659 research outputs found
Influence of 100% and 40% oxygen on penumbral blood flow, oxygen level, and T2*-weighted MRI in a rat stroke model
Accurate imaging of the ischemic penumbra is a prerequisite for acute clinical stroke research. T2* magnetic resonance imaging (MRI) combined with an oxygen challenge (OC) is being developed to detect penumbra based on changes in blood deoxyhemoglobin. However, inducing OC with 100% O2 induces sinus artefacts on human scans and influences cerebral blood flow (CBF), which can affect T2* signal. Therefore, we investigated replacing 100% O2 OC with 40% O2 OC (5âminutes 40% O2 versus 100% O2) and determined the effects on blood pressure (BP), CBF, tissue pO2, and T2* signal change in presumed penumbra in a rat stroke model. Probes implanted into penumbra and contralateral cortex simultaneously recorded pO2 and CBF during 40% O2 (n=6) or 100% O2 (n=8) OC. In a separate MRI study, T2* signal change to 40% O2 (n=6) and 100% O2 (n=5) OC was compared. Oxygen challenge (40% and 100% O2) increased BP by 8.2% and 18.1%, penumbra CBF by 5% and 15%, and penumbra pO2 levels by 80% and 144%, respectively. T2* signal significantly increased by 4.56%±1.61% and 8.65%±3.66% in penumbra compared with 2.98%±1.56% and 2.79%±0.66% in contralateral cortex and 1.09%±0.82% and â0.32%±0.67% in ischemic core, respectively. For diagnostic imaging, 40% O2 OC could provide sufficient T2* signal change to detect penumbra with limited influence in BP and CBF
The effects of hypercapnia on DTI quantification in anesthetized rat brain
Conference Theme: Engineering the Future of BiomedicineDiffusion Tensor Imaging (DTI) offers a valuable in vivo tool to characterize water diffusion behavior in biological tissues, particularly brain tissues. The accuracy of DTI derived parameters can directly affect the interpretation of underlying microstructures, physiology or pathologies. It is anticipated that measurement of apparent diffusion coefficient (ADC) using DTI could be influenced and complicated by the presence of water molecules in brain vasculature. However, little is known about to what degree does blood signal from vasculature affect the diffusion quantitation. In this study, we examined the effects of hypercapnia on DTI quantification in rat brains using inhalation of 5% carbon dioxide (CO2). It was found that statistically significant changes occurred in parametric DTI maps in response to cerebrovascular challenges, indicating that vascular factors could interfere with in vivo DTI characterization of neural tissues. Consequently, hemodynamic alterations can potentially affect the DTI quantitation and detection of tissue microstructures and pathological alterations. Therefore, cautions must be taken when interpreting DTI parameters in vivo. ©2009 IEEE.published_or_final_versionThe 31st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC 2009), Minneapolis, MN., 3-6 September 2009. In Proceedings of the 31st EMBC, 2009, p. 2711-271
Magnetic resonance imaging of resting cerebral oxygen metabolism : applications in Alzheimerâs disease
The BOLD contrast employed in functional MRI studies is an ambiguous signal composed of changes in blood flow, blood volume and oxidative metabolism. In situations where the vasculature and metabolism may have been affected, such as in aging and in certain diseases, the dissociation of the more physiologically-specific components from the BOLD signal becomes crucial. The latest generation of calibrated functional MRI methods allows the estimation of both resting blood flow and absolute oxygen metabolism. The work presented here is based on one such proof-of-concept approach, dubbed QUO2, whereby taking into account, within a generalized model, both arbitrary changes in blood flow and blood O2
