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Yun, Michael Jino. "Radiosurgery for Malignant Brain Tumors." VCU Scholars Compass, 1994. http://scholarscompass.vcu.edu/etd/5088.
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Radiosurgery using the Linear Accelerator or the Gamma Knife has proven to be an effective treatment modality for malignant brain tumors. In comparison to other treatments, radiosurgery can be performed on an outpatient basis and is noninvasive (Table 5). Due to the functional properties of radiosurgical devices, they are ideal for patients who are unable to undergo surgical removal of their brain tumors. The sharp dose drop—off beyond the tumor margin allows for high dosage tumor irradiation while sparing normal brain tissue. Many procedures that involve radiosurgery use it as a ”boost” therapy in conjunction with surgical resection and whole brain irradiation. ”Boost" therapy enhances the standard treatment procedure for malignant brain tumors.
Unfortunately, radiosurgery is not always able to halt the progression of malignant brain tumors. Patients with metastatic brain tumors usually succumb to systemic disease. Patients who have gliomas generally die due to the inability of local tumor control. However, the use of radiosurgery can contribute to increasing a patient’s quality of life. Often, treatment is followed by a decrease in corticosteroid administration and an improvement in a patient's neurological status. The future directions of radiosurgery could include the development and implementation of a randomized studies to determine a dose-volume protocol for gliomas and the different forms of metastases. Also, an investigation should be undertaken to determine whether the use of high (50 Gy or more) radiosurgical doses as the only treatment for gliomas and cerebral metastases would prove to be a more effective use than ”boost” therapy.
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Malhotra, Rajiv. "GENE EXPRESSION FOLLOWING TRAUMATIC BRAIN INJURY." VCU Scholars Compass, 1998. http://scholarscompass.vcu.edu/etd/5082.
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The pathology which results from traumatic brain injury (TBI) have long been believed to be immediate and irreversible. However, recently it has been shown that, although the primary effects are virtually unavoidable, the secondary effects manifest themselves through biochemical processes set in motion at the time of the injury. These events are frequently mediated through the process of excitotoxicity, which results from a widespread release of excitatory neurotransmitters. These neurotransmitters go on to activate both ionotropic and metabotropic receptors. The signal transduction initiated through these receptor populations gives rise to changes in gene expression.
One result of this release of neurotransmitter is an influx of calcium by means of excitatory receptors on the cell. The neurotransmitters upon which most research is focused are glutamate, aspartate, and acetylcholine. Current research is aimed at investigating antagonists to this process as well as elucidating steps within the process. Antagonists primarily function to reduce the calcium toxicity through modulation of receptor activity. However, the therapeutic window for effective antagonist usage is short. Therefore, although they may represent a viable treatment option, they need to be administered as early as possible following the injury to have the greatest effect.
The purpose of this paper is to provide a summary of the available literature on TBI and excitotoxicity with a focus on changes in gene regulation. This paper will summarize information on the steps inVolved in the intracellular signaling cascade following brain injury and provide insight to further sites for regulation and treatment. This will also allow for development hypotheses on the possible roles of some of the genes whose expression is already known to be altered.
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Kardegar, Nadia. "Electrical Brain Stimulation and Depressive-like Behavior in Guinea Pigs." Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1342408797.
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Knowles-Barley, Seymour Francis. "Proteins, anatomy and networks of the fruit fly brain." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6177.
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Our understanding of the complexity of the brain is limited by the data we can collect and analyze. Because of experimental limitations and a desire for greater detail, most investigations focus on just one aspect of the brain. For example, brain function can be studied at many levels of abstraction including, but not limited to, gene expression, protein interactions, anatomical regions, neuronal connectivity, synaptic plasticity, and the electrical activity of neurons. By focusing on each of these levels, neuroscience has built up a detailed picture of how the brain works, but each level is understood mostly in isolation from the others. It is likely that interaction between all these levels is just as important. Therefore, a key hypothesis is that functional units spanning multiple levels of biological organization exist in the brain. This project attempted to combine neuronal circuitry analysis with functional proteomics and anatomical regions of the brain to explore this hypothesis, and took an evolutionary view of the results obtained. During the process we had to solve a number of technical challenges as the tools to undertake this type of research did not exist. Two informatics challenges for this research were to develop ways to analyze neurobiological data, such as brain protein expression patterns, to extract useful information, and how to share and present this data in a way that is fast and easy for anyone to access. This project contributes towards a more wholistic understanding of the fruit fly brain in three ways. Firstly, a screen was conducted to record the expression of proteins in the brain of the fruit fly, Drosophila melanogaster. Protein expression patterns in the fruit fly brain were recorded from 535 protein trap lines using confocal microscopy. A total of 884 3D images were annotated and made available on an easy to use website database, BrainTrap, available at fruitfly.inf.ed.ac.uk/braintrap. The website allows 3D images of the protein expression to be viewed interactively in the web browser, and an ontology-based search tool allows users to search for protein expression patterns in specific areas of interest. Different expression patterns mapped to a common template can be viewed simultaneously in multiple colours. This data bridges the gap between anatomical and biomolecular levels of understanding. Secondly, protein trap expression patterns were used to investigate the properties of the fruit fly brain. Thousands of protein-protein interactions have been recorded by methods such as yeast two-hybrid, however many of these protein pairs do not express in the same regions of the fruit fly brain. Using 535 protein expression patterns it was possible to rule out 149 protein-protein interactions. Also, protein expression patterns registered against a common template brain were used to produce new anatomical breakdowns of the fruit fly brain. Clustering techniques were able to naturally segment brain regions based only on the protein expression data. This is just one example of how, by combining proteomics with anatomy, we were able to learn more about both levels of understanding. Results are analysed further in combination with networks such as genetic homology networks, and connectivity networks. We show how the wealth of biological and neuroscience data now available in public databases can be combined with the Brain- Trap data to reveal similarities between areas of the fruit fly and mammalian brain. The BrainTrap data also informs us on the process of evolution and we show that genes found in fruit fly, yeast and mouse are more likely to be generally expressed throughout the brain, whereas genes found only in fruit fly and mouse, but not yeast, are more likely to have a specific expression pattern in the fruit fly brain. Thus, by combining data from multiple sources we can gain further insight into the complexity of the brain. Neural connectivity data is also analyzed and a new technique for enhanced motifs is developed for the combined analysis of connectivity data with other information such as neuron type data and potentially protein expression data. Thirdly, I investigated techniques for imaging the protein trap lines at higher resolution using electron microscopy (EM) and developed new informatics techniques for the automated analysis of neural connectivity data collected from serial section transmission electron microscopy (ssTEM). Measurement of the connectivity between neurons requires high resolution imaging techniques, such as electron microscopy, and images produced by this method are currently annotated manually to produce very detailed maps of cell morphology and connectivity. This is an extremely time consuming process and the volume of tissue and number of neurons that can be reconstructed is severely limited by the annotation step. I developed a set of computer vision algorithms to improve the alignment between consecutive images, and to perform partial annotation automatically by detecting membrane, synapses and mitochondria present in the images. Accuracy of the automatic annotation was evaluated on a small dataset and 96% of membrane could be identified at the cost of 13% false positives. This research demonstrates that informatics technology can help us to automatically analyze biological images and bring together genetic, anatomical, and connectivity data in a meaningful way. This combination of multiple data sources reveals more detail about each individual level of understanding, and gives us a more wholistic view of the fruit fly brain.
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Ellison, Mary Draper Bennett. "Alterations in Blood-Brain Barrier Function Following Acute Hypertension: Comparison of the Blood-to-Brain Transfer of Horseradish Peroxidase with That of Alpha-Aminoisobutyric Acid." VCU Scholars Compass, 1985. http://scholarscompass.vcu.edu/etd/4537.
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The blood-brain barrier (BBB) selectively restricts the blood-to-brain passage of many solutes owing to unique properties of cerebrovascular endothelial cell membranes. This selective blood/brain interface participates in the maintenance of brain homeostasis by controlling nutrient, gas, and fluid exchange necessary for brain function. Normal BBB function can be altered under various pathological and experimental conditions, allowing the transfer into brain parenchyma of blood-borne solutes normally excluded. To date, experimental study of the BBB has been accomplished primarily through the use of two different methodological approaches. Some investigators have focused on the barrier's morphological correlates and its morphopathological alteration under various pathological conditions. Other investigators have attempted to define the physiological transport properties of the BBB.
Morphological studies have employed, for the most part, large molecular weight (MW) tracers to detect morphological alterations underlying increased permeability. Physiological studies, employing smaller, more physiologic tracers have been successful in describing, quantitatively, certain functional aspects of blood-to-brain transfer. The current work attempts to merge these two approaches and to consider barrier function/dysfunction from both a morphological and a functional perspective. Specifically, the study compares in rats, following acute hypertension (a condition well-known to elicit BBB alteration), the cerebrovascular passage of C-alpha-aminois obutyric acid (AIB), a small MW tracer employed in quantitative physiologic barrier studies, and that of horseradish peroxidase (HRP), a large MW protein tracer traditionally employed in morphological barrier studies. The blood-to-brain passage of AIB and HRP were compared, following acute hypertension, with regard to both the topographical distributions of the tracer extravasation patterns and the magnitude of tracer extravasation at two different levels of hypertension. Quantitative measures of cerebrovascular AIB transfer were obtained through macroautoradiography and computerized image analysis. The data, both qualitative and quantitative, revealed dramatic focal permeability increases to AIB in some brain loci which also showed permeability increases to HRP. Such loci included the cerebral cortices and the thalamus. However, many brain regions, such as the caudate-putamen, cerebellum, and brainstem, showed more subtly-elevated AIB passage where no corresponding HRP passage was observed. Linear regression analysis of the physiologic data showed that the rate of cerebrovascular AIB transfer was positively related to the abruptness of the onset of hypertension and not related to other physiologic parameters of the hypertensive insult. The qualitative and quantitative results of this study suggest that traditional morphological barrier studies a lone do not reveal all aspects of altered barrier status and that multiple mechanisms underlying increased BBB permeability may operate simultaneously during BBB dysfunction.
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Honey, Christopher J. "Fluctuations and flow in large-scale brain networks." [Bloomington, Ind.] : Indiana University, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3354912.
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Thesis (Ph.D.)--Indiana University, Dept. of Psychological Brain Sciences and Cognitive Science, 2009.Title from PDF t.p. (viewed on Feb. 4, 2010). Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2097. Adviser: Olaf Sporns.
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Oscarsson, Jacob. "Exploring the Brain : Interactivity and Learning." Thesis, Högskolan i Skövde, Institutionen för informationsteknologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-12329.
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This study has examined whether the use of an interactive 3D model of the human brain would be a more effective way of teaching it's anatomy in comparison to traditional book and paper-based techniques. The artefact created for the project was a three dimensional model of the brain made up of several anatomical structures that could be dissected to provide the user with a more accurate sense of the spatial relationships between each structure. The study conducted did not give sufficient information to accurately answer the research question, but interviews conducted during the experiment show interest in the technology. If developed, there could be potential for the use of this type of technology in the future.
