In imaging, short wavelength (high-frequency) particles scattered from targets typically yield greater spatial resolutions than longer wavelengths. X-Rays, for example are typically within 2 orders of magnitude of a nanometer wavelength to achieve desired resolutions for medical imaging. Although better for imaging, this poses a health risk for subjects as ionizing radiation and this limits its use. Functional Magnetic Resonance Imaging (fMRI) avoids this issue by using radiation of much larger wavelengths, 4.8 m (62.5 MHz), that are relatively harmless. Instead of scattering, these photons are used to excite protons between spin-states in an external magnetic field. Magnetization relaxation rates and dephasing as a function of space and time are then measured to reconstruct images. This dissertation develops experimental methods to understand and interpret the biophysical underpinnings of fMRI in terms of blood flow and oxygen concentration changes. In neuroscience, fMRI may be used to deduce brain activity. Brain activity is a general term related to neuronal firing rate, which metabolizes oxygen. Deoxygenated blood increases proton spin dephasing. This is the physical mechanism that ultimately yields contrast in the fMRI signal. This is known as Blood-Oxygen Level Dependent (BOLD) contrast. A critical piece of information in this process, hemodynamics, is the dynamics of cerebral (brain) oxygen concentrations in relation to blood flow. The hemodynamics of BOLD contrast fMRI and its relation to brain activity is vital. In this dissertation, I have classified hemodynamic data as a function of space and time in cerebral cortex as well as testing a rudimentary hemodynamic model. I have taken fMRI measurements in three human subjects to identify spatial and temporal hemodynamic trends in brain. Furthermore, I've analyzed laser-speckle imaging in three subjects to identify spatiotemporal trends in blood speed. The final portion of this dissertation relates developments of a hemodynamic model of BOLD. / text

O mecanismo de contraste mais utilizado em imagens funcionais por ressonância magnética (functional Magnetic Resonance Imaging, fMRI), também conhecido por sinal BOLD (Blood Oxygenation Level Dependent) mede indiretamente a atividade neural, sendo sensível a mudanças no fluxo cerebral sangüíneo (Cerebral Blood Flow, CBF), na taxa cerebral metabólica do oxigênio (Cerebral Metabolic Rate of Oxygen, CMRO2) e no volume cerebral sanguíneo (Cerebral Blood Volume, CBV) e, em princípio, ele pode ser utilizado para mapear perfusão cerebral. Desse modo, o objetivo principal deste trabalho foi investigar, quantitativamente, alterações perfusionais no cérebro humano mapeadas pelas mudanças do sinal BOLD em resposta à indução transitória do estado de apnéia. Para isso, imagens por ressonância magnética foram obtidas através de um scanner de 1.5 T Siemens (Magneton Vision) com seqüências do tipo EPI-BOLD. Nesta pesquisa, foi analisada a influência da duração da apnéia no sinal BOLD. Observou-se, também, a diferença ocasionada no sinal em duas situações: apnéia iniciando-se após a inspiração ou após a expiração. Além disso, foi estudada a propagação deste sinal BOLD pelas diferentes regiões cerebrais. Por último, fazendo uso deste sinal BOLD, construiu-se mapas para obter informações a respeito do volume cerebral sangüíneo. Pelos dados obtidos, foi possível analisar o comportamento do sinal BOLD quando na presença de diferentes PaO2 e PaCO2. Observaram-se, também, diferenças regionais na sensibilidade do sinal BOLD ocasionada pelo estado de apnéia induzido. Essa diferença pode estar relacionada à reatividade das artérias que irrigam cada região ou ao volume sangüíneo basal dessas artérias. Além disso, foi possível obter informações a respeito das características temporais da mudança do CBF para diferentes regiões do cérebro em resposta a hipercapnia. Também, foi feita a identificação de áreas corticais responsáveis pelo controle voluntário da respiração. Por fim, os mapas de B-CBV obtidos utilizando o contraste BOLD em resposta à apnéia foram capazes de refletir o volume sangüíneo local, embora, estudos para análise dos outros parâmetros que influenciam o sinal devam ser realizados. / The BOLD (Blood Oxygenation Level Dependent) signal, is the most used contrast mechanism of the so called functional Magnetic Resonance Imaging (fMRI). Although it indirectly measures neuronal activity, its response is directly related to cerebral blood flow (CBF), Cerebral Metabolic Rate of Oxygen (CMRO2) and Cerebral Blood Volume (CBV) and can be, in principle, used to map cerebral perfusion. Thus, the main purpose of this study was to investigate, quantitatively, some aspects of perfusional alterations in the human brain. These changes were mapped by changes in the BOLD signal as a result of a global and uniform stimulation: hypercapnia induced by breath holding paradigms. Magnetic resonance images were acquired in a 1.5 T scanner (Siemens, Magneton Vision) with EPI-BOLD fMRI sequences. It was analyzed the BOLD dependency on breath holding duration and differences on the BOLD signal due the employed breath holding techniques: breath holding after expiration or after inspiration. The regional variability of the BOLD signal propagation was also studied. Moreover, the signal was used to construct maps based on CBV information. It was possible to gain information about the BOLD signal behavior that respond to PaO2 and PaCO2 alterations. Besides, it was demonstrated its regional variations sensibility, which can be correlated with arterial reactivity or the rest CBV of this arteries. It was also possible acquire information about the temporal characteristics of CBF changes induced by hypercapnia across brain regions as well as the identification of cortical areas that were responsible to the voluntary breathing. Finally, the B-CBV maps that used the BOLD con-trast were able to reflect CBV information, although, it is necessary the study of other parameters that can influence the signal.