content during a combination of hypercapnia and hyperoxia breathing manipulations, yields voxel-wise estimates of resting oxygen extraction fraction and oxidative metabolism. In the first part of this thesis, the QUO2 acquisition protocol and data analysis were revisited in order to enhance the temporal stability of individual blood flow and BOLD responses, consequently improving reliability of the model-derived estimates. Thereafter, an assessment of the within and between-subject variability of the optimized QUO2 measurements was performed on a group of healthy volunteers. In parallel, an analysis was performed of the sensitivity of the model to different sources of random and systematic errors, respectively due to errors in measurements and choice of assumed parameters values. Moreover, the various impacts of the oxygen concentration administered during the hyperoxia manipulation were evaluated through a simulation and experimentally, indicating that a mild hyperoxia was beneficial. Finally, the influence of Alzheimerâs disease in vascular and metabolic changes was explored for the first time by applying the QUO2 approach in a cohort of probable Alzheimerâs disease patients and age-matched control group. Voxel-wise and region-wise differences in resting blood flow, oxygen extraction fraction, oxidative metabolism, transverse relaxation rate constant R2* and R2* changes during hypercapnia were identified. A series of limitations along with recommended solutions was given with regards to the delayed transit time, the susceptibility artifacts and the challenge of performing a hypercapnia manipulation in cohorts of elderly and Alzheimerâs patients.Le contraste BOLD employĂ© dans les Ă©tudes dâimagerie par rĂ©sonance magnĂ©tique
fonctionnelle (IRMf) provient dâune combinaison ambigĂŒe de changements du flux sanguin
cĂ©rĂ©bral, du volume sanguin ainsi que du mĂ©tabolisme oxydatif. Dans un contexte oĂč les
fonctions vasculaires ou mĂ©taboliques du cerveau ont pu ĂȘtre affectĂ©es, tel quâavec lâĂąge ou
certaines maladies, il est crucial dâeffectuer une dĂ©composition du signal BOLD en
composantes physiologiquement plus spĂ©cifiques. La derniĂšre gĂ©nĂ©ration de mĂ©thodes dâIRMf
calibrĂ©e permet dâestimer Ă la fois le flux sanguin cĂ©rĂ©bral et le mĂ©tabolisme oxydatif au
repos. Le présent travail est basé sur une telle technique, appelée QUantitative O2 (QUO2),
qui, via un model généralisé, prend en considération les changements du flux sanguin ainsi
que ceux en concentrations sanguine dâO2 durant des pĂ©riodes dâhypercapnie et dâhyperoxie,
afin dâestimer, Ă chaque voxel, la fraction dâextraction dâoxygĂšne et le mĂ©tabolisme oxydatif
au repos. Dans la premiĂšre partie de cette thĂšse, le protocole dâacquisition ainsi que la
stratĂ©gie dâanalyse de lâapproche QUO2 ont Ă©tĂ© revus afin dâamĂ©liorer la stabilitĂ© temporelle
des rĂ©ponses BOLD et du flux sanguin, consĂ©quemment, afin dâaccroĂźtre la fiabilitĂ© des
paramÚtres estimés. Par la suite, une évaluation de la variabilité intra- et inter-sujet des
diffĂ©rentes mesures QUO2 a Ă©tĂ© effectuĂ©e auprĂšs dâun groupe de participants sains. En
parallĂšle, une analyse de la sensibilitĂ© du model Ă diffĂ©rentes sources dâerreurs alĂ©atoires
(issues des mesures acquises) et systématiques (dues aux assomptions du model) a été réalisée.
De plus, les impacts du niveau dâoxygĂšne administrĂ© durant les pĂ©riodes dâhyperoxie ont Ă©tĂ©
Ă©valuĂ©s via une simulation puis expĂ©rimentalement, indiquant quâune hyperoxie moyenne Ă©tait
bĂ©nĂ©fique. Finalement, lâinfluence de la maladie dâAlzheimer sur les changements vasculaires
et métaboliques a été explorée pour la premiÚre fois en appliquant le protocole QUO2 à une
cohorte de patients Alzheimer et Ă un groupe tĂ©moin du mĂȘme Ăąge. Des diffĂ©rences en terme
de flux sanguin, fraction dâoxygĂšne extraite, mĂ©tabolisme oxydatif, et taux de relaxation
transverse R2* au repos comme en rĂ©ponse Ă lâhypercapnie, ont Ă©tĂ© identifiĂ©es au niveau du
voxel, ainsi quâau niveau de rĂ©gions cĂ©rĂ©brales vulnĂ©rables Ă la maladie dâAlzheimer. Une
liste de limitations accompagnĂ©es de recommandations a Ă©tĂ© dressĂ©e en ce qui a trait au temps de transit diffĂ©rĂ©, aux artĂ©facts de susceptibilitĂ© magnĂ©tique, de mĂȘme quâau dĂ©fi que
reprĂ©sente lâhypercapnie chez les personnes ĂągĂ©es ou atteintes de la maladie dâAlzheimer
Inhaled Oxygen as a Quantitative Intravascular MRI Contrast Agent
Increasing the fraction of inspired oxygen (FiO2) generates MR contrast by two distinct mechanisms: increased T2 from deoxyhemoglobin dilution in venous compartments (blood oxygenation level-dependent effect or BOLD) and reduced TÂ1 from paramagnetic molecular oxygen dissolved in blood plasma and tissues. Many research and clinical applications using hyperoxic contrast have recently emerged, including delineating ischemic stroke penumbra, oxygen delivery to tumors, and functional MRI data calibration. However, quantitative measurements using this contrast agent depend on the precise knowledge of its effects on the MR signal â of which there remain many crucial missing pieces.