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Lister, Andrea M. "MECHANISMS UNDERLYING PROTECTION AGAINST RT-2 GLIOMAGENESIS IN RAT BRAIN UTILIZING PRIMARY AND SECONDARY VACCINATION." VCU Scholars Compass, 2003. https://scholarscompass.vcu.edu/etd/5230.
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Primary brain tumor affects some 18,000 adults in the United States each year (Silverberg et al., 1990; Merchant et al., 1997) and over 30% are high-grade anaplastic astrocytoma or glioblastoma multiforme (GBM) (Parney et al., 1997). According to Kruse et al., 1989, the treatment of patients with recurrent or persistent high-grade gliomas represents a major therapeutic challenge. The use of conventional therapy consisting of surgery, followed by radiation therapy and chemotherapy for gliomas, has been relatively ineffective (Jaecle et al., 1994) despite the fact that these therapies are cytoreductive in nature (Black, 1991). Most malignancies will recur locally but may also reappear at a different site within the brain. A brain tumor, once established, usually continues to outstrip the inhibitory action of any immunobiological defense mechanisms against it. Thus, malignant intracranial (IC) brain tumors represent a lethal neoplastic disease in which treatment has failed to extend the lifespan of afllicted individuals, with a GBM having a median survival rate of less than one year (Harsh et al., 1987).This has prompted a search for other potentially useful methods to better understand the biology of brain tumors as well as better ways to treat them The studies outlined herein, addressed the mechanisms behind the protection against tumor development provided by the various cells of the innate and cellular immune response in a rat brain tumor model. Investigations consisted of: 1) primary (1°) vaccination involving a phenotypic examination and functional analysis of the cells of the innate immune response and the cells of the adaptive immune response infiltrating an RT-2 glioma and the expression of the CD25 receptor; 2) 1° and secondary (2°) vaccination that involved a follow-up on survival as well as the phenotyping of cells of the leukocytic immune response; 3) rechallenge of long-lived rats, from Experiment 2, in the contralateral (left) hemisphere; and 4) acquisition of memory T lymphocytes from vaccinated rats and the use of lymphocyte depletion studies to determine which cells were necessary to provide a protective vaccination against development of tumor. Thus, this study illustrated a potential therapeutic strategy to develop treatments for GBM patients as well as providing protection against development of tumor by the use of vaccines.
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Means, Sheila Marie. "Patterns and processes of brain diversification within esociform teleosts." Virtual Press, 1995. http://liblink.bsu.edu/uhtbin/catkey/941371.
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The richness of nervous systems represented by extant fishes has not yet been determined; the brain morphology of many species, indeed, many groups, remain undescribed. For this reason we have examined esociform teleosts and focused on three goals: 1) to provide the first basic descriptions of the brains of two esociform teleosts, Esox masquinongy (muskellunge) and Esox lucius (northern pike); 2) to describe the development of E. masquinongy brains; and 3) to compare the neuronal features between E. masquinongy and E. lucius in light of the ontogenic pattern of E. masquinongy. We demonstrate that a suite of differences exists between the brains of these two congeners. Relative to the brains of E. lucius, the brains of E. masquinongy exhibit a number of paedomorphic features. This heterochronic shift parallels the differences in non-neuralmorphological features previously described between these two species. We identify three features that cannot be explained by this heterochronic shift: 1) the optic nerves of E. masquinongy and E. lucius cross oppositely, E. masquinongy have optic nerves that cross left nerve dorsal, E. lucius cross right nerve dorsal; 2) Esox lucius have a consistent cellular discontinuity in the telencephalon between Dm, and Dd that is not present in E. masquinongy; and 3) adult E. lucius retain a neural canal opening that closes in larval E. masquinongy, a peramorphic exception to the paedomorphic pattern.Department of Physiology and Health Science
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Li, Joey, and 李穎文. "Sex-related differences in brain anatomy and brain functions associated with language processing : a MRI study with Chinese speakers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hdl.handle.net/10722/192781.
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Randall, Steven Ronald. "The effects of HIV-1 infection on subcortical brain structures in children receiving ART : a structural MRI study." Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/19894.
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INTRODUCTION This project investigated volumetric differences in certain subcortical structures as measured on high-resolution structural Magnetic Resonance Imaging (MRI) scans traced manually. The sample comprised 79 5-year old children, 52 with HIV and 27 uninfected controls. Infected children were all stable on antiretroviral therapy (ART) and were from the Children with HIV early antiretroviral (CHER) cohort who have been followed since birth. The study aimed to investigate the long-term effects of HIV and ART on the developing brain. While high-resolution structural data has been analysed using automated FreeSurfer to determine volume and cortical thickness, manual tracing remains the gold standard. Thus, manual tracing was used to validate automated measures and investigate subtle group differences in selected regions of interest. METHODS Extensive clinical data were available for all participants in the study. MR images were AC-PC transformed and converted to analyse format. Structures were traced using MultiTracer software. Structures selected included the caudate, nucleus accumbens (NA), putamen (Pu), globus pallidus (GP) and corpus callosum (CC). Four of these structures occur bilaterally. Tracing was performed in 79 subjects. Three subjects were excluded due to poor quality images or pathology; 5 HIV-1 infected children were excluded as they were not randomized between treatment groups. Certain subjects were retraced for inter and intrarater reliabilities. The effect and association of ethnicity, age, birthweight and sex as possible confounders were investigated. As the groups were not well matched for ethnicity, all Cape Coloured children were excluded from further analyses. Analysis of variance was used to test the effect on structure size between HIV-1 infected children and controls, as well as between 3 treatment arms (ART deferred until clinical criteria were met, early ART for 40 weeks, early ART for 96 weeks) and uninfected controls. Analysis of covariance was used to control for the possible confounding effects of sex and age. Each structure was tested for possible association with clinical variables (CD4, CD8, CD4/CD8 ratio and CD4%) both at enrolment and time of scanning. Linear regressions were modelled using clinical variables that showed significant correlation with structure size whilst controlling for covariates. Congruence between automated FreeSurfer and manual segmentation were evaluated via Bland-Altman, Pearson r and Cronbach's alpha.
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Fillard, Pierre. "Riemannian processing of tensors for diffusion MRI and computational anatomy of the brain." Nice, 2008. http://www.theses.fr/2008NICE4002.
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Symmetric, positive-definite matrices, or tensors, are nowadays a common geometrical tool for image processing and analysis. The recent emergence of diffusion tensor MRI (DTI) and computational anatomy (CA) brought importance of tensors out to the medical community. However, working with those is difficult: the positive-definite constraint must be satisfied at any cost, which cannot be ensured in general with standard matrix operations. In this work, we propose two alternatives to the standard Euclidean calculus on tensors. Instead of seeing the tensor space as a vector space, we consider it as a manifold, i. E. , a smooth curved space. Thanks to the Riemannian geometry, we are able to ``unfold'' this space, and to generalize any operation on tensors with astonishing simple implementations. In a second step, we review the applications of such frameworks in the context of clinical DTI and brain CA. In DTI, we show that very noisy data, typical of clinical acquisitions, can be optimally exploited and eventually produce a meaningful and clinically relevant fiber reconstruction. In brain CA, we show that, by considering simple brain anatomical landmarks - the sulcal lines - we are able to precisely measure the inter-individual variability of the cortex. Finally, we develop a new framework to study the anatomical correlations between brain regions, and present results of so far unknown relationships between symmetric sulcal positions, and between a-priori unrelated sulci, which raises new fundamental questions about the origin of such statistical dependenciesLes matrices symétriques et définies positives, ou tenseurs, sont aujourd'hui fréquemment utilisées en traitement et analyse des images. Leur importance a été mise à jour avec l'apparition récente de l'IRM du tenseur de diffusion (ITD) et de l'anatomie algorithmique (AA). Cependant, il est difficile de travailler avec : la contrainte de positivité doit être satisfaite à tout prix, ce qui n'est pas garanti avec les opérations matricielles standard. Dans ce travail, nous proposons deux alternatives au calcul euclidien sur les tenseurs. Au lieu de voir l'espace des tenseurs comme un espace vectoriel, nous le considérons comme une variété, i. E. , un espace courbe et lisse. Grâce à la géométrie riemannienne, il est alors possible de " déplier " cet espace et de généraliser aux tenseurs toute opération avec des implémentations étonnamment simples. Dans un deuxième temps, nous passons en revue les applications de tels cadres de calcul en ITD clinique et en AA du cerveau. En ITD, nous montrons qu'il est possible de traiter de manière optimale des données très bruitées typiques d'acquisitions cliniques, et de produire des reconstructions de fibres plausibles. En AA du cerveau, nous montrons qu'en considérant des repères anatomiques simples - les lignes sulcales - il est possible de mesurer précisément la variabilité interindividuelle du cortex. Finalement, nous développons un cadre nouveau pour étudier les corrélations anatomiques entre régions du cerveau, et présentons des résultats jusqu'à maintenant inconnus de dépendances entre sillons symétriques, et entre sillons à priori non reliés, soulevant ainsi de nouvelles questions sur l'origine de telles dépendances statistiques
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Regattieri, Neysa Aparecida Tinoco. "Avaliação morfológica e angiográfica por tomografia computadorizada e ressonância magnética do círculo arterial do cérebro." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42131/tde-29012013-083644/.
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O círculo arterial do cérebro (CAC) é objeto de estudo desde os princípios da anatomia moderna e ao longo dos séculos documentado e classificado de várias maneiras. Recentemente o desenvolvimento dos métodos diagnósticos por imagem e de ultraestrutura abriram um novo leque nas possibilidades de investigação. Neste trabalho o CAC foi avaliado por meio de exames por angiotomografia computadorizada, por angiorressonância magnética, fotografias de peças anatômicas, histologia, microscopia eletrônica por varredura e por transmissão. Verificou-se na amostra que o CAC possui tendência a simetria. Os achados foram similares na comparação entre os métodos de diagnóstico por imagem, porém não demonstraram todos os achados dos espécimes anatômicos. A metodologia utilizada permitiu verificar que as camadas das paredes das diferentes artérias podem explicar parcialmente as diferenças nos achados entre os métodos de imagem e as peças anatômicas. Os dados aqui apresentados revestem-se de grande importância clínica e cirúrgica uma vez que o CAC é um elemento chave na circulação cerebral.The Willis Polygon (WP) has been studied since the beginning of modern anatomy and documented and classified over the centuries in various ways. Recently the development of diagnostic imaging methods and ultra structure opened a new range of possibilities in the investigation. In this work the WP was assessed by computer tomography angiography examinations by magnetic resonance angiography, photographs of anatomical specimens, histology, scanning and transmission electron microscopy. It was found that the sample has a tendency to the WP symmetry. The findings were similar when comparing the methods of diagnostic imaging, but did not show all findings of anatomical specimens. The methodology has shown that the different layers of the walls of arteries may partly explain the differences in findings between imaging and anatomical parts. The data presented here are of great clinical and surgical importance, once the WP is a key element in the cerebral circulation.