O mecanismo de contraste mais utilizado em imagens funcionais por ressonância magnética (functional Magnetic Resonance Imaging, fMRI), também conhecido por sinal BOLD (Blood Oxygenation Level Dependent) mede indiretamente a atividade neural, sendo sensível a mudanças no fluxo cerebral sangüíneo (Cerebral Blood Flow, CBF), na taxa cerebral metabólica do oxigênio (Cerebral Metabolic Rate of Oxygen, CMRO2) e no volume cerebral sanguíneo (Cerebral Blood Volume, CBV) e, em princípio, ele pode ser utilizado para mapear perfusão cerebral. Desse modo, o objetivo principal deste trabalho foi investigar, quantitativamente, alterações perfusionais no cérebro humano mapeadas pelas mudanças do sinal BOLD em resposta à indução transitória do estado de apnéia. Para isso, imagens por ressonância magnética foram obtidas através de um scanner de 1.5 T Siemens (Magneton Vision) com seqüências do tipo EPI-BOLD. Nesta pesquisa, foi analisada a influência da duração da apnéia no sinal BOLD. Observou-se, também, a diferença ocasionada no sinal em duas situações: apnéia iniciando-se após a inspiração ou após a expiração. Além disso, foi estudada a propagação deste sinal BOLD pelas diferentes regiões cerebrais. Por último, fazendo uso deste sinal BOLD, construiu-se mapas para obter informações a respeito do volume cerebral sangüíneo. Pelos dados obtidos, foi possível analisar o comportamento do sinal BOLD quando na presença de diferentes PaO2 e PaCO2. Observaram-se, também, diferenças regionais na sensibilidade do sinal BOLD ocasionada pelo estado de apnéia induzido. Essa diferença pode estar relacionada à reatividade das artérias que irrigam cada região ou ao volume sangüíneo basal dessas artérias. Além disso, foi possível obter informações a respeito das características temporais da mudança do CBF para diferentes regiões do cérebro em resposta a hipercapnia. Também, foi feita a identificação de áreas corticais responsáveis pelo controle voluntário da respiração. Por fim, os mapas de B-CBV obtidos utilizando o contraste BOLD em resposta à apnéia foram capazes de refletir o volume sangüíneo local, embora, estudos para análise dos outros parâmetros que influenciam o sinal devam ser realizados. / The BOLD (Blood Oxygenation Level Dependent) signal, is the most used contrast mechanism of the so called functional Magnetic Resonance Imaging (fMRI). Although it indirectly measures neuronal activity, its response is directly related to cerebral blood flow (CBF), Cerebral Metabolic Rate of Oxygen (CMRO2) and Cerebral Blood Volume (CBV) and can be, in principle, used to map cerebral perfusion. Thus, the main purpose of this study was to investigate, quantitatively, some aspects of perfusional alterations in the human brain. These changes were mapped by changes in the BOLD signal as a result of a global and uniform stimulation: hypercapnia induced by breath holding paradigms. Magnetic resonance images were acquired in a 1.5 T scanner (Siemens, Magneton Vision) with EPI-BOLD fMRI sequences. It was analyzed the BOLD dependency on breath holding duration and differences on the BOLD signal due the employed breath holding techniques: breath holding after expiration or after inspiration. The regional variability of the BOLD signal propagation was also studied. Moreover, the signal was used to construct maps based on CBV information. It was possible to gain information about the BOLD signal behavior that respond to PaO2 and PaCO2 alterations. Besides, it was demonstrated its regional variations sensibility, which can be correlated with arterial reactivity or the rest CBV of this arteries. It was also possible acquire information about the temporal characteristics of CBF changes induced by hypercapnia across brain regions as well as the identification of cortical areas that were responsible to the voluntary breathing. Finally, the B-CBV maps that used the BOLD con-trast were able to reflect CBV information, although, it is necessary the study of other parameters that can influence the signal.

