It is emerging that the brain’s vasculature consists of a highly spatially heterogeneous network; however, information on how various vascular characteristics differ between brain regions is still lacking. Furthermore, aging studies rarely acknowledge regional differences in the changes of vascular features. The density of the capillary bed is one vascular feature that is important for the adequate delivery of nutrients to brain tissue. Additionally, capillary density may influence regional cerebral blood flow, a parameter that has been repeatedly correlated to cognitive-behavioural performance. Age-related decline in capillary density has been widely reported in various animal models, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we used confocal microscopy combined with a fluorescent dye-filling approach to label the vasculature, and subsequently quantified vessel length, tortuosity and diameter in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical gray matter regions, while some regions (visual cortex, amygdala, insular cortex) showed little decline with aging. Changes in capillary density are determined by a balance of pruning and sprouting events. Previous research showed that capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning without subsequent compensatory vessel sprouting. We therefore hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. Although the relationship between obstruction density and vessel loss was strong, it was clear obstruction rates were insufficient to explain vessel loss on their own. For that reason, we subsequently used in vivo two-photon microscopy to track microsphere-induced capillary obstructions and vascular network changes over 24 days in two areas of cortex that showed different magnitudes of vessel loss and obstruction densities: visual and retrosplenial cortex. Surprisingly, we did not find evidence for differences in vessel pruning rates between areas, as we would have expected. Instead, we observed brain region-specific differences in recanalization times and rates of angiogenesis. These findings indicate that age-related vessel loss is region specific and that regional susceptibilities to capillary plugging and angiogenesis must be considered to explain these differences. Altogether, this work supports the overarching hypothesis that regional differences in vascular structure and function contribute to a regionally heterogeneous phenotype in the aging brain. / Graduate

It is currently a well-established fact that the dynamics of interacting fluid compartments of the central nervous system (CNS) may play a role in the CNS fluid physiology and pathology of a number of neurological disorders, including neurodegenerative diseases associated with accumulation of waste products in the brain. However, the mechanisms and routes of waste clearance from the brain are still unclear. One of the main components of this interacting cerebral fluids dynamics is blood flow. In the last decades, mathematical modeling and fluid dynamics simulations have become a valuable complementary tool to experimental approaches, contributing to a deeper understanding of the circulatory physiology and pathology. However, modeling blood flow in the brain remains a challenging and demanding task, due to the high complexity of cerebral vascular networks and the difficulties that consequently arise to describe and reproduce the blood flow dynamics in these vascular districts. The first part of this work is devoted to the development of efficient numerical strategies for blood flow simulations in complex vascular networks. In cardiovascular modeling, one-dimensional (1D) and lumped-parameter (0D) models of blood flow are nowadays well-established tools to predict flow patterns, pressure wave propagation and average velocities in vascular networks, with a good balance between accuracy and computational cost. Still, the purely 1D modeling of blood flow in complex and large networks can result in computationally expensive simulations, posing the need for extremely efficient numerical methods and solvers. To address these issues, we develop a novel modeling and computational framework to construct hybrid networks of coupled 1D and 0D vessels and to perform computationally efficient and accurate blood flow simulations in such networks. Starting from a 1D model and a family of nonlinear 0D models for blood flow, with either elastic or viscoelastic tube laws, this methodology is based on (i) suitable coupling equations ensuring conservation principles; (ii) efficient numerical methods and numerical coupling strategies to solve 1D, 0D and hybrid junctions of vessels; (iii) model selection criteria to construct hybrid networks, which provide a good trade-off between accuracy in the predicted results and computational cost of the simulations. By applying the proposed hybrid network solver to very complex and large vascular networks, we show how this methodology becomes crucial to gain computational efficiency when solving networks and models where the heterogeneity of spatial