[ES] El daño cerebral es la mayor causa de discapacidad en la etapa adulta, particularmente afectando a la población anciana. Independientemente de la causa, los diferentes tipos de daño cerebral comparten eventos fisiopatológicos similares. Hasta ahora, la mayoría de los estudios se enfocaron en estudiar las respuestas inmediatas tras la lesión, mientras que los mecanismos que subyacen bajo los procesos de plasticidad y regeneración cortical aún son desconocidos. Neuregulina 1 (Nrg1) es una proteína esencial en el desarrollo de los circuitos corticales que se ha asociado a diferentes trastornos psiquiátricos, como la esquizofrenia. En las últimas décadas, varios trabajos proponen a Nrg1 como un factor neuroprotector emergente en el ámbito de lesión. No obstante, la mayoría de las investigaciones se centran en estudiar la respuesta temprana de la forma soluble de Nrg1 tras el daño, mediada por la activación de los receptores ErbB, la cual no recapitula totalmente la compleja señalización de Nrg1. De este modo, nuestro laboratorio ha demostrado previamente que la señalización intracelular de Nrg1 se activa en situaciones de hipoxia, promoviendo la supervivencia neuronal tras ictus. El principal objetivo de esta tesis es estudiar el papel de la señalización de Nrg1 en la regeneración y plasticidad cortical tras daño cerebral. Para ello, hemos desarrollado nuevos modelos para 1) ofrecer una metodología que permita estudiar la regeneración axonal in vitro e in vivo y 2) específicamente estudiar el papel de la señalización intracelular de Nrg1 en el ámbito de daño cortical. Primero, desarrollamos un nuevo modelo in vitro de lesión axonal en cultivos de neuronas corticales, utilizando técnicas de electroporación para marcar un número limitado de neuronas, combinado con una posterior lesión física basada en una transección mecánica de los axones. En este modelo, también se realizaron estudios de ganancia y pérdida de función para comprender el papel de Nrg1 en el crecimiento axonal. Nuestros resultados mostraron que Nrg1, y específicamente la activación de su vía intracelular, potencia el crecimiento axonal tras daño. Posteriormente, diseñamos una metodología novedosa en ratones para estudiar la regeneración cortical, combinando técnicas de trazado de conexiones cortico-corticales con una lesión focal y mecánica en la corteza primaria motora. Se realizó una extensa caracterización funcional empleando diversas pruebas comportamentales específicas para detectar déficits motores en lesiones unilaterales como la ofrecida en este modelo. Gracias al procesamiento del tejido cerebral en series flotantes, se combinaron diferentes tinciones para realizar reconstrucciones 3D del cerebro y, así, ofrecer un estudio completo incluyendo medidas volumétricas y un análisis de diferentes poblaciones celulares y estructuras subcelulares. Como ejemplo, se investigó la correlación entre la eliminación de redes perineuronales y la activación de células microgliales en la zona adyacente a la lesión. Esta metodología de lesión cortical in vivo se utilizó en innovadores modelos genéticos de ratón en esta tesis para entender el papel de Nrg1 tras daño cortical. Así, se eliminó la expresión del gen de Nrg1 en ratonas jóvenes y maduras previamente a la lesión, observando que la ausencia de Nrg1 promueve la respuesta neuroinflamatoria y una preservación axonal limitada, conllevando una menor recuperación motora espontánea tras la lesión. Finalmente, para ofrecer una visión mecanicista del papel de la señalización intracelular de Nrg1, su dominio intracelular se expresó específicamente en neuronas corticales, observando que la activación de esta vía de señalización reduce la respuesta inflamatoria tras lesión cortical. En conclusión, estos resultados señalan que Nrg1, y específicamente la activación de su vía intracelular, podría ser una diana molecular prometedora en el contexto de neuroprotección, regeneración y recuperación cortical tras daño cerebral. / [CA] El dany cerebral és la major causa de discapacitat en l'etapa adulta, particularment en la població anciana. Independentment de la causa, els diferents tipus de dany cerebral comparteixen esdeveniments fisiopatològics similars. Fins ara, la majoria dels estudis es van enfocar a estudiar les respostes immediates després de la lesió, mentre que els mecanismes que subjauen sota els processos de plasticitat i regeneració cortical encara són desconeguts. Neuregulina 1 (Nrg1) és una proteïna essencial en el desenvolupament dels circuits corticals que s'ha associat a diferents trastorns psiquiàtrics, com l'esquizofrènia. En les últimes