Use of methamphetamine ph MRI in humans to investigate the role of dopamine in reward and other functions related to mental illness A thesis submitted to The University of Manchester for the degree of MPhil in the Faculty of Medical and Human Sciences School of Medicine 2010 Patrick Horgan 1 Table of contents List of Figures 4 List of Tables 5 Abstract 6 Declaration 7 Copyright statement 7 Acknowledgements 7 Preface 7 Abbreviations 8 1. Introduction ...........................................................................................10 1.1. General introduction.................................................................................... 10 1.2. Description of drugs used in the study ......................................................... 11 1.2.1. Methamphetamine ............................................................................... 11 1.2.2. Amisulpride......................................................................................... 17 1.3. Overview of dopamine neurons and receptors.............................................. 19 1.3.1. Dopamine structure and dopamine neuron neuroanatomy .................... 19 1.3.2. Pharmacology of dopamine.................................................................. 22 1.3.3. Dopamine physiology.......................................................................... 25 1.4. Aspects of fMRI relevant to the study.......................................................... 29 1.4.1. Biological basis of fMRI...................................................................... 29 1.4.2. Challenge and modulation phMRI ....................................................... 31 1.4.3. Comparisons with PET........................................................................ 32 1.5. Cognitive processes related to the study involving dopamine....................... 34 1.5.1. Finger tapping tasks............................................................................. 34 1.5.2. Working memory................................................................................. 38 1.5.3. Learning paradigms ............................................................................. 44 1.6. General theories of dopamine function ........................................................ 53 1.7. Role of dopamine in psychiatric illnesses .................................................... 56 1.8. General aims of the study ............................................................................ 60 1.8.1. Rationale ............................................................................................. 60 1.8.2. Hypotheses of study............................................................................. 62 1.8.3. Implications for mental illness ............................................................. 64 2. Methods .................................................................................................67 2.1. Subjects....................................................................................................... 67 2.2. Experimental design.................................................................................... 68 2.3. Choice of pharmacological agents ............................................................... 69 2.4. Procedures................................................................................................... 70 2.4.1. Image acquisition................................................................................. 70 2.4.2. Challenge phMRI ................................................................................ 70 2.4.3. Resting state ........................................................................................ 71 2.4.4. N-back task.......................................................................................... 71 2.4.5. Finger tapping task .............................................................................. 71 2.4.6. Reward learning task ........................................................................... 71 2.4.7. Signal detection task............................................................................ 74 2.4.8. Scanning problems and unblinding ...................................................... 74 2.5. Statistical analysis ....................................................................................... 75 2.5.1. Overview of analysis ........................................................................... 75 2.5.2. Screening data and physiological data from visit 1 and visit 2.............. 76 2.5.3. Preprocessing of MRI data................................................................... 77 2.5.4. Challenge phMRI ................................................................................ 77 2 2.5.5. N-back task.......................................................................................... 79 2.5.6. Finger tapping task .............................................................................. 80 2.5.7. Reward learning task ........................................................................... 81 2.6. Truncation artifact....................................................................................... 87 3. Results ...................................................................................................89 3.1. Visit 1 and visit 2 screening and physiological data ..................................... 89 3.1.1. Visit 1 screening data........................................................................... 89 3.1.2. Visit 1 and visit 2 cardiovascular data.................................................. 90 3.1.3. Visit 2 prolactin levels......................................................................... 92 3.2. Challenge phMRI........................................................................................ 94 3.2.1. Behavioural data.................................................................................. 94 3.2.2. fMRI data analysis............................................................................... 99 3.3. N-back task ............................................................................................... 108 3.3.1. Behavioural data................................................................................ 108 3.3.2. fMRI data results............................................................................... 109 3.4. Finger tapping task.................................................................................... 115 3.4.1. fMRI data analysis............................................................................. 115 3.5. Reward learning task................................................................................. 120 3.5.1. Behavioural data................................................................................ 120 3.5.2. fMRI data analysis............................................................................. 124 4. Discussion...........................................................................................139 4.1. Screening data........................................................................................... 139 4.2. Challenge phMRI...................................................................................... 141 4.3. N-back task ............................................................................................... 149 4.4. Finger tapping task.................................................................................... 152 4.5. Reward learning task................................................................................. 155 5. Overall review of experiment .............................................................160 5.1. Screening data and performance data for all parts of the study................... 160 5.2. Reaction times........................................................................................... 160 5.3. fMRI data.................................................................................................. 161 5.4. General implications for theories of dopamine function............................. 161 5.5. Implications of results for mental illness.................................................... 162 5.6. Study Limitations...................................................................................... 163 5.7. Future directions........................................................................................ 165 5.8. Conclusion ................................................................................................ 166 6. Appendix..............................................................................................167 6.1. Fractals used in the reward learning task.................................................... 167 6.2. Supplementary table for N-back performance............................................ 167 6.3. Plots of reward learning task...................................................................... 168 6.4. Supplementary tables for reward learning task........................................... 172 7. References...........................................................................................173 Word Count Main Text : 49000 3 List of Figures Figure 1.3-1 .............................................................................................................. 20 Figure 1.3-2 .............................................................................................................. 21 Figure 1.3-3 .............................................................................................................