In recent years, increased focus has been placed on the role of intrauterine infection and inflammation in the pathogenesis of fetal brain injury leading to neurodevelopmental disorders such as cerebral palsy. At present, the mechanisms by which inflammatory processes during pregnancy cause this effect on the fetus are poorly understood. Our previous work has indicated an association between experimentally-induced intrauterine infection, increased proinflammatory cytokines, and increased white matter injury in the guinea pig fetus. In order to further elucidate the pathways by which inflammation in the maternal system or the fetal membranes leads to fetal impairment, a number of studies investigating aspects of the disease process have been performed. These studies represent a body of work encompassing novel research and results in a number of human and animal studies. Using a guinea pig model of inflammation, increased amniotic fluid proinflammatory cytokines and fetal brain injury were found after a maternal inflammatory response was initiated using endotoxin. In order to more closely monitor the fetal response to chorioamnionitis, a model using the chronically catheterized fetal ovine was carried out. This study demonstrated the adverse effects on fetal white matter after intrauterine exposure to bacterial inoculation, though the physiological parameters of the fetus were relatively stable throughout the experimental protocol, even when challenged with intermittent hypoxic episodes. The placenta is an important mediator between mother and fetus during gestation, though its role in the inflammatory process is largely undefined. Studies on the placental role in the inflammatory process were undertaken, and the limited ability of proinflammatory cytokines and endotoxin to cross the placenta are detailed herein. Neurodevelopmental disorders can be monitored in animal models in order to determine effective disease models for characterization of injury and use in therapeutic strategies. Our characterizations of postnatal behaviour in the guinea pig model using motility monitoring and spatial memory testing have shown small but significant differences in pups exposed to inflammatory processes in utero. The data presented herein contributes a breadth of knowledge to the ongoing elucidation of the pathways by which fetal brain injury occurs. Determining the pathway of damage will lead to discovery of diagnostic criteria, while determining the vulnerabilities of the developing fetus is essential in formulating therapeutic options. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2008-03-06 20:24:03.417

Ultrasound screening has been used for decades as the main modality to examine fetal brain development and to diagnose possible anomalies. However, basic clinical ultrasound examination of the fetal head is limited to axial planes of the brain and linear measurements which may have restrained its potential and efficacy. The recent introduction of three-dimensional (3D) ultrasound provides the opportunity to navigate to different anatomical planes and to evaluate structures in 3D within the developing brain. Regardless of acquisition methods, interpreting 2D/3D ultrasound fetal brain images require considerable skill and time. In this thesis, a series of automatic image analysis algorithms are proposed that exploit the rich sonographic patterns captured by the scans and help to simplify clinical examination. The original contributions include: 1. An original skull detection method for 3D ultrasound images, which achieves mean accuracy of 2.2 ± 1.6 mm compared to the ground truth (GT). In addition, the algorithm is utilised for accurate automated measurement of essential biometry in standard examinations: biparietal diameter (mean accuracy: 2.1 ± 1.4 mm) and head circumference (mean accuracy: 4.5 ± 3.7 mm). 2. A plane detection algorithm. It automatically extracts mid-sagittal plane that provides visualization of midline structures, which are crucial to assess central nervous system malformations. The automated planes are in accordance with manual ones (within 3.0 ± 3.5°). 3. A general segmentation framework for delineating fetal brain structures in 2D images. The automatically generated predictions are found to be agreed with the manual delineations (mean dice-similarity coefficient: 0.79 ± 0.07). As a by-product, the algorithm generated automated biometry. The results might be further utilized for morphological evaluation in future research. 4. An efficient localization model that is able to pinpoint the 3D locations of five key brain structures that are examined in a routine clinical examination. The predictions correlate with the ground truth: the average centre deviation is 1.8 ± 1.4 mm, and the size difference between them is 1.9 ± 1.5 mm. The application of this model may greatly reduce the time required for routine examination in clinical practice. 5. A 3D affine registration pipeline. Leveraging the power of convolutional neural networks, the model takes raw 3D brain images as input and geometrically transforms fetal brains into a unified coordinate system (proposed as a Fetal Brain Talairach system). The integration of these algorithms into computer-assisted analysis tools may greatly reduce the time and effort to evaluate 3D fetal neurosonography for clinicians. Furthermore, they will assist understanding of fetal brain maturation by distilling 2D/3D information directly from the uterus.

