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To request permissions please use the Feedback form on our webpage. http://researchspace.auckland.ac.nz/feedback General copyright and disclaimer In addition to the above conditions, authors give their consent for the digital copy of their work to be used subject to the conditions specified on the Library Thesis Consent Form and Deposit Licence. Determining the Effects of Active Methamphetamine Dependence on Grey Matter Structure and Function of the Human Brain using Magnetic Resonance Imaging Reem Kais Jan A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy in Medical and Health Sciences The University of Auckland, 2013. Abstract Methamphetamine dependence is a worldwide problem for which no effective treatment currently exists. Magnetic resonance imaging (MRI) allows the non-invasive study of the brains of methamphetamine-dependent individuals; however, most MRI studies have been conducted following varying periods of abstinence. This thesis focuses on the effects of active methamphetamine dependence on the human brain and examines changes associated with the use of methylphenidate, an agonist replacement therapy, versus placebo using structural and functional MRI (1.5 T); the former coupled with neuropsychological testing and the latter with the colour-word Stroop task. Active methamphetamine-dependent subjects (n=17) were compared to control subjects (n=20) at baseline, and following an acute oral methylphenidate (18mg) versus placebo challenge. Active methamphetamine-dependent subjects continued treatment with methylphenidate (54mg/day) or placebo and underwent testing again during their tenth week of treatment (n=8). At baseline, methamphetamine-dependent subjects showed increased right putamen volumes in comparison to control subjects, which correlated with improved performance during the Go/No-go task of response inhibition. Following 10 weeks of treatment with methylphenidate, right putamen volumes of methamphetamine-dependent subjects were decreased without worsening of cognitive function in comparison to placebo. This suggested a normalisation process whereby the underlying methamphetamine-induced putamen enlargement is reversed following treatment with methylphenidate. In general, methamphetamine-dependent subjects showed similar behavioural performance of the colour-word Stroop task to control subjects. However, they exhibited different patterns of fMRI activation. Increased activation of frontal, parietal and temporal regions of methamphetamine-dependent subjects during the incongruent and Stroop effect conditions was suggested to be essential for successful conflict resolution. After a methylphenidate (18mg) challenge, methamphetamine-dependent subjects exhibited deactivation of the insula in comparison to control subjects, a possible methylphenidate-induced adaptive effect to the incongruent condition which presents a higher cognitive load than the congruent condition. Following 10 weeks of treatment with methylphenidate (54mg/day), methamphetamine- dependent subjects showed faster responding during the Stroop task combined with increased activation of frontal and cingulate regions. These preliminary findings suggest that ii normalisation, at least in part, of brain function during cognitive control may occur following long-term methylphenidate treatment of methamphetamine-dependent subjects. Future studies are recommended to use a larger sample size and eliminate the confounding effects of other drug use. Finally, larger studies of active methamphetamine dependence using higher doses of methylphenidate for longer periods are recommended to consolidate the preliminary findings from this study. iii To my husband and best friend, Mustafa and the best parents in the world, Layla and Kais iv Acknowledgements I owe sincere thanks to my PhD supervisors, Dr Bruce Russell and Professor Rob Kydd, who made me believe in myself and guided me through the whole PhD process. I am sure that this PhD thesis would not have been possible without their support, understanding and encouragement. To Bruce, thank you for the opportunity to work on such a unique and exciting project. You have been more than a supervisor; you have showed me compassion during difficult times and unwavering faith that I can do this. In times that I didn‘t believe in myself, you never failed to remind me what I‘m capable of, and for that I am grateful. To Rob, you have been a wonderful mentor and a true inspiration. Your words of wisdom are always in my ear, helping me make and shape decisions and I‘m honoured to have received advice from you that will serve me a lifetime. So thank you Rob for believing in me and for being a great supervisor. To both of you, it has been a true honour being your student. I would like to express my special thanks and gratitude to the University of Auckland, and the New Zealand Federation of Graduate Women, for the honour of receiving the University of Auckland Doctoral Scholarship and the New Zealand Federation of Graduate Women Postgraduate Fellowship, respectively. I am grateful to the New Zealand Pharmacy Education Research Foundation Grant Number 208, the University of Auckland Faculty Development Research Fund, and the Oakley Mental Health Research Foundation for funding and supporting this project. Moreover, I would also like to express thanks to people who participated in my research, this thesis would not have been possible without them. A very special thank you to Professor John Shaw, the best role model and mentor any student could ask for. Thank you for your listening ear, sound advice and moral support. I am honoured to have been a student of yours. I would also like to thank Professor Julia Kennedy, head of School of Pharmacy, University of Auckland for her support. I would like to express my gratitude to Dr Donald McLaren (Department of Neurology and Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, USA), who has helped me tremendously with understanding and applying concepts of functional magnetic resonance imaging. Thank you for always answering my many questions, for delving into deep discussions with me, for entertaining some complicated research methodology ideas and for your sound statistical advice. Most of all, thank you for your friendship Donald. v Another special thank you to Dr Mark Jenkinson (FMRIB Centre, University of Oxford), Dr