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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
21

Mild traumatic brain injury and post traumatic epilepsy: biological relevance and strategies for treatment

MacMullin, Paul Castle 23 November 2021 (has links)
INTRO: There is mounting evidence to suggest a causal link between mild traumatic brain injury (mTBI) and post traumatic epilepsy (PTE). Significant ranges in the methods and definitions of “mild” TBI, each with their own limitations, make drawing cohesive conclusions from the state of the literature difficult. However, this body of work attempts to compile the literature in order to better elucidate the relationship between these populations. Ultimately, I hope this source to be a useful reference for understanding the state of the research such that one can make critical considerations in the future design of methods to definitively improve the quality of work in this field. Meaningful improvements could radically improve the outcomes for the millions of people who suffer as a result of these injuries and their lasting implications. METHODS: PubMed searches used keywords: Traumatic Brain injury (mild), Epilepsy, Concussion, Loss of cortical inhibition, Post Traumatic Epilepsy. Combinations of terms including mTBI or PTE AND MRI, fMRI, DTI, MRS, Biomarkers, TMS, EEG, and pathology. RESULTS: Strong trends persist despite the limitation in consistency of terminology and methods. Relative risk scores between 1.5 and 2.2 percent have been established across multiple long-term studies across decades of research and millions of person years, a 2-3-fold change over the baseline incidence of epilepsy in the general population (0.7%; less than one in every 100). Preclinical studies in mice have recently shown progressive increased seizure susceptibility after repeated mTBI. Within the first three weeks after injury, Glutamate homeostasis is altered meaningfully. Increased neural excitability results as the balance between excitation and inhibition shifts in the brain. An increased Glu/GABA ratio has also been linked to dysfunction in GABAergic cell populations, including parvalbumin positive inhibitory interneurons (PVI). Oxidative stress, as measured by a decreased GSH/GSSG ratio, suggests a dysregulation in homeostatic processes than can outlive clinical symptoms. Animals also display a decreased latency to induced seizure by Pentelynetetrazole (PTZ) a potent GABA receptor antagonist. Six weeks after injury, these mice have been shown to display; decreased GABA driving an increased Glu/GABA ratio, decreased EEG gamma power, and prominent signs of gliosis involving both astrocytes and microglia. Clinical investigations into the biology of this injury, utilizing a wide range of techniques, point to a loss of cortical inhibitory tone, an early hallmark of PTE. TMS findings of both reduced resting motor threshold and a shorter cortical silent period suggest a loss of cortical inhibitory tone likely shifting the excitation/inhibition balance. Signs of microstructural damage and altered cell permeability point to a disruption in chemical gradients which leads to greater functional deficits, as the parameters for normal cell function are no longer maintained. Changes in function and metabolism have been shown to outlast many of the behavioral and acute clinical symptoms suggesting a slow development but long duration of this insidious process. CONCLUSION: Mechanisms that link mTBI to PTE include a loss of cortical inhibition, increased oxidative stress and gliosis which over time increases Glu/GABA ratio, in turn increasing the likelihood of developing epilepsy. Although the relationship between mTBI and PTE has been suggested before through epidemiological studies, there is now emerging biochemical evidence to better describe this connection. Due to the high incidence of mTBI, any small increase in risk to develop PTE pursuant to concussion will affect millions of lives. With this new evidence, treatments can be designed to halt the progression and alleviate symptoms for those afflicted. The investigation of the biological mechanisms that link concussion and epilepsy is a critical step in developing treatment strategies and prophylaxis that could prove to be crucial for so many.
22

Exploration of the inter-areal cortico-cortical network of the macaque monkey / Exploration du réseau cortico-corticales inter-zonale du macaque