and/or temporal scales is relevant, still ensuring a good level of accuracy in the predicted results. Hence, the proposed hybrid network methodology represents a first step towards a high-performance modeling and computational framework to solve highly complex networks of 1D-0D vessels, where the complexity does not only depend on the anatomical detail by which a network is described, but also on the level at which physiological mechanisms and mechanical characteristics of the cardiovascular system are modeled. Then, in the second part of the thesis, we focus on the modeling and simulation of cerebral blood flow, with emphasis on the venous side. We develop a methodology that, departing from the high-resolution MRI data obtained from a novel in-vivo microvascular imaging technique of the human brain, allows to reconstruct detailed subject-specific cerebral networks of specific vascular districts which are suitable to perform blood flow simulations. First, we extract segmentations of cerebral districts of interest in a way that the arterio-venous separation is addressed and the continuity and connectivity of the vascular structures is ensured. Equipped with these segmentations, we propose an algorithm to extract a network of vessels suitable and good enough, i.e. with the necessary properties, to perform blood flow simulations. Here, we focus on the reconstruction of detailed venous vascular networks, given that the anatomy and patho-physiology of the venous circulation is of great interest from both clinical and modeling points of view. Then, after calibration and parametrization of the MRI-reconstructed venous networks, blood flow simulations are performed to validate the proposed methodology and assess the ability of such networks to predict physiologically reasonable results in the corresponding vascular territories. From the results obtained we conclude that this work represents a proof-of-concept study that demonstrates that it is possible to extract subject-specific cerebral networks from the novel high-resolution MRI data employed, setting the basis towards the definition of an effective processing pipeline for detailed blood flow simulations from subject-specific data, to explore and quantify cerebral blood flow dynamics, with focus on venous blood drainage.

No description available.

No description available.

Thèse réalisée en cotutelle avec Dre Christine Des Rosiers / Le processus de l’athérosclérose est associé à des changements vasculaires structuraux et mécaniques dont la rigidification carotidienne et aortique. Ce phénomème est bien connu et contraste avec l’augmentation paradoxale de la distensibilité cérébrovasculaire observée dans les artères cérébrales exposées aux facteurs de risque cardiovasculaire, tels que l’hypertension. L’impact de l’athérosclérose sur le remodelage, la compliance et la fonction des artères cérébrales est inconnu. En ciblant l’endothélium, l’athérosclérose induit une dysfonction endothéliale cérébrale sévère qui interfère avec le contrôle du débit sanguin cérébral et ultimement avec les fonctions cognitives. Dans les artères cérébrales, le remodelage de la paroi artérielle est toujours accompagné d’une perte des fonctions vasodilatatrices, ce qui suggère que ces deux évènements sont au cœur d’un cercle vicieux. Nos études visent à vérifier l’hypothèse selon laquelle le remodelage de la paroi est déterminé par la fonction endothéliale au niveau cérébrovasculaire alors qu’au niveau de la carotide, le stress mécanique du pouls sanguin régule les propriétés structurales et biomécaniques. Afin de vérifier cette hypothèse, dans une première étude, nous avons sélectionné trois interventions thérapeutiques aux mécanismes d’action différents qui modulent la fonction endothéliale indirectement en diminuant le stress mécanique exercé sur la paroi via une diminution de la fréquence cardiaque. Suite à un traitement chronique de trois mois chez la souris athérosclérotique, LDLr-/-; hApoB-100+/+, l’efficacité de l’ivabradine, du métoprolol et de l’exercice physique volontaire dans la prévention de l’augmentation de la compliance cérébrovasculaire s’est avérée proportionnelle à l’étendue des bénéfices sur la fonction endothéliale. La rigidification carotidienne n’a été prévenue que par les interventions qui réduisent vraiment la fréquence cardiaque, c’est-à-dire l’ivabradine et le métoprolol. Dans une deuxième étude, nous avons confirmé nos résultats en utilisant un traitement antioxydant dans le but de cibler plus directement l’endothélium. La catéchine ne réduit pas la fréquence cardiaque, mais elle est reconnue pour protéger l’endothélium cérébral en neutralisant le stress oxydant. Ainsi, la carotide est restée rigide alors que le remodelage cérébral a été prévenu. Une technique d’imagerie novatrice, la tomographie par cohérence optique, nous a permis de valider nos observations in vivo et de proposer que la catéchine prévient l’hypoperfusion du cerveau en protégeant la fonction endothéliale et l’intégrité de la paroi vasculaire cérébrale. Finalement, les deux