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Use of Methamphetamine Phmri in Humans to Investigate the Role of Dopamine in Reward and Other Functions Related to Mental Illness”

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Use of Methamphetamine Phmri in Humans to Investigate the Role of Dopamine in Reward and Other Functions Related to Mental Illness” 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 .............................................................................................................
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