The aim of this study was to further investigate the role of pro-inflammatory cytokines in the pathogenesis of fetal cererbral white matter injury associated with chorioamnionitis by charaterizing the time course of the cytokine response in the pregnant guinea pig following a maternal inflammatory insult. Chorioamnionitis increases the risk for fetal brain injury. In the guinea pig, a threshold maternal inflammatory response must be reached for significant fetal brain injury to occur. However, a previous study demonstrated that, by seven days after an acute maternal inflammatory insult, cytokine levels in both maternal and fetal compartments are not different from controls. The purpose of this study, therefore, was to test the hypothesis that a significant cytokine response occurs within the first seven days following an acute maternal inflammatory response. Pregnant guinea pigs (n=34) were injected intraperitoneally with 100µg/kg lipopolysaccharide (LPS) at 70% gestation and euthanized at 24 hours, 48 hours or 5 days following endotoxin exposure. Control animals were euthanized at 70% gestation without exposure. Concentrations of interleukin-6, interleukin 1-β and tumour necrosis factor-α (IL-6, IL-1β, TNF-α) were quantified in the maternal serum and amniotic fluid by enzyme-linked immunosorbent assay. IL-6 and IL-1β concentrations were elevated in the maternal serum at 24 hours and returned to control levels by five days. In the amniotic fluid, IL-6 peaked at 48 hours and IL-1β at 24 hours. TNF-α levels were not significantly increased. A single maternal LPS injection produces transient increases in cytokine concentrations in the maternal serum and amniotic fluid. This further implicates the cytokines as potential mediators of fetal white matter damage. Although this response might not be sufficient to produce the brain injury itself, it may initiate harmful pro-inflammatory cytokine cascades, which could even continue to harm the fetus following delivery. A human diagnostic protocol was developed to assess the use of serial serum biomarkers, including IL-6 and TNF-α, in the prediction of histological chorioamnionitis. Preliminary analysis of the pilot study suggests that certain biomarkers might be worthy of further investigation in a larger-scale study. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2007-11-28 08:23:04.327

La connaissance de la forme et de la fonction des faisceaux d'association aide à la modélisation des réseaux cognitifs, sert au développement d'abords neurochirurgicaux et à l'interprétation de la neuro-imagerie. Nous avons employé une approche hybride anatomique et neurophysiologique dont l'objectif principal a été la caractérisation des sous-parties du complexe faisceau longitudinal supérieur / faisceau arqué (FLS/FA) et de leur participation dans les fonctions langagières articulatoire, phonologique et sémantique. Soixante-huit hémisphères cérébraux ont été préparés par une variante de la technique de dissection de fibres connue sous le nom de méthode de Klingler. En parallèle, nous avons étudié les cartographies fonctionnelles électriques de quatorze patients opérés en condition éveillée pour des tumeurs cérébrales dans le carrefour temporo-pariétal de l'hémisphère dominant. En se basant sur nos constatations en laboratoire, sur la neuro-imagerie et sur la littérature disponible, nous avons procédé à la mise en corrélation des manifestations cliniques provoquées par la stimulation électrique et la topographie des faisceaux d'association. Les préparations anatomiques ont permis d'étudier l'organisation tridimensionnelle de la substance blanche hémisphérique, de réaliser la première description par dissection de fibres du faisceau longitudinal moyen et de caractériser trois composants du FLS/FA : le majeur, le ventral et l'arqué. L'existence d'un composant dorsal le long du bord supérieur de l'hémisphère, hypothèse basée sur l'anatomie du primate non humain et sur la neuro-imagerie, n'a pas été confirmée. L'anatomie fonctionnelle du lobule pariétal inférieur a été revisitée ainsi que celle des voies de substance blanche à l'intérieur. La variabilité interindividuelle dans la distribution des aires fonctionnelles a été évidente, surtout pour le langage. Ces aires ont servi à délimiter la résection tumorale, à savoir : le cortex sensitif primaire, en avant ; l'aire de Wernicke, en inféro-latéral ; et les voies de substance blanche du FLS/FA en profondeur. A ce niveau, l'observation des manifestations cliniques induites par la perturbation électrique ont permis de conclure que le composant ventral operculaire du FLS/FA joue un rôle dans la fonction articulatoire et que le composant arqué, plus profond, est impliqué dans la fonction phonologique. L'exploration fonctionnelle n'a pas fourni d'argument en faveur d'une participation de ce complexe associatif dans le traitement sémantique, une hypothèse de la littérature basée sur la neuro-imagerie uniquement. Ces constatations peuvent avoir des implications importantes, tant dans la pratique clinique que dans la recherche fondamentale, notamment en ce qui concerne la modélisation des bases neurales du langage. / The knowledge of the form and function of fiber pathways supports the modeling of cognitive networks, the development of neurosurgical approaches and the interpretation of neuroimaging. We used a hybrid anatomical and neurophysiological methodology whose main objective was to characterize the subunits of the complex comprised of the Superior Longitudinal and the Arcuate Fasciculus (SLF/AF) as well as their participation in the articulatory, phonological and semantic language functions. Sixty-eight cerebral hemispheres were prepared using a variant of the fiber dissection technique known as the Klingler's method. In parallel, we studied the electrical functional maps of fourteen patients operated on using a sleep-awake-sleep technique for brain tumors of the temporo-parietal junction in the dominant hemisphere. Based on our laboratory and neuroimaging findings, as well as on the available literature, we conducted a correlation of clinical manifestations caused by the electrical stimulation and the topography of the association bundles. The anatomical preparations allowed us to detail the three-dimensional organization of hemispheric white matter, to perform the first description of the Middle Longitudinal Fasciculus using fiber dissection, and to characterize three of the four components of the SLF: the major, the ventral and the arcuate. The existence of a dorsal component along the superior edge of the hemisphere was not confirmed by our findings, a hypothesis in the literature that was based on the anatomy of the nonhuman primate and on previous studies on neuroimaging. The functional anatomy of the inferior parietal lobule was revisited as well as the pathways of white matter in its depth. The inter-individual variability in the distribution of eloquent areas was evident, especially for language. These areas were used to delineate the tumor resection, namely: the primary sensory cortex, anteriorly; the Wernicke's area, inferiorly and laterally, and the white matter pathways from the SLF/AF in the white matter. At this level, the observation of the clinical manifestations in connection with the electrical disturbance caused by the cerebral stimulation allowed us to conclude that the ventral opercular component of the SLF has a role in the articulatory function and the deeper arcuate component is involved in the phonological function. The functional mapping does not provide any argument for a participation of this association complex in the treatment of semantics, an assumption in the literature that was based only on neuroimaging. These findings may have important implications, both in clinical practice and in fundamental research, including for modeling the neural basis of language.