Markov, Nikola 03 June 2010 (has links)
Pas de résumé en français / The cortex can be viewed as a network of functional areas. A cortical area, composed ofneurons forming local connections, interacts with other areas via long distance connections.Each neuron receives multiple inputs and has to integrate the incoming signals. This integrativecapacity is the basis of the computational power of the brain. Our work concentrates onunderstanding the principles that govern the structure of the cortical network i.e. the allocationof neural resources as well as the anatomical segregation between processing steams. Usingretrograde tracer injections we extract two quantitative parameters: (i) the proportion ofSupragranular Labelled Neurons (SLN) identifies the feedforward (FF) or feedback (FB)operation between the source and target area; (ii) the Fraction of Labelled Neurons (FLN)identifies the magnitude of a connection pathway.We have made repeat injections in V1, V2, V4 to investigate the consistency of corticalpathways. This showed that (i) connection weights are consistent between animals; (ii) the listof areas projecting to each injection site is highly reproducible. We find that there are fixedFLN values for each pair of interconnected areas. The FLN values of all the afferent pathwaysto a given target span over a factor of 6 levels of log and although there is some overdispersiontheir variability is not larger than one single level of log meaning that there is a specificconnectivity profile for each area. Futermore the FLN follow a lognormal distribution. Inlognormals the mode is lower than the median and the mean i.e. the majority of pathways haveFLN weaker than the average FLN, meaning that strong projections are rare. If instead thedistribution of FLN was to follow a power law, then high FLN values would have been evenrarer. We found, a regularity in that the strongest input is invariably from within the injectedarea, second strongest are the inputs from areas sharing common borders with the target area.Sub-cortical inputs have a weak FLN, even when they are associated with an importantfunctional role such as the LGN → V1 pathway. We found that projection distance is inverselyrelated to the FLN value and an exponential distance rule operates that constrains short distanceprojections to high FLN and long distance projections to low FLN.We injected a total of 26 cortical areas homogenously distributed across the cortex. Thisrevealed 1232 projection pathways. Roughly 30% of pathways that we reveal have notpreviously been reported in the literature. Our ability to find new connections is due to theimproved tracing and brain segmentation techniques. We scan the whole brain at up to 80μmintervals to detect projection neurons, and this, as discussed in the text, is a major advantage toexisting studies. The weak long distance connections were shown to contract the characteristicpath-length of the graph (number of hops needed to go between any two areas).Our analysis of the graph showed that contrary to current belief the cortical inter-areal networkis dense (i.e. 58% of the connection that could exist do exist). At such a density, models basedon binary features such as small world cannot capture the specificity of the graph. Hence thecortex does not correspond small–world network, with sparse clustered graph possessingempowered by few critical projecitons that ensure short characteristic path-lengths. Furtheranalysis of pathway efficiency showed that the short distance connections of high magnitudeprovide large bandwidth for local connectivity and form a backbone of clustered functionallyrelated areas. This backbone is embedded in a sea of weak connections providing direct linksbetween cortical areas. We refer to this architecture as a tribal–network. We speculate that thesmall scale and high density that characterize the cortico-cortical network is facilitating theemergence of synchrony between cortical areas.
23

Influência da anestesia sobre a propagação da depressão alastrante cortical em ratos normais e desnutridos

BARRETO, Juerila Moreira January 1991 (has links)
Made available in DSpace on 2014-06-12T17:34:40Z (GMT). No. of bitstreams: 2 arquivo4390_1.pdf: 2247934 bytes, checksum: 99fed6db94fdcf451eef6895df4e1ee0 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 1991 / A influência da anestesia intraperitoneal com a mistura de uréta na+cloralose (U+C, 1.000 mg/kg + 40 mg/kg, respectivamente) ou com othiopental sódico (TH, 50 mg/kg), sobre a incidência e a propagação da depressão alastrante (DA) foi investigada no córtex cerebral de ratos Wistar adultos (3 a 6 meses de idade), divididos em dois grupos, segundo o estado nutricional: controle (dieta com 23% de proteína) e desnutrido precocemente (da gestação aos 42 dias de idade) pelo uso da "dieta básica regional" (DBR, com 8% de proteínas) de populações humanas da zona da mata de Pernambuco. No dia da primeira sessão de registro, eram implantados três eletrodos (fios de prata recobertos por tubos de polietileno e com as pontas cloretadas em contacto com a superfície cortical): dois, na religião parietal de um dos hemisférios (para o registro) e o terceiro, nos ossos nasais (eletrodo de referência). A atividade elétrica cortical e a variação lenta de voltagem (VLV) que acompanha a DA foram simultaneamente registradas em dois pontos da superfície cortical, em sessões de duas a quatro horas por dia. ADA era deflagrada com KCl a 2%, aplicado por um minuto a um ponto da superfície cortical, a intervalos de 20 a 30 minutos. A primeira sessão era feita com o animal anestesiado. Nos dias seguintes, estando os ratos acordados, realizavam-se mais três sessões. Na última destas, após duas horas, o animal era novamente anestesiado, prosseguindo-se o registro por mais duas horas. Nos animais controle, os dois anestésicos causaram redução da velocidade de propagação da DA. O efeito do TH desaparecia no dia seguinte ao da anestesia inicial, enquanto o da mistura U+C perdurava por mais um a dois dias. No último registro, as velocidades obtidas após a anestesia eram significantemente mais baixas do que aquelas registradas antes da administração dos anestésicos. Nos animais desnutridos pela DBR os efeitos dos anestésicos sobre a propagação da DA foram menos intensos do que os observados nos animais submetidos à dieta controle. Os resultados permitem concluir que: 1 - A anestesia pela mistura U+C ou pelo TH influencia a propagação da DA, reduzindo a sua velocidade; 2 - A técnica utilizada mostrou-se valiosa para o registro da DA em animais não anestesiados, possibilitando a determinação da sua velocidade de propagação nessas condições; 3 - Na desnutrição precoce pela DBR, os efeitos dos anestésicos sobre a DA são reduzidos
24

