Rehabilitation of Executive Dysfunction in Multiple Sclerosis: Cognitive, Behavioural and Neurophysiological Effects of Goal Management Training by Nadine Marie Richard A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Psychology University of Toronto © Copyright by Nadine Marie Richard 2013 Rehabilitation of Executive Dysfunction in Multiple Sclerosis: Cognitive, Behavioural and Neurophysiological Effects of Goal Management Training Nadine Marie Richard Doctor of Philosophy Department of Psychology University of Toronto 2013 Abstract Multiple sclerosis (MS) is a chronic, progressive central nervous system disease characterized by distributed white matter injury. Particularly prevalent in Canada, MS is a leading cause of disability with extended personal and societal costs given its early onset (on average between 20- 40 years of age). Deficits in executive functioning are common and detrimental to employment, daily functioning and quality of life, however their precise nature remains underspecified. Two studies were undertaken to: (1) describe the executive processes affected in MS, including neurophysiological correlates, and (2) explore, in a double-blind randomized controlled trial, patients’ response to an intervention for improving behavioural self-regulation. Study 1 described significant functional limitations and impairments in processing speed and executive control of attention, memory and working memory in MS patients, both relative to neurologically healthy controls and as a monotonic function of disease severity. Mean amplitudes for event- related potentials (ERPs) including the P3 and the error-related negativity and positivity (ERN, Pe) were linked to behavioural markers of attention control and performance monitoring. ERP amplitudes and ERP-behavioural associations appeared sensitive to the presence and severity of executive dysfunction related to disease progression. In Study 2, these impaired MS patients ii were randomly assigned to a modified version of Goal Management Training (GMT) or a psycho-educational control group (Brain Health Workshop, BHW). In GMT, patients learned stepwise strategies ("Stop-State-Split") to keep "on track" in their daily activities, including mindfulness training to enhance attentional awareness and control. Rehabilitation outcomes were assessed post-training and at a 6-month follow-up using a multi-level battery. Compared to BHW, GMT was associated with greater improvement on tests of executive-attentional processes as well as functional task performance and observable functioning in daily life activities. ERP- behavioural changes provided corollary evidence of improved self-regulatory processing. This study is among the first to demonstrate improvement in executive functioning compared to an active control condition in MS patients with a range of disease severity and with effects remaining visible at six months. While replication in a larger sample size is needed, results suggest GMT as a potentially effective approach for executive and self-regulatory impairment in people with MS. iii Acknowledgments So many people contributed to this endeavor – either directly or, just as importantly, in keeping me passably sane all these years – that it will be impossible to thank them all. The obvious place to start is with Brian Levine… for showing me how to navigate in a field at once full of promise and pitfalls. I hope to keep that bar up where you set it. I also thank Randy McIntosh for helping me keep my stats up to snuff, and Gus Craik for the wisdom of his experience. I humbly appreciate the value of having had such a triumvirate for my supervisory committee. Our clinical collaborators on this project were numerous and illustrious; I especially thank Jon Ween, Pearl Gryfe, Colleen Ross, Liesly Lee, Kathleen Carr, Paul O’Connor and Anthony Feinstein for their contributions and feedback at various stages along the way. If Brian manned the wheel while I learned the ropes, everyone knows it’s the RAs who keep it all afloat. Without the Levine Lab K(h)u crew on deck – Wayne Khuu, Priya Kumar and, in it’s fledgling stage, Namita Kumar – this project would never have left the dock. (There. Now I’ve managed to work my Maritime heritage into my dissertation and it’s out of my system.) My deepest gratitude to you all. You made the journey not only possible, but fun. Thanks also to my labmates, past and present. Gary, Eva and Margaret, for your mentorship in my early days and then for showing me what I might hope to achieve when I grow up. Charlene and Daniela, for your advice and camaraderie. It’s been a pleasure and honour knowing you all. I can’t thank enough my family and friends for all their patience and support. A special thank you to Alex, for helping me through the tough bits and celebrating my little triumphs. I dedicate this work to my mum. We both wished you could have lived to see me cross this finish line, though you left me with your faith I would get here eventually. I literally couldn’t have done it without you and Dad. Your unwavering persistence all those years ago in finding a school that would “take” me… with Dad’s commitment to carrying me, every day until they made it wheelchair-accessible, up and down the stairs of that little primary school… that was really where this whole road started. I am eternally grateful and proud to have been your daughter. iv Table of Contents Acknowledgments .......................................................................................................................... iv Table of Contents ............................................................................................................................ v List of Abbreviations ................................................................................................................... viii List of Tables .................................................................................................................................. x List of Figures ............................................................................................................................... xii List of Appendices ........................................................................................................................ xv Chapter 1 Introduction .................................................................................................................... 1 1.1 Executive control, goal-directed behaviour and supervisory attention ............................... 2 1.1.1 Functional significance of executive processes ...................................................... 5 1.1.2 Neuropsychological assessment .............................................................................. 5 1.1.3 Neural correlates ..................................................................................................... 9 1.2 Mindfulness ....................................................................................................................... 17 1.3 Distributed brain injury ..................................................................................................... 22 1.4 Multiple sclerosis .............................................................................................................. 23 1.4.1 Aetiology and pathology of MS ............................................................................ 23 1.4.2 Cognitive impairment in MS ................................................................................ 28 1.5 Cognitive rehabilitation .................................................................................................... 33 1.5.1 Rehabilitation of executive and attentional functions ........................................... 34 1.5.2 Research in MS ..................................................................................................... 35 1.5.3 Goal Management Training .................................................................................. 39 Chapter 2 Rationale and Hypotheses ............................................................................................ 45 2.1 Combined neurophysiological and behavioural characterization of executive dysfunction in MS ............................................................................................................. 45 v 2.2 Rehabilitation of executive dysfunction in MS ................................................................ 47 Chapter 3 Methods ........................................................................................................................ 49 3.1 Participants ........................................................................................................................ 49 3.2 Materials ........................................................................................................................... 51 3.2.1 Neuropsychological measures: Cognitive, behavioural and functional ................ 51 3.2.2 Neurophysiological measures: Event-related potentials ....................................... 56 3.2.3 Rehabilitation programs ........................................................................................ 57 3.3 Data analysis ..................................................................................................................... 64 3.3.1 Neuropsychological measures .............................................................................. 64 3.3.2 Neurophysiological measures ..............................................................................