études identifient la métalloprotéinase de type 9 comme un joueur potentiellement impliqué dans l’augmentation de la compliance cérébrovasculaire. Nos études démontrent que les changements structuraux et biomécaniques affectant la paroi des artères cérébrales sont indubitablement dépendants de l’endothélium alors que dans la carotide, le stress mécanique est le paramètre le plus déterminant. Somme toute, en protégeant indirectement l’endothélium cérébral on empêche les processus de remodelage, telle que l’activation de la métalloprotéinase de type 9. De nombreuses études ont suggéré l’implication des dysfonctions cérébrovasculaires dans la maladie d’Alzheimer. En effet, les affections vasculaires qui compromettent chroniquement le débit sanguin cérébral, telles la dysfonction endothéliale et la réduction de la lumière artérielle, vont entraîner un déficit métabolique des neurones à l’origine de la neurodégénérescence. Les traitements préventifs cardioprotecteurs, tels que l’ivabradine, l’exercice physique et la catéchine améliorent la fonction endothéliale, la structure et la biomécanique des artères cérébrales, et pourraient donc prévenir l’hypoperfusion chronique du cerveau et le déclin cognitif dans l’athérosclérose. / Large artery stiffness and endothelial dysfunction are markers of atherosclerosis. Stiffening of the carotid arteries contrast with the paradoxical increase in distensibility of cerebral arteries that was reported in the presence of risk factors for cardiovascular diseases, such as hypertension. However, our knowledge concerning the influence of atherosclerosis on cerebrovascular compliance and structure remains incomplete. By targeting the endothelium, atherosclerosis induces a severe cerebral endothelial dysfunction affecting chronically the cerebral blood flow and potentially leading to cognitive dysfunctions. Few studies have shown that the paradoxical increase in cerebrovascular distensibility is consistently reported in animal model of risk factors for cardiovascular diseases exhibiting a cerebral endothelial dysfunction. That being said, we hypothesized that the compliance and structure of cerebral arteries is essentially controlled by the endothelium. To validate our hypothesis, in a first study, we selected three distinct therapeutic approaches that modulated the cerebral endothelial function and the mechanical stress imposed to the vascular wall by lowering heart rate in a mouse model of atherosclerosis, LDLr-/-; hApoB-100+/+ during three months. Ivabradine, metroprolol and voluntary physical training protected, with different efficiencies, the cerebral flow-mediated dilation and this was reflected by a prevention, or not, of the increase in compliance. A 13.5 % heart rate reduction with ivabradine and metoprolol limited carotid artery stiffening. Voluntary physical training did not induce an overall reduction of heart rate explaining the lack of effect on carotid mechanics and suggesting that carotids compliance is more influenced by the mechanical stress imposed to the vascular wall by the cardiac cycle. In a second study, we confirmed our previous findings using a diatery approach that targeted more directly the endothelium, the polyphenol antioxidant catechin. Catechin was previously proven, by us and others, to reverse endothelial dysfunction, reduce inflammation and neutralize reactive oxygen species in diverse vascular beds from animal models of atherosclerosis. Accordingly, we found that catechin prevents adverse cerebral wall remodeling but, again, without a significant heart rate reduction, carotids remained stiff. We also integrated a new live imaging technology allowing us to confirm our findings in vivo and to demonstrate that endothelial, structural and mechanical protection by catechin can result in an improvement of basal cerebral blood flow. Finally, both studies identified metalloproteinase -9 as a potential player in the process leading the weakening of the cerebral artery walls. Taken together, our studies highlight that structural and biomechanical alterations are genuinely triggered by endothelial dysfunction. In carotids, mechanicals stress seems to be the main factor controlling remodeling. In essence, indirect protection of the endothelium impedes in cerebral vessels the remodeling processes, such as the activation of metalloproteinase -9. Numerous studies have revealed that vascular, especially cerebral endothelial dysfunction is implicated in the pathogenesis of Alzheimer’s disease. When brain perfusion is compromised, the suboptimal energy delivery causes neuronal death. Deleterious cerebrovascular outcomes that promote the impairment of vasodilation and the encroachment of the lumen will limit cerebral blood flow in a chronic manner. Chronic treatment with ivabradine, voluntary physical training and catechin preserved the endothelial function, the structure and the mechanics of cerebral arteries, which guarantees a closer management of cerebral blow flow in atherosclerotic mice and a reduce propensity to develop cognitive deficiency.