This thesis aims to obtain a more quantitative understanding of intravascular hyperoxic contrast in vivo, with the hope of increasing its precision and utility. Specifically, our work focuses on the following areas: (1) paramagnetic effects of molecular oxygen BOLD and arterial spin labeling (ASL) data, (2) degree and temporal characteristics of hyperoxia-induced reductions in cerebral blood flow (CBF), (3) use of oxygen in quantitative measurements of metabolism, and (4) biophysical mechanisms of hyperoxic T1 contrast.
In Chapter 2, the artifactual influence of paramagnetic molecular oxygen on BOLD-modulated hyperoxic gas studies is characterized as a function of static field strength, and we show that optimum reduction in FiO2 mitigates this effect while maintaining BOLD contrast. Since ASL measurements are highly sensitive to arterial blood TÂ1 (T1a), the value of T1a in vivo is determined as a function of arterial oxygen partial pressure in Chapter 3. The effect of both the degree and duration of hyperoxic exposure on absolute CBF are quantified using simultaneous ASL and in vivo T1a measurements, as described in Chapter 4. In Chapter 5, hyperoxic gas calibration of BOLD/ASL data is used to measure cerebral oxygen metabolism in a hypermetabolic swine model, with our results comparing favorably to 17O2 measurements of absolute metabolism. In Chapter 6, a model to describe the relationship between CBF, oxygen consumption, and hyperoxic T1 reduction is developed, which allows for a more rigorous physiological interpretation of these data. Taken together, this work represents several important steps towards making hyperoxia a more quantitative MRI contrast agent for research and clinical applications
Dynamic Assessment of Cerebral Metabolic Rate of Oxygen (cmro2) With Magnetic Resonance Imaging
The brain is almost entirely dependent on oxidative metabolism to meet its energy requirements. As such, the cerebral metabolic rate of oxygen (CMRO2) is a direct measure of brain energy use. CMRO2 provides insight into brain functional architecture and has demonstrated potential as a clinical tool for assessing many common neurological disorders.
Recent developments in magnetic resonance imaging (MRI)-based CMRO2 quantification have shown promise in spatially resolving CMRO2 in clinically feasible scan times. However, brain energy requirements are both spatially heterogeneous and temporally dynamic, responding to rapid changes in oxygen supply and demand in response to physiologic stimuli and neuronal activation.
Methods for dynamic quantification of CMRO2 are lacking, and this dissertation aims to address this gap. Given the fundamental tradeoff between spatial and temporal resolution in MRI, we focus initially on the latter. Central to each proposed method is a model-based approach for deriving venous oxygen saturation (Yv) â the critical parameter for CMRO2 quantification â from MRI signal phase using susceptometry-based oximetry (SBO).
First, a three-second-temporal-resolution technique for whole-brain quantification of Yv and CMRO2 is presented. This OxFlow method is applied to measure a small but highly significant increase in CMRO2 in response to volitional apnea.
Next, OxFlow is combined with a competing approach for Yv quantification based on blood T2 relaxometry (TRUST). The resulting interleaved-TRUST (iTRUST) pulse sequence greatly improves T2-based CMRO2 quantification, while allowing direct, simultaneous comparison of SBO- and T2-based Yv. iTRUST is applied to assess the CMRO2 response to hypercapnia â a topic of great interest in functional neuroimaging â demonstrating significant biases between SBO- and T2-derived Yv and CMRO2.
To address the need for dynamic and spatially resolved CMRO2 quantification, we explore blood-oxygen-level-dependent (BOLD) calibration, introducing a new calibration model and hybrid pulse sequence combining OxFlow with standard BOLD/CBF measurement. Preliminary results suggest Ox-BOLD provides improved calibration âM-mapsâ for converting BOLD signal to CMRO2.
