THE UNIVERSITY OF MELBOURNE TREMOR IN MULTIPLE SCLEROSIS Neuroimaging perspective by Frederique Maria Christina Boonstra ORCID: 0000-0002-5861-4174 October 2019 A thesis presented to the University of Melbourne in fulfilment of the degree of Doctor in Philosophy in Medicine, Health and Dentistry Science Abstract Multiple sclerosis (MS) is a common autoimmune disorder of the central nervous system (CNS), characterised by inflammation, demyelination and neurodegeneration. The clinical presentation and disease course of MS is heterogeneous, which reflects the multifocal nature of damage within the CNS. Almost half of the MS population experiences a tremor in the later stages of the disease. Tremor significantly increases disease severity and worsens patients’ quality of life. Current understanding of tremor pathophysiology in MS is incomplete and mostly based on treatment studies, clinical observation studies, or neuroimaging studies of parkinsonian tremor and essential tremor. Focused imaging assessments of defined neural pathways associated with tremor can help improve our understanding of complex pathophysiology of MS tremor. This could benefit the current lack of effective, noninvasive and long-term treatment options for tremor. This thesis provides a comprehensive examination of the pathophysiology of tremor in MS. The first experimental chapter confirms the hypothesis that the cerebello-thalamo-cortical tract is involved in tremor pathophysiology. Specifically, the pilots study finds a positive correlation between thalamic and superior cerebellar peduncle atrophy and tremor severity. In the second experimental chapter, we aimed to develop a functional imaging task that will allow in vivo imaging of tremor pathology. We introduced a novel joystick task, which showed to elicit the MS-related tremor while playing the game. Furthermore, we showed good reproducibility, which is great for the longitudinal part of this thesis. In the third experimental chapter, we applied the joystick imaging task in a large sample of tremor and non-tremor MS patients. We supported that pathology along the cerebello-thalamo-cortical tract is instrumental in tremor pathology. Interestingly, we also found increased functional activation within sensorimotor integration and motor planning areas in MS tremor, which negatively correlated to tremor severity. In the final experimental chapter, we examined the central effects of onabotulinumtoxinA (BoNT-A) for the treatment of tremor in a randomized controlled trial. We found that patients that received BoNT-A had improved tremor and reduced activation within the sensorimotor integration regions. The change in tremor severity correlated with the change in activation, indicated that BoNT-A has a central effect as well as a local effect. i Collectively, these findings suggest that the clinical presentation of tremor in MS is influenced by a tremor network consisting of both structural and functional aspects. Specifically, atrophy and inflammation along the cerebello-thalamo-cortical tract is thought to be more causal to tremor. Contrarily, functional activation is thought to be compensatory to alleviate tremor severity. Intramuscular injection of BoNT-A reduced tremor severity and the activation within the sensorimotor integration area. The central effect of BoNT-A is thought to be due to the lower need for the compensatory functional activation. Together, both structural and functional aspects of the tremor network in MS need to be consider when trying to monitor tremor over time and to find effective treatments options. ii Declaration I, Frederique Maria Christina Boonstra, certify that: i. This thesis comprises only my original work towards the PhD. ii. Due acknowledgements have been made in the text to all other material used. iii. This thesis is less than 100,000 words in length, exclusive of tables, figures, and bibliographies. Frederique Maria Christina Boonstra iii Preface The author of this thesis has performed the extensive review of literature and research involved in all of the experimental chapters. Work was supervised by Dr Scott Kolbe and Dr Anneke van der Walt. The first experimental chapter is part of a randomized, double-blind clinical trial with a crossover design (clinical trial identifier: NCT01018485). Funding for this project was provided by the Box Hill MS Research Unit. All patient recruitment was complete before enrolment in the PhD, but all analyses, interpretation and writing has been done afterwards. Grace Florescu contributed to data analyses, interpretation and writing the manuscript. Dr Scott Kolbe and Dr Anneke van der Walt both contributed to interpretation and writing of the manuscript. Other co-authors provided general comments and/or helped with the project