L’épilepsie est une pathologie neurologique caractérisée par une activité neuronale excessive et hypersynchrone soit localisée soit diffuse. L’activité neuronale est principalement évaluée par la mesure de l’activité électrique neuronale en électroencéphalographie (EEG). L’EEG dispose d’une excellente résolution temporelle, mais d’une résolution spatiale médiocre. L’enjeu actuel est de développer une technique non-invasive capable d’explorer et de localiser l’activité neuronale avec une bonne résolution temporo-spatiale afin d’améliorer la prise en charge de l’épilepsie. L’activité neuronale peut également être définie par des modifications hémodynamiques et métaboliques (couplage neurovasculaire). L’imagerie par résonance magnétique fonctionnelle (IRMf) mesure ces dernières au travers de l’étude du signal BOLD (Blood Oxygenation Level Dependent) et permet l’exploration de l’activité neuronale avec une bonne résolution spatiale. L’EEG-IRMf permet l’étude du signal BOLD spécifiquement lors des événements EEG. Si cette technique a démontré un certain intérêt dans la localisation des générateurs des anomalies épileptiformes intercritiques, il n’est pas rare d’observer des discordances entre les réponses observées et le foyer épileptique supposé. En effet, les résultats représentent l’activité globale cérébrale au cours de l’anomalie EEG. Dans une première partie, nous avons cherché à améliorer la spécificité des réponses BOLD observées lors des anomalies intercritiques. Pour cela nous avons exploré l’effet des fluctuations de l’état de vigilance au cours de l’enregistrement EEG-IRMf. Les variations des rythmes EEG physiologiques, reflets de la vigilance, sont responsables de fluctuations du signal BOLD significatives. L’intégration de ces données dans le modèle linéaire général diminue la variance du signal BOLD de la période contrôle. Ainsi, les réponses BOLD obtenues pour les anomalies épileptiformes devraient être améliorées et moins discordantes avec la localisation du foyer supposé. Dans une deuxième partie, nous avons souhaité étudier les crises épileptiques. L’application de la technique d’EEG-IRMf dans les crises permettrait d’obtenir des informations spatiales plus fiables que les anomalies intercritiques (meilleur rapport signal sur bruit) et cruciales dans la définition de la zone épileptogène. Sur une série de 8 patients atteints de malformation de développement cortical, nous avons démontré la faisabilité de l’enregistrement des crises épileptiques en EEG-IRMf mais également l’intérêt des informations obtenues sur les structures impliquées lors de la décharge critique. Cependant, l’analyse actuelle modélise la crise comme un événement stationnaire dans le temps et dans l’espace. Et de façon plus nette que lors de l’étude des anomalies intercritiques, les réponses BOLD obtenues pour les crises sont diffuses et reflètent l’activité globale cérébrale sans distinction claire entre la zone génératrice et la zone de propagation. Au cours d’un deuxième travail, nous avons intégré dans l’analyse statistique les informations temporelles fournies par la mesure du signal BOLD. La résolution temporelle de l’IRMf apporte un bon échantillonnage de la réponse hémodynamique et permet une analyse fiable des variations temporelles du signal BOLD. Nous avons analysé les réponses BOLD des crises de 10 patients avec leur décours temporel. Les zones impliquées dans le départ des crises ont pu être discriminées de celles impliquées secondairement dans la propagation. Dans une troisième partie, nous avons utilisé les données BOLD non plus dans un but localisateur de l’activité neuronale mais afin de définir le rôle des structures impliquées dans l’activité épileptique. / "Epilepsy is a neurological disorder defined by an excessive and hypersynchronous neuronal activity. This abnormal cerebral activity can be focal or diffuse. The neuronal activity is commonly determined by the neuronal electric activity explored in electroencephalography (EEG). The EEG is characterized by a high temporal resolution and a low spatial resolution. The development of a new technique that can explore and localize the neuronal activity with a good temporal and spatial resolution is real challenge in the epilepsy field. The neuronal activity may also be defined by hemodynamic and metabolic changes (neurovascular coupling). These changes can be explored by the functional magnetic resonance imaging (fMRI).The fMRI records the BOLD signal (Blood Oxygenation Level Dependent) changes and allows the study of neuronal activity with an excellent spatial resolution. The simultaneous EEG-fMRI recording provides information about BOLD changes specifically correlated in time with EEG events. It has been demonstrated that this technique could provide valuable results on the generators of epileptiform interictal events. However, EEG-fMRI studies showed also some discrepancies between the location of BOLD responses and the suspected epileptic focus. Indeed, BOLD responses reflect not only the generator’s activity but also the global cerebral activity occurring at the time of the epileptiform event. In the first part, we tried to improve the specificity of the BOLD responses observed during interictal epileptiform abnormalities. Therefore, we explored the BOLD effect of the alertness fluctuations during prolonged EEG-fMRI recording. Physiological rhythms variations reflecting the brain state changes are responsible for noteworthy BOLD changes. Physiological EEG rhythms may be integrated to the EEG-fMRI analysis in studies with fluctuation of alertness, to eliminate possible confounding factors. The accuracy of the BOLD results obtained for interictal epileptiform events would be improved. In a second part, we proposed to use the EEG-fMRI technique to study epileptic seizures. This new application would provide information with a better spatial definition than the interictal study (better signal to noise ratio) and crucial for the definition of the epileptogenic zone in presurgical exploration. On a population of eight patients with a malformation of cortical development, we demonstrated that the EEG-fMRI recording during seizures is feasible and that the results showed original and valuable information on cerebral structures involved in the ictal discharge. However, the actual method uses a “bloc design” model and then suggests that the seizure is a stationary event in time and in space. With this method, BOLD responses obtained during ictal event are diffuse and reflect the cerebral global activity without discrimination between the seizure onset zone and the structures secondary involved in the propagation. In a second work, we proposed a new method adding in the statistical analysis the temporal information provided by the BOLD signal measurement. The temporal resolution of fMRI and the temporal sampling used in fMRI protocol are sufficient to study with a good accuracy the temporal variations of the BOLD signal. We analyzed the dynamic time course of the BOLD signal in ten patients with seizures inside the MRI.