Finally, OxFlow is applied clinically to patients with obstructive sleep apnea (OSA). A small clinical pilot study demonstrates OSA-associated reductions in CMRO2 at baseline and in response to apnea, highlighting the potential utility of dynamic CMRO2 quantification in assessing neuropathology
Quantitative functional MRI of the Cerebrovascular Reactivity to CO2
Le dioxyde de carbone (CO2) est un rĂ©sidu naturel du mĂ©tabolisme cellulaire, la troisiĂšme substance la plus abondante du sang, et un important agent vasoactif. Ă la moindre variation de la teneur en CO2 du sang, la rĂ©sistance du systĂšme vasculaire cĂ©rĂ©bral et la perfusion tissulaire cĂ©rĂ©brale subissent des changements globaux. Bien que les mĂ©canismes exacts qui sous-tendent cet effet restent Ă ĂȘtre Ă©lucidĂ©s, le phĂ©nomĂšne a Ă©tĂ© largement exploitĂ© dans les Ă©tudes de rĂ©activitĂ© vasculaire cĂ©rĂ©brale (RVC). Une voie prometteuse pour lâĂ©valuation de la fonction vasculaire cĂ©rĂ©brale est la cartographie de la RVC de maniĂšre non-invasive grĂące Ă lâutilisation de lâImagerie par RĂ©sonance MagnĂ©tique fonctionnelle (IRMf). Des mesures quantitatives et non-invasives de de la RVC peuvent ĂȘtre obtenus avec lâutilisation de diffĂ©rentes techniques telles que la manipu- lation du contenu artĂ©riel en CO2 (PaCO2) combinĂ©e Ă la technique de marquage de spin artĂ©riel (Arterial Spin Labeling, ASL), qui permet de mesurer les changements de la perfusion cĂ©rĂ©brale provoquĂ©s par les stimuli vasculaires. Toutefois, les prĂ©occupations liĂ©es Ă la sensibilitĂ© et la fiabilitĂ© des mesures de la RVC limitent de nos jours lâadoption plus large de ces mĂ©thodes modernes de IRMf. Jâai considĂ©rĂ© quâune analyse approfondie ainsi que lâamĂ©lioration des mĂ©thodes disponibles pourraient apporter une contribution prĂ©cieuse dans le domaine du gĂ©nie biomĂ©dical, de mĂȘme quâaider Ă faire progresser le dĂ©veloppement de nouveaux outils dâimagerie de diagnostique. Dans cette thĂšse je prĂ©sente une sĂ©rie dâĂ©tudes oĂč jâexamine lâimpact des mĂ©thodes alternatives de stimulation/imagerie vasculaire sur les mesures de la RVC et les moyens dâamĂ©liorer la sensibilitĂ© et la fiabilitĂ© de telles mĂ©thodes. Jâai aussi inclus dans cette thĂšse un manuscrit thĂ©orique oĂč jâexamine la possible contribution dâun facteur mĂ©connu dans le phĂ©nomĂšne de la RVC : les variations de la pression osmotique du sang induites par les produits de la dissolution du CO2.
Outre lâintroduction gĂ©nĂ©rale (Chapitre 1) et les conclusions (Chapitre 6), cette thĂšse comporte 4 autres chapitres, au long des quels cinq diffĂ©rentes Ă©tudes sont prĂ©sentĂ©es sous forme dâarticles scientifiques qui ont Ă©tĂ© acceptĂ©s Ă des fins de publication dans diffĂ©rentes revues scientifiques. Chaque chapitre dĂ©bute par sa propre introduction, qui consiste en une description plus dĂ©taillĂ©e du contexte motivant le(s) manuscrit(s) associĂ©(s) et un bref rĂ©sumĂ© des rĂ©sultats transmis. Un compte rendu dĂ©taillĂ© des mĂ©thodes et des rĂ©sultats peut ĂȘtre trouvĂ© dans le(s) dit(s) manuscrit(s). Dans lâĂ©tude qui compose le Chapitre 2, je compare la sensibilitĂ© des deux techniques ASL de pointe et je dĂ©montre que la derniĂšre implĂ©mentation de lâASL continue, la pCASL, offre des mesures plus robustes de la RVC en comparaison Ă dâautres mĂ©thodes pulsĂ©s plus ĂągĂ©es. Dans le Chapitre 3, je compare les mesures de la RVC obtenues par pCASL avec lâutilisation de quatre mĂ©thodes respiratoires diffĂ©rentes pour manipuler le CO2 artĂ©rielle (PaCO2) et je dĂ©montre que les rĂ©sultats peuvent varier de maniĂšre significative lorsque les manipulations ne sont pas conçues pour fonctionner dans lâintervalle linĂ©aire de la courbe dose-rĂ©ponse du CO2. Le Chapitre 4 comprend deux Ă©tudes complĂ©mentaires visant Ă dĂ©terminer le niveau de reproductibilitĂ© qui peut ĂȘtre obtenu en utilisant des mĂ©thodes plus rĂ©centes pour la mesure de la RVC. La premiĂšre Ă©tude a abouti Ă la mise au point technique dâun appareil qui permet des manipulations respiratoires du CO2 