Les études d’imagerie par résonance magnétique fonctionnelle (IRMf) ont pour prémisse générale l’idée que le signal BOLD peut être utilisé comme un succédané direct de l’activation neurale. Les études portant sur le vieillissement cognitif souvent comparent directement l’amplitude et l’étendue du signal BOLD entre des groupes de personnes jeunes et âgés. Ces études comportent donc un a priori additionnel selon lequel la relation entre l’activité neurale et la réponse hémodynamique à laquelle cette activité donne lieu restent inchangée par le vieillissement. Cependant, le signal BOLD provient d’une combinaison ambiguë de changements de métabolisme oxydatif, de flux et de volume sanguin. De plus, certaines études ont démontré que plusieurs des facteurs influençant les propriétés du signal BOLD subissent des changements lors du vieillissement. L’acquisition d’information physiologiquement spécifique comme le flux sanguin cérébral et le métabolisme oxydatif permettrait de mieux comprendre les changements qui sous-tendent le contraste BOLD, ainsi que les altérations physiologiques et cognitives propres au vieillissement. Le travail présenté ici démontre l’application de nouvelles techniques permettant de mesurer le métabolisme oxydatif au repos, ainsi que pendant l’exécution d’une tâche. Ces techniques représentent des extensions de méthodes d’IRMf calibrée existantes. La première méthode présentée est une généralisation des modèles existants pour l’estimation du métabolisme oxydatif évoqué par une tâche, permettant de prendre en compte tant des changements arbitraires en flux sanguin que des changements en concentrations sanguine d’O2. Des améliorations en terme de robustesse et de précisions sont démontrées dans la matière grise et le cortex visuel lorsque cette méthode est combinée à une manipulation respiratoire incluant une composante d’hypercapnie et d’hyperoxie. Le seconde technique présentée ici est une extension de la première et utilise une combinaison de manipulations respiratoires incluant l’hypercapnie, l’hyperoxie et l’administration simultanée des deux afin d’obtenir des valeurs expérimentales de la fraction d’extraction d’oxygène et du métabolisme oxydatif au repos. Dans la deuxième partie de cette thèse, les changements vasculaires et métaboliques liés à l’âge sont explorés dans un groupe de jeunes et aînés, grâce au cadre conceptuel de l’IRMf calibrée, combiné à une manipulation respiratoire d’hypercapnie et une tâche modifiée de Stroop. Des changements de flux sanguin au repos, de réactivité vasculaire au CO2 et de paramètre de calibration M ont été identifiés chez les aînés. Les biais affectant les mesures de signal BOLD obtenues chez les participants âgés découlant de ces changements physiologiques sont de plus discutés. Finalement, la relation entre ces changements cérébraux et la performance dans la tâche de Stroop, la santé vasculaire centrale et la condition cardiovasculaire est explorée. Les résultats présentés ici sont en accord avec l’hypothèse selon laquelle une meilleure condition cardiovasculaire est associée à une meilleure fonction vasculaire centrale, contribuant ainsi à l’amélioration de la santé vasculaire cérébrale et cognitive. / Functional MRI (fMRI) studies using the BOLD signal are done under the general assumption that the BOLD signal can be used as a direct index of neuronal activation. Studies of cognitive aging often compare BOLD signal amplitude and extent directly between younger and older groups, with the additional assumption that the relationship between neuronal activity and the hemodynamic response is unchanged across the lifespan. However, BOLD signal arises from an ambiguous mixture of changes in oxidative metabolism, blood flow and blood volume. Furthermore, previous studies have shown that several BOLD signal components may be changed during aging. More physiologically-specific information on blood flow and oxidative metabolism would allow a better understanding of these