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Regional tissue temperature dynamics in the brain are determined by the balance of the metabolic heat production rate and heat exchange with blood flowing through capillaries embedded in the brain tissue, the surrounding tissues and the environment. Local changes in blood flow and metabolism during functional activity can upset this balance and induce transient temperature changes. Invasive experimental studies in animal models have estab- lished that the brain temperature changes during functional activity are observable and a definitive relationship exists between temperature and brain activity. We present a theoreti- cal framework that links tissue temperature dynamics with hemodynamic activity allowing us to non-invasively estimate brain temperature changes from experimentally measured blood- oxygen level dependent (BOLD) signals. With this unified approach, we are able to pinpoint the mechanisms for hemodynamic activity-related temperature increases and decreases. In addition to these results, the potential uses and limitations of optical measurements are dis- cussed.

<p>Diffusion tensor (DT) and blood oxygen-level dependent (BOLD) imaging are two noninvasive magnetic resonance (MR) techniques that have been used to probe skeletal muscle microstructure and microvasculature, respectively. Over a series of four studies, the work in this thesis aimed at furthering our understanding of baseline DT metrics and BOLD signals in lower limb muscles (calf and foot) of healthy young subjects. Since postural changes have been shown to alter numerous quantities, including fluid volumes and muscle cross sectional area, DT indices and BOLD signal characteristics were examined in response to movement from upright to supine position.</p> <p>Reductions of 3.2-6.7% and 3.4-7.5% were measured in calf DT eigenvalues and apparent diffusion coefficient (ADC) in the various muscles, following 34 and 64 minutes of supine rest, respectively (P</p> <p>Establishment of baseline diffusion metrics in the foot region was feasible (chapter 6). Examination of foot DT indices in response to positional change showed that the metrics decreased from 2.7-4.6% following 34 minutes of supine rest (P</p> / Doctor of Philosophy (PhD)

The blood oxygen level dependent functional MRI (BOLD-fMRI) signal is an indirect measure of the neuronal activity that most BOLD studies are interested in. This thesis uses generative embedding algorithms to investigate some of the challenges and opportunities that this presents for BOLD imaging. It is standard practice to analyse BOLD signals using general linear models (GLMs) that assume fixed neurovascular coupling. However, this assumption may cause false positive or negative neural activations to be detected if the biological manifestations of brain diseases, disorders and pharmaceutical drugs (termed "neuromodulations") alter this coupling. Generative embedding can help overcome this problem by identifying when a neuromodulation confounds the standard GLM. When applied to anaesthetic neuromodulations found in preclinical imaging data, Fentanyl has the smallest confounding effect and Pentobarbital has the largest, causing extremely significant neural activations to go undetected. Half of the anaesthetics tested caused overestimation of the neuronal activity but the other half caused underestimation. The variability in biological action between anaesthetic modulations in identical brain regions of genetically similar animals highlights the complexity required to comprehensively account for factors confounding neurovascular coupling in GLMs generally. Generative embedding has the potential to augment established algorithms used to compensate for these variations in GLMs without complicating the standard (ANOVA) way of reporting BOLD results. Neuromodulation of neurovascular coupling can also present opportunities, such as improved diagnosis, monitoring and understanding of brain diseases accompanied by neurovascular uncoupling. Information theory is used to show that the discriminabilities of neurodegenerative-diseased and healthy generative posterior parameter spaces make generative embedding a viable tool for these commercial applications, boasting sensitivity to neurovascular coupling nonlinearities and biological interpretability. The value of hybrid neuroimaging systems over separate neuroimaging technologies is found to be greatest for early-stage neurodegenerative disease.

