Examining the Cognitive Consequences of White Matter Tract Damage in Mild Traumatic Brain Injury Lucy Elisabeth Oehr ORCID: 0000-0002-3144-7580 July 2019 Melbourne School of Psychological Sciences The University of Melbourne This thesis was submitted in partial fulfillment of the requirements for Doctor of Philosophy/Master of Psychology (Clinical Neuropsychology) ABSTRACT Mild traumatic brain injury (mTBI) has been the subject of an enormous body of research spanning back to the 10th century Despite the sheer volume of studies in this area, mTBI is still poorly understood, particularly in terms of cognitive consequences and injury to white matter tracts in the brain The research project central to this thesis employed innovative and novel cognitive and diffusion weighted-imaging (DWI) techniques The overarching aim of this project was to provide a more sensitive and specific examination of cognition and white matter tract damage following mTBI, than currently exists in the literature The thesis also aimed to examine the relationship between cognition and white matter tract damage following mTBI A Systematic Review and Meta-Analysis (Chapter 5) was conducted to examine the current understanding of this relationship; the findings revealed that this area has received relatively little attention within the broader body of mTBI research The study central to this thesis included a sample of patients with mTBI and a matched trauma control (TC) group who were recruited from the largest tertiary referral trauma hospital in Australasia, The Alfred hospital (Melbourne, Victoria, Australia) Approximately 6-10 weeks post-injury, participants returned to the hospital to take part in a comprehensive examination involving a neuropsychological assessment, select questionnaire measures, and a magnetic resonance imaging (MRI) scan that included DWI sequences i Study One comprised findings of the neuropsychological assessment The assessment was comprehensive in scope and included conventional “paper-andpen” tests as well as two computer-based tasks designed to place greater load on cognitive systems The design of the neuropsychological assessment addressed key limitations of existing research, such as the use of brief cognitive screens or use of only a small number of cognitive measures The findings of Study One revealed that the mTBI and TC groups performed similarly on conventional neuropsychological assessment tools; however, novel computerised cognitive measures revealed impairments specifically in the mTBI group Study Two addressed key limitations of DWI-based research in mTBI, namely the predominant use of diffusion-tensor imaging (DTI) The data acquisition, processing, and tractography-based methods were designed to provide a more thorough and specific examination of white matter tract microstructure following mTBI By use of an additional DWI-based modelling technique, neurite orientation dispersion and density imaging (NODDI), Study Two revealed more specific information about white matter tract microstructural changes relative to existing DTIbased research Within white matter tracts commonly implicated in mTBI, the combined use of DTI and NODDI revealed alterations to quantitative DWI metrics suggestive of axonal injury and degeneration The third study included in this thesis built upon the findings of the Systematic Review and Meta-Analysis and examined the relationship between white matter tract microstructure and cognition in both the mTBI and TC groups Study Three revealed distinct associations between cognitive and DWI quantitative measures ii within the two groups For the TC group, higher cognitive performance was associated with DWI metrics suggestive of greater diffusion of water molecules along fibre bundles, as well as greater density and coherence of white matter tracts These associations were consistent with expectations based on existing research within healthy adult populations In contrast, within the mTBI group, no associations were observed with measures of speed of information processing or attention While there were a small number of significant associations in the mTBI group between DWI metrics and performance on measures of memory and executive function, the relationships were in the opposite direction to those observed in the TC group That is, higher cognitive performance was associated with reduced diffusion of water molecules along fibre bundles, and both lower density and coherence of fibres within white matter tracts These associations were consistent across white matter tracts examined and cognitive domains Collectively, the studies included in this thesis make a significant contribution to the mTBI research literature While no marked impairment was found on conventional neuropsychological tests, changes to white matter tract microstructure were apparent 6-10 weeks following mTBI on measures of cognition that are sensitive to mTBI-related neuropathological change Use of NODDI in conjunction with DTI revealed more