Brain cerebrospinal fluid (CSF) bulk flow is maintained thanks to a balance between CSF secretion from the choroid plexus and CSF absorption by arachnoid villi, where it drains into nearby blood vessels, thereby reaching the general blood circulation. Congenital hydrocephalus starts during the first trimester of pregnancy with impeded CSF flow, and consequent CSF build-up within the brain ventricles. This event is followed by CSF compositional changes, increased intracranial pressure, and, if untreated, brain damage and fetal death. Previous research has revealed a unique folate delivery system which serves the developing cerebral cortex. Abnormal folate provision due to impairment of this system was directly connected to a decrease in a CSF folate enzyme: 10-Formyl-Tetrahydrofolate dehydrogenase (FDH). In light of these findings, low FDH was linked with folate deficiency and the poor cortical development found in congenital hydrocephalus. In this context, investigations were carried out to ascertain whether folates in the presence and absence of the folate enzyme FDH are beneficial for fetal brain development. The current study also aims to investigate the FDH -folate delivery system in the fetal brain in order to understand its role in CNS development and its relationship to currently known folate transport mechanisms (FRα). Furthermore, we hypothesize that folates may prevent congenital hydrocephalus through a re-establishment of CSF drainage and flow circulation at the level of the arachnoid membrane/villi. This assumption implies that the leptomeninge arachnoid may also be dysfunctional in the hydrocephalic brain due to a variation in hydrocephalic CSF composition (folates). Finally, an overall metabolic pathway analysis of the constituents uniquely present in abnormal CSF, hence missing in normal CSF, and vice versa, was carried out to establish associations with suggested activated and inactivated biological processes during congenital hydrocephalus.

Thesis (Ph.D) - University of Queensland, 2006. / Includes bibliography.

