralment: estudi de l'efecte de l'estimulació transversa. S'ha procedit a més a un registre de diferents llindars d'estimulació per a diverses programacions en una mostra de 26 pacients, mitjançant un estudi clínic observacional registrat en el CEIC (Comité Ètic d'Investigació Clínica) del Consorci Hospital General Universitari de València, per a validar el model. Com a resultat de la tesi, s'ha desenvolupat un model que permet estudiar l'efecte de l'estimulació tònica en qualsevol nivell metamèric i determinar la seua eficàcia en la creació de potencials d'acció, i s'han suggerit unes pautes per a l'elecció dels paràmetres associats a la teràpia que puguen ser d'utilitat clínica. / [EN] Chronic pain is a major social and economic problem. It is estimated that about 19% of the population suffers from this pathology and of them 12% are patients affected by severe pain. The economic cost associated with the consequences of pain in Spain is estimated at around 2.5% of GDP. Tonic spinal cord stimulation is one of the therapies of choice for patients suffering from severe chronic neuropathic and vascular pain, refractory to pharmacological treatments, for more than fifty years. The success of the therapy, in terms of pain relief, depends on many factors related to the patient himself (pathology, anatomical characteristics and psychological aspects), as well as technical aspects associated with the device used and its programming. A correct programming of the neurostimulator, as well as other factors associated with the choice of electrodes and their position in the epidural space, is one of the critical factors for the effectiveness of the therapy. However, there is a huge lack of information regarding these aspects, despite of the amount of clinical information that exists about the therapy. This thesis studies, using a model of spinal cord stimulation based on mathematical methods and computational simulation, several configurations of electrodes, position of these, and programming of polarities, in order to draw conclusions of clinical utility in tonic neurestimulation therapy. The model developed is based on two submodels: a three-dimensional model that calculates the distribution of the electric field in the spinal cord, at any metameric level, although the present work focuses on T8 and T10, called volume conductor, and a fiber model that allows to study if a myelinated fiber with certain diameter creates an action potential under the action of an external electric field. Using this model, the effect of different factors of big influence on clinical practice has been studied: - Choice of pre-implant material: effect of the distance between lead contacts on stimulation (lead choice). - Implant technique: effect of the lateral distance between parallel leads implanted at the same metameric level (positioning of the leads in the epidural space). - Programming tools: study of the effect of polarity on stimulation (results for the different polarities commonly used). - Technique to move paresthesia laterally: study of the effect of transverse stimulation. We have also registered different stimulation thresholds for several programs in a sample of 26 patients, through an observational clinical study registered in the CEIC (Clinical Research Ethics Committee) of the Consorcio Hospital General Universitario de Valencia, to validate the model. As a result of the thesis, a model has been developed that allows to study the effect of tonic stimulation at any metameric level and determine its effectiveness in the creation of action potentials, and some guidelines have been suggested for the choice of parameters associated with the therapy that may be clinically useful. / Durá Cantero, JL. (2022). Modelización de los efectos de la neuroestimulación medular [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/190245

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En raison de l’utilisation d’un mode de communication totalement différent de celui des entendants, le langage des signes, et de l’absence quasi-totale d’afférences en provenance du système auditif, il y a de fortes chances que d’importantes modifications fonctionnelles et structurales s’effectuent dans le cerveau des individus sourds profonds. Les études antérieures suggèrent que cette réorganisation risque d’avoir des répercussions plus importantes sur les structures corticales situées le long de la voie visuelle dorsale qu’à l’intérieur de celles situées à l’intérieur de la voie ventrale. L’hypothèse proposée par Ungerleider et Mishkin (1982) quant à la présence de deux voies visuelles dans les régions occipitales, même si elle demeure largement acceptée dans la communauté scientifique, s’en trouve aussi relativement contestée. Une voie se projetant du cortex strié vers les régions pariétales postérieures, est impliquée dans la vision spatiale, et l’autre se projetant vers les régions du cortex temporal inférieur, est responsable de la reconnaissance de la forme. Goodale et Milner (1992) ont par la suite proposé que la voie dorsale, en plus de son implication dans le traitement de l’information visuo-spatiale, joue un rôle dans les ajustements sensori-moteurs nécessaires afin de guider les actions. Dans ce contexte, il est tout à fait plausible de considérer qu’un groupe de personne utilisant un langage sensori-moteur comme le langage des signes dans la vie de