How is Sex Related to Autism? Meng-Chuan Lai Girton College University of Cambridge This dissertation is submitted for the degree of Doctor of Philosophy August 2011 Preface The works in this dissertation were carried out at the Autism Research Centre, Department of Psychiatry, University of Cambridge between October 2008 and August 2011, and was supported by funding from the Ministry of Education, Taiwan. Professor Simon Baron-Cohen acted as my primary supervisor and Professor John Suckling acted as co-supervisor. The dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration, except that the recruitment and testing of the male participants were carried out between July 2007 and November 2008 by the Medical Research Council Autism Imaging Multicentre Study (MRC AIMS) Consortium project. This dissertation is less than 60,000 words. Chapter 2 and parts of Chapter 1 are published in: Meng-Chuan Lai, Michael V. Lombardo, Greg Pasco, Amber N. V. Ruigrok, Sally J. Wheelwright, Susan A. Sadek, Bhismadev Chakrabarti, MRC AIMS Consortium and Simon Baron-Cohen. (2011). A behavioral comparison of male and female adults with high functioning autism spectrum conditions. PLoS ONE 6(6):e20835. Chapter 6 Study 1 is published in: Meng-Chuan Lai, Michael V. Lombardo, Bhismadev Chakrabarti, Susan A. Sadek, Greg Pasco, Sally J. Wheelwright, Edward T. Bullmore, Simon Baron-Cohen, MRC AIMS Consortium and John Suckling. (2010). A shift to randomness of brain oscillations in people with autism. Biological Psychiatry 68(12):1092-1099. i Chapter 3 is currently in preparation for publication as: Meng-Chuan Lai, Michael V. Lombardo, Amber N. V. Ruigrok, Bhismadev Chakrabarti, Sally J. Wheelwright, MRC AIMS Consortium and Simon Baron-Cohen. (in preparation). Sex-general and sex-specific cognition in adults with high-functioning autism spectrum conditions. Chapters 4 and 5 are currently in preparation for publication as: Meng-Chuan Lai, Michael V. Lombardo, Amber N. V. Ruigrok, Bhismadev Chakrabarti, John Suckling, Edward T. Bullmore, MRC AIMS Consortium and Simon Baron-Cohen. (in preparation). Do women with autism have an „extreme male brain‟? Chapter 6 Study 2 is in preparation for publication as: Meng-Chuan Lai, Michael V. Lombardo, Bhismadev Chakrabarti, Amber N. V. Ruigrok, Edward T. Bullmore, Simon Baron-Cohen, MRC AIMS Consortium and John Suckling. (in preparation). Differential complexity of resting brain oscillations between sexes and in autism spectrum conditions. ii Acknowledgements I am extremely grateful for my supervisors who contributed so much to my maturation as a scientist. Professor Simon Baron-Cohen, he himself being the main reason why I chose to pursue my PhD at Cambridge, has always been extraordinarily supportive, generous, trustful and patient, meanwhile enlightening and inspirational in nurturing my academic development. His wisdom, vision and elegant viewpoints in psychology, autism research and cognitive neuroscience have always been the most helpful guidance for me as a freshman to the research field. With Simon‟s tremendous supports I find the doctoral study very rewarding and enjoyable. Simon will always be my role model – the best mentor one can ever imagine. Professor John Suckling guided me to study neuroimaging and complex science from scratch, and helped me get over my (irrational) worries in learning in this completely new field at the beginning of my study. John is always constructively critical and at the same time extremely supportive and helpful. Not a single meeting with him do I not feel enlightened and empowered. I always come out of his office full of joy and courage, „charged‟ by his creativity, optimism and sharp viewpoints. John teaches me how to do science wholeheartedly but constantly keep a clear „metacognition‟. I believe I will benefit from this for life. I would also like to thank my advisors who have provided immense supports and guidance. I cannot be luckier to work with Michael Lombardo so closely throughout the whole PhD. Mike is always promptly responsive, extremely helpful, inspirational and supportive. He taught me everything an imager should know from scratch, guided me through the most basic (but boring for an experienced person!) bits of iii programming, and reviewed and commented on my very first immature drafts of each single manuscript I wrote. The most important thing I learned from him, probably owing to his „American spirit‟, is not hesitate to try and learn new things and face novel challenges. I used to think too much but do too little – Mike showed me how to achieve a balance in between. Without Mike I would not have the opportunity to learn the interesting themes in social neuroscience, and the various imaging methodologies that I have applied. I wholeheartedly thank him for all his supports. I am also very fortunate in having Bhismadev Chakrabarti enlightening me for nearly every aspect in autism research, from genetics to behaviour. Bhisma is a renaissance man. I benefit so much from his invariably insightful comments