signal changes and of the physiological and cognitive changes seen with aging. The work presented here demonstrates techniques to estimate oxidative metabolism at rest and during performance of a task. These techniques are extensions of previous calibrated fMRI methods and the first method presented is based on a generalization of previous models to take into account both arbitrary changes in blood flow and blood O2 content. The improved robustness and accuracy of this method, when used with a combined hypercapnia and hyperoxia breathing manipulation, is demonstrated in visual cortex and grey matter. The second technique presented builds on the generalization of the model and uses a combination of breathing manipulations including hypercapnia, hyperoxia and both simultaneously, to obtain experimentally-determined values of resting oxygen extraction fraction and oxidative metabolism. In the second part of this thesis, age-related vascular and metabolic changes are explored in a group of younger and older adults using a calibrated fMRI framework with a hypercapnia breathing manipulation and a modified Stroop task. Changes in baseline blood flow, vascular reactivity to the CO2 challenge and calibration parameter M were identified in the older participants. Potential biases in BOLD signal measurements in older adults arising from these physiological changes are discussed. Finally, the relationship between these cerebral changes and performance on the modified Stroop task, central vascular health and cardiovascular fitness are explored. The results of this thesis support the hypothesis that greater cardiovascular fitness is associated with improvements in central vascular function, contributing in turn to improved brain vascular health and cognition.

Cerebrovascular diseases are by far the largest causes of death in the UK, as well as one of the leading causes of adult disability. The brain's healthy function depends on a steady supply of oxygen, delivered through the microvasculature. Cerebrovascular diseases, such as stroke and dementia, can interrupt the transport of blood (and hence oxygen) rapidly, or over a prolonged period of time. An interruption in flow can lead to ischaemia, with prolonged interruptions leading to tissue death and eventual brain damage. The microvasculature plays a key role in the transport of oxygen and nutrients to brain tissue; however, its role in diseases such as dementia is poorly understood, primarily due to the inability of current clinical imaging techniques to resolve microvessels, and due to the complexity of the underlying microvasculature. Therefore, in order to understand cerebrovascular diseases, it is necessary to be able to resolve and understand the microvasculature. In particular, generating large-scale models of the human microvasculature that can be linked back to contemporary clinical imaging is important in helping plug the current imaging gap that exists. A novel statistical model is proposed here that generates such large-scale models efficiently. Homogenization theory is used to generate a porous continuum capillary bed (characterised by its permeability) that allows for the efficient scaling up of the microvasculature. A novel order-based density-filling algorithm is then developed which generates morphologically accurate penetrating arterioles and venules, also demonstrating that the topology of the vessels only has a minor influence on CBF compared to diameter. Finally, the capillary bed and penetrating vessels are coupled into a large voxel-sized model of the microvasculature from which pressure and flux variations through the voxel can be analysed. A decoupling of the pressure and flux, as well as a layering of flow, was observed within the voxel, driven by the topology of the penetrating vessels. Micro-infarctions were also simulated, demonstrating the large local effects they have on the pressure and flux, whilst only causing a minor drop in CBF within the voxel.

