Functional Neuroimaging of Placebo Inhibition in Capsaicin Induced Urge-to-Cough
نویسنده
چکیده
................................................................................................................................................................... II DECLARATION BY AUTHOR .................................................................................................................................. IV PUBLICATIONS DURING CANDIDATURE ........................................................................................................... V ACKNOWLEDGEMENTS ....................................................................................................................................... VIII LIST OF FIGURES ................................................................................................................................................... XIV LIST OF TABLES ....................................................................................................................................................... XV LIST OF ABBREVIATIONS ................................................................................................................................... XVI CHAPTER 1 -‐ INTRODUCTION ................................................................................................................................ 1 COUGH ............................................................................................................................................................................................... 1 CLINICAL CONDITIONS INVOLVING ABNORMAL COUGH .......................................................................................................... 2 ANTITUSSIVE MEDICATIONS ......................................................................................................................................................... 2 CHRONIC COUGH DISORDERS ........................................................................................................................................................ 2 IDIOPATHIC COUGH ......................................................................................................................................................................... 3 THE URGE-‐TO-‐COUGH .................................................................................................................................................................... 4 MODULATION OF THE URGE-‐TO-‐COUGH .................................................................................................................................... 4 PLACEBO MODULATION OF URGE-‐TO-‐COUGH ........................................................................................................................... 5 PLACEBO EFFECTS IN COUGH ....................................................................................................................................................... 5 PLACEBO EFFECTS IN PAIN ........................................................................................................................................................... 6 MODELS OF PLACEBO EFFECT ...................................................................................................................................................... 6 MODELS OF URGE-‐TO-‐COUGH ...................................................................................................................................................... 7 CORTICAL MODULATION OF URGE-‐TO-‐COUGH ......................................................................................................................... 8 FUNCTIONAL MAGNETIC RESONANCE IMAGING ....................................................................................................................... 9 FUNCTIONAL NEUROANATOMY OF COUGH AND URGE-‐TO-‐COUGH ....................................................................................... 9 FUNCTIONAL NEUROANATOMY OF PLACEBO EFFECT ........................................................................................................... 12 SUMMARY ...................................................................................................................................................................................... 14 AIMS ................................................................................................................................................................................................ 14 Experiment 1 .............................................................................................................................................................................. 14 Experiment 2 .............................................................................................................................................................................. 14 Experiment 3 .............................................................................................................................................................................. 15 SIGNIFICANCE ................................................................................................................................................................................ 15 CHAPTER 2 -‐ METHODS -‐ EXPERIMENTAL DESIGN, FUNCTIONAL MAGNETIC RESONANCE IMAGING AND ANALYSIS ...................................................................................................................................... 16 OVERVIEW OF THE PRINCIPLES OF FMRI ................................................................................................................................ 16 xi AIRWAY IRRITATIONS: MODELLING COUGH VERSUS THE URGE-‐TO-‐COUGH ..................................................................... 17 CHOOSING A PLACEBO “TREATMENT” ..................................................................................................................................... 18 DEVELOPMENT OF STUDY DESIGNS .......................................................................................................................................... 19 DEVELOPMENT OF PLACEBO MRI PROTOCOL ........................................................................................................................ 21 DEVELOPMENT OF BRAINSTEM PLACEBO MRI PROTOCOL ................................................................................................. 23 SUMMARY ...................................................................................................................................................................................... 25 CHAPTER 3 -‐ THE EFFECT OF PLACEBO CONDITIONING ON CAPSAICIN-‐EVOKED URGE-‐TO-‐ COUGH ........................................................................................................................................................................ 26 ABSTRACT ...................................................................................................................................................................................... 26 INTRODUCTION ............................................................................................................................................................................. 27 METHODS ....................................................................................................................................................................................... 28 Participants ................................................................................................................................................................................ 28 Capsaicin sensitivity testing ................................................................................................................................................ 28 Expectation ................................................................................................................................................................................. 29 Conditioning ............................................................................................................................................................................... 29 Testing ........................................................................................................................................................................................... 29 Effect of metered dose inhaler on urge-‐to-‐cough thresholds ................................................................................ 30 Statistical Methods .................................................................................................................................................................. 30 RESULTS ......................................................................................................................................................................................... 31 Participants ................................................................................................................................................................................ 31 Thresholds and Urge-‐to-‐Cough Ratings ......................................................................................................................... 31 Effect of metered dose inhaler on urge-‐to-‐cough ratings ....................................................................................... 35 Debriefing .................................................................................................................................................................................... 35 DISCUSSION ................................................................................................................................................................................... 