Ce projet illustre cinq études, mettant l'emphase sur le développement d'une nouvelle approche diagnostique cardiovasculaire afin d'évaluer le niveau d’oxygène contenu dans le myocarde ainsi que sa fonction microvasculaire. En combinant une séquence de résonance magnétique cardiovasculaire (RMC) pouvant détecter le niveau d’oxygène (OS), des manœuvres respiratoires ainsi que des analyses de gaz artériels peuvent être utilisés comme procédure non invasive destinée à induire une réponse vasoactive afin d’évaluer la réserve d'oxygénation, une mesure clé de la fonction vasculaire. Le nombre de tests diagnostiques cardiaques prescrits ainsi que les interventions, sont en pleine expansion. L'imagerie et tests non invasifs sont souvent effectués avant l’utilisation de procédures invasives. L'imagerie cardiaque permet d’évaluer la présence ou absence de sténoses coronaires, un important facteur économique dans notre système de soins de santé. Les techniques d'imagerie non invasives fournissent de l’information précise afin d’identifier la présence et l’emplacement du déficit de perfusion chez les patients présentant des symptômes d'ischémie myocardique. Néanmoins, plusieurs techniques actuelles requièrent la nécessité de radiation, d’agents de contraste ou traceurs, sans oublier des protocoles de stress pharmacologiques ou physiques. L’imagerie RMC peut identifier une sténose coronaire significative sans radiation. De nouvelles tendances d’utilisation de RMC visent à développer des techniques diagnostiques qui ne requièrent aucun facteur de stress pharmacologiques ou d’agents de contraste. L'objectif principal de ce projet était de développer et tester une nouvelle technique diagnostique afin d’évaluer la fonction vasculaire coronarienne en utilisant l' OS-RMC, en combinaison avec des manœuvres respiratoires comme stimulus vasoactif. Ensuite, les objectifs, secondaires étaient d’utilisés l’OS-RMC pour évaluer l'oxygénation du myocarde et la réponse coronaire en présence de gaz artériels altérés. Suite aux manœuvres respiratoires la réponse vasculaire a été validée chez un modèle animal pour ensuite être utilisé chez deux volontaires sains et finalement dans une population de patients atteints de maladies cardiovasculaires. Chez le modèle animal, les manœuvres respiratoires ont pu induire un changement significatif, mesuré intrusivement par débit sanguin coronaire. Il a été démontré qu’en présence d'une sténose coronarienne hémodynamiquement significative, l’OS-RMC pouvait détecter un déficit en oxygène du myocarde. Chez l’homme sain, l'application de cette technique en comparaison avec l'adénosine (l’agent standard) pour induire une vasodilatation coronarienne et les manœuvres respiratoires ont pu induire une réponse plus significative en oxygénation dans un myocarde sain. Finalement, nous avons utilisé les manœuvres respiratoires parmi un groupe de patients atteint de maladies coronariennes. Leurs myocardes étant altérées par une sténose coronaire, en conséquence modifiant ainsi leur réponse en oxygénation. Par la suite nous avons évalué les effets des gaz artériels sanguins sur l'oxygénation du myocarde. Ils démontrent que la réponse coronarienne est atténuée au cours de l’hyperoxie, suite à un stimuli d’apnée. Ce phénomène provoque une réduction globale du débit sanguin coronaire et un déficit d'oxygénation dans le modèle animal ayant une sténose lorsqu’un supplément en oxygène est donné. En conclusion, ce travail a permis d'améliorer notre compréhension des nouvelles techniques diagnostiques en imagerie cardiovasculaire. Par ailleurs, nous avons démontré que la combinaison de manœuvres respiratoires et l’imagerie OS-RMC peut fournir une méthode non-invasive et rentable pour évaluer la fonction vasculaire coronarienne régionale et globale. / This project encompasses five studies, which focus on developing a new cardiovascular diagnostic approach for assessing myocardial oxygenation and microvascular function. In combination with oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) imaging, breathing maneuvers and altered arterial blood gases can be used as a non-invasive method for inducing a vasoactive response to test the oxygenation reserve, a key measurement in vascular function. The number of prescribed cardiac diagnostic tests and interventions is rapidly growing. In particular, imaging and other non-invasive tests are frequently performed prior to invasive procedures. One of the most common uses of cardiac imaging is for the diagnosis of significant coronary artery stenosis, a critical cost factor in today’s health care system. Non-invasive imaging techniques provide the most reliable information for the presence and location of perfusion or oxygenation deficits in patients with symptoms suggestive of myocardial ischemia, yet many current techniques suffer from the need for radiation, contrast agents or tracers, and pharmacological or physical stress protocols. CMR imaging can identify significant coronary artery stenosis without radiation and new trends in CMR research aim to develop diagnostic techniques that do not require any pharmacological stressors or contrast agents. For this project, the primary aim was to develop and test a new diagnostic technique to assess coronary vascular function using OS-CMR in combination with breathing maneuvers as the vasoactive stimulus. Secondary aims then used OS-CMR to assess myocardial oxygenation and the coronary