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Cole, H. "A computerised atlas of the honeybee brain (Apis mellifera L.)." Thesis, Bucks New University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376424.
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Proal, Fernández Erika. "Brain anatomy of attention deficit/hyperactivity disorder in children and adults with childhood onset." Doctoral thesis, Universitat Autònoma de Barcelona, 2011. http://hdl.handle.net/10803/51438.
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El trastorno por déficit de atención e hiperactividad (TDAH) es uno de los trastornos del neurodesarrollo más comunes en niños. Los principales síntomas son la inatención, impulsividad e hiperactividad. El TDAH se presenta en un 8 a 12% de la población escolar mundial; la mayoría (60-85%) continua presentando los criterios diagnósticos durante la adolescencia.
Estudios de neuroimagen volumétricos en niños con TDAH han encontrado de manera consistente reducciones globales del volumen total cerebral con una mayor tendencia a la reducción de regiones fronto-estriatales, cerebelo y parietales-temporales comparándolos con niños controles (desarrollo típico). El diagnostico de TDAH en adultos requiere de haberse presentado en la niñez, en la actualidad ya se ha confirmado que la persistencia de los síntomas puede continuar hasta la edad adulta.
El uso de diferentes técnicas de neuroimagen realizados por diferentes grupos de investigación han ayudado a la mejora del entendimiento de los sustratos neurológicos que están por detrás de la patofisiología de TDAH. Hoy en día, los investigadores han hecho énfasis en las contribuciones potenciales de la disfunción de circuitos cerebrales, en vez de enfocarse solamente en anormalidades de regiones por separado. En consecuencia, el objetivo principal de la presente tesis es examinar los sustratos neurales del TDAH aplicando tres diferentes técnicas de neuroimagen. El objetivo secundario es analizar si estas diferencias están relacionadas con el diagnostico de TDAH en la niñez o si están relacionadas con la persistencia de los síntomas en la edad adulta.
Los resultados del presente estudio están divididos en dos principalmente. Primero, en una muestra grande de niños y adolescentes con TDAH, se encontró una reducción volumétrica significativa en el estriado ventral, una región considerada como clave en los procesos de recompensa y relacionada con los circuitos cortico-striato-thalamo-coticales (circuito de recompenza). En segundo lugar, los adultos que fueron diagnosticados con TDAH en la niñez, mostraron una reducción tanto en el grosor cortical como el volumen de la sustancia gris en regiones parietales y motoras (Circuito dorsal atencional). La mayoría de estas diferencias se observaron independientemente del diagnóstico actual de los sujetos. En otras palabras, estas diferencias fueron, estas diferencias fueron encontradas en aquellos sujetos que persistieron con los síntomas en la edad adulta y también en los que remitieron el diagnostico. En contraste, las regiones implicadas en el circuito de recompensa fueron disminuidas en los que persistieron pero no en los que remitieron. Por lo tanto, las diferencias en estas ultimas regiones (estriado ventral en niños, corteza orbitofrontal, parahipocampo, tálamo, polo frontal en adultos con TDAH) están relacionadas con el diagnostico actual del trastorno; mientras que las diferencias en el circuito dorsal atencional parecen estar más implicado con haber tenido TDAH en edad temprana.
Nuestros datos nos permiten sugerir una hipótesis integrativa de disfunción en el circuito de la recompesa, que esta particularmente afectado en niños y adolescentes con TDAH y en adultos con persistencia de TDAH; a su vez el circuito atencional dorsal está más relacionado con funciones ejecutivas y atencionales y esto se ve reflejado en los sujetos que han tenido TDAH en la niñez sin importar que en la actualidad (edad adulta) presenten o no síntomas de TDAH.
En base a nuestros datos, se propone un modelo de fisiopatología del TDAH que envuelve dos circuitos principalmente. El circuito dorsal atencional, que parece estar más reflejado con factores genéticos. Por el contrario, diferencias anatómicas en el circuito de recompensa está relacionado con los síntomas actuales de TDAH. Sin embargo no podemos diferenciar con nuestros datos, si las diferencias encontradas son la base de la remisión de los síntomas o si son cambios en los circuitos cerebrales que están reflejando una remodelación secundaria de los efectos del comportamiento, como aprendizaje o refuerzo selectivo. Esta pregunta deberá intentar abordarse en futuras investigaciones longitudinales y con técnicas de neuroimagen que incorporen también factores genéticos y métodos de seguimiento del tratamiento.Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders occurring in childhood. The main symptoms are developmentally excessive levels of inattention, impulsivity and hyperactivity. ADHD occurs in 8 to 12% of school age children worldwide; the majority (60%-85%) continues to meet criteria for the disorder during their teenage years. Volumetric studies in children with Attention-Deficit/Hyperactivity Disorder (ADHD) have consistently found global reductions of total brain volume with frontal-striatal regions, cerebellum and parieto-temporal regions particularly affected relative to typically developing subjects. The adult diagnosis of ADHD requires onset in childhood, but persistence of ADHD into adulthood is now well documented. This longitudinal course together with smaller brain volumes in children with ADHD has raised questions about brain development into adulthood. The use of different neuroimaging techniques by independent groups is leading to an improved understanding of the neural substrates underlying the pathophysiology of ADHD. Nowadays, researchers have begun to place more emphasis on the potential contributions of dysfunctional brain circuits, rather than isolated regional abnormalities. Therefore, the aim of this thesis is to examine the neural substrates of ADHD by applying three different anatomic neuroimaging approaches. A secondary aim is to analyze whether these brain differences are related with the diagnosis of ADHD in childhood or whether it is associated with the persistence of the diagnosis in adulthood. The results of the present dissertation are two-fold. First, in a large sample of children and adolescents with ADHD, we found a striking volumetric reduction in the ventral striatum, a region critically involved in reward processes that is a key relay in cortical-striatal-thalamo-cortical circuits (reward circuit). Second, in adults diagnosed with ADHD in childhood, we found reduced cortical thickness and voxel-based morphometry (VBM) gray matter volume in parietal and motor regions (Dorsal attentional network). Most of these differences were independent of current adult diagnoses status. In other words, these differences were largely found in both individuals with persistent ADHD and in those who were in remission. By contrast, reward-related regions were diminished in probands with persistent ADHD compared to controls but not in those who were in remission. Thus differences in reward-related circuitry (ventral striatum in children, orbitofrontal cortex, parahippocampus, thalamus, and frontal pole in adults) were associated with the current diagnosis of ADHD, whereas frontal-parietal motor cortex differences in adults with ADHD seem to reflect the trait of having had ADHD in childhood. Our data allow us to suggest an overall integrative hypothesis that dysfunction in the reward circuit, which was particularly prominent in children and adolescents with ADHD and in the adults with persistent ADHD, reflects ongoing symptoms of ADHD. By contrast, abnormalities in the top-down control dorsal attentional network seem to be related to the trait of having had ADHD in childhood, as the abnormalities were comparable in adults who had remitted or who had persistent ADHD. On the basis of our data, we propose a model of ADHD physiopathology in which two main circuits interact. These are the dorsal attentional network, which seems to be anatomically abnormal in individuals with a history of ADHD, whether or not they are currently affected. As such, we hypothesize that dorsal attentional network deficiencies may be related to the genetic factors associated with ADHD. By contrast, anatomic abnormalities in the reward circuit appear to be related to current ADHD symptoms. Based on our data, we cannot differentiate whether anatomic changes in the reward circuits are the basis for symptomatic remission, or whether such changes in brain circuits reflect brain remodeling secondary to behavioral effects, such as learning and selective reinforcement. This question will have to be addressed in the future through longitudinal brain imaging studies that can incorporate genetic factors and treatment tracking methods.
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Burns, J. Bracken. "Basic morphological and histological characterizations of the brain of the white sucker, catostomus commersoni." Virtual Press, 1997. http://liblink.bsu.edu/uhtbin/catkey/1048372.
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The white sucker, Catostomus commersoni, is among the many fishes classified as minnows (order Cypriniformes). Minnows are a morphologically diverse teleost (bony fish) group whose brains have been examined previously in both a morphological and experimental context. Two species of minnows, goldfish (Carasius auratus) and European carp (Cyprinus carpio) have been commonly used as model systems for experimental neuroanatomical studies.The purpose of this present study is to catalog the brain of the white sucker for its use in future studies and as a comparative reference for the study of other catostomids. In particular, the neuronal connections of the cranial nerves could be explored once the brain has been characterized. This species was chosen because of its position as the outgroup for all other members of the genus Catostomus, and the fact that it is relatively easy to obtain. This study focuses on two areas: descriptions of the gross morphology of the brain of the white sucker, and histological characterizations of the nuclei of the brain of the white sucker.Department of Physiology and Health Science
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Mudariki, Temba. "Diagnostic neuropathology of brain tumours using biophotonics and spectrometry." Thesis, University of Central Lancashire, 2016. http://clok.uclan.ac.uk/16665/.
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Classification of tumours such as gliomas, which are on a continuous spectrum of histology and malignancy into distinct categories is still a challenge using histopathology. There has been significant advances in the techniques used to fight cancer in the past two decades. A number of studies have looked at different approaches to improve the accuracy in diagnosis using histopathology. This study evaluated a number of techniques to compliment histopathology. One study looked at vibrational spectroscopy, Raman and attenuated total reflection-fourier transform infrared (ATR-FTIR) looking at brain tumour cell lines. This study investigated the potential application of vibrational spectroscopy in the segregation of different types of brain tumours using two tumour cell lines, U87MG, 1321N1 and a control, SVGP12. Another study looked at two approaches, elemental profiling of both tissue and serum using inductively coupled plasma-mass spectrometry. Trace elements increase or deficiency has been linked to cancer development and progression. The final study looked at the diagnostic application of Raman spectroscopy to distinguish between gliomas, meningiomas, medulloblastoma and several other brain tumours from histological normal brain tissue from brain tumour patients used as controls. The three cell lines U87MG, SVGP12 and 1321N1 were cultured and grown on calcium fluoride slides in triplicates. Spectra from each cell line was taken using both Raman and ATR-FTIR. The spectra was then analysed using multivariate statistics. In the elemental profiling study serum and tissue samples from 55 patients with brain tumours were collected and analysed using ICP-MS. The elemental data was then evaluated using multivariate statistics to investigate significant differences. In the analysis of human brain tumours tissue blocks of both tumour and histological normal brain that were formalin fixed and paraffin embedded (FFPE) were processed and mounted on low-E slides, dewaxed using Xylene, washed with alcohol and water before storage at room temperature until analysis. Raman and ATR-FTIR were able to separate U87MG, SVGP12 and 1321N1 with very high classification accuracy. All the brain tumour groups investigated showed a deficiency of Mg, Fe, Cu, and Zn concentrations against reported levels from healthy individuals in the literature. Raman spectroscopy coupled with multivariate statistics was able to distinguish between normal brain tissue and normal brain tumour tissue used as controls. Classification of gliomas based on the degree of malignancy was also apparent with very high classification accuracy. Spectral panels were developed that can be used as biomarkers in the diagnosis of brain tumours. Raman and Infrared spectroscopy are types of vibrational spectroscopy which have the potential to be used as diagnostic tools in neuropathology. They provide an intrinsic molecular fingerprint of the sample based on the interaction of light. The panels can accurately identify and classify specific brain tumours alleviating the need to use complex statistical models. Raman and ATR-FTIR were able to elucidate chemical information from the samples which was used to differentiate the three cell lines with very high classification accuracy. Diagnosis of a brain tumour is not always a straight forward process and the current techniques used lack the desired level of precision in diagnosis and cytoreductive surgery.
