The effects of sitting on cerebrovascular and cognitive function Sophie Elizabeth Carter A thesis submitted in partial fulfilment of the requirements of Liverpool John Moores University for the degree of Doctor of Philosophy July 2018 Abstract Sedentary behaviour (SB) has emerged as a risk factor for cardiovascular morbidity and mortality, independent of physical activity (PA) levels. Despite associations between SB and cerebrovascular disease, little research has assessed the influence of SB on cerebrovascular function, comprising cerebral blood flow (CBF), cerebral autoregulation (CA) and cerebrovascular carbon dioxide reactivity (CVR). This is of upmost importance since the maintenance of cerebrovascular function appears critical for cognition, mood and the prevention of cerebrovascular diseases. Consequently, the overarching aims of this thesis were to explore the effects of sitting on cerebrovascular function, cognition and mood and to explore the effect of breaking up sitting on these parameters. Study one assessed whether objectively measured workplace sitting and PA were associated with cognition and mood. Results showed workplace sitting was negatively associated with calm mood state, but not cognition. Standing and stepping whilst at work were positively associated with aspects of cognition (working memory and attention) and mood (positive affect and calm and content mood states), indicating PA throughout the workday should be encouraged as it may have beneficial effects on mental wellbeing and cognitive performance. In contrast to guidelines advising increasing light-intensity PA in the workplace, only moderate-intensity PA at work was positively associated with working memory, possibly indicating this higher intensity of PA should be encouraged during work hours to positively influence cognitive performance in desk workers. Study two aimed to determine the acute effects of a prolonged sitting period on cerebrovascular function, cognition and mood in healthy desk workers. Uninterrupted sitting for six hours reduced CBF and impaired aspects of CA but had no effect on CVR. Decreases in positive affect, and the alert and content mood states were also observed, but these were not related to the concurrent changes in cerebrovascular function. There was no change in cognition following prolonged sitting. Results may have important implications for the long-term mental and physical health of individuals who are repeatedly exposed to periods of uninterrupted sitting. Study three assessed the acute effects of breaking up sitting time on cerebrovascular function in healthy desk workers using two different walking break strategies. The decrease in CBF and CA observed following four hours of uninterrupted sitting was prevented using frequent, short duration walking breaks rather than less frequent, longer duration walking breaks. Results further demonstrate that prolonged uninterrupted sitting impairs cerebrovascular function and suggest that the frequency of the breaks used to interrupt sitting is an important component to preserve aspects of function. In contrast, both i walking break strategies caused a larger increase in CVR compared to prolonged sitting. This indicates that, for this aspect of cerebrovascular function, any duration or frequency of PA may have acute benefits. Study four assessed whether using a computer-based prompting software designed to break up prolonged sitting at work altered cerebrovascular function, cognition and mood in healthy office workers. Following the intervention, workplace sitting was reduced and replaced predominantly by increased time spent standing. This reduction in sitting improved aspects of CA but had no influence on other measures of cerebrovascular function, cognition or mood. Results provide preliminary evidence that long-term reductions in SB may improve aspects of cerebrovascular function. Overall, the major findings of this thesis are that prolonged, uninterrupted sitting acutely impairs aspects of cerebrovascular function, however this can be prevented by breaking up sitting with short duration, regular walking breaks. Prolonged sitting also acutely impairs aspects of mood but not cognition. Taken together this thesis provides the first evidence that SB negatively effects cerebrovascular function and further research should explore whether this leads to heightened cerebrovascular disease risk. ii Acknowledgments Thank you to my supervisory team, Dr Nicola Hopkins, Prof Dick Thijssen, Dr Richard Draijer and Dr Louise Brown, and other academics who have helped me during this journey, offering valuable scientific advice and support. In particular Niki, I hope I’ve dealt with the mantle of being your first PhD student! Special thanks for significantly improving my presentation skills, I now at least pronounce my words and talk at a reasonably comprehendible speed! Thank you to Dr Scott Pedersen, the brains behind the Exertime software, which allowed me to attempt to practise what I preach during my thesis