based on his deep and broad, focused but integrative knowledge across genetics, biology, statistics, imaging, affective and social neuroscience. Bhisma set the standard for me of what a „Doctor of Philosophy‟ should be like. Lastly, I am so honoured to have Professor Ed Bullmore advising me in learning complex science and graph theoretical network analysis. Ed has the amazingly clear mind and sharp eyes to see both the nuance within a study and how it is significant to the whole field. His advices and critiques always bring me up to a higher level to examine the works, which I think is the most precious experience one can ever have on working with such a great figure like him. I am also very grateful for my examiners Professor Digby Tantam, Drs. Graham Murray and Howard Ring for their insightful critiques and suggestions to my research and this dissertation. My major project for the dissertation, the Female Autism Imaging Multicentre Study (Female AIMS), is not attainable without the great helps from co-researchers. I am most grateful to Amber Ruigrok for her extraordinary contributions in realising all projects, all the way from preparation, recruitment, testing to data organisation. It is a iv great pleasure to work together with Amber. I would also like to express my gratitude to Renate van de Ven, Elisa Scheller and Mohammad Lone for their significant contributions in helping out the relevant projects. Most importantly, I sincerely appreciate the enthusiastic and generous volunteering and offering to help of all our participants. It is their contributions that push me (and the field) forward. My sincere gratitude also goes to several senior colleagues at the Autism Research Centre (ARC) who have helped me through a variety of challenges during the past years. Bonnie Auyeung‟s always warm and genuine concerns are great supports to me in the long journey pursuing my degree. I especially thank her for the prompt helps in commenting on some of my chapters. Sally Wheelwright‟s sharp discussions and critical eyes to science are still influential to me up to now even though she has left the lab. I miss her bright and straightforward characteristics very much. Greg Pasco‟s generous and warm supports to the research project cannot be overemphasised. I especially miss his fantastic British humour! Carrie Allison‟s careful looking after the ethical aspects of the project and the great helps in data cleaning and organisation are pivotal to the smooth completion of the projects. Rosa Hoekstra is my best consultant in statistics and has provided many wonderful suggestions. Liliana Ruta‟s passion in science and rich clinical experiences have substantially inspired me, and yes, we will certainly gather together sometime in the „academic house‟ at Taormina! I would also like to thank Teresa Tavassoli for her constant „unconditional positive regards‟ and supports to all aspects of my research. I am so grateful for all lab mates in the lovely ARC, who nurtured my academic perspectives in the broad field of autism research. Thank you all Mike Spencer, Gina Gómez, Jill Sullivan, Jon Breidbord, Alexia Rattazzi, Kimberly Armstrong, Lindsay v Chura, Caroline Robertson, Ed Sucksmith, Susan Sadek, Rosie Holt, Sophia Sun, Chris and Emma Ashwin, Ofer Golan and Matthew Belmonte. Particular thank goes to Fiona Scott for training me on administering the ADI-R and ADOS and sharing her rich clinical experiences and perspectives. The administrative colleagues also have provided immense supports and assistances, both administratively and personally. I would like to express my sincere gratitude to all of you – Gaenor Moore, Paula Niami, Rachel Jackson, Jenny Hannah and Chloe Gayer-Anderson. The colleagues at the Brain Mapping Unit are my strong backup whenever I am in trouble with trivial but crucial issues in neuroimaging – thank you Cinly Ooi, Anna Barnes and Julian Henty. I particularly want to thank a group of colleagues who have led me into the excitingly interesting field of complex network science and have guided me all the way from the very basics: Dani Bassett, Alex Fornito, David Meunier, Andrew Zalesky, Petra Vertes and Aaron Alexander-Bloch. My PhD is established on the achievements of the (male) MRC AIMS project. I am very grateful for the MRC, the consortium and all the researchers from London, Oxford and Cambridge sites that provide me with the resources and the invaluable data to build on and to establish my own projects. Particular appreciation goes to Christine Ecker and Professor Declan Murphy for their generous supports. I would also like to thank Michael Craig, Flavio Dell' Acqua and Marco Catani for their kind assistance in the Female AIMS project. I am also very grateful for the generous funding from the Ministry of Education, Taiwan, in supporting my whole doctoral study. I would also like to thank the miscellaneous funds that I have received for conference travel (INSAR, Cultural Division Taipei Representative Office in the UK, Girton College and Cambridge Philosophical Society).