response in the presence of altered arterial blood gases. An animal model was used to validate the vascular response to breathing maneuvers before translating the technique to human subjects into both healthy volunteers, and a patient population with cardiac disease. In the animal models, breathing maneuvers could induce a significant change in invasively measured coronary blood flow and it was demonstrated that in the presence of a haemodynamically significant coronary stenosis, OS-CMR could detect a myocardial oxygen deficit. This technique was then applied in a human model, with healthy participants. In a direct comparison to the infusion of the coronary vasodilator adenosine, which is considered a standard agent for inducing vasodilation in cardiac imaging, breathing maneuvers induced a stronger response in oxygenation of healthy myocardium. The final study then implemented the breathing maneuvers in a patient population with coronary artery disease; in which myocardium compromised by a coronary stenosis had a compromised oxygenation response. Furthermore, the observed effects of arterial blood gases on myocardial oxygenation were assessed. This demonstrated that the coronary response to breath-hold stimuli is attenuated during hyperoxia, and this causes an overall reduction in coronary blood flow, and consequently an oxygenation deficit in a coronary stenosis animal model when supplemental oxygen is provided. In conclusion, this work has improved our understanding of potential new diagnostic techniques for cardiovascular imaging. In particular, it demonstrated that combining breathing maneuvers with oxygenation-sensitive CMR can provide a non-invasive and cost-effective method for assessing global and regional coronary vascular function.

Blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging enables non-invasive spatial mapping of changes in cerebral blood flow (CBF). By applying a vasodilatory stimulus (such as inhaled CO2) during BOLD MR imaging, one can measure cerebral vasodilatory capacity. "Cerebrovascular reactivity" (CVR) is defined as the change in CBF per unit of vasodilatory stimulus. Vasodilatory capacity is clinically important as vasodilatation is a mechanism by which the brain maintains constant CBF despite reductions in cerebral perfusion pressure.ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). The third study arose from an unexpected observation: paradoxical reactivity in the white matter of young healthy subjects. I evaluated healthy subjects using BOLD CVR and ASL CVR, transformed all CVR maps into a common brain space, and generated composite maps of CVR. Composite maps confirmed regions of significant paradoxical iii reactivity in the white matter. These regions may represent the physiological correlate of previously anatomically defined border-zones (watershed zones). The regions match the locations where elderly patients develop white matter rarefaction, so-called leukoaraiosis.

Blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging enables non-invasive spatial mapping of changes in cerebral blood flow (CBF). By applying a vasodilatory stimulus (such as inhaled CO2) during BOLD MR imaging, one can measure cerebral vasodilatory capacity. "Cerebrovascular reactivity" (CVR) is defined as the change in CBF per unit of vasodilatory stimulus. Vasodilatory capacity is clinically important as vasodilatation is a mechanism by which the brain maintains constant CBF despite reductions in cerebral perfusion pressure.ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). ii Patients with arterial narrowing commonly demonstrate a paradoxical response: vasodilatory stimulus-induced reduction of BOLD MR signal. BOLD MR depends on CBF but on other factors too. Does a reduction of BOLD MR signal indicate a decrease in flow? Does BOLD MR CVR correlate with CVR measured using arterial spin labeling (ASL) MR? I studied thirty-eight patients with stenosis of brain-supplying arteries and found that the BOLD CVR and ASL CVR results correlate strongly (R=0.83, P<0.0001 for cerebral hemispheric gray matter). The second study aimed to determine whether preoperative CVR predicts the hemodynamic effect of extracranial-intracranial bypass surgery. Whereas prior studies relied on right-left interhemispheric CVR asymmetry indices, this study used “absolute” CVR from each hemisphere. I studied twenty-five patients with intracranial arterial stenosis. I found that the group with normal pre-operative CVR showed no change in CVR following bypass surgery (0.22% ± 0.05% to 0.22% ± 0.01% (mean ± SD)(P=0.881)), the group with reduced pre-operative CVR demonstrated an improvement (0.08% ± 0.05% to 0.21 ± 0.08% (mean ± SD)(P<0.001)), and the group with paradoxical pre-operative CVR demonstrated the greatest improvement (-0.04% ± 0.03% to 0.27% ± 0.03% (P=0.028)). The third study arose from an unexpected observation: paradoxical reactivity in the white matter of young healthy subjects. I evaluated healthy subjects using BOLD CVR and ASL CVR, transformed all CVR maps into a common brain space, and generated composite maps of CVR. Composite maps confirmed regions of significant paradoxical iii reactivity in the white matter. These regions may represent the physiological correlate of previously anatomically defined border-zones (watershed zones). The regions match the locations where elderly patients develop white matter rarefaction, so-called leukoaraiosis.