This thesis describes the development, implementation and application of various quantitative functional magnetic resonance imaging (fMRI) approaches at ultra-high magnetic field including the assessment with regards to applicability and reproducibility. Functional MRI (fMRI) commonly uses the blood oxygenation level dependent (BOLD) contrast to detect functionally induced changes in the oxy-deoxyhaemoglobin composition of blood which reflect cerebral neural activity. As these blood oxygenation changes do not only occur at the activation site but also downstream in the draining veins, the spatial specificity of the BOLD signal is limited. Therefore, the focus has moved towards more quantitative fMRI approaches such as arterial spin labelling (ASL), vascular space occupancy (VASO) or calibrated fMRI which measure quantifiable physiologically and physically relevant parameters such as cerebral blood flow (CBF), cerebral blood volume (CBV) or cerebral metabolic rate of oxygen (CMRO2), respectively. In this thesis a novel MRI technique was introduced which allowed the simultaneous acquisition of multiple physiological parameters in order to beneficially utilise their spatial and temporal characteristics. The advantages of ultra-high magnetic field were utilised to achieve higher signal-to-noise and contrast-to-noise ratios compared to lower field strengths. This technique was successfully used to study the spatial and temporal characteristics of CBV, CBF and BOLD in the visual cortex. This technique is the first one that allows simultaneous acquisition of CBV, CBF and BOLD weighted fMRI signals in the human brain at 7 Tesla. Additionally, this thesis presented a calibrated fMRI technique which allowed the quantitative estimation of changes in cerebral oxygen metabolism at ultra-high field. CMRO2 reflects the amount of thermodynamic work due to neural activity and is therefore a significant physical measure in neuroscience. The calibrated fMRI approach presented in this thesis was optimised for the use at ultra-high field by adjusting the MRI parameters as well as implementing a specifically designed radio-frequency (RF) pulse. A biophysical model was used to calibrate the fMRI data based on the simultaneous acquisition of BOLD and CBF weighted MRI signals during a gas-breathing challenge. The reproducibility was assessed across multiple brain regions and compared to that of various physiologically relevant parameters. The results indicate that the degree of intra-subject variation for calibrated fMRI is lower than for the classic BOLD contrast or ASL. Consequently, calibrated fMRI is a viable alternative to classic fMRI contrasts with regards to spatial specificity as well as functional reproducibility. This calibrated fMRI approach was also compared to a novel direct calibration technique which relies on complete venous oxygenation saturation during the calibration scan via a gas-breathing challenge. This thesis introduced several reliable quantitative fMRI approaches at 7 Tesla and the results presented are a step forward to the wider application of quantitative fMRI.