Thomas Zeffiro (Harvard University) and Dr Andreas Bartsch (Department of Neuroradiology, University of Heidelberg) for their help in solving some of the most complicated neuroimaging hurdles I came across during my PhD, and to the rest of the FSL and SPM course teams for invaluable training in neuroimaging data analysis techniques. I am tremendously grateful to Dr David O‘Connor (Melbourne School of Psychological Studies, University of Melbourne) and Dr Maartje Luijten (Erasmus University Rotterdam, Netherlands), for their kind help with setting up my next project. To David, thank you for visiting us in New Zealand and for your tremendously helpful input in bringing my task design to life. To Maartje, you have been a great friend and colleague, thank you for your advice in setting up my new task and for always keeping in touch. I would like to thank Dr Louise Curley who has been a colleague, friend and a sister in times of need; I am grateful we found each other. I would like to sincerely thank Joanne Lin who worked on a separate data set from the same project; we worked so hard together and shared many good times, and came out of challenging times stronger together. Thank you for your collegiality and friendship Jo. Many thanks to the rest of my colleagues and friends in my research group: Dr Valerie Anderson, for your invaluable advice on structural MRI analysis and for your friendship; Meghan McIlwain, Grace Wang and Dr Hee Seung Lee for your friendship and continuing encouragement during the past four years. I would like to express my sincere thanks to the following people for their valuable participation and various roles in project planning, administration, experimental design and participant recruitment: Associate Professor Wayne Miles, Professor Ian Kirk, Dr Nicolas McNair, Ms Maree Jensen, Ms Peta Hardley, Professor Jari Tiihonen (Karolinska Institutet, Finland), Associate Professor Janie Sheridan, Michelle Gordon and the staff and pharmacists at Community Alcohol and Drug Services in Point Chevalier, Auckland, New Zealand. Thank you to the staff at the Centre for Advanced MRI, University of Auckland, for their help and advice in MRI data acquisition; in particular Dr Brett Cowan, Ms Anna Lydon, Dr Beau Pontré, Ms Shelley Park, Ms Hillary McIntyre, Ms Rachel Heron and Ms Kate Handley. For statistical advice, I would like to sincerely thank Mr Avinesh Pillai, Professor Chris Triggs, Dr John Sollers and Associate Professor Nathan Consedine. vi Thank you to the following people who have offered advice and been great colleagues and friends: Dr Fiona Kelly, Ms Maree Jensen, Ms Mirelle Powell, Dr Victoria McLelland, Dr Sanya Ram, Dr Gjurgjica Badzakova, Dr Donna Addis and Dr Tracy Melzer (Van der Veer Research Institute, University of Otago). On a personal note, I would like to first and foremost thank God for guiding me through the last four years, and my whole life for that matter, and for letting me come out of challenging experiences stronger and having learnt a great deal. I don‘t know how to thank my mother, Layla, and father, Kais; there are really no words, you are not regular parents and I thank God for you every day. You have not only looked after me, you have wiped my tears and put smiles on my face, supported me no matter where I was and what I was doing and you love me unconditionally. You have taught me to always strive to be the best I can be, and I owe all that I am to you. To my husband Mustafa, you have been my rock; I could never have done this without your support, patience, compassion and never-ending love. I dedicate this thesis to you and my parents without a doubt; thank you my one and only. To the rest of my family, Shams, Dina, Safa, Tammuz, Ali, baby Yazan and my parents-in-law, Muna and Saib, thank you for being there for me, you are amazing and I love you. To my best friend Leena, I consider myself the luckiest person on earth to have found you; you know me better than I know myself, you complete my sentences and you have unwavering faith in me. Lulu, you are irreplaceable and I love you dearly. To my second best friend Maan, you have been the voice of reason throughout my life, you are the brother I never had; thank you for being an amazing friend throughout the years and for supporting me through this journey. To the rest of my friends who have been there for me throughout this process, thank you very much. In accordance with the University of Auckland Guide to Theses and Dissertations, I would like to acknowledge that I used a professional proofreading service who offered advice on grammar, punctuation and clarity in the penultimate draft of this thesis. All suggested changes were made by me, and no contribution was made to the intellectual content of the thesis by this service. vii Table of Contents Abstract ........................................................................................................................... ii Acknowledgements ........................................................................................................ v List of Figures .............................................................................................................. xiv List of Tables ............................................................................................................... xvi Glossary ...................................................................................................................... xvii List of Publications ...................................................................................................... xix List of Conference Abstracts ....................................................................................... xix Thesis Outline ................................................................................................................. 1 Chapter 1. Introduction ................................................................................................... 4 1.1. Drug dependence ......................................................................................................... 5 1.1.1. Epidemiology of drug dependence ................................................................................. 6 1.1.2. Dopamine and dopaminergic pathways .......................................................................... 7 1.1.2.1. The reward pathways ............................................................................................................... 