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Workman, L. "Lateralization of brain function and behavioural ontogeny in the chick under natural conditions." Thesis, University of Sussex, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375857.
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Horton, Paul Michael. "Investigating information processing within the brain using multi-electrode array (MEA) electrophysiology data." Thesis, University of Sussex, 2011. http://sro.sussex.ac.uk/id/eprint/6929/.
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How a stimulus, such as an odour, is represented in the brain is one of the main questions in neuroscience. It is becoming clearer that information is encoded by a population of neurons, but, how the spiking activity of a population of neurons conveys this information is unknown. Several population coding hypotheses have formulated over the years, and therefore, to obtain a more definitive answer as to how a population of neurons represents stimulus information we need to test, i.e. support or falsify, each of the hypotheses. One way of addressing these hypotheses is to record and analyse the activity of multiple individual neurons from the brain of a test subject when a stimulus is, and is not, presented. With the advent of multi electrode arrays (MEA) we can now record such activity. However, before we can investigate/test the population coding hypotheses using such recordings, we need to determine the number of neurons recorded by the MEA and their spiking activity, after spike detection, using an automatic spike sorting algorithm (we refer to the spiking activity of the neurons extracted from the MEA recordings as MEA sorted data). While there are many automatic spike sorting methods available, they have limitations. In addition, we are lacking methods to test/investigate the population coding hypotheses in detail using the MEA sorted data. That is, methods that show whether neurons respond in a hypothesised way and, if they do, shows how the stimulus is represented within the recorded area. Thus, in this thesis, we were motivated to, firstly, develop a new automatic spike sorting method, which avoids the limitations of other methods. We validated our method using simulated and biological data. In addition, we found our method can perform better than other standard methods. We next focused on the population rate coding hypothesis (i.e. the hypothesis that information is conveyed in the number of spikes fired by a pop- ulation of neurons within a relevant time period). More specifically, we developed a method for testing/investigating the population rate coding hypothesis using the MEA sorted data. That is, a method that uses the multi variate analysis of variance (MANOVA) test, where we modified its output, to show the most responsive subar- eas within the recorded area. We validated this using simulated and biological data. Finally, we investigated whether noise correlation between neurons (i.e. correlations in the trial to trial variability of the response of neurons to the same stimulus) in a rat's olfactory bulb can affect the amount of information a population rate code conveys about a set of stimuli. We found that noise correlation between neurons was predominately positive, which, ultimately, reduced the amount of information a population containing >45 neurons could convey about the stimuli by ~30%.
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Shin, Christoher. "DIFFERENTIAL GLIAL CELL RESPONSES IN THE DENTATE GYRUS IN YOUNG ADULT AND AGED BRAINS FOLLOWING TRAUMATIC BRAIN INJURY." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2511.
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Traumatic brain injury (TBI) affects 3 out of every 1000 Americans each year, and is the leading cause of morbidity and mortality after trauma, accounting for as many as 56,000 deaths per year (Dutton and McCunn, 2003). The Centers for Disease and Control and Prevention found that TBI most commonly occurs in adolescents and young adults aged from 15 to 24 years and in the elderly (75 years and older). Following injury, the secondary injury begins almost immediately after the primary injury and is the result of a number of cascades where once activated, exacerbate the already altered homeostasis of the injured brain. Brain trauma leads to complex secondary injury responses that trigger many cellular and molecular pathways, especially inflammation. The cerebral inflammation that occurs after TBI has been described through the processes of glial activation followed by leukocyte recruitment, and upreglation and secretion of cytokines and chemokines. With aging there is a decrease in the production of anti-inflammatory cytokines along with increasing amounts of pro-inflammatory cytokines by peripheral blood monoculear cells, microglia, and astrocytes. Studies have shown that inflammation has a strong negative effect on neurogenesis in the adult brain due to the impact of the pro-inflammatory cytokines that are released following the acute injury or disease. In this study, we first examined the differences in glial cells responses in young adult brain and aged brain following a moderate lateral fluid percussion injury and the correlation of glial cell activation with hippocampal neurogenesis. We then examined the effect of anti-inflammation treatment on glial cell response in the young and aged brain. The levels of astrocytic and microglial responses in the DG of the hippocampus following injury at 3, 7 or 28 days post-injury were measured using densitometry image analysis on GFAP or Iba1 immunofluorescent labeled brain tissue sections. We found that injury increased both astrocyte and microglial activation and proliferation in both young and aged brain. The young injured animals exhibited greater levels of GFAP while the aged injured animals exhibited greater levels of Iba1 expression at all three time points. We also found that short time anti-inflammatory treatment with minocycline decreased levels of Iba1 expression while increased levels of GFAP expression in both young and aged brain following injury. Our data suggests that there are differences in glial response in the injured young and aged brain that may contribute to the differences in the regenerative and recovery potential in the two age groups following injury.
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Zeigler, Michael. "THE EFFECTS OF bFGF TREATMENT IN THE AGED BRAIN FOLLOWING TRAUMATIC BRAIN INJURY." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2227.
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The mature mammalian brain continually generates new neurons in the subventricular zone and hippocampus throughout life. Adult neurogenesis in the hippocampus is associated with hippocampal-dependent learning and memory function. During aging, this endogenous neurogenic potential is reduced which is accompanied by decreased cognitive function seen in the aging population. We have previously found that the injured adult brain shows heightened levels of endogenous neurogenesis and this response is associated with innate cognitive recovery. We have also found that basic fibroblast growth factor (bFGF), a potent neurotrophic polypeptide, can enhance injury-induced hippocampal neurogenesis and improve cognitive recovery following TBI. In this study, we administered bFGF into the lateral ventricle of aged rats following TBI and assessed the effect of bFGF treatment on hippocampal neurogenesis and cognitive recovery in aged animals. Specifically, male Fisher-344 rats at the age of 20 months received intraventricular infusion of bFGF for 7 days through osmotic mini-pump immediately following a moderate lateral fluid percussion injury. To label cell proliferation, animals received daily single i.p. BrdU injections for 6 days beginning 48 hr after injury. One group of animals was perfused at 1 wk after injury to assess cell proliferation. Another group of animals was first assessed for cognitive performance using the Morris water maze (MWM) at 21-25 days post-injury, then sacrificed at 4 weeks after injury to examine differentiation of newly generated cells. Brain sections were sliced and immunostained for BrdU, early neuronal marker doublecortin (DCX) and other cell type specific markers. Results showed that at 1 week post-injury, injured-aged animals infused with either vehicle or bFGF had a significantly higher number of cell proliferation in the dentate gyrus compared to sham animals. However, cell proliferation in the bFGF-infused animals was not significantly higher than vehicle-treated animals. Nevertheless, the number of DCX-labeled early stage neurons was significantly higher in the injured bFGF-treated animals than in vehicle-treated sham and injured animals. In MWM tests, unlike what we have observed in bFGF-treated younger animals, injured aged rats treated with bFGF did not show improved cognitive function. Furthermore, at 4 weeks post-injury, higher numbers of BrdU-labeled proliferative cells persisted in both injured groups, many of these cells labeled with glial and inflammatory cell markers. Collectively, the current data suggests that bFGF can enhance neurogenesis in the injured-aged hippocampus; however, this effect is not sufficient to improve functional recovery of aged rats following TBI due to the profound injury-induced inflammatory response.
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Alahmadi, A. A. S. "Advancing our understanding of brain anatomy and function using MRI in healthy subjects and neurological diseases." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10049457/.
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Warren, Kelly. "Membrane-bound Matrix Metalloproteinases Influence Reactive Synaptogenesis Following Traumatic Brain Injury." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/118.
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Traumatic brain injury (TBI) produces axonal damage and deafferentation, triggering injury-induced synaptogenesis, a process influenced by matrix metalloproteinases (MMP) and their substrates. Here we report results of studies examining the expression and potential role of two membrane-bound MMPs, membrane-type 5-MMP (MT5-MMP) and a disintegrin and metalloproteinase-10 (ADAM-10), along with their common synaptic substrate N-cadherin, during the period of reactive synaptogenesis. Protein and mRNA expression of MT5-MMP, ADAM-10 and N-cadherin were compared in two TBI models, one exhibiting adaptive plasticity (unilateral entorhinal cortex lesion; UEC) and the other maladaptive plasticity (fluid percussion injury + bilateral EC lesions; TBI+BEC), targeting 2, 7, and 15d postinjury intervals. In adaptive UEC plasticity, membrane-bound MMP expression was elevated during synaptic degeneration (2d) and regeneration (7d), and normalized at 15d. By contrast, N-cadherin expression was significantly decreased at 2 and 7d after UEC, but increased during 15d synaptic stabilization. In maladaptive plasticity, 2d membrane-bound MMP expression was dampened compared to UEC, with persistent ADAM-10 elevation and reduced N-cadherin protein level at 15d. These results were supported by 7d microarray and qRT-PCR analyses, which showed transcript shifts in both hippocampus and dentate molecular layer (ML) for each model. Parallel immunohistochemistry revealed significant MT5-MMP, ADAM-10 and N-cadherin localization within ML reactive astrocytes, suggesting a glial synthetic or phagocytotic role for their processing during recovery. We also investigated the effect of MMP inhibition on molecular, electrophysiological, behavioral and structural outcome at 15d following TBI+BEC. MMP inhibitor GM6001 was administered at 6 and 7d postinjury, during elevated MT5-MMP/ADAM-10 expression and synapse regeneration. MMP inhibition showed: 1) reduced ADAM-10 and elevated N-cadherin protein expression, generating profiles similar to 15d post-UEC, 2) attenuation of deficits in the initiation phase of long-term potentiation, and 3) improved hippocampal dendritic and synaptic ultrastructure. Collectively, our results provide evidence that membrane-bound MMPs and N-cadherin influence both adaptive and maladaptive plasticity in a time and injury-dependent manner. Inhibition of membrane-bound MMPs during maladaptive plasticity produces more adaptive conditions, improving synaptic efficacy and structure. Thus, targeting MMP function and expression have potential to translate maladaptive plasticity into an adaptive process, facilitating improved recovery.
