A novel method of combining blood oxygenation and blood flow sensitive magnetic resonance imaging techniques to measure the cerebral blood flow and oxygen metabolism responses to an unknown neural stimulus.

Simultaneous implementation of magnetic resonance imaging methods for Arterial Spin Labeling (ASL) and Blood Oxygenation Level Dependent (BOLD) imaging makes it possible to quantitatively measure the changes in cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO(2)) that occur in response to neural stimuli. To date, however, the range of neural stimuli amenable to quantitative analysis is limited to those that may be presented in a simple block or event related design such that measurements may be repeated and averaged to improve precision. Here we examined the feasibility of using the relationship between cerebral blood flow and the BOLD signal to improve dynamic estimates of blood flow fluctuations as well as to estimate metabolic-hemodynamic coupling under conditions where a stimulus pattern is unknown. We found that by combining the information contained in simultaneously acquired BOLD and ASL signals through a method we term BOLD Constrained Perfusion (BCP) estimation, we could significantly improve the precision of our estimates of the hemodynamic response to a visual stimulus and, under the conditions of a calibrated BOLD experiment, accurately determine the ratio of the oxygen metabolic response to the hemodynamic response. Importantly we were able to accomplish this without utilizing a priori knowledge of the temporal nature of the neural stimulus, suggesting that BOLD Constrained Perfusion estimation may make it feasible to quantitatively study the cerebral metabolic and hemodynamic responses to more natural stimuli that cannot be easily repeated or averaged

CALIBRATED SHORT TR RECOVERY MRI FOR RAPID MEASUREMENT OF BRAIN-BLOOD PARTITION COEFFICIENT AND CORRECTION OF QUANTITATIVE CEREBRAL BLOOD FLOW

The high prevalence and mortality of cerebrovascular disease has led to the development of several methods to measure cerebral blood flow (CBF) in vivo. One of these, arterial spin labeling (ASL), is a quantitative magnetic resonance imaging (MRI) technique with the advantage that it is completely non-invasive. The quantification of CBF using ASL requires correction for a tissue specific parameter called the brain-blood partition coefficient (BBPC). Despite regional and inter-subject variability in BBPC, the current recommended implementation of ASL uses a constant assumed value of 0.9 mL/g for all regions of the brain, all subjects, and even all species. The purpose of this dissertation is 1) to apply ASL to a novel population to answer an important clinical question in the setting of Down syndrome, 2) to demonstrate proof of concept of a rapid technique to measure BBPC in mice to improve CBF quantification, and 3) to translate the correction method by applying it to a population of healthy canines using equipment and parameters suitable for use with humans. Chapter 2 reports the results of an ASL study of adults with Down syndrome (DS). This population is unique for their extremely high prevalence of Alzheimer’s disease (AD) and very low prevalence of systemic cardiovascular risk factors like atherosclerosis and hypertension. This prompted the hypothesis that AD pathology would lead to the development of perfusion deficits in people with DS despite their healthy cardiovascular profile. The results demonstrate that perfusion is not compromised in DS participants until the middle of the 6th decade of life after which measured global CBF was reduced by 31% (p=0.029). There was also significantly higher prevalence of residual arterial signal in older participants with DS (60%) than younger DS participants (7%, p = 0.005) or non-DS controls (0%, p \u3c 0.001). This delayed pattern of perfusion deficits in people with DS differs from observations in studies of sporadic AD suggesting that adults with DS benefit from an improved cardiovascular risk profile early in life. Chapter 3 introduces calibrated short TR recovery (CaSTRR) imaging as a rapid method to measure BBPC and its development in mice. This was prompted by the inability to account for potential changes in BBPC due to age, brain atrophy, or the accumulation of hydrophobic A-β plaques in the ASL study of people with DS in Chapter 2. The CaSTRR method reduces acquisition time of BBPC maps by 87% and measures a significantly higher BBPC in cortical gray matter (0.99±0.04 mL/g,) than white matter in the corpus callosum (0.93±0.05 mL/g, p=0.03). Furthermore, when CBF maps are corrected for BBPC, the contrast between gray and white matter regions of interest is improved by 14%. This demonstrates proof of concept for the CaSTRR technique. Chapter 4 describes the application of CaSTRR on healthy canines (age 5-8 years) using a 3T human MRI scanner. This represents a translation of the technique to a setting suitable for use with a human subject. Both CaSTRR and pCASL acquisitions were performed and further optimization brought the acquisition time of CaSTRR down to 4 minutes which is comparable to pCASL. Results again show higher BBPC in gray matter (0.83 ± 0.05 mL/g) than white matter (0.78 ± 0.04 mL/g, p = 0.007) with both values unaffected by age over the range studied. Also, gray matter CBF is negatively correlated with age (p = 0.003) and BBPC correction improved the contrast to noise ratio by 3.6% (95% confidence interval = 0.6 – 6.5%). In summary, the quantification of ASL can be improved using BBPC maps derived from the novel, rapid CaSTRR technique

