Placental vascular alterations are associated with early neurodevelopmental and pulmonary impairment in the rabbit fetal growth restriction model

Fetal growth restriction is one of the leading causes of perinatal mortality and morbidity and has consequences that extend well beyond the neonatal period. Current management relies on timely delivery rather than improving placental function. Several prenatal strategies have failed to show benefit in clinical trials after promising results in animal models. Most of these animal models have important developmental and structural differences compared to the human and/or are insufficiently characterized. We aimed to describe placental function and structure in an FGR rabbit model, and to characterize the early brain and lung developmental morbidity using a multimodal approach. FGR was induced in time-mated rabbits at gestational day 25 by partial uteroplacental vessel ligation in one horn. Umbilical artery Doppler was measured before caesarean delivery at gestational day 30, and placentas were harvested for computed microtomography and histology. Neonates underwent neurobehavioral or pulmonary functional assessment the day after delivery, followed by brain or lung harvesting, respectively. Neuropathological assessment included multiregional quantification of neuron density, apoptosis, astrogliosis, cellular proliferation, and oligodendrocyte progenitors. Brain region volumes and diffusion metrics were obtained from ex-vivo brain magnetic resonance imaging. Lung assessment included biomechanical tests and pulmonary histology. Fetal growth restriction was associated with labyrinth alterations in the placenta, driven by fetal capillary reduction, and overall reduced vessels volume. FGR caused altered neurobehavior paralleled by regional neuropathological deficits and reduced fractional anisotropy in the cortex, white matter, and hippocampus. In addition, FGR kittens presented functional alterations in the peripheral lung and structurally underdeveloped alveoli. In conclusion, in a uteroplacental insufficiency FGR rabbit model, placental vascular alterations coincide with neurodevelopmental and pulmonary disruption

Image computing tools for the investigation of the neurological effects of preterm birth and corticosteroid administration

In this thesis we present a range of computational tools for medical imaging purposes within two main research projects. The first one is a methodological project oriented towards the improvement of the performance of a numerical computation utilised in diffeomorphic image registration. The second research project is a pre-clinical study aimed at the investigation of the effects of antenatal corticosteroids in a preterm rabbit animal model. In the first part we addressed the problem of integrating stationary velocity fields. This mathematical challenge had originated with early studies in fluid dynamics and had been subsequently mathematically formalised in the Lie group theory. Given a tangent velocity field defined in the tridimensional space as in input, the goal is to compute the position of the particles to which the velocity field is applied. This computation, also called numerical Lie exponential, is a fundamental component of several medical image registration algorithm based on diffeomorphisms, i.e. bijective differentiable maps with differentiable inverse. It is as well a widely utilised tool in computational anatomy to quantify the differences between two anatomical shapes measuring the parameters of the transformation that belongs to a metric vector space. The resulting new class of algorithms introduced in this thesis was created combining the known scaling and squaring algorithm with a class of numerical integrators aimed to solve systems of ordinary differential equations called exponential integrators. The introduced scaling and squaring based approximated exponential integrator algorithm have improved the computational time and accuracy respect to the state- of-the-art methods. The second part of the research is a pre-clinical trial carried forward in collab- oration with the Department of Development and Regeneration, Woman and Child Cluster at the KU Leuven University. The clinical research question is related to the understanding of the possible negative effects of administering antenatal cor- ticosteroids for preterm birth. To tackle this problem we designed and started a pre-clinical study using a New Zealand perinatal rabbit model. In this part of the research I was involved in the research team to provide the tools to automatise the data analysis and to eliminate the time consuming and non reproducible manual segmentation step. The main result of this collaboration is the creation of the first multi-modal multi-atlas for the newborn rabbit brain. This is embedded in a segmentation propagation and label fusion algorithm at the core of the proposed open-sourced automatic pipeline, having as input the native scanner format and as output the main MRI readouts, such as volume, fractional anisotropy and mean diffusivity

Cerebral intraventricular hemorrhage and post-hemorrhagic ventricular dilatation in preterm infants: new mechanistic insights and potential treatment strategies