specific information about underlying white matter microstructural changes following mTBI, relative to existing research Furthermore, the discrepancy in findings between the mTBI and TC groups indicates that there is an abnormal relationship between white matter microstructure and cognitive function 6-10 weeks following mTBI iii DECLARATION This is to certify that: - this these comprises only my original work in partial fulfilment of the Master of Psychology/Doctor of Philosophy (Clinical Neuropsychology) except where indicated in the preface; - due acknowledgement has been made in the text to all other material used; - thesis is fewer than the maximum word limit in length, exclusive of tables, maps, bibliographies and appendices Lucy Oehr iv PREFACE The results presented in this thesis represent a sub-sample of a broader research project led by Dr Jacqueline Anderson and based at The Alfred hospital, Melbourne, Victoria, Australia Graduate student researchers enrolled in the Master of Psychology (Clinical Neuropsychology) degree between 2014 and 2019 were involved with recruitment and data collection The neuroimaging component of the study commenced in 2017 and was conducted in collaboration with the Baker IDI Heart and Diabetes Institute, The Alfred Centre, Melbourne, Victoria, Australia MRI technicians at the Baker IDI Heart and Diabetes Institute assisted with neuroimaging data collection Dr Marc Seal (Murdoch Children’s Research Institute) and Dr Benjamin Schmitt (Siemens) both contributed to the development of the MRI scanner protocol Finally, the Developmental Imaging lab of the Murdoch Children’s Research Institute assisted with development of the neuroimaging data preprocessing pipeline for this study All data included in this thesis—including both cognitive and neuroimaging data—were prepared and processed by me and represent my own original work Statistical analyses were planned and results interpreted in consultation with my supervisors and Dr Sandy Clarke from the Melbourne Statistical Consulting Platform, The University of Melbourne No included work this thesis was carried out prior to enrolment in this current degree No third-party editorial assistance was provided in preparation of this thesis v The included manuscript presented in this thesis was drafted entirely by me The co-author, Dr Jacqueline Anderson, contributed to the initial planning and conception of the manuscript, and was involved with revising and editing drafts She has agreed to use of the manuscript in this thesis and has provided a signed copy of the co-author authorisation form Finally, I would like to acknowledge funding received including an Australian Government Research Training Program Scholarship, including fee offset scholarship, and the Melbourne Neuroscience Institute STRAPA Award vi Publications and Conference Abstracts During Candidature Oehr, L., & Anderson, J (2017) Diffusion-Tensor Imaging Findings and Cognitive Function Following Hospitalized Mixed-Mechanism Mild Traumatic Brain Injury: A Systematic Review and Meta-Analysis Archives of physical medicine and rehabilitation, 98(11), 2308-2319 Oehr, L.E., Yang, J Y M., Chen, J., Seal, M L., & Anderson, J F I (2018, July) Quantifying the impact of mild traumatic brain injury on the relationship between white matter tract damage and cognitive function Platform presentation at the International Neuropsychological Society 2018 Mid-Year Meeting, Prague, Czech Republic Oehr, L & Anderson, J (2017, June) Is structural neuropathology associated with cognitive functioning following mild traumatic brain injury? Poster session presented at the 40th ASSBI Brain Impairment Conference, Melbourne, Australia Manuscripts to Arise from this Thesis Currently in Preparation Oehr, L., & Anderson, J Are conventional neuropsychological tests sufficiently sensitive to detect subtle cognitive changes following mild traumatic brain injury? A comparison of conventional and novel measures vii Oehr, L., Yang, J., Chen, J., Maller, J., Seal, M., & Anderson, J Moving beyond DTI: an investigation of sophisticated diffusion-weighted imaging techniques in the study of white matter tract microstructural changes following mild traumatic brain injury Oehr, L., Seal, M., Chen, J., Maller, J., Yang, J., & Anderson, J Investigating the cognitive consequences of white matter tract microstructural changes two-months following mild traumatic brain injury Awards Australian Government Research Training Program Scholarship (2016–2018) Melbourne Neuroscience Institute STRAPA Award (2016–2018) viii ACKNOWLEDGEMENTS First and foremost, I would like to thank my primary supervisor, Dr Jacqueline Anderson for your consultation, advice, and guidance throughout my candidature I am also very grateful for your wise and honest council which both prompted me to decide to commence my PhD, and to persevere despite the many challenges that I faced along the way During the course of my candidature, I was privileged to work with J in three different