Feasibility of high-resolution perfusion imaging using arterial spin labeling MRI at 3 Tesla

Cerebral blood flow (CBF) is a critical physiological parameter of brain health, and it can be non-invasively measured with arterial spin labeling (ASL) MRI. In this study, we evaluated and optimized whole-brain, high-resolution ASL as an alternative to the low-resolution ASL employed in the routine assessment of CBF in both healthy participants and patients. Two high-resolution protocols (i.e., pCASL and FAIR-Q2TIPS (PASL) with 2 mm isotropic voxels) were compared to a default clinical pCASL protocol (3.4 × 3.4 × 4 mm3), all of whom had an acquisition time of ≈ 5 min. We assessed the impact of high-resolution acquisition on reducing partial voluming and improving sensitivity to the perfusion signal, and evaluated the effectiveness of z-deblurring on the ASL data. We compared the quality of whole-brain ASL acquired using three available head coils with differing number of receive channels (i.e., 20, 32, and 64ch). We found that using higher coil counts (32 and 64ch coils as compared to 20ch) offers improved signal-to-noise ratio (SNR) and acceleration capabilities that are beneficial for ASL imaging at 3 Tesla (3 T). The inherent reduction in partial voluming effects with higher resolution acquisitions improves the resolving power of perfusion without impacting the sensitivity. In conclusion, our results suggest that high-resolution ASL (2 to 2.5 mm isotropic voxels) has the potential to become a new standard for perfusion imaging at 3 T and increase its adoption into clinical research and cognitive neuroscience applications

A Multimodality Myocardial Perfusion Phantom:Initial Quantitative Imaging Results

This proof-of-concept study explores the multimodal application of a dedicated cardiac flow phantom for ground truth contrast measurements in dynamic myocardial perfusion imaging with CT, PET/CT, and MRI. A 3D-printed cardiac flow phantom and flow circuit mimics the shape of the left ventricular cavity (LVC) and three myocardial regions. The regions are filled with tissue-mimicking materials and the flow circuit regulates and measures contrast flow through LVC and myocardial regions. Normal tissue perfusion and perfusion deficits were simulated. Phantom measurements in PET/CT, CT, and MRI were evaluated with clinically used hardware and software. The reference arterial input flow was 4.0 L/min and myocardial flow 80 mL/min, corresponding to myocardial blood flow (MBF) of 1.6 mL/g/min. The phantom demonstrated successful completion of all processes involved in quantitative, multimodal myocardial perfusion imaging (MPI) applications. Contrast kinetics in time intensity curves were in line with expectations for a mimicked perfusion deficit (38 s vs. 32 s in normal tissue). Derived MBF in PET/CT and CT led to under- and overestimation of reference flow of 0.9 mL/g/min and 4.5 mL/g/min, respectively. Simulated perfusion deficit (0.8 mL/g/min) in CT resulted in MBF of 2.8 mL/g/min. We successfully performed initial, quantitative perfusion measurements with a dedicated phantom setup utilizing clinical hardware and software. These results showcase the multimodal phantom’s potential.</p

A Multimodality Myocardial Perfusion Phantom:Initial Quantitative Imaging Results