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Robbins, Steven M. "Anatomical standardization of the human brain in euclidean 3-space and on the cortical 2-manifold." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84315.
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Anatomical standardization (also called spatial normalization) is a key process in cross-sectional studies of brain structure and function using MRI, fMRI, PET and other imaging techniques. This process has two components: (i) specification of a 3D template brain, which defines a common coordinate space for analysis of any subsequent datasets; and (ii) a method to align the template with an individual 3D brain image, thereby associating each point of the standard template to a point on the individual. The association should be able to consistently match a particular template location to an anatomically corresponding location on each individual of a population.Standardization methods in widespread use employ a 3D affine spatial transformation to map from the individual to the template, which matches only overall size and gross shape of the input brain. A wide range of more flexible image deformation algorithms have been developed in order to better match fine detail. All such algorithms involve design choices that are subject to debate, and most have numerical parameters whose value must be specified by the user. In order to provide guidance for such choices, the first part of this thesis develops two measures of alignment consistency that are used to evaluate performance of a standardization method. The performance of different choices for algorithm design, numerical parameters, and template selection strategy for 3D normalization are compared.
Since the processing of brain function occurs on a thin, highly convoluted sheet of cortex along the surface of the brain, there has been much recent interest in studying the structure and function along the brain cortex only, modelled as a 2D manifold. The second part of this thesis proposes an algorithm for highly-flexible deformation in 2D of a template cortex to an individual. The alignment consistency measures developed for 3D are reformulated for the 2D manifold and used to evaluate the algorithm design and numerical parameters. Finally, the question of whether it is better to standardize the 3D images or the 2D cortical manifold is addressed, identifying the problem classes which are best suited to each type of normalization.
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Ryan, E. N. "Studies on the role of calcium in the regulation of tyrosine hydroxylase in the rat brain." Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371575.
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Khalil, Omari S. "Effects on brain development of prenatal inhibition of Kynurenine-3-Monooxygenase." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5075/.
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Much is known about the disease pathology related to schizophrenia, however, little is known with regards to its aetiology. Recent evidences suggest a neurodevelopmental hypothesis for schizophrenia where environmental factors including: infection, stress and malnutrition, can adversely affect the pregnant mother thereby elevating the risk for schizophrenia developing in the offspring during adulthood (Meyer et al., 2008d; Meyer and Feldon, 2009; 2012; Forrest et al., 2012; Meyer, 2013). Since a variety of viral and bacterial infections in animal models have demonstrated to increase the risk in schizophrenia, it is proposed that factors common to the immune response may mediate this link. While many laboratories have reported several behavioural abnormalities following maternal immune activation, we sought to examine molecular changes following poly(I:C) exposure, a synthetic viral mimetic, in the pregnant mother and assessed a range of protein markers with known developmental roles, since an appreciable understanding of the molecular alterations taking place would permit suitable therapies to follow. Interestingly, poly(I:C) was able to induce a range of changes resembling those observed during schizophrenia, where the major NMDA receptor subunit GluN1 and α-Synuclein was reduced in postnatal day 21 animals born to mothers treated with poly(I:C) during gestation days 14, 16 and 18. Furthermore, these changes suggest a mechanism by which maternal immune activation may lead to the subsequent emergence of schizophrenia. Another aspect of this work examined the role of the kynurenine pathway on brain development. There is increasing evidence suggesting the involvement of the kynurenine pathway, a biochemical pathway responsible for the oxidative metabolism of tryptophan, in the disease pathology of schizophrenia, including neurodegenerative disorders such as Parkinson’s, Alzheimer’s and Huntington’s disease (Giorgini et al., 2005; Ting et al., 2009; Bonda et al., 2010). Since immune activation induces the activation of the kynurenine pathway, it was hypothesised that alterations in central kynurenine concentrations during development may be involved in mediating the subsequent increased risk for schizophrenia (Forrest et al., 2013, Khalil et al., 2013, 2014). As very little is known about the physiological activity of the kynurenine pathway during development, we sought to examine the potential consequence of disrupting this pathway and examining its effects upon brain development. Therefore, a kynurenine monooxygenase inhibitor, Ro61-8048, was administered to pregnant rats during gestation day 14, 16, and 18, that would inhibit the synthesis of the neurotoxic metabolite quinolinic acid, while redirecting the pathway to increase the neuroprotectant kynurenic acid. Brain development was assessed by examining changes in protein expression of markers intimately involved in synaptic transmitter release machinery, neurogenesis and many aspects of neuronal development. Interestingly, we found the kynurenine pathway is highly active during brain development, and induces a variety of changes in protein markers that may be involved in precipitating a range of neuronal and cognitive deficits. While Ro61-8048 induced no changes in the embryo brains at 5 and 24 h following treatment, delayed changes were seen in postnatal day 21 animals displaying a decrease in RhoB expression as examined in the western blots. Since the full blow symptoms of schizophrenia become apparent during early adulthood, we sought to examine any changes in protein expression in postnatal day 60 animals in regions of the cortex, hippocampus, midbrain and cerebellum. Interestingly, profound alterations were seen in doublecortin and the netrin receptors responsible for axonal guidance. Perhaps the most striking protein change in the postnatal day 60 animals is the significant alteration induced in the expression of disrupted in schizophrenia (DISC)-1, a protein strongly linked with schizophrenia. Glutamate function was assessed as indicated by the density of glutamate transporters, VGLUT-1 and VGLUT-2, in the CA1 region of the hippocampus of postnatal day 60 animals using immunocytochemistry. While the relative density of glutamate transporters were substantially increased, there were no changes in the GABA transporters, indicating that while GABA transmission remained the same, glutamate function may have increased in the absence of an increase in synaptic connections. Spine densities of pyramidal neurons in the hippocampus were also examined, using the golgi-impregnation method, to reveal a significant loss in spines of the apical and basal dendrites, consistent with reports in schizophrenia. To conclude, the kynurenine pathway is highly active during development, and alterations in central kynurenines during pregnancy, as induced by environmental factors such as stress and infection, may be involved in the subsequent emergence of neurodevelopmental disorders.
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Thomas, Adam G. "Brain plasticity and aerobic fitness." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:c941d5b2-4b37-420a-be3f-d71e753fc8d6.
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Regular aerobic exercise has a wide range of positive effects on health and cognition. Exercise has been demonstrated to provide a particularly powerful and replicable method of triggering a wide range of structural changes within both human and animal brains. However, the details and mechanisms of these changes remain poorly understood. This thesis undertakes a comprehensive examination of the relationship between brain plasticity and aerobic exercise. A large, longitudinal experiment was conducted in which healthy but sedentary participants were scanned before and after six-weeks of monitored aerobic exercise. Increases in the volume of the anterior hippocampus were observed, as previously reported in an older cohort after a longer exercise intervention. Multimodal imaging methods allowed an in-depth exploration of the mechanisms underlying this volume change, which proved to be dominated by white matter changes rather than the vascular changes that have been previously reported. A surprising global change in the balance of CSF, blood, and brain tissue within the cranial cavity was also observed. Cross-sectional differences in memory and brain structure associated with fitness were also observed. The volume of the anterior hippocampus was shown to correlate with a measure of working memory. Higher cerebral blood volume throughout the brain was found to correlate with greater fitness and better working memory. Focal associations between fitness and magnetic susceptibility, a measure of iron content, were also observed in the basal ganglia. These findings demonstrate that aerobic fitness is associated with improved cognition and brain structure throughout the lifespan rather than simply acting to mitigate age related brain atrophy or accelerate brain development. Finally, a new pipeline was developed for analysing hippocampal morphometry using high-resolution, 7 Tesla scans. Striking variability in the convolution of the hippocampal surface is reported. This technique shows promise for imaging the precise nature of the change in hippocampal volume associated with aerobic exercise. This thesis adds to the evidence that aerobic exercise is a potent catalyst for behavioural and brain plasticity while also demonstrating that the mechanisms for those plastic changes are likely different than previously supposed. Future work will refine these measurement techniques, perhaps to a point where brain changes can be monitored on a single subject level. This work will provide an important tool to understand how best to utilize aerobic exercise to facilitate adaptive behavioural changes, mitigate the negative effects of ageing and disease on the brain, and maximize the benefits of active lifestyles.
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Shukla, Anshu. "A Model for Studying Vasogenic Brain Edema." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/1690.
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Kulkarni, Praveen P. "Functional MRI Data Analysis Techniques and Strategies to Map the Olfactory System of a Rat Brain." Digital WPI, 2006. https://digitalcommons.wpi.edu/etd-dissertations/37.
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Understanding mysteries of a brain represents one of the great challenges for modern science. Functional magnetic resonance imaging (fMRI) has two features that make it unique amongst other imaging modalities used in behavioral neuroscience. First, it can be entirely non-invasive and second, fMRI has the spatial and temporal resolution to resolve patterns of neuronal activity across the entire brain in less than a minute. fMRI indirectly detects neural activity in different parts of the brain by comparing contrast in MR signal intensity prior to and following stimulation. Areas of the brain with increased synaptic and neuronal activity require increased levels of oxygen to sustain this activity. Enhanced brain activity is accompanied by an increase in metabolism followed by increases in blood flow and blood volume. The enhanced blood flow usually exceeds the metabolic demand exposing the active brain area to high level of oxygenated hemoglobin. Oxygenated hemoglobin increases the MR signal intensity that can be detected in MR scanner. This relatively straight forward scenario is, unfortunately, oversimplified. The fMRI signal change to noise ratio is extremely small. In this work a quantitative analysis strategy to analyze fMRI data was successfully developed, implemented and optimized for the rat brain. Therein, each subject is registered or aligned to a complete volume-segmented rat atlas. The matrices that transformed the subject's anatomy to the atlas space are used to embed each slice within the atlas. All transformed pixel locations of the anatomy images are tagged with the segmented atlas major and minor regions creating a fully segmented representation of each subject. This task required the development of a full 3D surface atlas based upon 2D non-uniformly spaced 2D slices from an existing atlas. A multiple materials marching cube (M3C) algorithm was used to generate these 1277 subvolumes. After this process, they were coalesced into a dozen major zones of the brain (amygdaloid complex, cerebrum, cerebellum, hypothalamus, etc.). Each major brain category was subdivided into approximately 10 sub-major zones. Many scientists are interested in behavior and reactions to pain, pleasure, smell, for example. Consequently, the 3D volume atlas was segmented into functional zones as well as the anatomical regions. A utility (program) called Tree Browser was developed to interactively display and choose different anatomical and/or functional areas. Statistical t-tests are performed to determine activation on each subject within their original coordinate system. Due to the multiple t-test analyses performed, a false-positive detection controlling mechanism was introduced. A statistical composite of five components was created for each group. The individual analyses were summed within groups. The strategy developed in this work is unique as it registers segments and analyzes multiple subjects and presents a composite response of the whole group. This strategy is robust, incredibly fast and statistically powerful. The power of this system was demonstrated by mapping the olfactory system of a rat brain. Synchronized changes in neuronal activity across multiple subjects and brain areas can be viewed as functional neuro-anatomical circuits coordinating the thoughts, memories and emotions for particular behaviors using this fMRI module.