roles; you’ve taught me so much beyond this research and been a very important mentor to me I look forward to working with you on future projects I would like to thank my co-supervisor, Dr Marc Seal, for making the neuroimaging component of this project possible and for welcoming me to the Developmental Imaging lab Not only did you provide unwavering support throughout the thorny process of learning to master the art of diffusion MRI data processing, but you did so with great patience, and you were well attuned to my well-being I am grateful for your wit (and vast supply of gifs) and of course your wise academic council, prompting me to consider the broader issues posed by my research and the question of what it all means To Dr Joseph Yang, my external supervisor, I would like to thank you firstly for introducing me to the truly amazing potential of DWI and its applications beyond mTBI research I would also like to extend my sincere gratitude for the many hours you spent helping me learn the techniques of processing diffusion MRI data and ix Figure C Scatterplots depicting significant associations between ADC of white matter tracts and Memory index scores, split by group 428 Figure C Scatterplots depicting significant associations between ADC of white matter tracts and Memory index scores, split by group 429 Figure C Scatterplots depicting significant associations between ICVF of white matter tracts and Memory index scores, split by group 430 Figure C Scatterplots depicting significant associations between ICVF of white matter tracts and Memory index scores, split by group 431 Executive function index Figure C Scatterplots depicting significant associations between FA of white matter tracts and Executive function index scores, split by group 432 Figure C Scatterplots depicting significant associations between FA of white matter tracts and Executive function index scores, split by group 433 Figure C Scatterplots depicting significant associations between ADC of white matter tracts and Executive function index scores, split by group Figure C 10 Scatterplots depicting significant association between ODI of white matter tracts and Executive function index scores, split by group 434 Figure C 11 Scatterplots depicting significant associations between ICVF of white matter tracts and Executive function index scores, split by group 435 Figure C 12 Scatterplots depicting significant associations between ICVF of white matter tracts and Executive function index scores, split by group 436 Increasing Distractors Paradigm (IDP) task Figure C 13 Scatterplots depicting significant associations between FA of white matter tracts and Level IDP task performance, split by group 437 Figure C 142 Scatterplots depicting significant associations between ADC of white matter tracts and Level IDP task performance, split by group Figure C 153 Scatterplots depicting significant associations between ODI of white matter tracts and Level IDP task performance, split by group 438 Figure C 164 Scatterplots depicting significant associations between ICVF of white matter tracts and Level IDP task performance, split by group 439 Figure C 17 Scatterplots depicting significant associations between FA of white matter tracts and Level IDP task performance, split by group Figure C 186 Scatterplots depicting significant associations between ICVF of white matter tracts and Level IDP task performance, split by group 440 n-back task Figure C 197 Scatterplots depicting significant associations between FA of white matter tracts and 1-back level performance, split by group Figure C 208 Scatterplots depicting significant associations between ODI of white matter tracts and 1-back level performance, split by group 441 Minerva Access is the Institutional Repository of The University of Melbourne Author/s: Oehr, Lucy Elisabeth Title: Examining the cognitive consequences of white matter tract damage in mild traumatic brain injury Date: 2019 Persistent Link: http://hdl.handle.net/11343/233595 File Description: Final thesis file Terms and Conditions: Terms and Conditions: Copyright in works deposited in Minerva Access is retained by the copyright owner The work may not be altered without permission from the copyright owner Readers may only download, print and save electronic copies of whole works for their own personal non-commercial use Any use that exceeds these limits requires permission from the copyright owner Attribution is essential when quoting or paraphrasing from these works ... provided by the Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine (ACRM; Kay et al., 1993) These... characteristics of the long-coursing white matter tracts pertinent to this thesis Defining mTBI: Diagnosis and Clinical Identification MTBI is the most prevalent type of traumatic brain injury (TBI),... Anderson, J Investigating the cognitive consequences of white matter tract microstructural changes two-months following mild traumatic brain injury Awards Australian Government Research Training Program