tous les jours, s’expose à une réorganisation cérébrale ciblant effectivement la voie dorsale. L’objectif de la première étude est d’explorer ces deux voies visuelles et plus particulièrement, la voie dorsale, chez des individus entendants par l’utilisation de deux stimuli de mouvement dont les caractéristiques physiques sont très similaires, mais qui évoquent un traitement relativement différent dans les régions corticales visuelles. Pour ce faire, un stimulus de forme définie par le mouvement et un stimulus de mouvement global ont été utilisés. Nos résultats indiquent que les voies dorsale et ventrale procèdent au traitement d’une forme définie par le mouvement, tandis que seule la voie dorsale est activée lors d’une tâche de mouvement global dont les caractéristiques psychophysiques sont relativement semblables. Nous avons utilisé, subséquemment, ces mêmes stimulations activant les voies dorsales et ventrales afin de vérifier quels pourraient être les différences fonctionnelles dans les régions visuelles et auditives chez des individus sourds profonds. Plusieurs études présentent la réorganisation corticale dans les régions visuelles et auditives en réponse à l’absence d’une modalité sensorielle. Cependant, l’implication spécifique des voies visuelles dorsale et ventrale demeure peu étudiée à ce jour, malgré plusieurs résultats proposant une implication plus importante de la voie dorsale dans la réorganisation visuelle chez les sourds. Suite à l’utilisation de l’imagerie cérébrale fonctionnelle pour investiguer ces questions, nos résultats ont été à l’encontre de cette hypothèse suggérant une réorganisation ciblant particulièrement la voie dorsale. Nos résultats indiquent plutôt une réorganisation non-spécifique au type de stimulation utilisé. En effet, le gyrus temporal supérieur est activé chez les sourds suite à la présentation de toutes nos stimulations visuelles, peu importe leur degré de complexité. Le groupe de participants sourds montre aussi une activation du cortex associatif postérieur, possiblement recruté pour traiter l’information visuelle en raison de l’absence de compétition en provenance des régions temporales auditives. Ces résultats ajoutent aux données déjà recueillies sur les modifications fonctionnelles qui peuvent survenir dans tout le cerveau des personnes sourdes, cependant les corrélats anatomiques de la surdité demeurent méconnus chez cette population. Une troisième étude se propose donc d’examiner les modifications structurales pouvant survenir dans le cerveau des personnes sourdes profondes congénitales ou prélinguales. Nos résultats montrent que plusieurs régions cérébrales semblent être différentes entre le groupe de participants sourds et celui des entendants. Nos analyses ont montré des augmentations de volume, allant jusqu’à 20%, dans les lobes frontaux, incluant l’aire de Broca et d’autres régions adjacentes impliqués dans le contrôle moteur et la production du langage. Les lobes temporaux semblent aussi présenter des différences morphométriques même si ces dernières ne sont pas significatives. Enfin, des différences de volume sont également recensées dans les parties du corps calleux contenant les axones permettant la communication entre les régions temporales et occipitales des deux hémisphères. / Due to the use of a mode of communication completely different from hearing people, Due to [the use of] a communication mode completely different from hearing people, the sign language and the absence of afferences from the auditory system, it is likely that significant functional and structural changes take place in the brains of profoundly deaf individuals. Previous studies suggest this reorganization may have greater impact on cortical structures located along the dorsal visual pathway than within the regions located inside the ventral pathway. The hypothesis, widely accepted by the scientific community, proposed by Ungerleider and Mishkin (1982) for the presence of two visual pathways in the occipital regions is also fairly contested. According to this hypothesis, one stream projecting from the striate cortex to the posterior parietal regions is involved in spatial vision and a second stream projecting to regions of the inferior temporal cortex underlying form recognition. Goodale and Milner (1992) subsequently proposed that the dorsal pathway, in addition to its involvement in the processing of visuospatial information, takes part in the necessary sensorymotor adjustments to guide actions. In this context, it is plausible to consider that a group of people using sensorimotor language (e.g., sign language) in their everyday life, the cerebral reorganization is more suited to target the dorsal pathway. The first objective of the study is to explore both visual pathways, especially the dorsal pathway, in hearing subjects by the use of two similar motion stimuli that evoke different types of processing. This was done with a form-from-motion stimuli and a global motion stimuli. Our results indicate that both dorsal and ventral pathways process forms defined by motion, while only the dorsal pathway is activated during a task of global motion whose psychophysical characteristics are relatively similar. Subsequently, we used these stimuli to activate the dorsal and ventral stream to investigate functional differences in the visual and auditory brain regions in profoundly deaf