35 CONCLUSIONS ................................................................................................................................................................................ 38 CHAPTER 4 -‐ BRAIN ACTIVITY ASSOCIATED WITH PLACEBO SUPPRESSION OF THE URGE-‐TO-‐ COUGH IN HUMANS ................................................................................................................................................ 39 ABSTRACT ...................................................................................................................................................................................... 39 INTRODUCTION ............................................................................................................................................................................. 40 METHODS ....................................................................................................................................................................................... 41 Participants ................................................................................................................................................................................ 41 Capsaicin sensitivity testing ................................................................................................................................................ 41 Expectation, conditioning and testing ............................................................................................................................ 41 Image Acquisition .................................................................................................................................................................... 42 Experimental Protocol ........................................................................................................................................................... 42 Statistical Methods .................................................................................................................................................................. 43 fMRI Analysis .............................................................................................................................................................................. 44 xii RESULTS ......................................................................................................................................................................................... 45 Psychophysical Results ........................................................................................................................................................... 45 Regional Brain Activation During Control Trials ...................................................................................................... 47 Regional Brain Activation During Placebo Trials ...................................................................................................... 51 DISCUSSION ................................................................................................................................................................................... 57 Placebo antitussive suppression of the urge-‐to-‐cough ............................................................................................ 58 Regional brain responses during capsaicin inhalation and the effect of placebo ....................................... 60 Concluding Remarks ............................................................................................................................................................... 62 CHAPTER 5 -‐ BRAINSTEM ACTIVITY ASSOCIATED WITH PLACEBO SUPPRESSION OF THE URGE-‐ TO-‐COUGH ................................................................................................................................................................. 63 INTRODUCTION ............................................................................................................................................................................. 63 METHODS ....................................................................................................................................................................................... 65 Participants ................................................................................................................................................................................ 65 Capsaicin threshold testing .................................................................................................................................................. 66 Image Acquisition .................................................................................................................................................................... 66 Conditioning ............................................................................................................................................................................... 66 Identification of Brainstem Regions Involved in the Placebo Effect on Urge-‐to-‐Cough ............................ 66 Statistical Analysis ................................................................................................................................................................... 67 Registration ................................................................................................................................................................................ 67 General Linear Modelling ..................................................................................................................................................... 67 RESULTS ......................................................................................................................................................................................... 68 Psychophysical Results ........................................................................................................................................................... 68 Confirmation of Placebo Related Changes in Activation in Expected Cortical Regions ............................ 70 Decreased Brainstem Activation During Capsaicin Inhalation Following Placebo .................................... 71 Correlation of Regional Placebo-‐Induced Signal Reduction with Behavioural Measures ....................... 72 DISCUSSION ................................................................................................................................................................................... 75 Summary ...................................................................................................................................................................................... 75 Placebo Suppression of the Urge-‐to-‐Cough ................................................................................................................... 75 Brainstem Activity Associated with Placebo Suppression of the Urge-‐to-‐Cough ......................................... 76 Similarity to Placebo Analgesia ......................................................................................................................................... 76 Conclusions ................................................................................................................................................................................. 77 CHAPTER 6 -‐ CONCLUSION ................................................................................................................................... 78 SUMMARY OF FINDINGS .............................................................................................................................................................. 78 EXPERIMENTALLY INDUCED PLACEBO EFFECT IN URGE-‐TO-‐COUGH ................................................................................ 78 REGIONAL CORTICAL ACTIVATION ASSOCIATED WITH PLACEBO EFFECT IN URGE-‐TO-‐COUGH .................................. 79 BRAINSTEM ACTIVATION ASSOCIATED WITH PLACEBO INHIBITION OF URGE-‐TO-‐COUGH ........................................... 79 IMPLICATIONS OF STUDIES ......................................................................................................................................................... 79 xiii LIMITATIONS OF EXPERIMENTAL METHODS AND FUTURE DIRECTIONS FOR RESEARCH .............................................. 80 CONCLUSIONS ................................................................................................................................................................................ 81 REFERENCES ............................................................................................................................................................. 82 APPENDICES ............................................................................................................................................................. 96 APPENDIX A .................................................................................................................................................................................. 96 Information Leaflet ................................................................................................................................................................. 96 APPENDIX B ................................................................................................................................................................................... 99 Pre Scan Questionnaire ......................................................................................................................................................... 99 Post Debriefing Questionnaire ......................................................................................................................................... 100
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