dècades, diversos treballs proposen a Nrg1 com un factor neuroprotector emergent en l'àmbit de lesió. No obstant això, la majoria de les investigacions se centren en estudiar la resposta primerenca de la forma soluble de Nrg1 després del mal, mediada per l'activació dels receptors ErbB, la qual no recapitula totalment la complexa senyalització de Nrg1. D'aquesta manera, el nostre laboratori ha demostrat prèviament que la senyalització intracel·lular de Nrg1 s'activa en situacions d'hipòxia, promovent la supervivència neuronal després de l'ictus. El principal objectiu d'aquesta tesi és estudiar el paper de la senyalització de Nrg1 en la regeneració i plasticitat cortical després de dany cerebral. Per a això, hem desenvolupat nous models per a 1) oferir una metodologia que permeta estudiar la regeneració axonal in vitro i in vivo i 2) específicament estudiar el paper de la senyalització intracel·lular de *Nrg1 en l'àmbit de mal cortical. Primer, desenvolupem un nou model in vitro de lesió axonal en cultius de neurones corticals, utilitzant tècniques de electroporació per a marcar un nombre limitat de neurones, combinat amb una posterior lesió física basada en una secció mecànica dels axons. En aquest model, també es van realitzar estudis de guany i pèrdua de funció per a comprendre el paper de Nrg1 en el creixement axonal. Aquests resultats van mostrar que Nrg1, i específicament l'activació de la seua via intracel·lular, potència el creixement axonal després de mal. Posteriorment, dissenyem una metodologia nova en ratolins per a estudiar la regeneració cortical, combinant tècniques de traçat de connexions cortico-corticals amb una lesió focal i mecànica en l'escorça primària motora. Es va realitzar una extensa caracterització funcional emprant diverses proves comportamentals específiques per a detectar dèficits motors en lesions unilaterals com l'oferida en aquest model. Gràcies al processament del teixit cerebral en sèries flotants, es van combinar diferents tincions per a realitzar reconstruccions 3D del cervell i, així, oferir un estudi complet incloent mesures volumètriques i una anàlisi de diferents poblacions cel·lulars i estructures subcel·lulars. Com a exemple, es va investigar la correlació entre l'eliminació de xarxes perineuronals i l'activació de cèl·lules microglials en la zona adjacent a la lesió. Aquesta metodologia de lesió cortical in vivo es va utilitzar en innovadors models genètics de ratolí per a entendre el paper de Nrg1 després de mal cortical. Es va eliminar l'expressió del gen de Nrg1 en ratolins joves i madurs prèviament a la lesió, observant que l'absència de Nrg1 promou la resposta neuroinflamatoria i una preservació axonal limitada, el que comporta una menor recuperació motora espontània després de la lesió. Finalment, per a oferir una visió mecanicista del paper de la senyalització intracel·lular de Nrg1, el seu domini intracel·lular es va expressar específicament en neurones corticals, observant que l'activació d'aquesta via de senyalització redueix la resposta inflamatòria després de lesió cortical. En conclusió, aquests resultats assenyalen que la senyalització de Nrg1, i específicament l'activació de la seua via intracel·lular, podria ser una diana molecular prometedora en el context de neuroprotecció, regeneració i recuperació cortical després de dany cerebral. / [EN] Brain damage is the leading cause of disability in adults, particularly in the elderly population. Regardless of the cause, different types of brain injury share similar physiopathological events. Most studies to date have focused on the immediate post-injury response, whereas less is known about cortical regeneration and plasticity after brain injury. Neuregulin 1 (Nrg1) is essential for the development of cortical circuits and has been implicated in several psychiatric disorders, such as schizophrenia. In the last decades, several works proposed Nrg1 signaling as an emergent modulator of neuroprotection upon damage. However, most research has focused on the early response of Nrg1 diffusible isoforms mediated by ErbB receptor activation after injury, which does not fully recapitulate the complexity of Nrg1 signaling. In this context, we have previously shown that Nrg1 intracellular signaling is activated under hypoxic conditions and promotes neuronal survival after cortical stroke. The overall goal of this dissertation is to investigate the role of Nrg1 signaling in cortical regeneration and plasticity after cortical damage. To achieve this goal, we developed novel, refined models to 1) provide new methodological approaches to study axonal regeneration