Orientador: Cleisson Fábio Andrioli Peralta / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-11-27T11:52:28Z (GMT). No. of bitstreams: 1 SantosNeto_OrlandoGomesdos_M.pdf: 1132176 bytes, checksum: d5202b7fe95c1aed116aef2fa03d7e3b (MD5) Previous issue date: 2013 / Resumo: Introdução: As lesões neurológicas fetais são importante causa de morbimortalidade neonatal. Uma condição relativamente frequente que expõe os fetos a maior risco de lesão cerebral é a síndrome da transfusão feto-fetal grave (STFF). O tratamento de escolha para STFF consiste na ablação dos vasos placentários com laser (AVPL) e mesmo após a sua realização existe possibilidade de lesão neurológica fetal. A ultrassonografia (USG) é ainda o método de escolha para a avaliação de anormalidades encefálicas fetais, e a ressonância magnética (RNM) pode melhorar o diagnóstico em condições específicas. Entretanto, a USG e as imagens ponderadas T1 e T2 da RM não são apropriadas para a detecção de lesões isquêmicas. A Restrição de Difusão da ressonância magnética (RD-RNM) permite a detecção de eventos isquêmicos agudos no cérebro através da avaliação subjetiva e objetiva da difusão microscópica da água. Esta última pode ser obtida por meio da medida do coeficiente de difusão aparente (CDA) e sua reprodutibilidade no cérebro fetal normal, em gestações únicas, foi recentemente demonstrada. Objetivo: Testar a factibilidade e a reprodutibilidade da restrição de difusão da ressonância magnética nas avaliações do cérebro fetal em casos de síndrome de transfusão feto-fetal tratados com a ablação dos vasos placentários com laser. Materiais e Métodos: Este estudo foi realizado no período de maio de 2011 a junho de 2012, após aprovação pelo Comitê de Ética em Pesquisa da FCM/UNICAMP. Pacientes com STFF grave realizaram uma ressonância magnética para a avaliação do cérebro dos fetos antes e depois da AVPL. Os dados foram analisados off-line em imagens axiais da restrição de difusão (RD) e em mapas do coeficiente de difusão aparente por dois radiologistas. A avaliação subjetiva foi descrita como a ausência ou a presença de restrição de difusão da água. A avaliação objetiva foi realizada através da colocação de regiões de interesse circulares de 20 mm2 nas imagens de RD e em mapas de CDA. A concordância subjetiva inter observadores foi avaliada pelo coeficiente de correlação de Kappa. As medidas do CDA realizadas pelo mesmo observador e por observadores diferentes foram comparadas por meio de testes de Bland-Altman proporcionais. Resultados: As análises foram realizadas em 23 pacientes (46 fetos) com STFF grave, antes e após a AVPL, totalizando noventa e dois exames RD-RNM. Destes, 62 (67%) foram considerados de boa qualidade para avaliação. A concordância entre os radiologistas foi de 100% tanto para a ausência (55/62 = 89%) quanto para a presença (7/62=11%) de restrição de difusão da água. Com relação às concordâncias intra e inter-observadores das medidas do CDA, o teste de Bland-Altman mostrou diferenças percentuais médias de menos de 1,5% e Intervalo de Confiança (IC) de 95% em menos de 18% em todos os locais avaliados. Conclusões: Nossos dados sugerem que a avaliação RD-RNM do cérebro fetal em STFF é factível e reprodutível. Este método pode representar uma ferramenta útil para o aconselhamento dos pais sobre a evolução neurológica de seus filhos / Abstract: Introduction: The fetal neurological injuries are an important cause of neonatal morbidity and mortality. Severe twin-twin transfusion syndrome (TTTS) is a relatively frequent condition that exposes the fetuses to a higher risk of brain injury. The treatment of choice for TTTS consists in laser ablation of placental vessels (LAPV) and even after its completion there is the possibility of fetal neurologic injury. Ultrasonography (USG) is still the method of choice for evaluation of fetal brain abnormalities, and magnetic resonance imaging (MRI) can improve the diagnostic in specific conditions. However, ultrasonography and the T1 and T2 weighted images of MRI are not suitable for detection of ischemic lesions. Diffusion-weighted (DW) MRI enables the detection of acute hypoxic-ischemic events in the brain through subjective and objective evaluation of the microscopic diffusion of water. An objective evaluation consists of measuring the apparent diffusion coefficient (ADC): the reproducibility of this method in the normal fetal brain in singleton pregnancies was recently demonstrated. Purpose: To test the feasibility and reproducibility of diffusion-weighted magnetic resonance imaging (DW-MRI) evaluations of fetal brains in cases of twin-twin transfusion syndrome treated with laser ablation of placental vessels. Materials and Methods: This study was conducted from May 2011 to June 2012, after approval by the Institutional Review Board of FCM/UNICAMP. Patients with severe TTTS received an MRI scan for the evaluation of fetal brain before and after LAPV. Datasets were analyzed offline on axial DW images and apparent diffusion coefficient (ADC) maps by two radiologists. The subjective evaluation was described as the absence or presence of water diffusion restriction. The objective evaluation was performed by the placement of 20-mm2 circular regions of interest on the DW image and ADC maps. Subjective inter-observer agreement was assessed by the Kappa correlation coefficient. ADC measurements performed by the same observer and by different observers were compared using proportionate Bland-Altman tests. Results: Analyses were performed in 23 patients (46 fetuses) with severe TTTS before and after LAVP totaling 92 examinations RD-RM. Of these, 62 (67%) were of good quality for evaluation. The agreement between radiologists was 100% in the absent (55/62 = 89%) and in the presence (7/62 = 11%) of restricted diffusion of water. With respect to intra and inter-observer measurements of the ADC, the Bland-Altman plots showed average percentage differences of less than 1.5% and Confidence Interval (CI) of 95% in less than 18% in all regions evaluated. Conclusions: Our data suggest that DW-MRI evaluation of the fetal brain in TTTS is feasible and reproducible. This method may represent a useful tool for counseling parents about the neurological outcome of their infants / Mestrado / Saúde Materna e Perinatal / Mestre em Tocoginecologia

Abstract available in the Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy.

No description available.

Stereology supplies image sampling rules to estimate geometric quantities such as volume, surface area, feature length and number. The method is well suited to non-invasive image acquisition methods such as Magnetic Resonance Imaging (MRI). Meanwhile, in Magnetic Resonance (MR) images analysis area, automated software packages have been continuously developed and become well-established tools especially in human brainMR images processing. The aims of the thesis are (1) to combine proper rules to sample MR images with automated or semi-automated data acquisition methods, in order to implement four different design unbiased stereological volume estimators in the study of the human brain, and (2) to compare volume estimates with those obtained from automated software packages.