Intraventricular hemorrhage (IVH) is one of the major co-morbidities of premature birth associated with post-hemorrhagic ventricular dilatation (PHVD) development, long-term neurodevelopmental impairment, behavioral problems, special educational needs, and dependency on social security.Hypothesis and aims: We believe that extravasated blood and further release of extracellular hemoglobin (Hb) are crucial in brain injury following IVH and consequent development of PHVD. The overall goal of this project focuses on further pathogenetic insights of white and gray matter (GM) injury following IVH and the development of possible neuroprotective treatment strategies that may promote brain development in preterm infants.Methods: Paper I. We characterized extracellular Hb distribution within preriventricular white matter (WM) in preterm rabbit pups following IVH. Paper II. We evaluated the cerebral biodistribution and possible functional neuroprotection of intracerebroventricularly administered alpha-1-microglobulin (A1M), a heme and free radical scavenger, in preterm rabbit pups following IVH. Paper III. We conducted a comprehensive review of preclinical and clinical studies on WM injury following IVH. Paper IV. We evaluated high-frequency ultrasound (HFU) as a tool for the reconstruction of volumetric volume in preterm rabbit pups with PHVD and compared its accuracy and reliability with that of a gold-standard – magnetic resonance imaging (MRI). Paper V. We established a novel model of PHVD in preterm rabbit pups and characterized the survival, neurobehavior, WM, and GM injury, as well as altered corticogenesis.Results: Paper I. Following IVH extracellular Hb was widely distributed throughout the brain WM, particularly in periventricular white matter areas with high extracellular plasticity following IVH. Paper II. Exogenous A1M (recombinant) was extensively distributed within brain WM with further extension into cerebellar WM following IVH. Moreover, A1M exhibited high co-existence with extracellular Hb. Administration of A1M (human) decreased pro-inflammatory and oxidative damage. Paper III. A wide range of animal models have been used to explore pathogenetic mechanisms of IVH and related brain damage; possible targets involved in enhancing brain damage have been identified. Nevertheless, the effectiveness of potential interventions is still limited. Paper IV. HFU-based volumetric reconstruction of brain ventricles is highly accurate and reliable as compared to MRI and may be a promising bed-side tool for evaluating of progression of PHVD in preterm infants. Paper V. IVH and PHVD lead to a long-term alteration of cortical myelination microstructure, disruption of cortical organization, selectively reduction in neurogenesis and synaptogenesis, reduction in parvalbumin-positive interneurons and their dysmaturation.Conclusions: Extracellular Hb travels easily throughout brain WM following IVH and it may be one of the key factors for induction of brain damage by triggering pro-inflammatory and oxidative cascades. Furthermore, IVH, leading to PHVD, disrupts normal corticogenesis, alters myelin microstructure, causes a selective reduction in neurons, interneurons, and synapses. A1M, as a heme and free radicals scavenger, may attenuate WM damage, confirming that extracellular Hb is causative in ongoing neuroinflammation following IVH. Thus, A1M may be a possible treatment strategy in preterm infants with IVH. HFU represents a highly accurate tool for volumetric reconstruction of ventricles for diagnosis and management of PHVD

A magnetic resonance multi-atlas for the neonatal rabbit brain

The rabbit model has become increasingly popular in neurodevelopmental studies as it is best suited to bridge the gap in translational research between small and large animals. In the context of preclinical studies, high-resolution magnetic resonance imaging (MRI) is often the best modality to investigate structural and functional variability of the brain, both in vivo and ex vivo. In most of the MRI-based studies, an important requirement to analyze the acquisitions is an accurate parcellation of the considered anatomical structures. Manual segmentation is time-consuming and typically poorly reproducible, while state-of-the-art automated segmentation algorithms rely on available atlases. In this work we introduce the first digital neonatal rabbit brain atlas consisting of 12 multi-modal acquisitions, parcellated into 89 areas according to a hierarchical taxonomy. Delineations were performed iteratively, alternating between segmentation propagation, label fusion and manual refinements, with the aim of controlling the quality while minimizing the bias introduced by the chosen sequence. Reliability and accuracy were assessed with cross-validation and intra- and inter-operator test-retests. Multi-atlas, versioned controlled segmentations repository and supplementary materials download links are available from the software repository documentation at https://github.com/gift-surg/SPOT-A-NeonatalRabbit.status: publishe

A magnetic resonance multi-atlas for the neonatal rabbit brain

International audienceKeywords: Newborn rabbit brain animal model MRI multi-atlas Multi-atlas based segmentation A B S T R A C T The rabbit model has become increasingly popular in neurodevelopmental studies as it is best suited to bridge the gap in translational research between small and large animals. In the context of preclinical studies, high-resolution magnetic resonance imaging (MRI) is often the best modality to investigate structural and functional variability of the brain, both in vivo and ex vivo. In most of the MRI-based studies, an important requirement to analyze the acquisitions is an accurate parcellation of the considered anatomical structures. Manual segmentation is time-consuming and typically poorly reproducible, while state-of-the-art automated segmentation algorithms rely on available atlases. In this work we introduce the first digital neonatal rabbit brain atlas consisting of 12 multi-modal acquisitions, parcellated into 89 areas according to a hierarchical taxonomy. Delineations were performed iteratively, alternating between segmentation propagation, label fusion and manual refinements, with the aim of controlling the quality while minimizing the bias introduced by the chosen sequence. Reliability and accuracy were assessed with cross-validation and intra-and inter-operator test-retests. Multi-atlas, versioned controlled segmentations repository and supplementary materials download links are available from the software repository documentation at https://github.com/gift-surg/SPOT-A-NeonatalRabbit

A magnetic resonance multi-atlas for the neonatal rabbit brain - Dataset

<p>Dataset related to the Neuroimage paper https://doi.org/10.1016/j.neuroimage.2018.06.029.  Download links, documentation and code for the manipulation are available from the software repository https://github.com/gift-surg/SPOT-A-NeonatalRabbit</p