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nottingham, charles. "modeling pure vasogenic edema in the rat brain." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1578.
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Targeted drug delivery to the brain is difficult to achieve using conventional techniques, largely due to the blood-brain barrier’s (BBB) impediment to drug diffusion into the brain parenchyma. In response, development of convection-enhanced delivery (CED) offers the ability to circumvent the BBB and target specific areas of the brain. Predictability of infusate movement in pathological brain states during CED will maximize the effectiveness of this treatment, and therefore modeling of infusate movement must be characterized. Previous work from our lab effectively modeled CED in rats using the middle carotid artery occlusion model of cytotoxic edema. However, previous models examined for vasogenic edema study did not show pure vasogenic edema. The purpose of this study was to develop a model of pure vasogenic edema in the rat brain. In this study, we show that stereotactic 9 µL infusion of 1.0 mM DCA over 45 minutes into the rat corpus callosum reproducibly creates pure vasogenic edema, as observed in the peritumoral white matter surrounding gliomas.
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McCarthy, Gerald Francis. "The production and fate of astrocytes and oligodendrocytes in the brain of the adult and aged mouse as shown by radioautography of the corpus callosum following pulse injection and continuous 3H-thymidine infusion /." Thesis, McGill University, 1985. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=72048.
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Glial cells are actively produced during the growth of the mouse central nervous system, during young adult life, but it is not known whether this cell production continues throughout the life of an animal. This problem was examined by radioautography of the corpus callosum of aged, 9 to 10-month old and adult, 4-month old mice, each given an intraperitoneal pulse injection or continuous subcutaneous infusion of 3H-thymidine and then randomly assigned to one of the following experimental groups: aged and adult mice, a 2 hour group of 5 and 6 mice, respectively, which received a single intraperitoneal pulse injection of 5 uCi per g body weight and were sacrificed 2 hours later; aged mice, a 30 day group in which 5 mice were continuously infused with 3H-thymidine at the rate of 1 uCi per g body weight per day and were sacrificed by perfusion at day 30; aged mice, a 30 + 60 day group of 2 mice and a 30 + 180 day group of 3 mice which were continuously infused with 3H-thymidine for 30 days and then left untreated for 60 or 180 days, respectively, before sacrifice; adult mice, a 7 and 15 day group in which 6 and 5 mice, respectively, were continuously infused with 3H-thymidine at the rate of 1 uCi per g body weight per day and were sacrificed by perfusion at day 7 and 15, respectively. A total of 11,114 and 14,169 glial cells were counted in the corpus callosum of aged and adult mice using toluidine-blue stained preparations. The results for the aged mice are as follows. In the 2 hour group, the labelled cells were found to be immature glial precursor cells with a labelling index of 8.15%. These cells showed a labelling index of 18.69% in the 30 day group and 0% and 0%, respectively, in the 30 + 60 and 30 + 180 day groups. These results indicate "renewal" of the precursor cells. Mature oligodendrocytes or astrocytes were not labelled in the 2 hour group. In the 30 day group their labelling index was 1.12% and 11.90%, respectively. The oligodendrocyte index remained at
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Osburn, James Roy. "Importance of the kappa opoid system for ultrasonic vocalizations of young rats: Role of peripherally-versus centrally-located kappa opioid receptors." CSUSB ScholarWorks, 2008. https://scholarworks.lib.csusb.edu/etd-project/3378.
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Clark, Jordan Mills. "ROLE OF CYCLOPHILIN D IN SECONDARY SPINAL CORD AND BRAIN INJURY." UKnowledge, 2009. http://uknowledge.uky.edu/gradschool_diss/730.
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In the hours and days following acute CNS injury, a secondary wave of events is initiated that exacerbate spinal tissue damage and neuronal cell death. A potential mechanism driving these secondary events is opening of the mitochondrial permeability transition pore (mPTP) and subsequent release of several cell death proteins. Previous studies have shown that inhibition of cyclophilin D(CypD), the key regulating component in mPTP opening, was protective against insults that induce necrotic cell death. We therefore hypothesized that CypD-null mice would show improved functional and pathological outcomes following spinal cord injury (SCI) and traumatic brain injury (TBI). Moderate and severe spinal contusion was produced in wild-type (WT) and CypD-null mice at the T-10 level using the Infinite Horizon impactor. Changes in locomotor function were evaluated using the Basso Mouse Scale (BMS) at 3 days post-injury followed by weekly testing for 4 weeks. Histological assessment of tissue sparing and lesion volume was performed 4 weeks post SCI. Calpain activity, measured by calpain-mediated spectrin degradation, was assessed in moderate injury only by western blot 24 hours post SCI. Results showed that following moderate SCI, CypD-null mice had no significant improvement in locomotor recovery or tissue sparing compared to wild-type mice. Following severe SCI, CypD-null mice showed significantly lower locomotor recovery and decreased tissue sparing compared to WT mice. Calpain-mediated spectrin degradation was not significantly reduced in CypD-null mice compared to WT mice 24h post moderate SCI. The lack of protective effects in CypD-null mice suggests that more dominant mechanisms are involved in the pathology of SCI. In addition, CypD may have a pro survival role that is dependent on the severity of the spinal cord injury.
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Harvin, Ashley. "The Effect of Minocycline Treatment on Cell Proliferation and Neurogenesis in the Hippocampus in Young and Aged Brains Following Traumatic Brain Injury." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2747.
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Following traumatic brain injury, there is an enhanced cell proliferative and neurogenic response in the young adult hippocampus, which may be associated with innate cognitive recovery. However, in the aged brain, an increased level of inflammatory cell responses was observed following injury concomitant to decreased hippocampal neurogenesis and cognitive recovery in the aging population. This suggests that excessive inflammation produced in the injured aging brain has a detrimental effect on neurogenesis and cognitive function. In this study, we examined the effect of anti-inflammatory treatment with minocycline on cell proliferation and generation of new neurons in the dentate gyrus (DG) of the hippocampus in both young and aged rats. Fisher 344 rats aged at 3 months and 20 months were subjected to a moderate lateral fluid percussion injury (LFPI) or cortical impact injury (CCI). Minocycline was administered intraperitoneally starting either at 30 minutes or 4 hours post-injury, thereafter twice daily for 2 days. BrdU was injected at 2 days post-injury to label injury-induced proliferating cells. To examine the effect of minocycline on cell proliferation, generation of new neurons, and inflammatory cell response at the acute stage post-injury, the rats were perfused 3 days post-injury. Brain sections were immunostained for BrdU and early neuronal marker doublecortin (DCX). The results show that short-term anti-inflammatory treatment with minocycline reduces the cell proliferative response, presumably inflammatory cell responses, in young and aged rats following LFPI and CCI injury, and enhances generation of new neurons in the hippocampus in both young and aged rats following LFPI and in aged rats following CCI injury. Therapies that enhance hippocampal neurogenesis may also have potential to improve cognitive recovery following TBI.
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Seto, David. "Anatomical and functional study of interleukin-2 in the brain : possible neuromodulatory significance." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0003/NQ30382.pdf.
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Hallgren, Stefan. "Brain Aromatase in the guppy, Poecilia reticulata : Distribution, control and role in behaviour." Doctoral thesis, Stockholm : Zoologiska institutionen, Stockholms universitet : Södertörns högskola, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-26942.
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Gilmer, Lesley Knight. "AGE MAY BE HAZARDOUS TO OUTCOME FOLLOWING TRAUMATIC BRAIN INJURY: THE MITOCHONDRIAL CONNECTION." Lexington, Ky. : [University of Kentucky Libraries], 2009. http://hdl.handle.net/10225/1135.
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Thesis (Ph. D.)--University of Kentucky, 2009.Title from document title page (viewed on May 11, 2010). Document formatted into pages; contains: viii, 161 p. : ill. Includes abstract and vita. Includes bibliographical references (p. 130-154).
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Daus, Janice Mabutas. "Assessing Epidermal Growth Factor Expression in the Rodent Hippocampus Following Traumatic Brain Injury." VCU Scholars Compass, 2006. http://hdl.handle.net/10156/1463.
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Davis, Laurie Michelle Helene. "THE UNDERLYING MECHANISM(S) OF FASTING INDUCED NEUROPROTECTION AFTER MODERATE TRAUMATIC BRAIN INJURY." UKnowledge, 2008. http://uknowledge.uky.edu/gradschool_diss/673.
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Traumatic brain injury (TBI) is becoming a national epidemic, as it accounts for 1.5 million cases each year. This disorder affects primarily the young population and elderly. Currently, there is no treatment for TBI, which means that ~2% of the U.S. population is currently living with prolonged neurological damage and dysfunction. Recently, there have been many studies showing that TBI negatively impacts mitochondrial function. It has been proposed that in order to save the cell from destruction mitochondrial function must be preserved. The ketogenic diet, originally designed to mimic fasting physiology, is effective in treating epilepsy. Therefore, we have used fasting as a post injury treatment and attempted to elucidate its underlying mechanism. 24 hours of fasting after a moderate TBI increased tissue sparing, cognitive recovery, improved mitochondrial function, and decreased mitochondrial biomarkers of injury. Fasting results in hypoglycemia, the production of ketones, and the upregulation of free fatty acids (FFA). As such, we investigated the neuroprotective effect of hypoglycemia in the absence of fasting through insulin administration. Insulin administration was not neuroprotective and increased mortality in some treatment groups. However, ketone administration resulted in increased tissue sparing. Also, reduced reactive oxygen species (ROS) production, increased the efficiency of NADH utilization, and increased respiratory function. FFAs and uncoupling proteins (UCP) have been implicated in an endogenously regulated anti-ROS mechanism. FFAs of various chain lengths and saturation were screened for their ability to activate UCP mediated mitochondrial respiration and attenuate ROS production. We also measured FFA levels in serum, brain, and CSF after a 24 hour fast. We also used UCP2 transgenic overexpressing and knockout mice in our CCI injury model, which showed UCP2 overexpression increased tissue sparing, however UCP2 deficient mice did not show a decrease in tissue sparing, compared with their wild type littermates. Together our results indicate that post injury initiated fasting is neuroprotective and that this treatment is able to preserve mitochondrial function. Our work also indicates ketones and UCPs may be working together to preserve mitochondrial and cellular function in a concerted mechanism, and that this cooperative system is the underlying mechanism of fasting induced neuroprotection.
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Reid, Wendy. "THE EFFECTS OF ATOMOXETINE ON COGNITIVE PERFORMACE AND NEUROPLASTICITY AFTER TRAUMATIC BRAIN INJURY." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1562.