individuals. Several studies show cortical reorganization in the visual and auditory areas in response to the absence of a sensory modality. However, few studies have explored the specific involvement of dorsal and ventral visual streams, despite several results suggesting greater involvement of the dorsal pathway in visual reorganization with the deaf population. Following the use of functional brain imaging to investigate these issues, our results differed from the hypothesis suggesting a reorganization specifically targeting the dorsal pathway. Rather, our results indicate a non-specific reorganization to the different types of stimulations used. Indeed, the superior temporal gyrus was activated with the deaf following the presentation of our visual stimuli, regardless of their complexity. The group of deaf participants also showed activation of the posterior association cortex, possibly recruited to process visual information in the absence of competition from the temporal auditory regions. These results add to data already collected on the functional changes that may occur throughout the brains of deaf people, however, the anatomical correlates of deafness remains unknown in this population. A third study aimed to explore the structural changes occurring in the brains of prelingual and congenital profoundly deaf. Our results show that several brain regions appear to be different between the groups of participants composed of the deaf and hearing. Our analysis showed volume increases of up to 20% in the frontal lobe, including Broca's area and adjacent regions involved in motor control and language production. The temporal lobes also presented some morphometric differences even if they are not significant. Though not significant, the temporal lobes also presented some morphometric differences. Finally, differences in volume were also found in parts of the corpus callosum considered to carry fibers connecting the temporal and occipital lobes of both hemispheres.

A inferência do curso temporal da atividade neural a partir do efeito BOLD é um importante problema, ainda em aberto. A forma da curva BOLD não reflete diretamente as características temporais da atividade eletrofisiológica dos neurônios. Nessa tese, é introduzido o conceito de tempo de processamento neural (TPN) como um dos parâmetros do modelo biofísico da função de resposta hemodinâmica (HRF). O objetivo da introdução desse conceito é obter estimativas mais acuradas da duração da atividade neural a partir do efeito BOLD, que possui auto grau de nãolinearidade. Duas formas de estimar os parâmetros do modelo do efeito BOLD foram desenvolvidas. A validade e aplicabilidade do conceito de TPN e das rotinas de estimação foram avaliadas por simulações computacionais e análise de séries temporais experimentais. Os resultados das simulações e da aplicação foram comparados com medidas da forma da HRF. O experimento analisado consistiu em um paradigma de tomada de decisão na presença de distratores emocionais. Esperase que o TPN em áreas sensoriais primárias seja equivalente ao tempo de apresentação de estímulos. Por outro lado, o TPN em áreas relacionadas com a tomada de decisão deve ser menor que a duração dos estímulos. Além disso, o TPN deve depender da condição experimental em áreas relacionadas ao controle de distratores emocionais. Como predito, o valores estimados do TPN no giro fusiforme foram equivalentes à duração dos estímulos e o TPN no giro do cíngulo dorsal variou com a presença de distrator emocional. Observou-se ainda lateralidade do TPN no córtex pré-frontal dorsolateral. As medidas da forma da HRF obtidas por um método convencional não dectectaram as variações observadas no TPN / The extraction of information about neural activity dynamics related to the BOLD signal is a challenging task. The temporal evolution of the BOLD signal does not directly reflect the temporal characteristics of electrical activity of neurons. In this work, we introduce the concept of neural processing time (NPT) as a parameter of the biophysical model of the hemodynamic response function (HRF). Through this new concept we aim to infer more accurately the duration of neuronal response from the highly nonlinear BOLD effect. We describe two routines to estimate the parameters of the HRF model. The face validity and applicability of the concept of NPT and the estimation procedures are evaluated through simulations and analysis of experimental time series. The results of both simulation and application were compared with summary measures of HRF shape. We analysed an experiment based on a decision-making paradigm with simultaneous emotional distracters. We hypothesize that the NPT in primary sensory areas is approximately the stimulus presentation duration. On the other hand, the NPT in brain areas related to decisionmaking processes should be less than the stimulus duration. Moreover, in areas related to processing of an emotional distracter, the NPT should depend on the experimental condition. As predicted, the NPT in fusiform gyrus is close to the stimulus duration and the NPT in dorsal anterior cingulate gyrus depends on the presence of an emotional distracter. Interestingly, the estimated NPTs in the dorsolateral prefrontal cortex indicate functional laterality of this region. The analysis using standard measures of HRF did not detect the variations observed in our method (NPT)