Multiparametric measurement of cerebral physiology using calibrated fMRI

The ultimate goal of calibrated fMRI is the quantitative imaging of oxygen metabolism (CMRO2), and this has been the focus of numerous methods and approaches. However, one underappreciated aspect of this quest is that in the drive to measure CMRO2, many other physiological parameters of interest are often acquired along the way. This can significantly increase the value of the dataset, providing greater information that is clinically relevant, or detail that can disambiguate the cause of signal variations. This can also be somewhat of a double-edged sword: calibrated fMRI experiments combine multiple parameters into a physiological model that requires multiple steps, thereby providing more opportunity for error propagation and increasing the noise and error of the final derived values. As with all measurements, there is a trade-off between imaging time, spatial resolution, coverage, and accuracy. In this review, we provide a brief overview of the benefits and pitfalls of extracting multiparametric measurements of cerebral physiology through calibrated fMRI experiments

Assessing the repeatability of absolute CMRO 2 , OEF and haemodynamic measurements from calibrated fMRI

As energy metabolism in the brain is largely oxidative, the measurement of cerebral metabolic rate of oxygen consumption (CMRO2) is a desirable biomarker for quantifying brain activity and tissue viability. Currently, PET techniques based on oxygen isotopes are the gold standard for obtaining whole brain CMRO2 maps. Among MRI techniques that have been developed as an alternative are dual calibrated fMRI (dcFMRI) methods, which exploit simultaneous measurements of BOLD and ASL signals during a hypercapnic-hyperoxic experiment to modulate brain blood flow and oxygenation. In this study we quantified the repeatability of a dcFMRI approach developed in our lab, evaluating its limits and informing its application in studies aimed at characterising the metabolic state of human brain tissue over time. Our analysis focussed on the estimates of oxygen extraction fraction (OEF), cerebral blood flow (CBF), CBF-related cerebrovascular reactivity (CVR) and CMRO2 based on a forward model that describes analytically the acquired dual echo GRE signal. Indices of within- and between-session repeatability are calculated from two different datasets both at a bulk grey matter and at a voxel-wise resolution and finally compared with similar indices obtained from previous MRI and PET measurements. Within- and between-session values of intra-subject coefficient of variation (CVintra) calculated from bulk grey matter estimates 6.7 ± 6.6% (mean ± std.) and 10.5 ± 9.7% for OEF, 6.9 ± 6% and 5.5 ± 4.7% for CBF, 12 ± 9.7% and 12.3 ± 10% for CMRO2. Coefficient of variation (CV) and intraclass correlation coefficient (ICC) maps showed the spatial distribution of the repeatability metrics, informing on the feasibility limits of the method. In conclusion, results show an overall consistency of the estimated physiological parameters with literature reports and a satisfactory level of repeatability considering the higher spatial sensitivity compared to other MRI methods, with varied performance depending on the specific parameter under analysis, on the spatial resolution considered and on the study design

Expanding the role of functional mri in rehabilitation research

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) contrast has become a universal methodology in functional neuroimaging. However, the BOLD signal consists of a mix of physiological parameters and has relatively poor reproducibility. As fMRI becomes a prominent research tool for rehabilitation studies involving repeated measures of the human brain, more quantitative and stable fMRI contrasts are needed. This dissertation enhances quantitative measures to complement BOLD fMRI. These additional markers, cerebral blood flow (CBF) and cerebral blood volume (CBV) (and hence cerebral metabolic rate of oxygen (CMRO₂) modeling) are more specific imaging markers of neuronal activity than BOLD. The first aim of this dissertation assesses feasibility of complementing BOLD with quantitative fMRI measures in subjects with central visual impairment. Second, image acquisition and analysis are developed to enhance quantitative fMRI by quantifying CBV while simultaneously acquiring CBF and BOLD images. This aim seeks to relax assumptions related to existing methods that are not suitable for patient populations. Finally, CBF acquisition using a low-cost local labeling coil, which improves image quality, is combined with simultaneous acquisition of two types of traditional BOLD contrast. The demonstrated enhancement of CBF, CBV and CMRO₂measures can lead to better characterization of pathophysiology and treatment effects.Ph.D.Committee Chair: Hu, Xiaoping; Committee Member: Benkeser, Paul; Committee Member: Keilholz, Shella; Committee Member: Sathian, Krish; Committee Member: Schuchard, Ronal

Elimination of visually evoked BOLD responses during carbogen inhalation: Implications for calibrated MRI

Breathing a mixture of 10% CO2 with 90% O2 (referred to here as carbogen-10) increases blood flow due to the vasodilatory effect of CO2, and raises blood O2 saturation due to the enriched oxygen level. These effects both tend to reduce the level of deoxygenated hemoglobin in brain tissues, thereby reducing the potential for further increases in BOLD contrast. In the present study, blocks of intense visual stimulation (60 s) were presented amid longer blocks (180 s) during which subjects breathed various fractional concentrations (0–100%) of carbogen-10 diluted with medical air. When breathing undiluted carbogen-10, the BOLD response to visual stimulation was reduced below the level of noise against the background of the carbogen-10 response. At these concentrations, the total (visual+carbogen) BOLD response amplitude (7.5±1.0%, n=6) converged toward that seen with carbogen alone (7.5 ± 1.0%, n = 6). In spite of the almost complete elimination of the visual BOLD response, pseudo-continuous arterial spin-labeling on a separate cohort indicated a largely preserved perfusion response (89±34%, n=5) to the visual stimulus during inhalation of carbogen-10. The previously discussed observations suggest that venous saturation can be driven to very high levels during carbogen inhalation, a finding which has significant implications for calibrated MRI techniques. The latter methods involve estimation of the relative change in venous O2 saturation by expressing activation-induced BOLD signal increases as a fraction of the maximal BOLD signal M that would be observed as venous saturation approaches 100%. While the value of M has generally been extrapolated from much smaller BOLD responses induced using hypercapnia or hyperoxia, our results suggest that these effects could be combined through carbogen inhalation to obtain estimates of M based on larger BOLD increases. Using a hybrid BOLD calibration model taking into account changes in both blood flow and arterial oxygenation, we estimated that inhalation of carbogen-10 led to an average venous saturation of 91%, allowing us to compute an estimated M value of 9.5%

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

Investigating the field-dependence of the Davis model: Calibrated fMRI at 1.5, 3 and 7 T

Gas calibrated fMRI in its most common form uses hypercapnia in conjunction with the Davis model to quantify relative changes in the cerebral rate of oxygen consumption (CMRO2) in response to a functional stimulus. It is most commonly carried out at 3 T but, as 7 T research scanners are becoming more widespread and the majority of clinical scanners are still 1.5 T systems, it is important to investigate whether the model used remains accurate across this range of field strengths. Ten subjects were scanned at 1.5, 3 and 7 T whilst performing a bilateral finger-tapping task as part of a calibrated fMRI protocol, and the results were compared to a detailed signal model. Simulations predicted an increase in value and variation in the calibration parameter M with field strength. Two methods of defining experimental regions of interest (ROIs) were investigated, based on (a) BOLD signal and (b) BOLD responses within grey matter only. M values from the latter ROI were in closer agreement with theoretical predictions; however, reassuringly, ROI choice had less impact on CMRO2 than on M estimates. Relative changes in CMRO2 during motor tasks at 3 and 7 T were in good agreement but were over-estimated at 1.5 T as a result of the lower signal to noise ratio. This result is encouraging for future studies at 7 T, but also highlights the impact of imaging and analysis choices (such as ASL sequence and ROI definition) on the calibration parameter M and on the calculation of CMRO2