Quantitative functional MRI of the Cerebrovascular Reactivity to CO2

Le dioxyde de carbone (CO2) est un résidu naturel du métabolisme cellulaire, la troisième substance la plus abondante du sang, et un important agent vasoactif. À la moindre variation de la teneur en CO2 du sang, la résistance du système vasculaire cérébral et la perfusion tissulaire cérébrale subissent des changements globaux. Bien que les mécanismes exacts qui sous-tendent cet effet restent à être élucidés, le phénomène a été largement exploité dans les études de réactivité vasculaire cérébrale (RVC). Une voie prometteuse pour l’évaluation de la fonction vasculaire cérébrale est la cartographie de la RVC de manière non-invasive grâce à l’utilisation de l’Imagerie par Résonance Magnétique fonctionnelle (IRMf). Des mesures quantitatives et non-invasives de de la RVC peuvent être obtenus avec l’utilisation de différentes techniques telles que la manipu- lation du contenu artériel en CO2 (PaCO2) combinée à la technique de marquage de spin artériel (Arterial Spin Labeling, ASL), qui permet de mesurer les changements de la perfusion cérébrale provoqués par les stimuli vasculaires. Toutefois, les préoccupations liées à la sensibilité et la fiabilité des mesures de la RVC limitent de nos jours l’adoption plus large de ces méthodes modernes de IRMf. J’ai considéré qu’une analyse approfondie ainsi que l’amélioration des méthodes disponibles pourraient apporter une contribution précieuse dans le domaine du génie biomédical, de même qu’aider à faire progresser le développement de nouveaux outils d’imagerie de diagnostique. Dans cette thèse je présente une série d’études où j’examine l’impact des méthodes alternatives de stimulation/imagerie vasculaire sur les mesures de la RVC et les moyens d’améliorer la sensibilité et la fiabilité de telles méthodes. J’ai aussi inclus dans cette thèse un manuscrit théorique où j’examine la possible contribution d’un facteur méconnu dans le phénomène de la RVC : les variations de la pression osmotique du sang induites par les produits de la dissolution du CO2. Outre l’introduction générale (Chapitre 1) et les conclusions (Chapitre 6), cette thèse comporte 4 autres chapitres, au long des quels cinq différentes études sont présentées sous forme d’articles scientifiques qui ont été acceptés à des fins de publication dans différentes revues scientifiques. Chaque chapitre débute par sa propre introduction, qui consiste en une description plus détaillée du contexte motivant le(s) manuscrit(s) associé(s) et un bref résumé des résultats transmis. Un compte rendu détaillé des méthodes et des résultats peut être trouvé dans le(s) dit(s) manuscrit(s). Dans l’étude qui compose le Chapitre 2, je compare la sensibilité des deux techniques ASL de pointe et je démontre que la dernière implémentation de l’ASL continue, la pCASL, offre des mesures plus robustes de la RVC en comparaison à d’autres méthodes pulsés plus âgées. Dans le Chapitre 3, je compare les mesures de la RVC obtenues par pCASL avec l’utilisation de quatre méthodes respiratoires différentes pour manipuler le CO2 artérielle (PaCO2) et je démontre que les résultats peuvent varier de manière significative lorsque les manipulations ne sont pas conçues pour fonctionner dans l’intervalle linéaire de la courbe dose-réponse du CO2. Le Chapitre 4 comprend deux études complémentaires visant à déterminer le niveau de reproductibilité qui peut être obtenu en utilisant des méthodes plus récentes pour la mesure de la RVC. La première étude a abouti à la mise au point technique d’un appareil qui permet des manipulations respiratoires du CO2 de manière simple, sécuritaire et robuste. La méthode respiratoire améliorée a été utilisée dans la seconde étude – de neuro-imagerie – où la sensibilité et la reproductibilité de la RVC, mesurée par pCASL, ont été examinées. La technique d’imagerie pCASL a pu détecter des réponses de perfusion induites par la variation du CO2 dans environ 90% du cortex cérébral humain et la reproductibilité de ces mesures était comparable à celle d’autres mesures hémodynamiques déjà adoptées dans la pratique clinique. Enfin, dans le Chapitre 5, je présente un modèle mathématique qui décrit la RVC en termes de changements du PaCO2 liés à l’osmolarité du sang. Les réponses prédites par ce modèle correspondent étroitement aux changements hémodynamiques mesurés avec pCASL ; suggérant une contribution supplémentaire à la réactivité du système vasculaire cérébral 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 brain’s 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 – neuroimaging – 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