Investigating the role of gamma EEG as a solution to the binding problem

Brown, Caroline Calandra January 2001 (has links)
No description available.
25

A study of inherent and evoked arousals within sleep

Whitehead, Clare Jane January 1999 (has links)
No description available.
26

Muscarinic receptor activation of the MAP kinase signalling pathway and its physiological consequences

Futter, Marie January 2000 (has links)
No description available.
27

The identification of the unstable carotid plaque on ultrasound

Tegos, Thomas Ioannis January 2001 (has links)
No description available.
28

Cortical spreading depression upregulates calcitonin gene-related peptide expression in the ipsilateral cerebral cortex

Tye, Anne Elizabeth 01 December 2016 (has links)
Migraine affects ~15% of the US population (nearly 40 million people), making it one of the most common neurological disorders; however currently available therapeutic options for migraine relief are often ineffective. Moreover, acute and prophylactic drugs are both commonly associated with contraindications and serious side effects, and routine use of acute treatments may result in medication overuse-headaches. Elevated levels of the neuropeptide calcitonin gene-related peptide (CGRP) are known to be a primary factor in migraine pathogenesis, although the mechanisms by which CGRP expression becomes errantly modulated are unclear. CGRP is a product of the trigeminal ganglion and can be released both peripherally onto the dura mater, leading to neurogenic inflammation, and centrally at the spinal trigeminal nucleus, leading to neuromodulation. A great deal of CGRP-relevant migraine research has focused on the trigeminovascular system, but whether the cerebral cortex may have a role in migraine pathophysiology been less well studied. A subset of migraineurs experience a premonitory aura, which often manifests as a disturbance in one visual hemifield. An aberration called cortical spreading depression (CSD) is the likely electrophysiological substrate of the migraine aura, but whether CSD and CGRP are functionally related is not known. CSD is characterized by an initial transient wave of neuronal and glial depolarization, followed by a prolonged period of quiescence that is largely refractory to subsequent stimulation. Converging evidence supports a facilitatory role for cortical spreading depression (CSD) in migraine with and without aura, and CSD propagation has been shown to be dependent on functional CGRP receptors. Moreover, reported effects of CSD overlap with those of CGRP-mediated neurogenic inflammation. The experiments described herein seek to test the hypothesis that induction of CSD in vivo will lead to increased CGRP expression in the rodent cerebral cortex. Preliminary data in rats suggests that 3M KCl-induced CSD can trigger increased CGRP expression in the ipsilateral cortex. Preliminary data in mice has been less conclusive. Presented here are the data obtained from mice and rats, as well as speculation on the cause(s) of the differences in CGRP expression between species and how these findings relate to human studies.
29

Etude de l'expression du gène EphA7 et de son ligand ephrine-A5 dans le cortex en développement/ Transcriptional regulation of EphA7 and ephrin-A5 gene in the developing forebrain

