Salience and Motivated Behaviour in Schizophrenia By Suzanne Rosalie Neumann A thesis submitted for the degree of Doctor of Philosophy At the University of Otago, Dunedin, New Zealand April 2019 Page ii Page iii Abstract Schizophrenia is a long-term psychotic disorder that affects approximately 1% of the population worldwide. Schizophrenia is characterised by negative symptoms, such as anhedonia and social withdrawal, and positive symptoms, such as hallucinations and delusions. The impact of schizophrenia reaches beyond the impaired social and cognitive function of the individual, affecting families and wider communities. Therefore, despite its low prevalence, there is a long history of multidisciplinary research investigating the causes of schizophrenia. The effect of antipsychotics in reducing the intensity of symptoms, through their antagonistic effect on dopamine, has led to dopaminergic based theories of schizophrenia. One such theory is based on aberrant salience, the assignment of importance to stimuli that have no intrinsic or learned value or salience. The aberrant salience hypothesis links hyperdopaminergic activation to symptoms of schizophrenia through the intermediary effect of motivational salience. Specifically, it is proposed that hyperdopaminergic activation in schizophrenia creates an aberrant motivational association with a stimulus, leading to cognitive explanations for the unexplained importance that contribute to the development of symptoms. Behavioural and neural evidence supports heightened aberrant salience in schizophrenia, although specific measures of aberrant salience have yielded inconsistent results. There is also a large body of evidence suggesting cognitive functions anchored in dopaminergic activation, such as reward processing and motivated behaviour, are impaired in schizophrenia. To date, however, the assumption that motivational salience mediates the relationship between hyperdopaminergic activation and aberrant salience has not been tested. The current project sought to elucidate the relationship between aberrant salience and motivational salience. The convergent validity among measures of aberrant salience (Salience Attribution Task and Aberrant Salience Inventory) and motivated behaviour (Effort Expenditure for Rewards Task and Stimulus Chase Task) were investigated in undergraduates. To assess whether aberrant salience, and the underlying relationship with motivational salience, is Page iv unique to schizophrenia, the same measures were completed by individuals diagnosed with schizophrenia, experiencing symptoms of anxiety, or unaffected by mental health. Whereas schizophrenia was associated with heightened aberrant salience, the aberrant salience indices lacked specificity, sensitivity, and convergent validity. Furthermore, whereas schizophrenia was associated with maladaptive motivated behaviour, there was limited evidence supporting a relationship between measures of aberrant salience and motivational salience. The failure to find evidence of such a relationship may be due to issues with the aberrant salience measures or the underlying assumption that motivational salience mediates aberrant salience. Further research is needed to develop measures of aberrant salience that are anchored to known neural systems underlying salience processing. Page v Acknowledgements 1. Foremost, I would like to thank my supervisors for their wisdom and patience. Richard, thank you for challenging and encouraging me, for helping me become a better writer. I shall forever associate you with the oxford comma. Your legendary transformations during fancy dress competitions will also not be forgotten. Neil, thank you for maintaining humour and teaching me to take a breath, step back to look at the wider picture, while simultaneously focusing on the detail, and to write shorter sentences! Thank you also for hosting wonderful lab dinners and for always getting the first- round in. Paul, thank you for your guidance on recruiting and opening doors for my future career development. And David, thank you for your friendly words of support. 2. I am so very fortunate to have the most amazing family, who made my PhD journey possible. Mum and Dad, thank you for your strength, love, and unwavering support. Thank you so much for the homegrown, home cooked meals, the words of wisdom and encouragement, the beach sessions, and the chats. I am blessed to have you as my parents. Richard, Rachel, and Nicholas, thank you for sending me off to follow my goals, for getting on with your lives, facing your challenges, and overcoming them. I am so very proud of you and grateful to call such amazing humans my children. Thank you also to my wider family, especially Aunty Pam and Aunty Carolyn, for always being there. 3. To my friends, from both sides of the world, thank you for being amazing, for not giving up on me, and for enduring the PhD process. Joanna, for our nights of thesis engagement and abandonment, for always listening and encouraging. Jayde, for simply being amazing and always knowing what to say. Jammy, my post-graduate buddy, thank you for propping me up, for threatening to send me inspirational memes (ironically) until I believed in myself. Ollie, thank you for helping me let my hair down when in Brighton then promptly sending me back to NZ, even when I wanted to stay. Emma, Nicky, and Lucas, thank you for believing in me, listening to me complain, Page vi then telling me to get on with it. And to Fudge, my loyal dog, for getting me out on daily walks during write up, for being my constant companion. There are many more - Rebecca, Joey, Elena, Niall, Mica, Josh, Sarah, and Mark - you all supported me in different ways and I'm grateful for each of you. 4. I also need to thank the University staff who supported and encouraged me over the years. Jackie and Ted, thank you for the informal chats, sound advice, and the occasional crosswords. Tim Jowett, thank you for your assistance in navigating the depths of mixed effects modelling in R! Michelle, thank you for always making time and being a great support through difficult personal times. Anne, thank you for helping me to become a better teacher. Thank you also to my lab-mates. To the S Lab, for creating a supportive, encouraging environment. The McNaughton Lab, thank you all for sharing your space, for giving me a second home during statistical analysis, and for making Friday pub nights a wonderful mix of knowledge sharing, debate, and camaraderie. Page vii Table of Contents Abstract iii Acknowledgements ........................................................................................................................ v List of Abbreviations ..................................................................................................................... xi 1 Chapter One Introduction ............................................................................................... 13 1.1 Background ............................................................................................................................ 13 1.1.1 Schizophrenia ........................................................................................................................ 13 1.1.2 Aberrant Salience .................................................................................................................. 15 1.1.3 Motivational Salience ............................................................................................................ 16 1.1.4 The Missing Link .................................................................................................................... 16 1.2 Research aims ........................................................................................................................ 16 1.3 Thesis Outline ........................................................................................................................ 17 2 Chapter Two Is Aberrant Salience the Core of Schizophrenia? ......................................... 21 2.1 Dopamine and Aberrant Salience .......................................................................................... 21 2.1.1 Dopamine and salience ......................................................................................................... 21 2.1.2 Dopamine and aberrant salience .......................................................................................... 22 2.2 Evidence supporting Aberrant Salience in Schizophrenia ..................................................... 23 2.2.1 Aberrant attentional processing in individuals at risk of schizophrenia ................................ 23 2.2.2 Increased aberrant salience and reduced adaptive salience in schizophrenia ...................... 24 2.2.3 Summary ................................................................................................................................ 26 2.3 Neural Functions and Networks that Contribute to Aberrant Salience ................................. 27 2.3.1 Sensory gating ....................................................................................................................... 27 2.3.2 Salience Network ................................................................................................................... 28 2.3.3 Default Mode Network .......................................................................................................... 30 2.3.4 The potential contribution of the salience and default mode networks to aberrant salience ..............................................................................................................................................