FACULTY OF MEDICINE Infra-slow oscillations in chronic orofacial neuropathic pain and the effects of palmitoylethanolamide Zeynab Alshelh A thesis submitted to the University of Sydney in fulfilment of the requirement for the degree of Doctor of Philosophy Laboratory of Neural Imaging Department of Anatomy and Histology June 2018 “There is something fascinating about science. One gets such wholesome returns of conjecture out of such a trifling investment of fact.” Mark Twain (1883) Table of Contents Originality statement.......................................................................................................................... vi Abstract ............................................................................................................................................. vii Acknowledgements ............................................................................................................................. x Publications and awards .................................................................................................................... xi Co-authors contributions ..................................................................................................................xiv Chapter one: Introduction ..................................................................................................................... 1 1. Chronic pain .................................................................................................................................... 2 1.1. Chronic neuropathic pain ........................................................................................................ 4 1.2. Trigeminal neuropathic pain ................................................................................................... 4 1.2.1. Background and presentation ......................................................................................... 4 1.2.2. Incidence and prognosis ................................................................................................. 5 1.2.3. Treatments ...................................................................................................................... 6 1.3. Models of chronic neuropathic pain ....................................................................................... 6 1.3.1. Central sensitization ........................................................................................................ 6 1.3.2. Pain matrix ...................................................................................................................... 7 1.3.3. Thalamocortical dysrhythmia ........................................................................................ 8 1.4. Nervous system ....................................................................................................................... 9 1.4.1. Pain pathways ................................................................................................................. 9 1.5. Central nervous system ........................................................................................................ 10 1.5.1. Dorsal horn ................................................................................................................... 10 iii 1.5.1. Dorsal horn ................................................................................................................... 10 1.5.2. Thalamus ...................................................................................................................... 14 1.5.3. Primary somatosensory cortex ..................................................................................... 20 1.6. Astrocytes in neuropathic pain ............................................................................................. 22 1.6.1. Anatomy and function of astrocytes ............................................................................. 22 1.6.2. Role of astrocytes in neuropathic pain ......................................................................... 24 1.7. Neuroimaging: Magnetic resonance imaging ....................................................................... 27 1.7.1. Functional magnetic resonance imaging ...................................................................... 27 1.7.2. T2 relaxometry .............................................................................................................. 28 1.8. Overarching aims of the thesis ............................................................................................. 29 1.8.1. Specific aims of the thesis ............................................................................................. 29 References ........................................................................................................................................ 30 Chapter two: Chronic neuropathic pain: It’s about the Rhythm ........................................................ 39 2.1. Abstract ................................................................................................................................. 40 2.2. Introduction .......................................................................................................................... 40 2.3. Materials and Methods ......................................................................................................... 41 2.4. Results ................................................................................................................................... 44 2.5. Discussion .............................................................................................................................. 46 2.6. References ............................................................................................................................ 48 Chapter three: Altered regional brain T2 relaxation times in individuals with chronic orofacial neuropathic pain .................................................................................................................................. 51 3.1. Abstract ................................................................................................................................. 52 iv 3.2. Introduction .......................................................................................................................... 52 3.3. Methods ................................................................................................................................ 53 3.4. Results ................................................................................................................................... 53 3.5. Discussion .............................................................................................................................. 56 3.6. Acknowledgements ............................................................................................................... 57 3.7. References ............................................................................................................................ 58 Chapter four: Effects of the glial modulator palmitoylethanolamide on chronic pain intensity and brain function ....................................................................................................................................... 59 4.1. Abstract ................................................................................................................................. 61 4.2. Introduction .......................................................................................................................... 62 4.3. Results ................................................................................................................................... 63 4.4. Discussion .............................................................................................................................. 68 4.5. Online Methods .................................................................................................................... 71 4.7. References ............................................................................................................................ 74 Chapter five: Conclusions ..................................................................................................................... 80 5.1. Main findings ........................................................................................................................ 81 5.2. Implications ........................................................................................................................... 83 5.3. Recommendations for future research ................................................................................. 92 5.4. References ............................................................................................................................ 94 Appendix ............................................................................................................................................. 116 v Originality statement The work presented in this thesis is, to the best of my knowledge and belief, original except as acknowledged in the text. I hereby declare that I have not submitted this material, either in full or in part, for a degree at this or any other institution. …………………………………………………….. Zeynab Alshelh Department of Anatomy and Histology, Faculty of Medicine, The University of Sydney, Australia vi Abstract For centuries, chronic pain was denied as being real by physicians, mainly because there