Mechanisms of central nervous system damage and recovery in demyelinating and other neurological disorders: structural and functional MRI studies David John Werring A thesis submitted to the University of London for the degree of Doctor of Philosophy September 2000 NMR Research Unit Department of Clinical Neurology Institute of Neurology, University College London Queen Square London WCIN 3BG United Kingdom ProQuest Number: U643058 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U643058 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract This thesis is concerned with multiple sclerosis (MS), a chronic, multifocal demyelinating disease of the central nervous system (CNS). In its early stages MS is characterised by reversible deficits, but with time recovery usually becomes incomplete, causing progressive disability. To understand this transition requires knowledge of mechanisms of recovery and fixed neurological deficit. Functional recovery from demyelination can occur despite irreversible conduction abnormalities and axon loss in affected pathways, suggesting that cortical adaptive mechanisms may contribute. To investigate this hypothesis, patients who had recovered from a single episode of optic neuritis were studied using functional magnetic resonance imaging (fMRI). Monocular visual stimulation to the recovered eye induced an anatomically and temporally abnormal response in areas outside the visual cortex, to which activation in control subjects was confined. The extra-occipital activation was most marked in those with delayed optic nerve conduction, suggesting a role in adaptation to persistently abnormal visual input. Mechanisms of tissue damage in MS were investigated using MR diffusion imaging, which quantifies water molecule mobility non-invasively and is sensitive to tissue structural integrity. Heterogeneous diffusion properties were demonstrated in MS lesions, and subtle abnormalities in the magnitude and directional restriction (anisotropy) of diffusion were found in widespread areas of normal-appearing white matter (NAWM). Diffusion in lesions correlated with that in NAWM, suggesting that the underlying pathogenic mechanisms are closely linked. In patients with ischaemic stroke, anisotropy changes were demonstrated in tracts distant to the lesion, indicating an ability to detect fibre degeneration. Finally, fMRI and diffusion imaging were combined to obtain complementary functional and structural information. In a traumatic CNS injury causing hemiplegia, excellent motor recovery was associated with a preservation of corticospinal tract structural integrity and motor cortex activation. In the human visual system, fibre tract structure and orientation, and cortical activation were demonstrated in single maps. Acknowledgements Ali of the work described herein was performed in the NMR Research Unit at the Institute of Neurology, which is funded by a generous grant from the MS Society of Great Britain and Northern Ireland. My research post was funded by the Brain Research Trust and funds available to Professor Alan Thompson. I thank all of the patients who kindly gave their time to participate in the studies. Many thanks are due to my principle supervisor, Professor Alan Thompson, who provided enthusiastic support and encouragement throughout, enabling me to see the work in a wider context, yet at the same time showing meticulous attention to detail. 1 am grateful to Professor David Miller for supervising many aspects of the projects, but particularly for guidance in the interpretation of diffusion MRI data. Dr Gareth Barker provided expert supervision, patient explanations of physics principles, and solved many analysis and computer problems. It has been a privilege to work with Professor Ian McDonald, who gave invaluable encouragement and guidance, especially on the optic neuritis project. 1 warmly thank Dr Christopher Clark for help with understanding and applying diffusion imaging, and Dr Martin King for statistical advice. Thanks to Dr Geoff Parker for useful discussions and help in displaying diffusion tensor imaging data. Dr Aidan Droogan collected some of the EPl diffusion data, and gave guidance on storing and manipulating it. Dr Peter Brex helped to recruit the patients for the optic neuritis study. Dr Ahmed Toosy contributed to analysing the optic neuritis and stroke studies. 1 am grateful to Drs Ed Bullmore, Mick Brammer and Vincent Giampietro for expert assistance with implementing fMRI analysis. 