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Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-TBI pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The studies in this dissertation were designed to test the efficacy of atomoxetine for treating cognitive deficits following experimental TBI and the potential mechanism for any beneficial effect. The first part of the study focused on behavioral recovery following atomoxetine treatment. Several important questions of dose, therapeutic window, and duration of treatment were addressed in these studies. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- .05). Four experiments were performed. In the first study, atomoxetine (.3 mg/kg, 1mg/kg, 3 mg/kg, or 9 mg/kg) or vehicle was administered daily on post injury days (PID) 1-15. Cognitive assessment was performed using the Morris water maze on PID 11-15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine (.3mg/kg, 1mg/kg, and 3mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9mg/kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/kg atomoxetine. In the second study, treatment with atomoxetine (1mg/kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days and cognitive assessment was performed on PID 25-29. In this study, treatment with atomoxetine (1 mg/kg) did not result in improved cognitive performance. In the next study atomoxetine was given daily on PID 1-7 and then treatment was terminated. The animals were tested in the MWM on PID 11-15. We found that atomoxetine treatment for 7 days post-injury provides an enhancement of cognitive deficits that is not significantly different from sham animals. We then investigated whether a single treatment of atomoxetine 24 h after brain injury could influence behavioral outcome on days 11-15. From this study, we found a single dose of atomoxetine is not as effective as chronic treatment. Finally, we investigated changes in the protein expression of brain-derived neurotrophic factor, growth-associated protein-43, and synaptophysin on day 7 PID to investigate what effect atomoxetine may have on brain plasticity and regeneration. We found that atomoxetine can enhance both GAP-43 and BDNF, but not synaptophysin at this time point. In conclusion, this is the first study to show that low doses of atomoxetine initiated early after experimental traumatic brain injury results in improved cognition. Furthermore, we show that enhancement of catecholamines via atomoxetine treatment during periods of postinjury-induced plasticity can provide long-term functional and structural benefits.
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Aravamuthan, Bhooma Rajagopalan. "Comparing the radiological anatomy, electrophysiology, and behavioral roles of the pedunculopontine and subthalamic nuclei in the normal and parkinsonian brain." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:9a735b39-c1fe-4d5f-b05f-3385f27e6e58.
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Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and DBS of the pedunculopontine nucleus (PPN) have been shown to be effective surgical therapies for Parkinson’s disease (PD). To better understand the PPN and STN as DBS targets for PD, this research compares the anatomy, electrophysiology, and motor control roles of these nuclei. PPN and STN connections were examined in vivo in human subjects and in the non-human primate using probabilistic diffusion tractography. Both the PPN and STN were connected with each other and with the motor cortex (M1) and basal ganglia. After studying these anatomical connections in primates, their functional significance was further explored in an anesthetized rat model of PD. Examination of the electrophysiological relationship between the PPN and basal ganglia in the presence of slow cortical oscillatory activity suggested that excitatory input from the STN may normally modulate PPN spike timing but that inhibitory oscillatory input from the basal ganglia output nuclei has a greater effect on PPN spike timing in the parkinsonian brain. To examine transmission and modulation of oscillatory activity between these structures at higher frequencies, LFP activity was recorded from the PPN and STN in PD patients performing simple voluntary movements. Movement-related modulation of oscillatory activity predominantly occurred in the α (8-12 Hz) and low β (12-20 Hz) frequencies in the STN but in the high β (20-35 Hz) frequencies in the PPN, supporting observations from rodent studies suggesting that oscillatory activity is not directly transmitted from the STN to the PPN in PD. Finally, to better understand the roles of the STN and PPN in large-scale movement, the effects of STN and PPN DBS on gait abnormalities in PD patients were studied. DBS of the STN appeared to improve gait by optimising executive gait control while DBS of the PPN appeared to restore autonomic gait control. These results have several implications for DBS patient selection, surgical targeting, and for understanding the mechanisms underlying DBS efficacy.
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Morhardt, Ashley C. "Gross Anatomical Brain Region Approximation (GABRA): Assessing Brain Size,Structure, and Evolution in Extinct Archosaurs." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1470743129.
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Schmidt, Verena [Verfasser]. "Comparative anatomy of the pig brain : an integrative magnetic resonance imaging (MRI) study of the porcine brain with special emphasis on the external morphology of the cerebral cortex / Verena Schmidt." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1073547787/34.
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Harris, Janna. "THE EXPRESSION AND FUNCTION OF PHOSPHACAN/RPTPβ IN ADAPTIVE SYNAPTOGENESIS AFTER TRAUMATIC BRAIN INJURY." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1839.
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Traumatic brain injury (TBI) affects 1.5 million Americans annually and is a major health concern. Increasing evidence suggests that the brain extracellular environment regulates plasticity and synaptic recovery following TBI. Here we have focused on phosphacan/RPTPβ, an alternatively spliced group of chondroitin sulfate proteoglycans which are prominent within the mature brain extracellular matrix (ECM). Previous studies show that phosphacan/RPTPβ influences neuronal migration, adhesion, neurite outgrowth, and morphogenesis. However, our understanding of how these important ECM components are involved in recovery from brain trauma remains unclear. In the present study, we used unilateral entorhinal cortex lesion (UEC), a model which induces robust hippocampal reactive plasticity, to investigate the role(s) of phosphacan/RPTPβ isoforms in adaptive synaptogenesis after TBI. Using detailed protein and mRNA quantification, immunohistochemistry, and qualitative ultrastructural analyses, we show elevated phosphacan expression in the deafferented hippocampus at the early degenerative phase and during the subsequent period of active sprouting. By contrast, the receptor variant sRPTPβ is persistently elevated in hippocampus over the first two weeks following UEC. We have further characterized a process for validating appropriate reference genes for quantitative real-time RT-PCR studies of plasticity and recovery after TBI. From these studies we conclude that injury model, brain region, survival period and correlative protein expression are critical factors which must be considered for reference gene selection. Finally, we investigated functional implications of sRPTPβ increase during reactive synaptogenesis, showing that the sRPTPβ substrate β-catenin, an important cytoskeletal regulator, is altered in hippocampus during injury-induced plasticity. Together, these results support a role for phosphacan/RPTPβ in both degenerative and regenerative phases of reactive synaptogenesis. Phosphacan may promote adaptive plasticity at earlier post-injury phases through interactions with adhesion molecules or growth factors in the extracellular space. The prolonged increase in sRPTPβ after UEC, along with its localization at postsynaptic profiles, suggests that this isoform may work with intracellular substrates to influence spine morphogenesis and/or stabilization of new synapses. Gaining a better understanding of the roles of ECM components in recovery from TBI will be an essential part of defining the difference between injuries where recovery is successful, and those where recovery fails.
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Deng, Ying. "ROLE OF THE REACTIVE OXYGEN SPECIES PEROXYNITRITE IN TRAUMATIC BRAIN INJURY." UKnowledge, 2008. http://uknowledge.uky.edu/gradschool_diss/667.
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Reactive oxygen species (ROS) is cytotoxic to the cell and is known to contribute to secondary cell death following primary traumatic brain injury (TBI). We described in our study that PN is the main mediator for both lipid peroxidation and protein nitration, and occurred almost immediately after injury. As a downstream factor to oxidative damage, the peak of Ca2+-dependent, calpainmediated cytoskeletal proteolysis preceded that of neurodegeneration, suggesting that calpain-mediated proteolysis is the common pathway leading to neuronal cell death. The time course study clearly elucidated the interrelationship of these cellular changes following TBI, provided window of opportunity for pharmacological intervention.
Furthermore, we conducted a pharmacological study to solidify our hypothesis. First of all, we tested the potency of a membrane permeable, catalytic scavenger of PN-derived free radicals, tempol for its ability to antagonize PN-induced oxidative damage. Tempol successfully inhibited PNinduced protein nitration at dosages of 30, 100 and 300mg/kg. Moreover, early single dose of 300mg/kg was administered and isolated mitochondria were examined for respiratory function and oxidative damage level. Our data showed that tempol reduced mitochondrial oxidative damage, and maintained mitochondrial function within normal limits, which suggested that tempol is efficiently permeable to mitochondrial membrane and mitochondrial oxidative damage is essential to mitochondrial dysfunction. Next, we found that calpainmediated proteolysis is reduced at early treatment with a single dose of tempol. However, the effect of tempol on calpain is short-lived possibly due to systematic elimination. In our multiple dose study, tempol showed a significant inhibitory effect on SBDPs. Consequently, we measured neuordegeneration with the de Olmos aminocupric silver staining method at 7 days post-injury and detected a significant decrease of neuronal cell death.
Together, the time course study and pharmacological study strongly support the hypothesis that PN is the upstream mediator in secondary cell death in the CCI TBI mouse model. Moreover, inhibition of PN-mediated oxidative damage with the antioxidant, tempol, is able to attenuate multiple downstream injury mechanisms. However, targeting PN alone may be clinically impractical due to its limited therapeutic window. This limitation may be overcome in future studies by a combination of multiple therapeutic strategies.
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Connell, John J. "Selective permeabilisation of the blood-brain barrier at sites of metastasis." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:8c027208-8ea6-4de4-be78-ccead5121509.
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Over one in five cancer patients will develop brain metastases and prognosis remains poor. Effective chemotherapeutics for primary systemic tumours have limited access to brain metastases owing to the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilising the BBB at sites of cerebral metastases. Tumour necrosis factor was injected intravenously into mouse models of haematogenously induced brain metastasis. BBB permeability was assessed through histology and in vivo MRI and SPECT. Tumour burden and neuroinflammation were assessed after injection of TNF with Caelyx or a novel therapeutic. Mechanism of permeabilisation was investigated through histology and receptor-specific agonist antibodies. Administration of TNF dose-dependently permeabilised the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect after six hours. Metastasis-specific uptake of radiolabelled trastuzumab was also demonstrated following systemic cytokine administration. Administration of liposomal doxorubicin formulations in conjunction with TNF reduced tumour burden and mean metastasis size. Localised expression of TNFR1 was evident on the vascular endothelium associated with brain metastases. Human brain metastases displayed a similar TNF receptor profile compared to the mouse model. These findings describe a new approach to selectively permeabilise the BBB at sites of brain metastases, thereby enabling detection of currently invisible micrometastases and facilitating tumour-specific access of chemotherapeutic agents. We hypothesize that this permeabilisation works primarily though TNFR1 activation and, owing to the similar TNFR1 expression profiles in mouse models and human condition, the strategy has the potential for clinical translation.
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O'Brien, Haley D. "Macroevolutionary Impact of Selective Brain Cooling on the Mammalian Order Artiodactyla." Ohio University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1470865971.
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Hinzman, Jason Michael. "DISRUPTIONS IN THE REGULATION OF EXTRACELLULAR GLUTAMATE IN THE RAT CENTRAL NERVOUS SYSTEM AFTER DIFFUSE BRAIN INJURY." UKnowledge, 2012. http://uknowledge.uky.edu/neurobio_etds/2.