in vitro and in vivo and 2) specifically target Nrg1 signaling and particularly investigate the role of Nrg1 intracellular pathway upon cortical injury. First, we developed a novel in vitro model of axonal injury in cortical neuron cultures. Specifically, we performed sparse labeling of the cultures by electroporation techniques and induced physical injury by mechanical transection of the axons. In this model, we also performed gain- and loss-of-function approaches to investigate the role of Nrg1 in axonal outgrowth. Our results showed that Nrg1, and specifically the activation of its intracellular signaling, potentiates axonal outgrowth upon injury. Second, we developed a novel methodology in mice that combines cortico-cortical projection tracing with focal mechanically controlled cortical damage (CCD) to study cortical regeneration. We performed extensive functional characterization of the model and provided meaningful behavioral tasks to detect motor impairment in unilateral focal injuries. Since tissue processing is performed in serial floating sections, we combined different immunolabeling and 3D brain reconstruction to evaluate stereological measurements and analysis of axonal projections and different cell populations. As a biological result, we showed a correlation between perineuronal nets (PNNs) disruption and microglial activation in the perilesional region. Later, we applied the CCD methodology in novel genetic mouse models to better understand the role of Nrg1 signaling in vivo after cortical injury. We induced acute Nrg1 deletion prior to injury in young and aged mice and observed that Nrg1 deletion promoted neuroinflammatory response and limited axonal preservation and spontaneous motor recovery after cortical injury. Finally, we specifically expressed Nrg1-ICD to provide a mechanistic perspective and observed that activation of this intracellular pathway decreased the neuroinflammatory response. Collectively, our results shed light on Nrg1 signaling, and specifically the activation of its intracellular pathway, as a promising molecular target in neuroprotection, cortical regeneration, and recovery after brain injury. / González Manteiga, A. (2023). Understanding the Role of Nrg1 Signaling Upon Brain Damage: Novel Models of Cortical Regeneration [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/200224

The studies in this thesis research were conducted to investigate if sensitivity to induced cortical spread depression (CSD) or the consequence of a CSD event is affected by sumatriptan induced latent sensitization. Previous studies in our lab showed persistent exposure of sumatripan to rats produced a latent state of sensitization. Using persistent sumatripan exposed rats as a model for medication overuse headache, behavior, electrical stimulation threshold to provoke a CSD event and the immunoreactivity of c-Fos in the trigeminal nucleus caudalis (TNC) were characterized. Current results showed no statistical difference of electrically induced CSD thresholds in anesthetized rats measured at day 20 in sumatripan exposed rats compared with saline treated rats. Topiramate (80 mg/kg, i.p.) used clinically for prophylaxis of migraine headache significantly increased CSD threshold in both saline and sumatriptan infused rats. CSD events appear to be associated with trigeminal vascular system activation in TNC because c-Fos expression significantly enhanced in rats with electrically stimulated CSD events. As compared to saline treated rats, sumatriptan-exposed rats demonstrated a significantly higher number of c-Fos positive cells following the electrically stimulated CSD event. Under environmental stress (bright light), sumatripan exposed rats demonstrated decreased response thresholds to periorbital and hindpaw tactile stimuli (i.e., allodynia) and enhanced c-Fos expression in TNC. A single dose of topiramate (80 mg/kg, i.p.) reversed environmental stress induced allodynia and c-Fos over-activity. Taken together, these results suggest that latent sensitization induced by persistent sumatripan exposure seems not correlated to the threshold of electrically stimulated CSD in current model. However, CSD enhanced the responses of trigeminal system in rats with sumatriptan-induced latent sensitization. The protective effects of topiramate shown in this model may be related to blocking the initiation of CSD events resulting from environmental stimulation as well as inhibiting the consequences of CSD events in primary afferents. These findings correlate with clinical observations of protective effects of topiramate for migraine prophylaxis.