de maniĂšre simple, sĂ©curitaire et robuste. La mĂ©thode respiratoire amĂ©liorĂ©e a Ă©tĂ© utilisĂ©e dans la seconde Ă©tude â de neuro-imagerie â oĂč la sensibilitĂ© et la reproductibilitĂ© de la RVC, mesurĂ©e par pCASL, ont Ă©tĂ© examinĂ©es. La technique dâimagerie pCASL a pu dĂ©tecter des rĂ©ponses de perfusion induites par la variation du CO2 dans environ 90% du cortex cĂ©rĂ©bral humain et la reproductibilitĂ© de ces mesures Ă©tait comparable Ă celle dâautres mesures hĂ©modynamiques dĂ©jĂ adoptĂ©es dans la pratique clinique. Enfin, dans le Chapitre 5, je prĂ©sente un modĂšle mathĂ©matique qui dĂ©crit la RVC en termes de changements du PaCO2 liĂ©s Ă lâosmolaritĂ© du sang. Les rĂ©ponses prĂ©dites par ce modĂšle correspondent Ă©troitement aux changements hĂ©modynamiques mesurĂ©s avec pCASL ; suggĂ©rant une contribution supplĂ©mentaire Ă la rĂ©activitĂ© du systĂšme vasculaire cĂ©rĂ©bral en lien avec le CO2.Carbon dioxide (CO2) is a natural byproduct of cellular metabolism, the third most abundant substance of blood, and a potent vasoactive agent. The resistance of cerebral vasculature and perfusion of the brain tissue respond to the slightest change in blood CO2 content. The physiology of such an effect remains elusive, yet the phenomenon has been widely exploited in studies of the cerebral vascular function. A promising avenue for the assessment of brainâs vascular function is to measure the cerebrovascular reactivity to CO2 (CVR) non-invasively using functional MRI. Quantitative and non-invasive mapping of CVR can be obtained using respiratory manipulations in arterial CO2 and Arterial Spin Labeling (ASL) to measure the perfusion changes associated with the vascular stimulus. However, concerns related to the sensitivity and reliability of CVR mea- sures by ASL still limit their broader adoption. I considered that a thorough analysis and amelioration of available methods could bring a valuable contribution in the domain of biomedical engineering, helping to advance new diagnostic imaging tools. In this thesis I present a series of studies where I exam the impact of alternative manipulation/ASL methods on CVR measures, and ways to improve the sensitivity and reliability of these measures. I have also included in this thesis a theoretical paper, where I exam the possible contribution of an unappreciated factor in the CVR phenomenon: the changes in blood osmotic pressure induced by the products of CO2 dissolution.
Apart from a general introduction (Chapter 1) and conclusion (Chapter 6), this thesis comprises 4 other chapters, in which five different research studies are presented in the form of articles accepted for publication in scientific journals. Each of these chapters begins with its own specific introduction, which consists of a description of the background motivating the study and a brief summary of conveyed findings. A detailed account of methods and results can be found in the accompanying manuscript(s). The study composing Chapter 2 compares the sensitivity of two state-of-the-art ASL techniques and show that a recent implementation of continuous ASL, pCASL, affords more robust measures of CVR than older pulsed methods. The study described in Chapter 3 compares pCASL CVR measures obtained using 4 different respiratory methods to manipulate arterial CO2 (PaCO2) and shows that results can differ significantly when manipulations are not designed to operate at the linear range of the CO2 dose-response curve. Chapter 4 encompasses two complementary studies seeking to determine the degree of reproducibility that can be attained measuring CVR using the most recent methods. The first study resulted in the technical development of a breathing apparatus allowing simple, safe and robust respiratory CO2 manipulations. The improved respiratory method was used in the second â neuroimaging â study, in which I and co-authors investigate the sensitivity and reproducibility of pCASL measuring CVR. The pCASL imaging technique was able to detect CO2-induced perfusion responses in about 90% of the human brain cortex and the reproducibility of its measures was comparable to other hemodynamic measures already adopted in the clinical practice. Finally, in Chapter 5 I present a mathematical model that describes CVR in terms of PaCO2-related changes in blood osmolarity. The responses predicted by this model correspond closely to the hemodynamic changes measured with pCASL, suggesting an additional contribution to the reactivity of cerebral vasculature to CO2