A simple breathing circuit allowing precise control of inspiratory gases for experimental respiratory manipulations

BACKGROUND: Respiratory manipulations modulating blood flow and oxygenation levels have become an important component of modern functional MRI applications. Manipulations often consist of temporarily switching inspired fractions of CO(2) and O(2); and have typically been performed using simple oxygen masks intended for applications in respiratory therapy. However, precise control of inspired gas composition is difficult using this type of mask due to entrainment of room air and resultant dilution of inspired gases. We aimed at developing a gas delivery apparatus allowing improved control over the fractional concentration of inspired gases, to be used in brain fMRI studies. FINDINGS: The breathing circuit we have conceived allowed well controlled step changes in FiO(2) and FiCO(2), at moderate flow rates achievable on standard clinical flow regulators. In a two run test inside the scanner we demonstrate that tightly controlled simple gas switching manipulations can afford good intra-subject reproducibility of induced hyperoxia/hypercapnia responses. Although our approach requires a non-vented mask fitting closely to the subject’s face, the circuit ensures a continuous supply of breathable air even if the supply of medical gases is interrupted, and is easily removable in case of an emergency. The apparatus we propose is also compact and MRI compatible, allowing subject placement in confined spaces such as an MRI scanner for brain examinations. CONCLUSIONS: We have reported a new approach for the controlled administration of medical gases, and describe an implementation of the breathing circuit that is MRI compatible and uses commercially available parts. The resultant apparatus allows simple, safe and precise manipulations of FiO(2) and FiCO(2)

The impact of inspired oxygen levels on calibrated fMRI measurements of M, OEF and resting CMRO2 using combined hypercapnia and hyperoxia.

Recent calibrated fMRI techniques using combined hypercapnia and hyperoxia allow the mapping of resting cerebral metabolic rate of oxygen (CMRO2) in absolute units, oxygen extraction fraction (OEF) and calibration parameter M (maximum BOLD). The adoption of such technique necessitates knowledge about the precision and accuracy of the model-derived parameters. One of the factors that may impact the precision and accuracy is the level of oxygen provided during periods of hyperoxia (HO). A high level of oxygen may bring the BOLD responses closer to the maximum M value, and hence reduce the error associated with the M interpolation. However, an increased concentration of paramagnetic oxygen in the inhaled air may result in a larger susceptibility area around the frontal sinuses and nasal cavity. Additionally, a higher O2 level may generate a larger arterial blood T1 shortening, which require a bigger cerebral blood flow (CBF) T1 correction. To evaluate the impact of inspired oxygen levels on M, OEF and CMRO2 estimates, a cohort of six healthy adults underwent two different protocols: one where 60% of O2 was administered during HO (low HO or LHO) and one where 100% O2 was administered (high HO or HHO). The QUantitative O2 (QUO2) MRI approach was employed, where CBF and R2* are simultaneously acquired during periods of hypercapnia (HC) and hyperoxia, using a clinical 3 T scanner. Scan sessions were repeated to assess repeatability of results at the different O2 levels. Our T1 values during periods of hyperoxia were estimated based on an empirical ex-vivo relationship between T1 and the arterial partial pressure of O2. As expected, our T1 estimates revealed a larger T1 shortening in arterial blood when administering 100% O2 relative to 60% O2 (T1LHO = 1.56±0.01 sec vs. T1HHO = 1.47±0.01 sec, P < 4*10-13). In regard to the susceptibility artifacts, the patterns and number of affected voxels were comparable irrespective of the O2 concentration. Finally, the model-derived estimates were consistent regardless of the HO levels, indicating that the different effects are adequately accounted for within the model

Regional Reproducibility of BOLD Calibration Parameter M, OEF and Resting-State CMRO2 Measurements with QUO2 MRI.