<p>This thesis explored the epidemiology of Posttraumatic Stress Disorder (PTSD) and different aspects of the disorder. Firstly, we investigated the lifetime prevalence of traumatic experiences and PTSD in the general adult population in Sweden and evaluated the impact of different trauma types, trauma frequency, and perceived distress. The results show that traumatic experiences are common and PTSD is not rare; roughly one out of ten traumatic events results in PTSD, with a 5.6% lifetime prevalence. The female/male ratio is 2:1. The risk for PTSD increases considerably with a high trauma-associated emotional impact. The distressing impact of a given trauma appears to be higher in women than in men, indicating an increased vulnerability in women. Secondly, we hypothesized that traffic road accidents (TRA’s) are one of the most prevalent types of traumatic events in Swedish society; therefore, we examined the impact of event and response characteristics associated with TRA’s on PTSD development. The data demonstrate that of those who had experienced a TRA (n=1074, 58.9%), 6.1% reported lifetime PTSD. TRA’s associated with fatal accidents and injury to oneself and related to high distress more than double the risk for PTSD. Thirdly, we compared the relative merits of the DSM-IV’s three-factor solution for PTSD symptoms to alternative models. We found that the symptomatology is equally well accounted for using all factor analytic models as yet presented in the literature; the DSM-IV, we found, provides as good a fit to data as other models. Fourthly, we examined the neurofunctional correlates of PTSD symptoms and whether a treatment-induced (serotonin reuptake inhibitor - SSRI) reduction of PTSD symptoms is associated with altered rCBF during symptom provocation. Our results indicate that PTSD symptoms correlates with areas involved in memory, emotion, attention, and motor control and that SSRI treatment normalizes provocation-induced rCBF in these areas.</p>

This thesis explored the epidemiology of Posttraumatic Stress Disorder (PTSD) and different aspects of the disorder. Firstly, we investigated the lifetime prevalence of traumatic experiences and PTSD in the general adult population in Sweden and evaluated the impact of different trauma types, trauma frequency, and perceived distress. The results show that traumatic experiences are common and PTSD is not rare; roughly one out of ten traumatic events results in PTSD, with a 5.6% lifetime prevalence. The female/male ratio is 2:1. The risk for PTSD increases considerably with a high trauma-associated emotional impact. The distressing impact of a given trauma appears to be higher in women than in men, indicating an increased vulnerability in women. Secondly, we hypothesized that traffic road accidents (TRA’s) are one of the most prevalent types of traumatic events in Swedish society; therefore, we examined the impact of event and response characteristics associated with TRA’s on PTSD development. The data demonstrate that of those who had experienced a TRA (n=1074, 58.9%), 6.1% reported lifetime PTSD. TRA’s associated with fatal accidents and injury to oneself and related to high distress more than double the risk for PTSD. Thirdly, we compared the relative merits of the DSM-IV’s three-factor solution for PTSD symptoms to alternative models. We found that the symptomatology is equally well accounted for using all factor analytic models as yet presented in the literature; the DSM-IV, we found, provides as good a fit to data as other models. Fourthly, we examined the neurofunctional correlates of PTSD symptoms and whether a treatment-induced (serotonin reuptake inhibitor - SSRI) reduction of PTSD symptoms is associated with altered rCBF during symptom provocation. Our results indicate that PTSD symptoms correlates with areas involved in memory, emotion, attention, and motor control and that SSRI treatment normalizes provocation-induced rCBF in these areas.

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) contrast has become a universal methodology in functional neuroimaging. However, the BOLD signal consists of a mix of physiological parameters and has relatively poor reproducibility. As fMRI becomes a prominent research tool for rehabilitation studies involving repeated measures of the human brain, more quantitative and stable fMRI contrasts are needed. This dissertation enhances quantitative measures to complement BOLD fMRI. These additional markers, cerebral blood flow (CBF) and cerebral blood volume (CBV) (and hence cerebral metabolic rate of oxygen (CMRO₂) modeling) are more specific imaging markers of neuronal activity than BOLD. The first aim of this dissertation assesses feasibility of complementing BOLD with quantitative fMRI measures in subjects with central visual impairment. Second, image acquisition and analysis are developed to enhance quantitative fMRI by quantifying CBV while simultaneously acquiring CBF and BOLD images. This aim seeks to relax assumptions related to existing methods that are not suitable for patient populations. Finally, CBF acquisition using a low-cost local labeling coil, which improves image quality, is combined with simultaneous acquisition of two types of traditional BOLD contrast. The demonstrated enhancement of CBF, CBV and CMRO₂measures can lead to better characterization of pathophysiology and treatment effects.