Quantitative functional neuroimaging of cerebral physiology in healthy aging
Les Ă©tudes dâimagerie par rĂ©sonance magnĂ©tique fonctionnelle (IRMf) ont pour prĂ©misse gĂ©nĂ©rale lâidĂ©e que le signal BOLD peut ĂȘtre utilisĂ© comme un succĂ©danĂ© direct de lâactivation neurale. Les Ă©tudes portant sur le vieillissement cognitif souvent comparent directement lâamplitude et lâĂ©tendue du signal BOLD entre des groupes de personnes jeunes et ĂągĂ©s. Ces Ă©tudes comportent donc un a priori additionnel selon lequel la relation entre lâactivitĂ© neurale et la rĂ©ponse hĂ©modynamique Ă laquelle cette activitĂ© donne lieu restent inchangĂ©e par le vieillissement. Cependant, le signal BOLD provient dâune combinaison ambiguĂ« de changements de mĂ©tabolisme oxydatif, de flux et de volume sanguin. De plus, certaines Ă©tudes ont dĂ©montrĂ© que plusieurs des facteurs influençant les propriĂ©tĂ©s du signal BOLD subissent des changements lors du vieillissement. Lâacquisition dâinformation physiologiquement spĂ©cifique comme le flux sanguin cĂ©rĂ©bral et le mĂ©tabolisme oxydatif permettrait de mieux comprendre les changements qui sous-tendent le contraste BOLD, ainsi que les altĂ©rations physiologiques et cognitives propres au vieillissement. Le travail prĂ©sentĂ© ici dĂ©montre lâapplication de nouvelles techniques permettant de mesurer le mĂ©tabolisme oxydatif au repos, ainsi que pendant lâexĂ©cution dâune tĂąche. Ces techniques reprĂ©sentent des extensions de mĂ©thodes dâIRMf calibrĂ©e existantes. La premiĂšre mĂ©thode prĂ©sentĂ©e est une gĂ©nĂ©ralisation des modĂšles existants pour lâestimation du mĂ©tabolisme oxydatif Ă©voquĂ© par une tĂąche, permettant de prendre en compte tant des changements arbitraires en flux sanguin que des changements en concentrations sanguine dâO2. Des amĂ©liorations en terme de robustesse et de prĂ©cisions sont dĂ©montrĂ©es dans la matiĂšre grise et le cortex visuel lorsque cette mĂ©thode est combinĂ©e Ă une manipulation respiratoire incluant une composante dâhypercapnie et dâhyperoxie. Le seconde technique prĂ©sentĂ©e ici est une extension de la premiĂšre et utilise une combinaison de manipulations respiratoires incluant lâhypercapnie, lâhyperoxie et lâadministration simultanĂ©e des deux afin dâobtenir des valeurs expĂ©rimentales de la fraction dâextraction dâoxygĂšne et du mĂ©tabolisme oxydatif au repos. Dans la deuxiĂšme partie de cette thĂšse, les changements vasculaires et mĂ©taboliques liĂ©s Ă lâĂąge sont explorĂ©s dans un groupe de jeunes et aĂźnĂ©s, grĂące au cadre conceptuel de lâIRMf calibrĂ©e, combinĂ© Ă une manipulation respiratoire dâhypercapnie et une tĂąche modifiĂ©e de Stroop. Des changements de flux sanguin au repos, de rĂ©activitĂ© vasculaire au CO2 et de paramĂštre de calibration M ont Ă©tĂ© identifiĂ©s chez les aĂźnĂ©s. Les biais affectant les mesures de signal BOLD obtenues chez les participants ĂągĂ©s dĂ©coulant de ces changements physiologiques sont de plus discutĂ©s. Finalement, la relation entre ces changements cĂ©rĂ©braux et la performance dans la tĂąche de Stroop, la santĂ© vasculaire centrale et la condition cardiovasculaire est explorĂ©e. Les rĂ©sultats prĂ©sentĂ©s ici sont en accord avec lâhypothĂšse selon laquelle une meilleure condition cardiovasculaire est associĂ©e Ă une meilleure fonction vasculaire centrale, contribuant ainsi Ă lâamĂ©lioration de la santĂ© vasculaire cĂ©rĂ©brale 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
Vascular physiology drives functional brain networks