Osteocytes, the most abundant cell within bone, have been linked to the processes of mechanosensation and transduction. Based upon relatively limited empirical evidence, variations in their abundance and morphology have been linked to sex, age, biomechanics and disease. In order to better elucidate lacunar variation within a healthy cohort, samples from 30 women aged 20-86 and 36 men aged 18-92 were studied utilizing synchrotron radiation micro-CT. Initial studies of normal variation within the femoral proximal shaft cross-section found high variation in lacunar density (up to ~54%) and associated morphological differences linked to biomechanical regions. In women, a non-significant trend in lacunar density reduction was apparent with age; however, a significant reduction in lacunar volume with age (~30%) was observed. Also noted were differences in lacunar morphology, with the lacunae of younger women characterized as flatter and less equant than their older counterparts. The males, who demonstrated lacunar density decline with age and a tendency towards more equant and less elongate lacunae, did not share these characteristics. Intriguingly, the previously noted reductions in lacunar volume were not observed in males. The results of this research indicate that normal variation in osteocyte lacunar parameters is high. To our knowledge the observation that lacunar volume differs in women with age is novel, potentially resulting from preferential surface infilling within the extracellular space. The functional impact of this infilling is unclear but such a change in scale likely impacts the mechanosensing function of the osteocyte network. This hypothesis warrants further investigation as, if confirmed, it would represent a profound negative impact on the osteocyte network and may provide new insights into age-related bone loss.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Epilepsy is the most common neurologic condition seen in children. Focal cortical dysplasia (FCD), a seizure disorder characterized by abnormal cortical laminar development, comprises approximately 75% of medically intractable epilepsies in the pediatric population. A greater appreciation of the pathology and intrinsic properties of the epileptogenic zone may help in understanding why FCD lesions are drug‐resistant, and could potentially lead to more effective treatments in the pediatric population. Neuronal support cells such as microglia and astrocytes have shown to have a role in FCD pathology. These cells are also activated during aging and traumatic brain injury as evidence by morphological change. This study aims to characterize the spatial distribution of microglia and astrocytes using immunohistochemistry in dysplastic tissue of eight male pediatric patients diagnosed with FCD. Cortical specimens from patients who underwent surgical resection of focally dysplastic cortex at Phoenix Children’s Hospital between 2008 and 2014 were examined using immunohistochemistry. Primary antibodies against GFAP and Iba1, as well as structural staining using hematoxylin and eosin (H&E), were incubated on sections and further analyzed using bright‐field microscopy. A pattern of perivascular activated microglia was observed in five patients around at least one blood vessel, while a pattern of non‐localized ramified microglia was observed in the other three patients. No identifiable pattern of astrocytic distribution was found. Thus, distinct patterns of microglia, rather than astrocytes, suggest dual underlying mechanisms of epileptogenesis.

No description available.