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Glutamate, the predominant excitatory neurotransmitter in the central nervous system, is involved in almost all aspects of neurological function including cognition, motor function, memory, learning, decision making, and neuronal plasticity. For normal neurological function, glutamate signaling must be properly regulated. Disrupted glutamate regulation plays a pivotal role in the acute pathophysiology of traumatic brain injury (TBI), disrupting neuronal signaling, initiating secondary injury cascades, and producing excitotoxicity. Increases in extracellular glutamate have been correlated with unfavorable outcomes in TBI survivors, emphasizing the importance of glutamate regulation.
The aim of this thesis was to examine disruptions in the regulation of extracellular glutamate after experimental TBI. In these studies, we used glutamate-sensitive microelectrode arrays (MEAs) to examine the regulation of extracellular glutamate two days after diffuse brain injury. First, we examined which brain regions were vulnerable to post-traumatic increases in extracellular glutamate. We detected significant increases in extracellular glutamate in the dentate gyrus and striatum, which correlated to the severity of brain injury. Second, we examined the regulation of extracellular glutamate by neurons and glia to determine the mechanisms responsible for post-traumatic increases in extracellular glutamate. In the striatum of brain-injured rats, we detected significant disruptions in release of glutamate by neurons and significant decreases in the removal of glutamate from the extracellular space by glia. Third, we examined if a novel therapeutic strategy, a viral-vector mediated gene delivery approach, could improve the regulation of extracellular glutamate. Infusion of an adeno-associated virus expressing a glutamate transporter into the rat striatum produced significant improvements in glutamate clearance, identifying a novel strategy to reduce excitotoxicity. Lastly, we examined the translational potential of MEAs as novel neuromonitoring device for clinical TBI research. Overall, these studies have demonstrated the translational potential of MEAs to aid in the diagnosis and treatment of TBI survivors.
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Lam, Wilfred W. "Quantification of microscopic brain structures using diffusion magnetic resonance." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:6b10e322-3d26-4b37-aa5c-f230ffca4c85.
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Diffusion-weighted magnetic resonance imaging can be used to estimate microstructural parameters of white matter in the brain. Two complementary techniques are investigated: the use of the temporal diffusion spectrum to explore small length scales and the STEAM technique to probe larger features. The diffusion spectrum has the potential to be more sensitive to small pores compared to conventional time-dependent diffusion. However, analytical expressions for the diffusion spectrum of particles only exist for simple geometries such as cylinders, which are often used as a model for intra-axonal diffusion. We propose a mathematical model for the extra-axonal space with parameters that are related to the microstructural properties of pore size, tortuosity, and surface-to-volume ratio. Measurements were made with an extra-axonal space phantom to validate the model. Fitted values for the phantom pore size match those from simulation. We extend the model to include the intra-axonal signal contribution. However, the parameters used to describe the intra- and extra-axonal spaces are related and it is important to remove redundant parameters to avoid overparameterization, which would make the model less robust. We propose analytical expressions to simplify the model. The model was then applied to measurements on fixed corpus callosum, which is a model system consisting of parallel axons. The estimated values of the axon volume fraction and mean and standard deviation of the axon radius distribution are comparable to those found in literature. Temporal diffusion spectra are useful for measuring the geometric properties of small spaces such as axon radii. However, longer diffusion times accessible using the STEAM sequence are necessary to probe structures with longer diffusion distances such as those parallel to the direction of axons. We used a model from the literature originally developed for use with animal magnetic resonance scanners and simplified it to quantify axial hindrance from data acquired on healthy volunteers in a clinical scanner. The interpretation of axial hindrance, which is a largely unexplored area of research, is discussed.
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Fregeac, Julien. "Rôle du microARN 146a dans le développement cérébral et pertinence pour les maladies du neurodéveloppement The emerging roles of MicroRNAs in autism spectrum disorders Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders Loss of miR-146a impairs neural progenitor differentiation and causes learning and memory deficits." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB120.
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Les maladies du neurodéveloppement (MND) regroupent des pathologies caractérisées par des troubles de la cognition, de la communication, du comportement en conséquence d'un développement cérébral atypique. Les MND incluent la déficience intellectuelle (DI), les troubles du spectre autistique (TSA), le trouble du déficit de l'attention et les troubles de l'apprentissage. Avec une prévalence globale de 3%, les MND sont responsables de 10% des dépenses de santé dans les pays développés et constituent donc un défi médical et socioéconomique majeur. Les microARNs (miARNs) sont de petits ARNs non codant de ~20-22 nucléotides. Ils exercent une régulation post-transcriptionnelle de l'expression génique en dégradant ou réprimant la traduction d'ARNs messagers spécifiques. Chaque miARN ciblant plusieurs centaines de transcrits, ils constituent des médiateurs clés de l'expression génique. Les microARNs régulent la majorité des processus biologiques et notamment le développement cérébral. Plusieurs miARNs ont été associés à des pathologies neurologiques comme la maladie d'Alzheimer ou la sclérose latérale amyotrophique mais aussi à des MND telles que le TSA, la DI et l'épilepsie. Des études d'expression réalisées sur divers échantillons de patients TSA ont identifié miR-146a comme le miARN le plus fréquemment dérégulé. Une expression anormale de ce miARN a également été observée dans des cas de DI et d'épilepsie. Il est important de noter que moduler l'expression de miR-146a est suffisant pour réduire la latence, la durée et l'intensité des crises d'épilepsie induites dans des modèles rongeurs d'épilepsie télencéphalique. miR-146a est un régulateur connu des voies de signalisation NFκB, Notch et Wnt/β-caténine et a été associé à des cas de cancers et de maladies inflammatoires mais peu de choses sont connues sur ses fonctions dans le cerveau. Des travaux in vitro décrivent le rôle de miR-146a dans la survie et l'apoptose des neurones, la croissance axonale et l'endocytose des récepteurs AMPA. Notre groupe a également montré l'effet pro-neuronal de la sur-expression de miR-146a dans des cellules souches neurales humaines H9. Collectivement, ces données donnent un aperçu des fonctions de miR-146a dans des cellules en culture mais ne fournissent que peu d'informations quant à son rôle in vivo au cours du neurodéveloppement. Nous avons donc caractérisé la souris Mir146a-/- par des techniques d'imagerie, de biologie cellulaire et moléculaire ainsi que des études de comportement. Nous avons démontré que la neurogenèse est altérée dans les souris Mir146a-/-. Au jour embryonnaire 14 (E14), les embryons mutants ont plus de progéniteurs neuraux engagés vers un destin neuronal ainsi qu'un plus grand nombre de neurones post-mitotiques dans le néocortex. Grâce à des cultures de cellules primaires, nous avons montré que l'absence de miR-146a cause une augmentation de la croissance dendritique ainsi qu'une altération de la recapture du glutamate par les astrocytes et nous avons prouvé que le transporteur de glutamate GLT-1 est une cible directe de miR-146a. Des analyses transcriptomiques sur des échantillons de cerveau à E14, P30 et P60 indiquent que la perte de miR-146a affecte principalement les neurones. Enfin, des analyses par IRM et des études de comportement montrent une anatomie anormale de l'hippocampe ainsi qu'une altération des capacités d'apprentissage chez les souris mutantes. Ce travail décrit une des premières caractérisations du neurodéveloppement d'un modèle murin inactivé pour un miARN. Il montre que miR-146a est impliqué dans le contrôle de la balance entre renouvellement des progéniteurs neuraux et différentiation neuronale. Il démontre également que plusieurs signes retrouvés chez les patients comme l'altération de la neurogenèse, l'anatomie anormale du cerveau et les défauts d'apprentissage, sont également observés chez les souris Mir146a-/-, soulignant la pertinence de ce modèle pour l'étude des maladies du neurodéveloppementDevelopmental brain disorders (DBD) encompass a group of diseases characterised by impairments in cognition, communication, behaviour or motor functioning as a result of atypical brain development. This group includes intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder, specific learning disorder and motor disorders. With an overall prevalence of 3 %, DBD accounts for 10% of the total health care cost in Western countries and is thus a major medical and socio-economical challenge. MicroRNAs (miRNAs) are small non coding RNAs of ~20-22 nucleotides. They play a key role in post-transcriptional gene expression regulation by targeting specific messenger RNA (mRNA) for degradation or translation repression. miRNAs are key mediator of gene expression as each of them can target hundreds of transcripts. miRNAs are expressed throughout the development and life of most eukaryote organisms and regulate a wide range of biological processes including brain development. Consistently, several miRNAs have been associated with neurological pathologies such as Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS) but also with (DBD) namely ASD, ID and epilepsy. Expression studies performed on various sources of samples from ASD patients identified miR-146a as the most commonly deregulated miRNA. It has been reported in four different cohorts and tissue types including post-mortem brain, olfactory mucosal stem cells, fibroblasts and lymphoblastoid cell lines. Abnormal miR-146a expression has also been reported in ID and epilepsy. Importantly, modulating the expression of this particular miRNA was shown to reduce the latency, the duration as well as the intensity of the induced epilepsy in rodent models of telecephalon epilepsy. miR-146a is a known regulator of NFkB, Notch and Wnt/B-catenin pathways and has been associated with cancers and inflammatory disorders but little is known about its functions in the brain. A body of in vitro work describes the role of miR-146a in neuron survival and apoptosis, axonal growth and AMPA receptor endocytosis. Our group also showed the pro-neuronal effects of miRNA overexpression in a H9 model of human neural stem cells. Altogether, these data provide insight into the roles of miR-146a in cultured cells but give no indication on its functions in vivo during neurodevelopment. To investigate this aspect further, we studied a miR146a-/- mouse model using a combination of imaging, molecular and cell biology techniques as well as behavioral studies. We first demonstrated that neurogenesis is altered in miR146a-/-mice. At embryonic day 14 (E14), mutant embryos display increased number of neural progenitors committed towards a neuronal fate as well as more post-mitotic neurons in the neocortex compared to controls. Using primary cell cultures,we found that loss of miR-146a causes increased neurite outgrowth and impaired astrocyte glutamate uptake capacities and we proved the glutamate transporter GLT-1 to be a direct target of miR-146a. Transcriptomic analyses of brain samples at E14, P30 and P60 indicated spatial- and temporal-specific effects of miR-146a inactivation and, consistent with our findings, we observed that loss of miR-146a mainly impacts neuron development. Lastly, brain MRI and behavior investigations revealed an abnormal hippocampal anatomy as well as impaired learning capacities in mutant mice. This work reports the first characterization of a mouse model inactivated for a miRNA in the context of neurodevelopment. We demonstrated the role of miR-146a in brain development and its role in the control of the balance between neural progenitor cell renewal and neuronal differentiation. Lastly, we show the relevance of the miR146a-/-mouse model to study DBD as several aspects recapitulate the features observed in patients, including impaired neurogenesis, abnormal brain anatomy and learning deficits