This proof-of-concept study explores the multimodal application of a dedicated cardiac flow phantom for ground truth contrast measurements in dynamic myocardial perfusion imaging with CT, PET/CT, and MRI. A 3D-printed cardiac flow phantom and flow circuit mimics the shape of the left ventricular cavity (LVC) and three myocardial regions. The regions are filled with tissue-mimicking materials and the flow circuit regulates and measures contrast flow through LVC and myocardial regions. Normal tissue perfusion and perfusion deficits were simulated. Phantom measurements in PET/CT, CT, and MRI were evaluated with clinically used hardware and software. The reference arterial input flow was 4.0 L/min and myocardial flow 80 mL/min, corresponding to myocardial blood flow (MBF) of 1.6 mL/g/min. The phantom demonstrated successful completion of all processes involved in quantitative, multimodal myocardial perfusion imaging (MPI) applications. Contrast kinetics in time intensity curves were in line with expectations for a mimicked perfusion deficit (38 s vs. 32 s in normal tissue). Derived MBF in PET/CT and CT led to under- and overestimation of reference flow of 0.9 mL/g/min and 4.5 mL/g/min, respectively. Simulated perfusion deficit (0.8 mL/g/min) in CT resulted in MBF of 2.8 mL/g/min. We successfully performed initial, quantitative perfusion measurements with a dedicated phantom setup utilizing clinical hardware and software. These results showcase the multimodal phantom’s potential

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) – the critical parameter for CMRO2 quantification – 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 – a topic of great interest in functional neuroimaging – 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 “M-maps” 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

Non-contrast MR imaging of blood-brain barrier permeability to water

Neuro Imaging Researc

A Non-Contrast Magnetic Resonance Imaging Technique to Assess Blood-Brain Barrier Permeability

The Blood-brain barrier (BBB) regulates the entry of compounds between the blood and the brain, thus plays an important role in brain homeostasis. Studies indicate in disease states such as Alzheimer’s the BBB integrity is compromised. The motive of this project is to investigate the sensitivity of the diffusion-weighted arterial spin labeling (DW-ASL) technique to detect water exchange. Testing the sensitivity requires a reliable method of opening the barrier at specific locations of the brain. Here, a unique technology named focused ultrasound (FUS) has been used to mimic a compromised BBB environment. A series of experiments were conducted in a piglet model to determine the ideal settings for a successful BBB opening. The combination of 2.5 W of power, 0.02 ml/kg of microbubble concentration while saturated O2 levels in the piglet were controlled revealed the most effective BBB opening without causing hemorrhage. Although the study was able to show a significant BBB opening in contrast-enhanced MRI, the DW-ASL images showed no significant difference between the sonicated and non-sonicated ROIs. However, the average water exchange rate (kw) of 106 min-1 measured in this study corresponds to a permeability surface area product (PSw) of 159 ml/100 g/min, which was comparable to the measurements in the prior study involving humans

Absolute Oxygenation Metabolism Measurements Using Magnetic Resonance Imaging

Cerebral oxygen metabolism plays a critical role in maintaining normal function of the brain. It is the primary energy source to sustain neuronal functions. Abnormalities in oxygen metabolism occur in various neuro-pathologic conditions such as ischemic stroke, cerebral trauma, cancer, Alzheimer’s disease and shock. Therefore, the ability to quantitatively measure tissue oxygenation and oxygen metabolism is essential to the understanding of pathophysiology and treatment of various diseases. The focus of this review is to provide an introduction of various blood oxygenation level dependent (BOLD) contrast methods for absolute measurements of tissue oxygenation, including both magnitude and phase image based approaches. The advantages and disadvantages of each method are discussed

Applicability of Quantitative Functional MRI Techniques for Studies of Brain Function at Ultra-High Magnetic Field