The current generation of calibrated MRI methods goes beyond simple localization of task-related responses to allow the mapping of resting-state cerebral metabolic rate of oxygen (CMRO2) in micromolar units and estimation of oxygen extraction fraction (OEF). Prior to the adoption of such techniques in neuroscience research applications, knowledge about the precision and accuracy of absolute estimates of CMRO2 and OEF is crucial and remains unexplored to this day. In this study, we addressed the question of methodological precision by assessing the regional inter-subject variance and intra-subject reproducibility of the BOLD calibration parameter M, OEF, O2 delivery and absolute CMRO2 estimates derived from a state-of-the-art calibrated BOLD technique, the QUantitative O2 (QUO2) approach. We acquired simultaneous measurements of CBF and R2* at rest and during periods of hypercapnia (HC) and hyperoxia (HO) on two separate scan sessions within 24 hours using a clinical 3 T MRI scanner. Maps of M, OEF, oxygen delivery and CMRO2, were estimated from the measured end-tidal O2, CBF0, CBFHC/HO and R2*HC/HO. Variability was assessed by computing the between-subject coefficients of variation (bwCV) and within-subject CV (wsCV) in seven ROIs. All tests GM-averaged values of CBF0, M, OEF, O2 delivery and CMRO2 were: 49.5 ± 6.4 mL/100 g/min, 4.69 ± 0.91%, 0.37 ± 0.06, 377 ± 51 μmol/100 g/min and 143 ± 34 μmol/100 g/min respectively. The variability of parameter estimates was found to be the lowest when averaged throughout all GM, with general trends toward higher CVs when averaged over smaller regions. Among the MRI measurements, the most reproducible across scans was R2*0 (wsCVGM = 0.33%) along with CBF0 (wsCVGM = 3.88%) and R2*HC (wsCVGM = 6.7%). CBFHC and R2*HO were found to have a higher intra-subject variability (wsCVGM = 22.4% and wsCVGM = 16% respectively), which is likely due to propagation of random measurement errors, especially for CBFHC due to the low contrast-to-noise ratio intrinsic to ASL. Reproducibility of the QUO2 derived estimates were computed, yielding a GM intra-subject reproducibility of 3.87% for O2 delivery, 16.8% for the M value, 13.6% for OEF and 15.2% for CMRO2. Although these results focus on the precision of the QUO2 method, rather than the accuracy, the information will be useful for calculation of statistical power in future validation studies and ultimately for research applications of the method. The higher test-retest variability for the more extensively modeled parameters (M, OEF, and CMRO2) highlights the need for further improvement of acquisition methods to reduce noise levels

Literature values of <i>M</i>, OEF and resting-state CMRO₂.

<p>Literature values of <i>M</i>, OEF and resting-state CMRO₂.</p

Precision of group GM-averaged values—sensitivity to random errors.

<p>Observed effects, on <i>M</i> and OEF estimates, of error in BOLD and CBF measurements, are summarized. Estimates were based on group-averaged Test A de-PCASL measurements in GM and ETO₂ (‘true’ values), while a simulated error was added to each observed input independently. Evaluated error ranged from -33% to 33%, which is equivalent to a maximum measurement CV of 28% (when underestimated) and 20% (when overestimated). The HC and HO curves resulting from six different errors in CBF_HC, BOLD_HC and BOLD_HO are shown (A1, A2 and A3 respectively). Each red dot represents the HC and HO curves intersection (hence one <i>M</i> and OEF solution) when either one of the extremity in the observed range is in use. The remaining <i>M</i> and OEF solutions lie on a line connecting both red dots and passing by the subsequent intersections. OEF and <i>M</i> estimates (B1 and B2 respectively) in addition to CV between simulated and ‘true’ OEF/<i>M</i> values (C1 and C2) were computed for each source of errors (colored lines). Without addition of error in measurements, ‘true’ group-averaged Test A <i>M</i> and OEF estimates were 4.96% and 0.39 respectively (shown by the blue stars and the perforated grey lines).</p

Detection rate of solutions in ROI (%)

<p>Detection rate of solutions in ROI (%)</p

ROI analysis of within- and between-subject reproducibility.

<p>Within each ROI, are shown the within- and between-subject coefficient of variation (respectively wsCV (blue) and bsCV (red)) for each metric.</p

Reproducibility of QUO2 measurements in different ROI.

<p>Reproducibility of QUO2 measurements in different ROI.</p