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Investigating Cerebrovascular Health and Functional Plasticity Using Investigating Cerebrovascular Health and Functional Plasticity using Quantitative FMRI By Catherine Foster A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree Doctorate of Philosophy Cardiff University © Copyright by Catherine Foster, September 2017 i Doctor of Philosophy (2017) (Psychology) Cardiff University, Cardiff, Wales Title: Investigating cerebrovascular health and functional plasticity using quantitative fMRI Author: Catherine Foster Supervisors: Prof. Richard G. Wise, Dr. Valentina Tomassini Number of pages: 292 Declaration Form The following declaration is required when submitting your PhD thesis under the University's regulations. Declaration This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Candidate Date Statement 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD. Candidate Date Statement 2 i This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Candidate Date Statement 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Candidate Date Statement 4: Previously approved bar on access I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loans after expiry of a bar on access previously approved by the Graduate Development Committee. Candidate Date ii Abbreviations for Frequently Used Terms AF Aerobic fitness ASL Arterial spin labelling BOLD Blood oxygen-level dependent BP Blood pressure CASL Continuous arterial spin labelling CBF Cerebral blood flow CBV Cerebral blood volume CSF Cerebrospinal fluid CMRO2 Cerebral metabolic rate of oxygen consumption CNS Central nervous system CVR Cerebrovascular reactivity EDSS Expanded Disease Status Scale EPI Echo planar imaging FSL FMRIB’s software library FSPGR Fast spoiled gradient echo recalled FMRI Functional magnetic resonance imaging GM Grey matter Hb Haemoglobin HR Heart rate MNI Montreal Neurological Institute MS Multiple Sclerosis MRI Magnetic resonance imaging MTI Multiple inversion time OEF Oxygen extraction fraction PASL Pulsed arterial spin labelling PCASL Pulsed continuous arterial spin labelling PICORE Proximal control for off resonance effects iii Abbreviations for Frequently Used Terms PO2 Oxygen pressure PtO2 Tissue oxygen pressure QUIPSS II Quantitative imaging of perfusion using a Single Subtraction II SNR Signal to noise ratio SRT Serial reaction time TE Echo time TI Inversion time TR Repetition time VBM Voxel based morphometry 푉̇ O2max Maximal volume of oxygen uptake 푉̇ O2peak Peak oxygen uptake volume WM White matter iv Acknowledgements I would like to acknowledge several people who contributed to the work in this thesis. Firstly, a huge thanks to my supervisor Richard Wise who guided the conception, design and analysis of each chapter and for being extremely supportive throughout my PhD and post-PhD grant applications and career planning. I would also like to thank Kevin Murphy for assisting with the analysis using Afni in Chapter 3 but also for the valuable advice on many things throughout my time in CUBRIC. Thanks also to Jessica Steventon who made it possible to conduct the two exercise studies and collect the data in Chapter 7. These studies involved many hours of set-up and data collection which would not have been possible without Jessica’s presence and guidance. Thanks to Hannah Chandler and Rachael Stickland who assisted data collection for Chapter 8 and, collected almost all the data in Chapter 9 as well as processing the patient data due to unforeseeable delays with study approval. Many thanks also to my second supervisor Valentina Tomassini for informing the design of the MS study and assisting with patient recruitment. Data collected in the new centre (Chapters 5, 8 and 9) would not have been possible without the MR sequences developed by Michael Germuska, who also developed the MR processing and analysis pipeline for these chapters. I would like to thank Esther Warnert for developing the analysis pipeline used in Chapter 4, and Joe Whittaker for helping to improving my code over the years. Also thanks to Ian Driver for his valuable input on data acquisition and analysis. A huge thank you also to Ilona Lipp for her support with analysis of the SRT task data, and all things Matlab related. v Table of Contents Abbreviations for Frequently Used Terms ................................................................................. iii Acknowledgements ..................................................................................................................... v Table of Contents ....................................................................................................................... vi Thesis Summary ........................................................................................................................xii Research Background and Rationale ..................................................................................... xiii Quantitative FMRI as a Tool to Study Human Brain Function ................................................. xvii Chapter 1 ................................................................................................................................... 19 The Energetic Brain: Functional Processes in Health and Disease ........................................... 19 1.1 Neuronal Activity ...................................................................................................... 19 1.2 Organisation of the Cerebrovasculature ................................................................... 21 1.3 Regulation and Modulation of Cerebral Blood Flow ................................................ 24 1.4 Cerebrovascular Reactivity ....................................................................................... 25 1.5 Oxygen and Carbon Dioxide Transport in the Brain ................................................. 26 1.6 Cerebral Blood Flow and Oxygen Metabolism ......................................................... 28 1.7 Impaired Oxygen Availability and Metabolism in Disease ........................................ 31 1.8 Multiple Sclerosis ...................................................................................................... 33 1.9 What is Functional Brain Plasticity? .......................................................................... 34 1.10 The Role of Aerobic Fitness in Cerebrovascular Function ........................................ 34 Chapter 2 ................................................................................................................................... 37 2. Functional Magnetic Resonance Imaging: Basis and Application in Cerebrovascular Research .................................................................................................................................... 37 2.1 Nuclear Spin .............................................................................................................. 37 2.2 Relaxation and Decay ................................................................................................ 39 2.3 Slice Selection and Image Formation ........................................................................ 40 2.4 Signal Processing in K-space ..................................................................................... 40 2.5 MR Contrast Mechanisms ......................................................................................... 43 2.6 Spin Echo and Gradient Echo Imaging ...................................................................... 44 2.7 The Blood Oxygen Level Dependent (BOLD) Signal .................................................. 46 2.8 Arterial Spin Labelling ............................................................................................... 49 2.9 Types of ASL .............................................................................................................. 50 2.10 Dual echo and Dual Excitation .................................................................................. 55 2.11 Single and Multiple Inversion Time ASL .................................................................... 57 2.12 Quantification of Cerebral Haemodynamics ............................................................. 57 2.13 Calibrated FMRI......................................................................................................... 58 2.14 Measurement of Cerebrovascular Reactivity ........................................................... 60 2.15 Signal Contamination in BOLD and ASL .................................................................... 61 2.16 Summary Comparison of BOLD and ASL ................................................................... 62 2.17 Overview of Statistical Approaches .......................................................................... 63 2.1.1 Sample Sizes ...................................................................................................... 63 2.1.2 Multiple Comparison Corrections ..................................................................... 64 2.1.3 Outliers .............................................................................................................. 65 Chapter 3 ..................................................................................................................................
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