1 wish to thank David MacManus, who provided radiographic assistance, particularly in the early days of applying the new techniques. 1 thank the many other members of the NMR Reasearch Unit with whom 1 worked during the project. In particular. Dr Siobhan Leary and Andrew Lowe helped me to remain (reasonably) sane throughout by providing support and reassurance, often over a drink or two. Drs Jeremy Hobart and Alex Leff could always be relied upon for words of humour and encouragement. Finally, 1 thank Lucy Wood for continuing moral support and proof reading the manuscript. Publications associated with this thesis Werring DJ, Clark CA, Barker GJ, Miller DH, Parker GJM, Brammer MJ, Bullmore ET, Giampietro VP, Thompson AJ. The structural and functional mechanisms of motor recovery: complementary use of diffusion tensor and functional magnetic resonance imaging in a traumatic injury of the internal capsule. J Neurol Neurosurg Psychiatry 1998; 65: 863-869. Werring DJ, Clark CA, Miller DH, Thompson AJ, Barker GJ. A direct demonstration of both structure and function in the visual system: combining diffusion tensor imaging with functional magnetic resonance imaging. Neuroimage 1999; 9: 352-361. Werring DJ, Clark CA, Barker GJ, Thompson AJ, Miller DH. Diffusion tensor imaging of lesions and normal appearing white matter in multiple sclerosis. Neurology 1999; 52: 1626-1632. Werring DJ, Bullmore ET, Toosy AT, Miller DH, Barker GJ, MacManus DG, Brammer MJ, Giampietro VP, Brusa A, Brex PA, Moseley IF, Plant GT, McDonald WI, Thompson AJ. Recovery from optic neuritis is associated with a reorganisation of the cerebral response to visual stimulation. J Neurol Neurosurg Psychiatry 2000; 68: 441-9. (see also: “Brain may reorganise to compensate for damage caused by multiple sclerosis.” Lancet 1999; 354: 1361; “Flexible thinking.” Daily Telegraph Oct 28, 1999,p24.) Werring DJ, Toosy AT, Clark G A, Parker GJM, Barker GJ, Miller DH, Thompson AJ. Diffusion tensor imaging can detect and quantify corticospinal tract degeneration after stroke J Neurol Neurosurg Psychiatry 2000; 69: 269-72. Droogan AG, Clark CA, Werring DJ, Barker GJ, McDonald WI, Miller DH. Comparison of multiple sclerosis clinical subgroups using navigated spin-echo diffusion-weighted imaging. Magnetic Resonance Imaging 1999; 17: 653-661. Werring DJ, Brassat D, Droogan AG, Clark CA, Symms MR, Barker GJ, MacManus DG, Thompson AJ, Miller DH. The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain 2000; 123: 1667-76. Clark CA, Werring DJ, Miller DH. Diffusion imaging of the spinal cord in vivo: estimation of the principle diffusivities and application to multiple sclerosis. Magn Reson Med 2000; 43: 133-8. Parker GJM, Schnabel JA, Symms MR, Werring DJ, Barker GJ. Nonlinear smoothing for reduction of systematic and random errors in diffusion tensor imaging. J Magn Reson Imaging 2000; 11: 702-10. Table of Contents Page Abstract 2 Acknowledgements 3 Publications associated with this thesis 4 Table of contents 6 List of figures 12 List of tables 17 Chapter 1. Introduction to demyelinating diseases and the principles of magnetic resonance imaging. Introduction 19 1.1 Multiple Sclerosis 20 Background 20 Aetiology 21 Clinical course, symptoms and diagnosis 24 Pathology 28 Pathophysiology 30 1.2 Magnetic Resonance Imaging 42 Physical description o f nuclear magnetic resonance 42 Simple spin echo experiment 48 Making an image 51 The concept o f k-space 55 Echoplanar Imaging 57 Page The role o f magnetic resonance imaging in multiple sclerosis 59 Chapter 2. Introduction to the principles and clinical applications of functional MRI and magnetic resonance diffusion imaging. 2.1 Functional magnetic resonance imaging 72 Basic principles of brain functional organization 72 Functional imaging: historical overview 74 Principles o f functional imaging using magnetic resonance 75 fMRI data acquisition and hardware 80 Experimental design 82 Spatial and temporal resolution 85 Data analysis 87 Overview of some applications 92 2.2 Magnetic resonance diffusion imaging 96 Background 96 Diffusion-weighted imaging 98 Quantification o f water diffusion 98 Anisotropy 100 The diffusion tensor 100 Motion artifacts in diffusion imaging 103 Clinical applications o f diffusion MRI 104 Page Chapter 3. Mechanisms of recovery in demyelinating disease: fMRI studies in optic neuritis. 3.1 Introduction 108 Mechanisms o f neurological recovery: the concept o f cerebral 108 plasticity Recovery