Pietri, Sandra 26 October 2010 (has links)
Le cortex cérébral constitue l’une des structures les plus évoluées et complexes de notre cerveau. Sa surface est divisée en de nombreuses aires fonctionnelles. La mise en place des aires corticales dépend à la fois de facteurs intrinsèques comme la sécrétion de morphogènes ou l’expression en gradient de différents facteurs de transcription, mais elle dépend aussi de facteurs extrinsèques au cortex, en particulier l'innervation par le thalamus. Les ephrines et leurs récepteurs Eph constituent une famille multigénique de facteurs de signalisation impliqués dans divers événements clé du développement cortical où ils sont exprimés selon des profils spatio-temporels complexes. Aux stades tardifs du développement, EphA7 et l’ephrine-A5 sont exprimés en gradients complémentaires au sein de chaque territoire des aires présomptives, constituant ainsi les marqueurs les plus précoces de ces aires corticales. Par la combinaison d’approches in-vitro utilisant la technique d’électroporation focale de tranches corticales embryonnaires, puis in-vivo en utilisant la technique de transgénèse d’addition, nous avons identifié une séquence régulatrice de EphA7 appelée pA7, capable de mimer l’expression endogène de EphA7 au sein du télencéphale dorsal en développement. La lignée de souris pA7-GFP ainsi générée exprime la GFP spécifiquement au sein du télencéphale dorsal durant les stades précoces. Aux stades périnataux cette expression se régionalise au sein de la plaque corticale de chacune des aires présomptives selon des gradients récapitulant ceux observés pour EphA7. Nous avons ensuite purifié des neurones exprimant différents niveaux d’EphA7 par la technique de FACS «Fluorescence-Activated Cell Sorting » et l’analyse de leur transcriptome nous a permis de trouver un grand nombre de gènes différentiellement exprimés. Tous ceux testés par la technique d’hybridation in situ sont exprimés selon un gradient latéral fort et médial faible dans le cortex pariétal, similaire à celui d’EphA7. L’examination de leur profil au sein de cortex de souris dépourvus d’afférences thalamiques, nous a permis de conclure que l’expression de ces gènes incluant EphA7 s’établit indépendamment de celles-ci. Ainsi, notre étude a permis d'identifier un répertoire de gènes neuronaux, pouvant agir en amont ou en combinaison avec EphA7 pour contrôler les facteurs intrinsèques essentiels à l’établissement des aires corticales./ The cerebral cortex is subdivided into distinct cortical areas characterized by specific patterns of gene expression and neuronal connectivity. The patterning of cortical areas is thought to be controlled by a combination of intrinsic factors that are expressed in the cortex, and external signals such as inputs from the thalamus. EphA7 is a member of the ephrin/Eph family of guidance factors that is involved in key aspects of the development of the cortex, and is expressed in several gradients within developing cortical areas. By combining in vitro transcriptional assays and mouse transgenics, we identified a regulatory element of the EphA7 promoter, named pA7, that can recapitulate salient features of the pattern of expression of EphA7 in the developing forebrain, including gradients in the cortex. Using a mouse reporter line where GFP expression recapitulates EphA7 expression, we developed a GFP-based cell sorting procedure to isolate cortical neuron populations displaying different levels of EphA7 expression. Transcriptome analysis of these populations enabled to identify a specific array of differentially expressed genes. All genes validated further in vivo were confirmed to be expressed along distinct gradients in the developing cortical plate, similarly to EphA7. The expression of these genes was unchanged in mutant mice defective for thalamocortical projections, indicating that their graded pattern is largely intrinsic to the cortex. Our study identifies a novel repertoire of cortical neuron genes that may act upstream of, or together with EphA7, to control the intrinsic patterning of cortical areas.
30

Genetic and genomic studies of mouse and human NR2E1 in cortical disorders, aggressive behaviour, and psychiatric disease

Kumar, Ravinesh A. 11 1900 (has links)
Brain and behavioural disorders represent a leading cause of morbidity and suffering worldwide. The 'fierce' mouse has a spontaneous deletion of Nr2e1 that results in a complex phenotype that includes cortical hypoplasia and socially abnormal behaviours. Notably, functional protein and regulatory equivalency of mouse and human NR2E1 has been established. Furthermore, human studies implicate the genomic region containing NR2E1 in mental illness, although a role for NR2E1 in humans is currently unknown. Here, I integrate mouse models and human molecular genetics to understand the involvement of NR2E1 in human brain-behaviour development. First, we test the hypothesis that the spontaneous 'fierce' deletion involves onlyNr2el. It was demonstrated that the 'fierce' mutation results in the loss of all Nr2e1 exons without affecting neighbouring genes. Next, the hypothesis that some humans with cortical malformations will harbour NR2E1 mutations was tested by sequencing the coding, untranslated, splice-site, proximal promoter, and evolutionarily conserved regions of this gene in 60 subjects with microcephaly. Four candidate regulatory mutations were identified. To help interpret these findings, the genomic architecture and molecular evolution of NR2E1 were characterized in 94ethnically-diverse humans and 13 non-human primates, which indicated strong functional constraint. Finally, the hypothesis that some humans with behavioural and psychiatric disorders will harbour mutations in NR2E1 was tested by sequencing the regions outlined above in 126humans with impulsive-aggressive disorders, bipolar disorder, or schizophrenia. Eleven candidate regulatory mutations were identified. Taken together, the findings presented in this thesis are consistent with the proposal that non-coding regulatory mutations may be important to the pathogenesis of brain-behavioural disorders in some humans.

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