at large. The second, third and fourth experimental chapter are part of a large randomized controlled clinical trial studying the efficacy of onabotulinumtoxinA for MS-related tremor (ACTRN12617000379314). This project was funded by a National Health and Medical Research Council (NHMRC) Project Grant (1085461 CIA Van der Walt) and Fellowship (1135683 Vogel). The Bionics Institute receives Operational Infrastructure Support from the Victorian Government. This trial started in early 2015 before enrolment in the PhD program; however, all participants included in the presented work were recruited after enrolment. All other aspects of work towards this thesis have been completed after enrolment. Dr Anneke van der Walt is the principal investigator of the study and was of great importance in the participant recruitment, data collection, data interpretation and writing on the manuscripts. Dr Scott Kolbe has significantly contributed to data analyses, interpretation and editing of the manuscripts. Dr Andrew Evans has contributed to the study design, data interpretation and writing of the manuscripts. All other co-authors of respective manuscripts provided general comments and/or helped with the project at large. None of this work has been submitted for other qualifications. None of this work was carried out prior to this PhD. iv Publications, Presentations and Scholarships Published journal articles Motor speech signature of behavioral variant frontotemporal dementia: refining the phenotype. Vogel, A. P., Poole, M. L., Pemberton, H., Caverlé, M. W. J., Boonstra, F. M. C., Low, E., Darby, D., Brodtmann, A. Neurology (2017) Tremor in multiple sclerosis is associated with cerebello-thalamic pathology. Boonstra, F. M. C., Florescu, G., Evans, E. H., Steward, C., Mitchell, P., Desmond, P., Moffat, B. A., Butzkueven, H., Kolbe, S. C., Van der Walt, A. Journal of Neural Transmission (2017) Technologies for Advanced Gait and Balance Assessments in People with Multiple Sclerosis. Boonstra, F. M. C., Shanahan, C. J., Cofré Lizama, L. E., Strik, M., Moffat, B. A., Khan, F., Kilpatrick, T. J., Van der Walt, A., Galea, M. P., Kolbe, S. C. Frontiers in Neurology (2018) Novel Functional MRI Task for Studying the Neural Correlates of Upper Limb Tremor. Boonstra, F. M. C., Perera, T., Noffs, G., Marotta, C., Vogel, A. P., Evans, A. H., Butzkueven, H., Moffat, B. A., Van der Walt, A., Kolbe, S. C. Frontiers in Neurology (2018) Validation of a precision tremor measurement system for multiple sclerosis. Perera, T., Lee, W., Yohanandan, S. A. C., Nguyen, A., Cruse, B., Boonstra, F. M. C., Noffs, G., Vogel, A. P., Kolbe, S. C., Butzkueven, H., Evans, A. H., Van der Walt, A. Journal of Neuroscience Methods (2018) What speech can tell us: A systematic review of dysarthria characteristics in Multiple Sclerosis. Noffs, G., Perera, T., Kolbe, S. C., Shanahan, C. J., Boonstra, F. M. C., Evans, A. H., Butzkueven, H., Van der Walt, A., Vogel, A. P. Autoimmunity Reviews (2018) v Functional neuroplasticity in response to cerebello-thalamic injury underpins the clinical presentation of tremor in multiple sclerosis. Boonstra, F. M. C., Noffs, G., Perera, T., Jokubaitis, V. G., Vogel, A. P., Moffat, B. A., Butzkueven, H., Evans, A. H., Van der Walt, A., Kolbe, S. C. Multiple Sclerosis Journal (in press) Journal articles under review Reduced fMRI response in central sensory-motor integration areas following intramuscular onabotulinumtoxinA for tremor in multiple sclerosis. Boonstra, F. M. C., Evans, A. H., Noffs, G., Perera, T., Jokubaitis, V. G., Stankovic, J., Vogel, A. P., Moffat, B. A., Butzkueven, H., Kolbe, S. C., Van der Walt, A. Manuscript submitted for publication. Conference abstracts The thalamus as a neural correlate for tremor in MS. Florescu G., Boonstra F. M. C., Mitchell, P., Steward C., Kolbe, S. C., Van der Walt A. Australian and New-Zealand association of neurologists (2016) The cerebello-thalamic tract as a neural correlate for tremor in MS. Boonstra F. M. C., Florescu G., Kolbe S. C., Steward C., Evans A. H., Butzkueven H., Mitchell P., Van der Walt A. European conference of treatment and intervention in multiple sclerosis (ECTRIMS) (2016) Pathophysiology of MS tremor: an fMRI study. Boonstra, F. M. C., Noffs, G., Perera, T., Shanahan, C. J., Vogel, A. P., Evans, A. H., Butzkueven, H., Van der Walt, A., Kolbe, S. C. International Society for Magnetic Resonance in Medicine (2017), ECTRIMS (2017) & Multiple sclerosis research Australia (2017) Functional neuroplasticity in response to cerebello-thalamic injury underpins the clinical presentation of tremor in multiple sclerosis. Boonstra, F. M. C., Noffs, G., Perera, T., Jokubaitis, V. G., Vogel, A. P., Moffat, B. A., Butzkueven, H., Evans, A. H., Van der Walt, A., Kolbe, S. C. ECTRIMS