UNIVERSITY OF CALIFORNIA, SAN DIEGO Beyond BOLD: Toward the application of quantitative functional magnetic resonance imaging to the study of brain function and physiology A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Bioengineering with a Specialization in Multi-Scale Biology by Aaron Benjamin Simon Committee in charge: Professor Gabriel Silva, Chair Professor Richard Buxton, Co-Chair Professor David Dubowitz Professor Andrew McCulloch Professor Eric Wong 2014 Copyright © Aaron Benjamin Simon, 2014 All rights reserved. SIGNATURE PAGE The Dissertation of Aaron Benjamin Simon is approved, and it is acceptable in quality and form for publication on microfilm and electronically: _____________________________________________________________________________ _____________________________________________________________________________ _____________________________________________________________________________ _____________________________________________________________________________ Co-Chair _____________________________________________________________________________ Chair University of California, San Diego 2014 iii DEDICATION To Zaida, for being my favorite guinea pig iv TABLE OF CONTENTS SIGNATURE PAGE .................................................................................................................... iii DEDICATION ............................................................................................................................. iv TABLE OF CONTENTS .............................................................................................................. v LIST OF ABBREVIATIONS ...................................................................................................... vi LIST OF SYMBOLS .................................................................................................................. vii LIST OF FIGURES .................................................................................................................... viii LIST OF TABLES ........................................................................................................................ x ACKNOWLEDGEMENTS ......................................................................................................... xi VITA .......................................................................................................................................... xiii ABSTRACT OF THE DISSERTATION .................................................................................. xiv INTRODUCTION ......................................................................................................................... 1 References ............................................................................................................................... 12 CHAPTER 1 : 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 ........................................................... 14 References ............................................................................................................................... 24 Supplemental Section ............................................................................................................. 26 Supplemental References ........................................................................................................ 32 Acknowledgements ................................................................................................................. 33 CHAPTER 2 : Understanding the dynamic relationship between fluctuations in cerebral blood flow and the BOLD signal: Implications for quantitative functional imaging of dynamic hemodynamic and metabolic fluctuations in the brain ............................................................... 34 Acknowledgements ................................................................................................................. 79 References ............................................................................................................................... 80 CHAPTER 3 : A novel approach to accounting for uncertainty in fMRI-derived estimates of cerebral oxygen metabolism changes. ......................................................................................... 84 Acknowlegements ................................................................................................................. 141 References ............................................................................................................................. 142 CHAPTER 4 : The oxygen metabolic response to visual stimulation and CO2 in hypoxia ..... 147 Acknowledgements ............................................................................................................... 174 References ............................................................................................................................. 175 CONCLUSION ......................................................................................................................... 177 References ............................................................................................................................. 190 v LIST OF ABBREVIATIONS ASL Arterial spin labeling, BCP BOLD constrained perfusion BOLD Blood oxygenation level dependent CBF Cerebral blood flow CBV Cerebral blood volume CBVv Venous cerebral blood volume CO2 Carbon dioxide CMRO2 Cerebral metabolic rate of oxygen metabolism CSF cerebral spinal fluid fMRI Functional magnetic resonance imaging GESSE Gradient Echo Sampling of Spin Echo GRE Gradient recalled echo Hct Hematocrit O2 Oxygen OEF Oxygen extraction fraction PaCO2 Arterial partial pressure of carbon dioxide PaO2 Arterial partial pressure of oxygen Ya Arterial hemoglobin saturation Yv Venous hemoglobin saturation Yc Capillary hemoglobin saturation TE Echo time TR Repetition time TRUST T2-relaxation under spin tagging VERVE Venous refocusing for volume estimation vi LIST OF SYMBOLS a characteristic capillary radius in detailed model B0 Main magnetic field strength D Diffusion constant for water in tissue M Scaling parameter of the Davis and heuristic models k BOLD-CBF scaling parameter in BCP Transverse signal decay rate measured in GRE experiment R2* R2′ Transverse signal decay rate recoverable by spin echo R2 Transverse signal decay rate not recoverable by spin echo T1 Longitudinal Signal recovery time constant Va,c,v,p,e Compartment volume (arterial, capillary, venous, parenchyma, CSF) Yoff Hemoglobin saturation producing equal blood-tissue susceptibility αv Exponent relating the venous CBVv to CBF change in heuristic model β Davis model parameter Δχ Difference in magnetic susceptibility of fully de/oxygenated blood Δν CSF off-resonance frequency with respect to gray matter γ gyromagnetic ratio κ capillary weighting between venous and arterial blood λ Ratio of blood flow to oxygen metabolic response ρ proton density ϕ Exponent relating the total CBV change to CBF change ϕv Exponent relating the venous CBV change to CBF change ϕc Exponent relating the capillary CBV change to CBF change vii LIST OF FIGURES Figure 1.1. Schematic of the BOLD-constrained Perfusion (BCP) estimation process. ............. 16 Figure 1.2. BCP estimation improves precision of CBF estimates without inducing estimation bias. ..................................................................................................................................... 20 Figure 1.3. Calibrated BCP allows estimation of CMRO2-CBF coupling without prior knowledge of the stimulus paradigm. ................................................................................. 21 Supplementary Figure S1.1.4: Calibrated BCP Estimation with the Davis model. .................... 30 Supplementary Figure S1.1.5: Danger of attributing physiological significance to simultaneously estimated values of λ and M ...................................................................... 31 Figure 2.1: Characteristic simulated responses to boxcar and sinusoidal stimuli for coupled or decoupled physiological response dynamics. ..................................................................... 71 Figure 2.2: CBF and BOLD responses to contrast-oscillating visual stimuli. ............................ 72 Figure 2.3: BOLD and CBF responses to contrast-oscillating stimuli averaged over a stimulus cycle. ................................................................................................................................... 72 Figure 2.4: Comparison of simulated CBF and BOLD responses to contrast-oscillating stimuli with measured responses. ................................................................................................... 73 Figure 2.5: Simulated CBF, CMRO2 and, CBVv responses over single stimulation cycle. ....... 74 Figure 2.6: Effect of slow CBVv dynamics on BCP-derived estimates of CBF. ........................ 75 Figure 2.7: Residual bias in BCP-derived estimates of CBF response after referencing CBF and BOLD fluctuations to mean values over the analysis window. .......................................... 76 Figure 2.8: Relationship between BOLD signal correlation and magnitude of estimated CBF fluctuations. ........................................................................................................................ 77 Figure