La complexité de la connaissance humaine est révèlée dans l'organisation spatiale et temporelle de la dynamique du cerveau. Nous pouvons connaître cette organisation grâce à l'analyse des signaux dépendant du niveau d'oxygène sanguin (BOLD), lesquels sont obtenus par l'imagerie par résonance magnétique fonctionnelle (IRMf). Nous observons des dépendances statistiques entre les régions du cerveau dans les données BOLD. Ce phénomène s' appelle connectivité fonctionnelle (CF). Des modèles computationnels sont développés pour reproduire la connectivité fonctionnelle (CF). Comme les études expérimentales précédantes, ces modèles assument que la CF est stationnaire, c'est-à-dire la moyenne et la covariance des séries temporelles BOLD utilisées par la CF sont constantes au fil du temps. Cependant, des nouvelles études expérimentales concernées par la dynamique de la CF à différentes échelles montrent que la CF change dans le temps. Cette caractéristique n'a pas été reproduite dans ces modèles computationnels précédants. Ici on a augmenté la non-linéarité de la dynamique locale dans un modèle computationnel à grande échelle. Ce modèle peut reproduire la grande variabilité de la CF observée dans les études expérimentales. / The complexity of human cognition is revealed in the spatio-temporal organization of brain dynamics. We can gain insight into this organization through the analysis of blood oxygenation-level dependent (BOLD) signals, which are obtained from functional magnetic resonance imaging (fMRI). In BOLD data we can observe statistical dependencies between brain regions. This phenomenon is known as functional connectivity (FC). Computational models are being developed to reproduce the FC of the brain. As in previous empirical studies, these models assume that FC is stationary, i.e. the mean and the covariance of the BOLD time series used for the FC are constant over time. Nevertheless, recent empirical studies focusing on the dynamics of FC at different time scales show that FC is variable in time. This feature is not reproduced in the simulated data generated by some previous computational models. Here we have enhanced the non-linearity of local dynamics in a large-scale computational model. By enhancing this non-linearity, our model is able to reproduce the variability of the FC found in empirical data.

Abstract Multimodal measurements are increasingly being employed in the study of human physiology. Brain studies in particular can draw advantage of simultaneous measurements using different modalities to analyse correlations, mechanisms and relationships of physiological signals and their dynamics in relation to brain functions. Moreover, multimodal measurements help to identify components of physiological dynamics generated specifically by the brain. This thesis summarizes the study, design and development of non-invasive medical instruments that can be utilized in conjunction with magnetic resonance imaging (MRI). A key challenge in the development of measurement methods is posed by the extraordinary requirements that the MRI environment poses - all materials need to be MR-compatible and the selected instruments and devices must not be affected by the strong magnetic field generated by the MRI scanner nor the MRI by the instruments placed within its scanning volume. The presented methods allow simultaneous continuous measurement of heart rate (HR) and metabolism from the brain cortex as well as pulse wave velocity (PWV) and blood pressure measurements in synchrony with electroencephalography (EEG) and MRI. Furthermore, the thesis explored the reliability and accuracy of the responses gathered by the developed instruments and, using new experimental methods, estimated the propagation of near-infrared light in the human brain. The goal of the novel multimodal measurement environment is to provide more extensive tools for medical researchers, neurologists in particular, to acquire accurate information