For years F. Scott Fitzgeralds <i>The Great Gatsby</i> has garnered attention from critics as having a relationship to American transcendentalist thought. While most acknowledge Jay Gatsbys corruption and materialism, they continue to hold on to a belief in his supposed idealism and difference from other characters in the novel. Even critics who note irony in the novel do not recant their arguments regarding Gatsbys romanticism. One cannot make a straightforward connection between transcendentalists such as Ralph Waldo Emerson and Henry David Thoreau without noting how Gatsby is truly a perversion of transcendental ideals. Specifically, in examining Gatsby with Emersons concept of self-reliance in mind, it is clear that Fitzgerald could never see Gatsby as a self-reliant individual. Indeed, Gatsby fails in every test that can identify him as being a self-reliant man. He is materialistic; he breaks the law for no larger purpose; he loves an insignificant and vapid woman who is as materialistic as the rest of this corrupt society; he has no true identity; does not dispute the contention that the ideal of self-reliance is noble, it argues that such an ideal is unrealizable in the corrupt and materialistic society of the Jazz Age.

For years F. Scott Fitzgeralds <i>The Great Gatsby</i> has garnered attention from critics as having a relationship to American transcendentalist thought. While most acknowledge Jay Gatsbys corruption and materialism, they continue to hold on to a belief in his supposed idealism and difference from other characters in the novel. Even critics who note irony in the novel do not recant their arguments regarding Gatsbys romanticism. One cannot make a straightforward connection between transcendentalists such as Ralph Waldo Emerson and Henry David Thoreau without noting how Gatsby is truly a perversion of transcendental ideals. Specifically, in examining Gatsby with Emersons concept of self-reliance in mind, it is clear that Fitzgerald could never see Gatsby as a self-reliant individual. Indeed, Gatsby fails in every test that can identify him as being a self-reliant man. He is materialistic; he breaks the law for no larger purpose; he loves an insignificant and vapid woman who is as materialistic as the rest of this corrupt society; he has no true identity; does not dispute the contention that the ideal of self-reliance is noble, it argues that such an ideal is unrealizable in the corrupt and materialistic society of the Jazz Age.

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is the dominant tool used for mapping human brain function because it is non-invasive, does not use ionizing radiation, and offers relatively high spatial and temporal resolution compared to other neuroimaging techniques. Unfortunately, conventional fMRI techniques cannot map brain function in the inferior temporal cortex (ITC) and orbitofrontal cortex (OFC). These brain regions experience severe magnetic field distortions due to magnetic susceptibility mismatch with the neighboring air-filled ear-canals (ITC) or sinus cavities (OFC), causing loss of the fMRI signal. Functional imaging capability is important for gaining a better understanding of these brain regions and the diseases that commonly affect them (Alzheimer’s disease and epilepsy (ITC), Parkinson’s disease and schizophrenia (OFC)). Balanced steady state free precession (balanced SSFP) is a relatively new fMRI technique that can measure function in all brain regions. Rather than diffuse signal loss, balanced SSFP images exhibit signal loss in spatially periodic, narrow bands. Banding artifacts cannot be eliminated in a single scan, but the phase of the banding artifacts can be controlled by the experimenter, permitting the combination of two antiphase balanced SSFP images to produce a single image free of banding artifacts. Unfortunately, image-corrupting transient signal oscillations limit the rate at which the banding artifact phase can be modified, such that the banding-artifact-free image acquisition rate is prohibitively slow for most clinical and neuroscience applications. This work describes the development of a modified balanced SSFP fMRI technique, alternating SSFP, which permits rapid, banding-artifact-free balanced SSFP fMRI. Theoretical modeling was used to find a rapid transition between antiphase balanced SSFP images with minimal transient signal oscillations. Monte Carlo simulations were used to optimize alternating SSFP acquisition parameters for BOLD sensitivity, with comparison to established balanced SSFP acquisitions. Rat fMRI was used to confirm these predictions. Finally, the ability of alternating SSFP to provide rapid, banding-artifact-free balanced SSFP fMRI in humans at 4 T was demonstrated.

Typescript (photocopy) / xiii, 207 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Botany, 1982

RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and in vivo T1 maps acquired 50 min (T1(50 min)) after injection of 0.05 mmol/kg Gd-LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx-001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T150 min at 1 h post-drug was significantly longer than pre-drug tumor T150 min in all three tumor models, with the T150 min remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T150 min of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd-LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics.