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Nadine Katrin Gut Phd Thesis MODELLING THE EFFECTS OF DEEP BRAIN STIMULATION IN THE PEDUNCULOPONTINE TEGMENTAL NUCLEUS IN PARKINSON'S DISEASE Nadine Katrin Gut A Thesis Submitted for the Degree of PhD at the University of St Andrews 2014 Full metadata for this item is available in Research@StAndrews:FullText at: http://research-repository.st-andrews.ac.uk/ Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/4893 This item is protected by original copyright Modelling the effects of deep brain stimulation in the pedunculopontine tegmental nucleus in Parkinson’s disease Nadine Katrin Gut This thesis is submitted in partial fulfilment for the degree of PhD at the University of St Andrews March 2014 1. Candidate’s declarations: I, Nadine Katrin Gut, hereby certify that this thesis, which is approximately 60000 words in length, has been written by me, that it is the record of work carried out by me and that it has not been submitted in any previous application for a higher degree. I was admitted as a research student in September 2009 and as a candidate for the degree of PhD in September 2009; the higher study for which this is a record was carried out in the University of St Andrews between 2009 and 2014. Date signature of candidate 2. Supervisor’s declaration: I hereby certify that the candidate has fulfilled the conditions of the Resolution and Regulations appropriate for the degree of Ph.D. in the University of St Andrews and that the candidate is qualified to submit this thesis in application for that degree. Date signature of supervisor 3. Permission for electronic publication: In submitting this thesis to the University of St Andrews we understand that we are giving permission for it to be made available for use in accordance with the regulations of the University Library for the time being in force, subject to any copyright vested in the work not being affected thereby. We also understand that the title and the abstract will be published, and that a copy of the work may be made and supplied to any bona fide library or research worker, that my thesis will be electronically accessible for personal or research use unless exempt by award of an embargo as requested below, and that the library has the right to migrate my thesis into new electronic forms as required to ensure continued access to the thesis. We have obtained any third-party copyright permissions that may be required in order to allow such access and migration, or have requested the appropriate embargo below. The following is an agreed request by candidate and supervisor regarding the electronic publication of this thesis: PRINTED and ELECTRONIC COPY (i) No embargo on print or electronic copy Date signature of candidate signature of supervisor Acknowledgements I would like to express my deepest gratitude to Professor Philip Winn for providing me with the best conditions a PhD student could wish for – to spark and nourish the passion for research and to develop as a scientist. Thank you for your encouragement and motivation by giving me responsibilities and trusting in my abilities. Thank you for contributing to my development as a focused and thorough researcher and always reminding me to ‘ask the question’. Thank you for continuously offering your support and providing opportunities to learn, gain new experiences and get to know the world of science. I also would like to thank Dr James Ainge for being my primary contact in St Andrews and for shortening the distance between Glasgow and St Andrews. I am very grateful to Duncan MacLaren and Morag Farquhar not only for teaching, guiding, supporting, and pushing me to become a rigorous and critical researcher but also for being good friends and supporting me in difficult times. I would like to acknowledge Dr David Wilson and Mary Latimer whose support was crucial in enabling a successful start in the lab in St Andrews. I also want to thank my patient and resilient undergraduate student helpers and the technicians in Strathclyde. I wish to dedicate this work to my Mum and my late Dad, who tirelessly gave all their support, understanding and patience and allowed me to follow my chosen path – wherever it took me – and to achieve my goals. I thank my brother for all his encouragement and simply for always being my big brother. I want to convey my thanks to Julia – one could not wish for a better way to go on such a journey than with a friend like you. Thank you for the lovely time. Finally, I am grateful for the financial support from the Medical Research Council, the School of Psychology and Neuroscience, University of St Andrews, and the Scottish Universities Life Sciences Alliance. ii Abstract Based on the belief that it is a locomotor control structure, the pedunculopontine tegmental nucleus (PPTg) has been considered a potential target for deep brain stimulation (DBS) for Parkinson’s disease (PD) patients with symptoms refractory to medication and/or stimulation of established target sites. To date, a number of patients have been implanted with PPTg electrodes with mostly disappointing results. Exact target site in PPTg, possible mechanisms of PPTg-DBS and likely potential benefits need to be systematically explored before consideration of further clinical application. The research described here approaches these questions by (i) investigating the role of the PPTg in gait per se; (ii) developing a refined model of PD that mimics the underlying pathophysiology by including partial loss of the PPTg itself; (iii) adapting a wireless device to let rats move freely while receiving DBS; and (iv) investigating the effect of DBS at different sites in the PPTg on gait and posture in the traditional and refined model of PD. Underlining the concern that understanding the PPTg as a locomotor control structure is inadequate, the experiments showed that neither partial nor complete lesions of PPTg caused gait deficits. The refined model showed hardly any differences compared to the standard one, but the effect of DBS in each was very different, highlighting the need to take degeneration in the PPTg into consideration when investigating it as a DBS target. The differential results of anterior and posterior PPTg-DBS show the critical importance of intra-PPTg DBS location: Anterior PPTg electrodes caused severe freezing and worsened gait while some gait parameters improved with stimulation of posterior PPTg. The results suggest mechanisms of PPTg-DBS beyond the proposed activation of over-inhibited PPTg neurons, including aggravation of already dysfunctional inhibitory input by anterior PPTg- DBS and activation of ascending projections from posterior PPTg to the forebrain. iii Contents Declarations i Acknowledgements ii Abstract iii Table of Contents v List of figures and tables xi List of abbreviations xiv iv Table of Contents Chapter 1 - General Introduction 1 1. Parkinson’s disease 2 1.1. Clinical features 2 1.2. Towards the understanding of the disease 6 1.2.1. Basal Ganglia circuitry 6 1.2.2. Underlying brain pathology of PD 15 1.3. Gait and freezing of gait 16 2. Pedunculopontine tegmental nucleus 20 2.1. PPTg involvement in PD 20 2.1.1. Change of firing activity 21 2.1.2. Loss of neurons 23 2.1.3. Relationship of PPTg degeneration to loss of dopamine neurons in SN 24 2.2. Interspecies differences 26 2.3. PPTg anatomy and physiology 26 2.3.1. Neurochemical diversity and heterogeneous structure of the PPTg 26 2.3.2. Connectivity of the PPTg 29 2.4. PPTg functions 33 2.4.1. Motor 33 2.4.2. Ascending reticular activation system and sleep 40 2.4.3. Reward perception and motivation 41 2.4.4. Attention 42 2.4.5. Learning 43 3. Treatment for PD 48 3.1. Medical treatment 48 3.2. Deep brain stimulation 49 3.3. Deep brain stimulation of the pedunculopontine tegmental nucleus 50 4. Parkinson’s disease models 56 4.1. 6-hydroxydopamine 56 4.2. Combination of dopamine depletion in SN and lesions of the PPTg 57 4.3. Deep brain stimulation of the PPTg in rodent models of Parkinson’s disease 58 5. Aims 59 v Chapter 2 - General Methods 61 1. Subjects 62 2. Surgical procedures 63 2.1. Anaesthesia 64 2.2. Bilateral PPTg lesions 64 2.3. Partial PPTg lesions 65 2.4. Bilateral DA depletions of the SNc (6-OHDA lesions) 65 2.5. Combination of DA depletions and partial bilateral PPTg lesions (Combined lesions) 67 2.6. Electrode implantation 67 3. Post surgery animal care 68 4. Behavioural procedures 69 4.1. Food restriction 69 4.2. CatWalk training and testing 69 4.3. CatWalk settings 70 4.4. Gait parameters 70 4.5. Freezing of Gait 71 4.6. Stimulation protocol (intensity setting, battery changes and regular checks) 72 4.7. L-DOPA injections and scoring of abnormal involuntary movements 73 5. Histological procedures 74 5.1. Perfusions 74 5.2. Sectioning 74 5.3. Immunohistochemical staining 75 5.3.1. Stains performed 75 5.3.2. Protocols 76 Chat 76 NeuN/Cresyl protocol 76 TH/Cb protocol 77 6. Histological analysis 78 6.1. Lesion assessment 78 6.1.1. NeuN+ 78 6.1.2. Chat+ counting 79 6.1.3. TH+ counting 79 6.2. Electrode placement 81 vi 7. Behavioural data analysis 81 7.1. CW data labelling 81 7.2. CW data analysis 82 7.3. FOG 82 7.4. Dyskinesias/ Stereotypies 82 Chapter 3 - The effect of full lesions of the PPTg on gait 83 1. Introduction 84 2. Methods 86 2.1. Subjects 86 2.2. Experimental protocol 86 2.3.
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