A esquizofrenia (SZ) é uma doença mental crônica e grave, que compromete o funcionamento psicossocial do indivíduo nos mais variados graus. Atinge 1% da população mundial, considerando todo seu espectro de sintomas (DSM-IV). O pobre funcionamento cognitivo é um dos principais fatores que explicam as elevadas taxas de prejuízos e encargos associados à esquizofrenia. A etiologia da SZ é desconhecida, tendo muitas hipóteses etiológicas como fatores genéticos, epidemias virais durante a gestação, época de nascimento, traumatismos de parto, infecções perinatais, condições neurológicas ou neuropsiquiátricas que geram sintomas tipo esquizofrênicos ou desenvolvimento anormal (avaliados por testes psicológicos, estudos de neuroimagem e neuropatológicos que sugerem alterações no desenvolvimento cerebral). A fisiopatologia da SZ pode ser resultante de uma desregulação na plasticidade sináptica por alterações de neurotofinas, radicais livres e processos inflamatórios. Existe uma larga evidência que os radicais livres podem ter um papel importante na fisiopatologia da SZ, podendo induzir danos na membrana celular, em proteínas e DNA. Problemas com estresse oxidativo, como o aumento da peroxidação lipídica foram relatados previamente em pacientes com SZ em primeiro episódio, virgens de tratamento e naqueles cronicamente medicados. As citocinas inflamatórias têm sido estudadas como importantes participantes na etiologia e desenvolvimento das doenças psiquiatricas. Seu papel ainda não é bem estabelecido, porém diversas alterações têm sido vistas nas doenças psiquiátricas. Dentre as citocinas, destacam-se as interleucinas (IL) e o fator de necrose tumoral alfa (TNF-α), que podem ter ação inflamatória e anti-inflamatória. Dentre as próinflamatórias, podemos destacar a IL-6 e o TNF-α. Alteração de IL na SZ tem sido relatada nesses últimos anos, relacionada à etiologia e à atividade da doença. Pacientes em episódio agudo da doença apresentaram aumento dos níveis séricos de IL pró-inflamatórias sugerindo atividade inflamatória sistêmica. Identificar, além dos sintomas clínicos, possíveis alterações bioquímicas e de neuroimagem em pacientes com SZ pode ajudar em futuras intervenções tanto para identificar, como para prevenir ou atenuar o curso da SZ. Estudos que permitam avançar no entendimento da psicopatologia deste grupo de pacientes são de grande importância, na medida em que proporcionarão futuras abordagens terapêuticas. Está bem estabelecido que a matéria cinzenta cortical e o volume de córtex préfrontal estão diminuídos em pacientes com SZ. Entretanto, os fatores que levam à perda de tecido não estão claras. Uma hipótese para esse fato é que o estado próinflamatório aumentado em SZ está relacionado com a diminuição volumétrica da massa cinzenta. O objetivo deste estudo piloto foi correlacionar os níveis séricos de IL-6 com o volume cortical total de pacientes com SZ e controles. Foram selecionados 36 pacientes com SZ (28 do sexo masculino, com idade média de 37,17 ± 12,05; anos de doença 15,56 ± 11,75), 35 controles pareados idade (21 do sexo masculino, idade média= 36,97 ± 13,04). As imagens foram adquiridas por um equipamento de ressonância magnética Philips Achieva 1.5T no Hospital de Clínicas de Porto Alegre, Brasil. Todas as imagens foram processadas usando o pipeline automatizado de FreeSurfer v5.1. Concluímos que a IL-6 está negativamente correlacionada com o volume cortical total (p= 0,027; rho= -0,370) nos pacientes com esquizofrenia, tal correlação não foi vista nos controles (p= 0,235, rho= -0,206). Nosso resultado sugere que a ativação inflamatória crônica em pacientes com SZ pode estar relacionada com a diminuição volumétrica total do córtex. / Schizophrenia (SZ) is a chronic and severe mental illness, which affects the psychosocial functioning of the individual in many degrees. It reaches 1% of the population, considering all its spectrum of symptoms (DSM-IV). Poor cognitive functioning is one of the main factors responsible for the high rates of disability and costs associated with schizophrenia. The etiology of SZ is unknown, and many etiological assumptions are taken, as genetic factors, viral epidemics during pregnancy, time of birth, birth trauma, perinatal infections, neuropsychiatric or neurological conditions that produce symptoms like schizophrenia or unnatural development (assessed by psychological tests, neuroimaging and neuropathological studies