on the function of the brain and the human body. Measurements have been performed on more than 70 persons using the presented multimodal setup to study such factors as the correlation between blood oxygen level-dependent (BOLD) data and low-frequency oscillations (LFOs) during the resting state. / Tiivistelmä Multimodaalisia kuvantamismenetelmiä käytetään enenevässä määrin ihmisen fysiologian ja elintoimintojen tutkimisessa. Erityisesti aivotutkimuksessa samanaikaisesti useammalla modaliteetilla mittaaminen mahdollistaa erilaisten fysiologisten mekanismien ja niiden korrelaatioiden tutkimisen kehon ja aivotoimintojen välillä. Lisäksi multimodaaliset mittaukset auttavat yksilöimään fysiologiset komponentit toisistaan ja identifioimaan aivojen tuottamia fysiologisia signaaleja. Tämä väitöskirja kokoaa tutkimustyön sekä laite- ja instrumentointisuunnittelun ja sen kehittämistyön ei-invasiivisesti toteutettujen lääketieteen mittausmenetelmien käyttämiseksi magneettikuvauksen aikana. Erityishaasteena työssä on ollut magneettikuvausympäristö, joka asettaa erityisvaatimuksia mm. mittalaitteissa käytettäville materiaaleille sekä laitteiden häiriönsiedolle magneettikuvauslaitteen aiheuttaman voimakkaan magneettikentän takia. Kehitettävät mittausmenetelmät eivät myöskään saa aiheuttaa häiriöitä magneettikuvauslaitteen tuottamalle kuvainformaatiolle. Väitöskirjassa esitettävät mittausmenetelmät tekevät mahdolliseksi mitata magneettikuvausympäristössä ihmisen sydämen sykettä, veren virtauksen kulkunopeutta ja verenpaineen vaihteluja sekä aivokuoren metaboliaa - kaikki synkronissa aivosähkökäyrän mittaamisen ja magneettikuvantamisen kanssa. Lisäksi väitöskirjassa tutkitaan kehitettyjen mittausmenetelmien antamaa mittaustarkkuutta sekä arvioidaan lähi-infrapunavalon etenemistä ihmisen aivoissa uudenlaisella menetelmällä. Kehitetyllä multimodaalisella mittausympäristöllä on tavoitteena antaa lääketieteen alan tutkijoille, erityisesti neurologeille, käyttöön mittausmenetelmiä, joiden avulla voidaan tutkia ihmisen aivojen ja kehon välisiä toimintoja aiempaa kattavammin. Laitekokonaisuudella on tutkittu jo yli 70:tä henkilöä. Näissä mittauksissa on tutkittu mm. veren happitasojen hitaita vaihteluja ihmisen aivojen ollessa lepotilassa, ns. resting state -tilassa.

<p>An objective measure of muscular low back pain (LBP) symptoms eludes clinicians. This study assessed efficacy of magnetic resonance imaging (MRI) of the lumbar multifidus using diffusion tensor imaging (DTI), blood oxygen level dependent (BOLD) signal fractal dimension (FD) analysis and muscle cross sectional area (CSA) in LBP assessment. MRI results were compared to two questionnaires, the Oswestry disability index (ODI) and visual analog score (VAS).</p> <p>Right-left asymmetry in both DTI metrics and T2-weighted (T2W) CSA were greater in the injured. Also, asymmetry measures were correlated with body mass index (BMI) but not age, height, or level of physical activity (measured via Godin activity questionnaire). The relationship between asymmetry and LBP symptoms in T2W and DTI scans increased for subjects with BMI below 35kg/m².</p> <p>BOLD FD did not scale with LBP symptoms. However, FD analysis showed promise following therapeutic Swedish massage, hypothesized as being related to local perfusion changes, indicating that FD is sensitive to changes in the lumbar muscle, just not LBP symptoms. Thus the BOLD FD does change with treatment, just not with the symptoms of LBP.</p> <p>When combining data from multiple scan types, the symptoms of LBP correlated best with the unweighted mean of DTI fractional anisotropy (FA) and T2W CSA asymmetry, and the correlation was greatest (R²=0.88) when only <em>symptomatic (not both symptomatic and control)</em> subjects with BMIs from 18-25kg/m² were considered. From these results there appears to be clinical utility in characterizing the symptoms of non-acute LBP using DTI and CSA.</p> / Doctor of Philosophy (PhD)