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.:1 Introduction 3 2 Background to Functional Magnetic Resonance Imaging 7 2.1 Magnetic Resonance 7 2.1.1 Quantum Mechanics 7 2.1.2 The Classical Point of View 10 2.1.3 Radio Frequency Pulses 12 2.1.4 Relaxation Effects 13 2.1.5 The Bloch Equations 15 2.2 Magnetic Resonance Imaging 16 2.2.1 Data Acquisition 16 2.2.2 Image Formation 17 2.2.2.1 Slice Selection 17 2.2.2.2 Frequency Encoding 18 2.2.2.3 Phase Encoding 19 2.2.2.4 Mathematics of Image Formation 20 2.2.2.5 Signal Formation 22 2.3 Advanced Imaging Methods 24 2.3.1 Echo-Planar Imaging (EPI) 24 2.3.2 Partial Fourier Acquisition 25 2.3.3 Generalised Autocalibrating Partially Parallel Acquisition (GRAPPA) 25 2.3.4 Inversion Recovery (IR) 26 2.3.5 Adiabatic Inversion 26 2.3.5.1 Hyperbolic Secant (HS) RF pulses 28 2.3.5.2 Time Resampled Frequency Offset Corrected Inversion (tr-FOCI) RF Pulses 28 2.4 Physiological Background 29 2.4.1 Neuronal Activity 30 2.4.2 Energy Metabolism 31 2.4.3 Physiological Changes During Brain Activation 32 2.4.4 The BOLD Contrast 34 2.4.5 Disadvantages of the BOLD Contrast 35 2.5 Arterial Spin Labelling (ASL) 35 2.5.1 Pulsed Arterial Spin Labelling 37 2.5.2 Arterial Spin Labelling at Ultra-High Field 41 2.6 Vascular Space Occupancy (VASO) 42 2.6.1 VASO at Ultra-High Field 44 2.6.2 Slice-Saturation Slab-Inversion (SS-SI) VASO 45 2.7 Calibrated Functional Magnetic Resonance Imaging 47 2.7.1 The Davis Model 47 2.7.2 The Chiarelli Model 50 2.7.3 The Generalised Calibration Model (GCM) 52 3 Materials and Methods 53 3.1 Scanner Setup 53 3.2 Gas Delivery and Physiological Monitoring System 53 3.3 MRI Sequence Developments 55 3.3.1 Tr-FOCI Adiabatic Inversion 55 3.3.2 Optimisation of the PASL FAIR QUIPSSII Sequence Parameters 60 3.3.3 Multi-TE Multi-TI EPI 64 4 Experiment I: Comparison of Direct and Modelled fMRI Calibration 68 4.1 Background Information 68 4.2 Methods 69 4.2.1 Experimental Design 69 4.2.2 Visuo-Motor Task 70 4.2.3 Gas Manipulations 71 4.2.4 Scanning Parameters 71 4.2.5 Data Analysis 72 4.2.6 M-value Modelling 72 4.2.7 Direct M-Value Estimation 73 4.3 Results 74 4.4 Discussion 79 4.4.1 M-value Estimation 79 4.4.2 BOLD Time Courses 82 4.4.3 M-Maps and Single Subject Analysis 82 4.4.4 Effects on CMRO2 Estimation 83 4.4.5 Technical Limitations and Implications for Calibrated fMRI 84 4.5 Conclusion 89 5 Experiment II: Reproducibility of BOLD, ASL and Calibrated fMRI 90 5.1 Background Information 90 5.2 Methods 91 5.2.1 Experimental Design 91 5.2.2 Data Analysis 91 5.2.3 Reproducibility 93 5.2.4 Learning and Habituation Effects 95 5.3 Results 95 5.4 Discussion 101 5.4.1 Breathing Manipulations 102 5.4.2 Functional Reproducibility 107 5.4.3 Habituation Effects on Reproducibility 109 5.4.4 Technical Considerations for Calibrated fMRI 110 5.5 Conclusion 112 6 Experiment III: Simultaneous Acquisition of BOLD, ASL and VASO Signals 113 6.1 Background Information 113 6.2 Methods 114 6.2.1 SS-SI VASO Signal Acquisition 114 6.2.2 ASL and BOLD Signal Acquisition 114 6.2.3 Experimental Design 114 6.2.4 Data Analysis 115 6.3 Results 115 6.4 Discussion 116 6.5 Conclusion 120 7 Conclusion and Outlook 12