that suggest changes in brain development). The pathophysiology of SZ may be due to a deregulation in synaptic plasticity caused by changes in neurotrophins, free radicals and inflammatory processes. There is a wide evidence that free radicals may have a main role in the pathophysiology of SZ, and can induce damage into the membrane cell, in proteins and DNA. Problems with oxidative stress, such as increased lipid peroxidation have been previously reported in treatment virgem patients with SZ in first episodes and in those chronically treated. And inflammatory cytokines have been studied as important parts in the etiology of psychiatric diseases’ development. Its role is not well established, however a number of changes have been noticed in psychiatric illnesses. Among the cytokines, the Interleukins (IL) and the tumor necrosis factor alpha (TNF-α) stand out, these two may have inflammatory and anti-inflammatory action. Among the pro-inflammatory, we can highlight IL-6 and TNF-α. IL change in the SZ has been reported in these last few years, related to the etiology and disease activity. Patients with acute episode of the disease showed increased serum levels of IL proinflammatory suggesting systemic inflammatory activity. Identify not only the clinical symptoms, possible biochemical and neuroimaging abnormalities in patients with SZ can help in future interventions both to identify and prevent or slow down the course of SZ. Studies to enable progress in the understanding of psychopathology this group of patients are of great importance to the extent that provide future therapeutic approaches. It is well established that cortical gray matter and the prefrontal cortex volume are reduced in patients with SZ. However, the factors that lead to tissue loss are unclear. One possible explanation is that the increased proinflammatory state in SZ is related to the volumetric reduction of the gray matter. The objective of this pilot study was to correlate serum levels of IL-6 in the hole cortex volume of schizophrenic patients and controls. We selected 36 patients with SZ (28 male, average age 37.17±12.05; years of illness 15.56±11.75), 35 matched controls (21 male, average age= 36.97±13.04). Images were obtained by an MRI equipment, brand Philips Achieva 1.5T at Hospital de Clinicas de Porto Alegre, Brazil. All images were processed using automated pipeline FreeSurfer v5.1. We concluded thatIL-6 is negatively correlated with the total cortical volume in patients (p= 0.027, rho= -0.370), this correlation was not seen in controls (p= 0.235; rho= -0.206). Our results suggest that chronic inflammatory activation in patients with SZ can be related to the total volumetric reduction of the cortex.

Made available in DSpace on 2015-04-14T13:35:11Z (GMT). No. of bitstreams: 1 430803.pdf: 10582763 bytes, checksum: f13a8b6e46e593111e0bbe6a37a24855 (MD5) Previous issue date: 2011-03-17 / INTRODU??O: A displasia cortical focal tipo Taylor (DCF) est? frequentemente associada ? epilepsia refrat?ria ao tratamento medicamentoso e, em alguns casos, os pacientes s?o submetidos ao tratamento cir?rgico para o controle das crises. Este estudo utilizou as t?cnicas de tensor de difus?o e tractografia para avaliar as altera??es na conectividade na DCF. METODOLOGIA: Um estudo transversal controlado, com pacientes do PCE, do HSL da PUCRS, foi desenhado para avaliar as altera??es intra-corticais e a extens?o das altera??es estruturais na displasia cortical focal tipo Taylor utilizando as t?cnicas de imagem por tensor de difus?o e tractografia, nos pacientes encaminhados para tratamento cir?rgico. As imagens de resson?ncia magn?tica foram obtidas em um equipamento GE 1,5 T Signa Excite HD 8 Canais (General Electric, Milwaukee, WI, EUA) com protocolo de tensor de difus?o priorizando a pequena espessura de corte. A ?rea displ?sica foi definida pelos crit?rios de resson?ncia magn?tica. RESULTADOS: A compara??o entre os grupos aconteceu em duas etapas. Primeiro, num plano axial ao n?vel do t?lamo a uma dist?ncia m?dia da linha que passa entre a comissura anterior e posterior com respectivo desvio padr?o de 10,94 ? 3,08 mm. Em seguida, a compara??o foi feita ao n?vel do foco displ?sico. Os valores de AF s?o maiores nas ?reas perilesionais situadas a uma dist?ncia m?xima de 3 mm do limite considerado para as margens da displasia quando comparados aos valores de AF nas ?reas correspondentes no hemisf?rio contralateral no mesmo individuo e no mesmo hemisf?rio no individuo controle, com p igual a 0,04 e 0,02, respectivamente, IC 95%. Isto sugere que a ?rea displ?sica recruta fibras ao redor da les?o tornando a difus?o mais anisotr?pica. O uso da estat?stica discriminativa, Wilks lambda distribution, evidenciou o valor de T2, ao n?vel do limbo posterior da c?psula interna direita, com o poder de identificar o paciente em rela??o aos grupos displ?sico e controle (p = 0,023, IC 95%). Os autores apresentam os valores do CDA e da AF para subst?ncia branca em pacientes com displasia cortical focal. CONCLUS?O: As t?cnicas de imagem por tensor de difus?o e tractografia fornecem dados objetivos que podem ser usados na avalia??o pr?-operat?ria e no segmento cl?nico dos pacientes com displasia cortical focal. Contudo, os autores recomendam a realiza??o de outros estudos sobre a conectividade do c?rtex displ?sico para avaliar as anormalidades dos mecanismos envolvidos.

Many neurological disorders are a result of widespread changes in the excitability of brain tissue. The specific changes in neuronal excitability produces or worsens many of the symptoms associated with these disorders. Pharmacological methods are effective, but their associated side-effects are substantial, and often approximate the severity of the symptoms of the original disorder. The ketogenic diet, a high-fat, low-carbohydrate diet, has been shown to improve many neurological diseases by reducing hyperexcitability without the aforementioned side effects. The current study tested the hypothesis that a ketogenic diet would be associated with alterations in cerebral excitability. Animals were fed either a control or ketogenic diet for at least 21 days prior to experimentation. Power spectral analysis was conducted using EEG data across frequency bands, and compared between diet groups. Current source density analysis was also performed to visualize potential alterations in cerebral excitability.. In the second part of the experiment, a non-invasive ischemic stroke was delivered, and the excitability of the contralateral cortex was monitored. No significant differences were observed between ketogenic and control experiments in regards to overall excitability, although ketogenic diet experiments showed a significantly higher number of acute EEG depressions. No cortical spreading depression events were observed in contralateral recordings. Our findings are in contrast with data showing that ketogenic diets change overall basal excitability, but are in concert with other studies that show that ketogenic diets may not be associated with changes in excitability, but in changes in neuroplasticity.

L’objectif de ce travail était d’étudier certains aspects de la géométrie ou macroarchitecture afin de mieux comprendre la contribution de la géométrie sur le risque de fracture. Pour les os tubulaires, l’apposition périostée tente de compenser la perte osseuse après la ménopause et il existe peu d’études pour les vertèbres. Dans une étude prospective, les dimensions des corps vertébraux augmentent significativement à 3 ans chez les femmes ménopausées ostéoporotiques et que cette augmentation est fortement associée à la taille initiale des os suggérant que les os plus grands ont besoin d’une expansion périostée plus importante pour maintenir la résistance osseuse. Des études antérieures ont suggéré qu’il fallait évaluer la géométrie du rachis dans sa globalité en étudiant le rôle des courbures rachidiennes. Dans une deuxième étude prospective de 3 ans chez des femmes ménopausées ostéoporotiques, la cyphose thoracique est un facteur de risque de fractures vertébrales même après ajustement sur la présence de fractures vertébrales prévalentes. Une troisième étude prospective qui a cherché à identifier les paramètres géométriques associés au risque de fracture de hanche chez les femmes ménopausées ostéoporotiques non traitées montre que l’épaisseur corticale fémorale mesurée par l’outil HSA (Hip Structural Analysis) améliore la prédiction du risque de fracture de hanche indépendamment de la mesure de la densité minérale osseuse (DMO). L’outil géométrique que nous avons développé pour s’affranchir de l’influence de la DMO montre que l’augmentation de la distance intertrochantérienne est associée à une augmentation du risque de fracture indépendamment de la DMO. En revanche l’outil actuel est peu reproductible pour la mesure de la corticale fémorale. / The aim of the study was to study certain aspects of bone geometry or macroarchitecture to understand better the contribution of bone geometry on the risk of fracture. For tubular bones, periosteal apposition can occur to compensate bone loss after the menopause and there is no data concerning the prospective changes in vertebral body dimensions. In a prospective study of women with postmenopausal osteoporosis, vertebral body dimensions increase over 3 years in women and the bigger bones need more periosteal expansion to maintain bone strength. Previous studies showed that whole spine geometry and especially the spinal curvatures need be evaluated to understand the role of vertebral geometry on the risk of fracture. In a second prospective study in postmenopausal osteoporotic women, thoracic kyphosis is a risk factor for vertebral fractures over 3 years, even after adjusting on presence of prevalent fractures. A third prospective study aimed at identifying the geometric parameters associated with an increase risk of hip fracture in postmenopausal osteoporotic women untreated. Femoral cortical thickness measured by HSA tool (Hip Structural Analysis) is associated with an increase risk of hip fracture, independently of bone mineral density (BMD). The geometrical tool which we developed to eliminate the influence of the BMD shows that increase in the intertrochanteric distance is associated with an increase risk of hip fracture.

Extra-corporeal membrane oxygenation (ECMO) is a life-saving procedure for patients in respiratory or cardiac distress. Prior studies have demonstrated several known risks to the procedure, such as hypoxia, stroke, and other neurological complications (Cheng et al., 2014) that can lead to temporary or permanent deficits in motor abilities, developmental trajectory, academic abilities, and cognition (Glass et al., 1995). Although several studies have investigated morbidity and mortality rates of pediatric ECMO patients, few have looked at cognitive deficits, and even fewer at magnetic resonance imaging in relation to neuropsychological outcome and behavioral, emotional, or social functioning. The aims of this study were to investigate cognitive ability and behavioral functioning in a group of ECMO-treated patients compared to a normative sample, and to examine brain morphometry in hippocampal regions as they relate to cognitive outcome. Participants for this study were recruited from Primary Children's Hospital in Salt Lake City, UT. The total number of participants recruited was 8 (63% female; M age at testing = 16.75, SD = 4.5), and all participants were at least 1 year post-ECMO procedure (M=5.6 years; SD=2.1) for acute respiratory or cardiac illness. Neuropsychological testing was completed using the NIH Toolbox Cognition Battery. Scores were compared to normative data for age to investigate potential impairment in multiple cognitive domains. Each participant and the parent or guardian of minor participants completed brief questionnaires measuring executive functioning, behavior, and social skills, namely The Behavior Rating Inventory of Executive Functioning, The Behavioral Assessment System for Children, Second Edition, and the Social Skills Improvement System Rating Scales. Six of the participants also underwent MR imaging to obtain measures of cortical thickness in the frontal areas of the brain, as well as hippocampal and total intracranial volume. Performance results on the NIH Toolbox Cognition Battery was impaired in over half of the tested individuals who underwent ECMO as children. Attention, executive function, processing speed, and visual memory were well below the expected range for age in the majority of participants. Crystallized intelligence tasks, such as vocabulary, were in the average to above average range for most participants, likely indicating normal baseline functioning. Self- and informant report revealed variable results across participants, with various behavioral, emotional, and social difficulties reported in the group. Bilateral hippocampal volume was positively correlated with scores on tasks of episodic and working memory, though further study with a larger sample and control group is warranted. Preliminary MRI data for cortical thickness and volume of frontal regions are presented. Interpretation of results, limitations, and future directions are discussed.