write up! I would also like to thank the often underappreciated technical staff within the department; Gemma and Dean, who have supported my research projects and provided an endless supply of blue roll when needed! Additionally, I am grateful to all the participants who volunteered to take part, some of which had to spend up to six hours listening to my small talk! The Squad To my fellow postgraduate students I have had the pleasure of sharing office 1.47 with over the last few years, thanks for the fun we have had both in and out of work, words cannot explain these moments but I’m sure a double thumbs up summarises it perfectly! In particular I owe so much thanks to my fellow ‘Team FMD’ members: Sophie ‘Holder’ and Joe ‘Maxwell’. Together you have had me crying with laughter and generally at my own expense! Maxwell; in between tequila, skiing and ultra duathlons, we have done some good scanning and sciencing together. However, not sure I bargained on becoming a PhD student, life coach and financial advisor! Holder; I could always guarantee you’d be ready to pick up on a ‘Carts Classic’! I Can’t Get No Sleep Craig, thanks for being with me and accepting my football team and my indecisiveness! If I ever needed someone to listen to my overthinking you’ve always been there and, of course, reminding me to get that all important sleep!! It’s been a busy 2018 finishing my PhD but it has been made much easier having someone who understands why I need to get up at 6 am to squeeze in a quick run before a day of testing, or why I need to spend my evenings and weekends analysing data. I am looking forward to us both becoming Doctors and being less tired together; maybe then I can keep awake for Match of the Day! The Only Way Is Essex I am extremely grateful to Dr Mark Rakobowchuk who first introduced me to the world of research whilst I was at the University of Essex and gave up his time to teach a quiet undergraduate student the principles of vascular ultrasound. Thank you for instilling confidence in my writing and scientific ability; my time working with you gave me the desire to pursue an academic career and take on a PhD, something I never believed I would be capable of. I would probably have settled for a life of gym inductions and setting up badminton courts otherwise! Coach Carters To my parents, thanks for their continuing support despite never really understanding what it is I am actually doing! To my sister, Alice/Twinny, for (unfortunately for her) knowing a bit more what I am doing and therefore having to be sympathetic to my moans about early morning testing and late evening data analyses messing up my running plans; alongside providing all sorts of other sisterly guidance! Finally, I would like to dedicate this thesis to my grandparents; they did not get to see either of their grandchildren begin their journeys at University and beyond, but I would like to think we have done them proud. iii Declaration I declare that the work contained within this thesis is entirely my own. Publications directly based on the work described in this thesis Carter, S. E., Draijer, R., Holder, S. M., Brown, L., Thijssen, D. H. J. and Hopkins, N. D. (2018). Regular walking breaks prevent the decline in cerebral blood flow associated with prolonged sitting. Journal of Applied Physiology, DOI: 10.1152/japplphysiol.00310.2018. Carter, S. E., Draijer, R., Holder, S. M., Brown, L., Thijssen, D. H. J. and Hopkins, N. D. (under review). Breaking up sitting with different frequencies and durations of physical activity: effects on femoral artery endothelial function. Journal of Science and Medicine in Sport. Carter, S. E., Draijer, R., Brown, L., Thijssen, D. H. J. and Hopkins, N. D. (under review). Acute effects of prolonged sitting on cerebrovascular function, cognition and mood. American Journal of Physiology-Heart and Circulatory Physiology. Other publications completed by the candidate during PhD tenure Carter, S., Hartman, Y., Holder, S., Thijssen, D. H. J. and Hopkins, N. D. (2017). Sedentary behavior and cardiovascular disease risk: mediating mechanisms. Exercise and Sport Sciences Reviews, 45;2:80-86. iv Thijssen, D. H. J., Carter, S. E. and Green, D. J. (2016). Arterial structure and function in vascular ageing: are you as old as your arteries? Journal of Physiology, 15;594(8):2275-84. Holder, S. M., Low, D. A., Graves, L. E. F., Carter, S. E., Brislane, Á. M. and Hopkins N. D. (in preparation). The effect of sedentary behaviour on cardiovascular biomarkers in active, healthy adults. Brislane, Á., Carter, S. E. Holder, S. M., Jones, H., Low, D. and Hopkins, N. D. (in preparation). How does age and menopausal status affect peripheral and cerebrovascular adaptations across the female lifespan? Roberts, K. A., Draijer, R., Thijssen, D. H, J., Hopkins, N. D., de Graaf, Y., Holder, S. M., Carter, S. E. and Low, D. A. (in preparation). Green tea attenuates the deleterious impact on peripheral vascular function associated with an unhealthy lifestyle. Oral communications Carter, S.