We present the first evidence for vascular regulation driving fMRI signals in specific functional brain networks. Using concurrent neuronal and vascular stimuli, we collected 30 BOLD fMRI datasets in 10 healthy individuals: a working memory task, flashing checkerboard stimulus, and CO2 inhalation challenge were delivered in concurrent but orthogonal paradigms. The resulting imaging data were averaged together and decomposed using independent component analysis, and three âneuronal networksâ were identified as demonstrating maximum temporal correlation with the neuronal stimulus paradigms: Default Mode Network, Task Positive Network, and Visual Network. For each of these, we observed a second network component with high spatial overlap. Using dual regression in the original 30 datasets, we extracted the time-series associated with these network pairs and calculated the percent of variance explained by the neuronal or vascular stimuli using a normalized R2 parameter. In each pairing, one network was dominated by the appropriate neuronal stimulus, and the other was dominated by the vascular stimulus as represented by the end-tidal CO2 time-series recorded in each scan. We acquired a second dataset in 8 of the original participants, where no CO2 challenge was delivered and CO2 levels fluctuated naturally with breathing variations. Although splitting of functional networks was not robust in these data, performing dual regression with the network maps from the original analysis in this new dataset successfully replicated our observations. Thus, in addition to responding to localized metabolic changes, the brainâs vasculature may be regulated in a coordinated manner that mimics (and potentially supports) specific functional brain networks. Multi-modal imaging and advances in fMRI acquisition and analysis could facilitate further study of the dual nature of functional brain networks. It will be critical to understand network-specific vascular function, and the behavior of a coupled vascular-neural network, in future studies of brain pathology
Validation of diffuse correlation spectroscopy measurements of rodent cerebral blood flow with simultaneous arterial spin labeling MRI; towards MRI-optical continuous cerebral metabolic monitoring.
Cerebral blood flow (CBF) during stepped hypercapnia was measured simultaneously in the rat brain using near-infrared diffuse correlation spectroscopy (DCS) and arterial spin labeling MRI (ASL). DCS and ASL CBF values agree very well, with high correlation (R=0.86, p< 10(-9)), even when physiological instability perturbed the vascular response. A partial volume effect was evident in the smaller magnitude of the optical CBF response compared to the MRI values (averaged over the cortical area), primarily due to the inclusion of white matter in the optically sampled volume. The 8.2 and 11.7 mm mid-separation channels of the multi-distance optical probe had the lowest partial volume impact, reflecting ~75 % of the MR signal change. Using a multiplicative correction factor, the ASL CBF could be predicted with no more than 10% relative error, affording an opportunity for real-time relative cerebral metabolism monitoring in conjunction with MR measurement of cerebral blood volume using super paramagnetic contrast agents.R01 EB006385 - NIBIB NIH HHS; R01 EB001954 - NIBIB NIH HHS; R01 NS057476 - NINDS NIH HHS; P41 RR014075 - NCRR NIH HHS; R01 HD042908-07 - NICHD NIH HHS; R01 EB002066 - NIBIB NIH HHS; R01 HD042908-06 - NICHD NIH HHS; R01 HD042908 - NICHD NIH HHSPublished versio
Imagerie multimodale des corrélats vasculaires du vieillissement cérébral
RĂSUMĂ
Plusieurs décennies de recherche ont permis de démontrer que le vieillissement a des effets sur
une multitudes de composantes du cerveau. En particulier, des preuves s'accumulent Ă l'effet qu'il
existe un lien entre le fonctionnement du cerveau au niveau cognitif et la santé du systÚme
vasculaire, notamment le débit sanguin cérébral (DSC) qui diminue avec l'ùge, ainsi que la santé
cardiorespiratoire qui pourrait corréler à la performance cognitive selon certaines études.