7 1.1.2.2. Motor control ........................................................................................................................... 9 1.2. Methamphetamine ..................................................................................................... 10 1.2.1. History and classification of methamphetamine ........................................................... 10 1.2.2. Epidemiology of methamphetamine dependence ......................................................... 11 1.2.3. Pharmacology and mechanism of action of methamphetamine .................................... 12 1.2.4. Physiological and cognitive effects of methamphetamine ............................................ 13 1.2.5. Pharmacokinetics of methamphetamine ....................................................................... 14 1.2.6. Treatment of methamphetamine dependence ................................................................ 15 1.3. Methylphenidate ........................................................................................................ 16 1.3.1. History of methylphenidate ........................................................................................... 16 1.3.2. Pharmacology and mechanism of action of methylphenidate ....................................... 16 1.3.3. Cognitive effects of methylphenidate ........................................................................... 17 1.3.4. Pharmacokinetics of methylphenidate .......................................................................... 17 1.4. Neuroimaging ............................................................................................................ 19 1.4.1. Positron emission tomography ...................................................................................... 19 1.4.2. Magnetic resonance imaging ........................................................................................ 19 1.4.2.1. Functional magnetic resonance imaging ................................................................................ 21 1.4.2.1.1. Advantages and disadvantages of functional magnetic resonance imaging ...................................... 22 1.4.2.2. Structural magnetic resonance imaging ................................................................................. 23 viii 1.5. Cognitive control ....................................................................................................... 23 1.5.1. The colour-word Stroop task ......................................................................................... 23 1.6. Literature review: Findings from neurotoxicity and neuroimaging studies in methamphetamine dependence ............................................................................................ 25 Functional and structural brain changes associated with methamphetamine abuse ...................... 27 Abstract ......................................................................................................................................... 27 1.6.1. Epidemiology and clinical pharmacology of methamphetamine abuse ........................ 28 1.6.2. Methamphetamine-induced neurotoxicity .................................................................... 28 1.6.2.1. Methamphetamine-induced monoaminergic neurotoxicity in animal models ....................... 28 1.6.2.2. Possible mechanisms of methamphetamine-induced neurotoxicity in animal models ........... 30 1.6.2.3. Methamphetamine-induced neurotoxicity in humans: Post-mortem studies.......................... 33 1.6.3. Dopaminergic transmission and glucose metabolism changes in methamphetamine abusers using positron emission tomography imaging ................................................................. 33 1.6.3.1. Positron emission tomography studies of postsynaptic dopamine receptors in methamphetamine abusers ....................................................................................................................... 39 1.6.3.2. Positron emission tomography studies of brain glucose metabolism in methamphetamine abusers 41 1.6.3.3. Positron emission tomography studies of presynaptic monoamine nerve terminals in methamphetamine abusers ....................................................................................................................... 44 1.6.4. Functional and cognitive deficits in methamphetamine abusers using functional magnetic resonance imaging ......................................................................................................... 47 1.6.4.1. Functional magnetic resonance imaging studies of decision-making and reward processing in methamphetamine abusers ....................................................................................................................... 51 1.6.4.1.1. Functional magnetic resonance imaging studies of decision-making in methamphetamine abusers 51 1.6.4.1.2. Functional magnetic resonance imaging studies of reward processing in methamphetamine abusers 53 1.6.4.2. Functional magnetic resonance imaging studies of cognitive control in methamphetamine abusers 55 1.6.5. Structural brain abnormalities in methamphetamine abusers using structural magnetic resonance imaging ........................................................................................................................ 59 1.6.5.1. Structural magnetic resonance imaging studies of grey matter changes in methamphetamine abusers 63 1.6.5.1.1. Structural magnetic resonance imaging studies of cortical grey matter changes in methamphetamine abusers 63 1.6.5.1.2. Structural magnetic resonance imaging studies of subcortical grey matter changes in methamphetamine abusers .................................................................................................................................... 66 1.6.5.2. Structural magnetic resonance imaging studies of white matter changes in methamphetamine abusers 66 1.6.6. Summary of findings ..................................................................................................... 67 Acknowledgements ....................................................................................................................... 68 Conflict of Interest ........................................................................................................................ 69 ix