Plusieurs techniques d'imagerie cérébrale couramment utilisées en recherche, telles que le signal
dépendant du niveau d'oxygénation du sang en imagerie par résonance magnétique (BOLDIRM),
se basent sur les corrélats vasculaires de l'activité des neurones. Cela en fait des outils
propices pour l'Ă©tude des effets vasculaires du vieillissement, qui influencent directement les
signaux mesurés. Cette thÚse a utilisé plusieurs techniques d'imagerie cérébrale basées sur
l'hémodynamique pour étudier les effets du vieillissement sur le cerveau à différentes échelles
spatiales, chez l'humain et dans un modĂšle animal chez le rat. Dans un premier temps, la
microscopie biphotonique a été utilisée pour mesurer la vitesse des globules rouges, le diamÚtre
et la densité des capillaires ainsi que l'hématocrite local dans prÚs de 1000 capillaires chez 12 rats
Long-Evans jeunes (3 mois) et 12 rats ùgés (24 mois) anesthésiés. Il a été mesuré que la vitesse
des globules rouges et le diamÚtre étaient plus élevés dans les capillaires de rats ùgés (par 48 et
7% respectivement), tandis que l'hématocrite et la densité volumiques des capillaires étaient plus
faibles (par 32 et 20%). Ces résultats suggÚrent que la diminution du DSC avec l'ùge serait
surtout attribuable à une baisse de densité vasculaire. En second lieu, l'IRM et la spectroscopie
résolue en temps de vol ont permis de mesurer le débit, l'oxygénation (sO2) et la concentration
totale d'hémoglobine (HbT) dans les cerveaux d'humains jeunes (18-30 ans) et ùgés (62-72 ans),
en plus de la réponse à une tùche cognitive de Stroop en termes de BOLD et de DSC. La capacité
cardiorespiratoire des sujets et été mesurée par un test de VO2max. Nous avons mesuré, dans le
cortex préfrontal gauche sollicité par la tùche de Stroop, des valeurs plus faibles de DSC (par
19%), sO2 (par 6%) et HbT (par 21%) chez les sujets ùgés. Dans le groupe ùgé, les mesures de
sO2 étaient corrélées à la performance cognitive dans la tùche Stroop ainsi qu'au VO2max, mais pas
celles de DSC ni de HbT. Ces résultats suggÚrent un effet protecteur de l'exercice physique sur la
santé cognitive dans le vieillissement, dont les mécanismes seraient liés à une amélioration de
l'oxygĂ©nation cĂ©rĂ©brale. Enfin, les mĂȘmes groupes de rats jeune et ĂągĂ© ont Ă©tĂ© soumis Ă un
stimulus vasodilatateur, l'hypercapnie, afin de mesurer la réponse hémodynamique à l'aide de----------ABSTRACT
Several decades of research have demonstrated that aging affects a multitude of components in
the brain. In particular, evidence is accumulating on the relation between brain function and
vascular health, including cerebral blood flow (CBF), which decreases with age, and
cardiopulmonary health which could correlate with cognitive performance according to some
studies. Several brain imaging techniques commonly used in research, such as the blood
oxygenation level dependent signal in magnetic resonance imaging (BOLD-MRI), are based on
the vascular correlates of neural activity. This makes them suitable tools for the study of the
vascular effects of aging, which directly influence the measured signals. This thesis used several
imaging modalities based on hemodynamics to study the effects of aging on the brain at different
spatial scales, in humans and in an animal model, the rat. Initially, two-photon microscopy was
used to measure the velocity of red blood cells (RBCs), the diameter and the density of capillaries
and the local hematocrit in nearly 1000 capillaries in 12 young (3 months-old) and 12 aged
anesthetized Long-Evans rats (24 months-old). We measured higher RBCs velocity and diameter
in the capillaries of aged rats (by 48 and 7 % respectively), while the hematocrit and volumetric
capillary density were lower (by 32 and 20 %). These results suggest that the decrease in CBF
with age is due primarily to a decrease in vascular density. Second, MRI and time-resolved
spectroscopy were used to measure the CBF, oxygenation (sO2) and total hemoglobin
concentration (HbT) in the brains of young (18-30 years-old) and elderly (62-72 years-old)
humans, in addition to the response to a cognitive Stroop task in terms of BOLD and CBF.
Cardiorespiratory fitness was measured by a VO2max test. In the left prefrontal cortex activated by
the Stroop task, we measured lower values of CBF (by 19%), sO2 (by 6%) and HbT (by 21%) in
the elderly. In the older group, measures of sO2 were correlated with Stroop task cognitive
performance and with VO2max, while CBF and HbT were not. These results suggest a protective
effect of physical activity on cognitive health in aging, mediated by an improvement in cerebral
oxygenation. Finally, the same groups of young and old rats were subjected to a vasodilating
stimulus, hypercapnia, for measuring the hemodynamic response with several imaging
modalities. The data demonstrated a decrease in the hemodynamic response to hypercapnia in
terms of CBF, HbT and HbO (oxygenated hemoglobin) in aged rats, suggesting decreased
vascular reactivity. The vessels' compliance could also be reduced with age, as the ratio o
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