ADVANCES IN DEEP BRAIN STIMULATION FOR PARKINSON’S DISEASE PhD Thesis in Biomedical Engineering CARMEN CÁMARA Kevin Warwick Ernesto Pereda PhD in Electrical Engineering PhD in Neuroscience UNIVERSIDAD POLITÉCNICA DE MADRID PhD in Biomedical Engineering EscueIa Técnica Superior de Ingenieros de Telecomunicación (ETSIT UPM) Centre for Biomedical Technology (CTB) ADVANCES IN DEEP BRAIN STIMULATION FOR PARKINSON’S DISEASE Carmen Cámara Núñez MSc in Biomedical Engineering PhD in Computer Science Advisors Kevin Warwick Ernesto Pereda PhD in Electrical Engineering PhD in Neuroscience Contents Acknowledgements iii Summary ix Resumen xi Acronyms xiii I Introduction 1 1 Introduction to Parkinson’s Disease 3 1.1 Brief introduction to the brain . 4 1.2 Functioning of the basal ganglia . 8 1.3 Pathophysiology of Parkinson’s disease. 10 1.4 Treatments . 16 1.5 Deep brain stimulation . 17 2 Introduction to Neuroimaging and Analysis Methods 21 2.1 Intracraneal Recordings . 25 2.2 Magnetoencephalography . 26 2.3 Analysis Methods. 31 2.3.1 Spectral Analysis . 31 2.3.2 Synchronization Analysis . 33 2.3.3 Non-linear Dynamical Analysis . 37 2.4 Statistical Methods. 39 2.4.1 Machine Learning . 40 2.4.2 Cluster-based permutation test . 42 II DBS Mistery 45 3 DBS effects on cortico-cortical functional connectivity 47 3.1 Effects of deep brain stimulation . 48 3.2 Subjects . 50 3.3 MEG . 51 3.4 Analysis . 53 3.5 Results . 58 3.6 Conclusions . 63 III Closed-loop DBS 65 4 Closed-loop Deep Brain Stimulation 67 4.1 Dataset. 71 i ii Contents 5 Resting tremor classification and detection in Parkinson’s dis- ease patients 75 5.1 Tremor . 76 5.2 Data Preparation and feature extraction . 77 5.3 Proposed System & Results. 79 5.4 Discussion (Performance Evaluation) . 88 5.5 Conclusions . 88 6 A fuzzy inference system for closed-loop deep brain stimula- tion in Parkinson’s disease 91 6.1 Methods . 92 6.2 Fuzzy System . 93 6.3 System . 95 6.4 Results . 99 6.5 Discussion. 102 6.6 Conclusions . 103 7 Non-linear dynamical analysis of resting tremor for demand- driven deep brain stimulation 105 7.1 Data Preparation . 106 7.2 Recurrence Networks . 107 7.3 Network Measures . 109 7.4 System . 112 7.5 Discussion. 117 7.6 Conclusions . 119 8 Closed-loop deep brain stimulation based on a stream-clustering system 121 8.1 Neural oscillations versus synchronization . 122 8.2 Signal Preprocessing . 124 8.3 Synchronization analysis . 124 8.4 Data Stream Mining . 126 8.5 Stream Clustering . 128 8.6 System Description . 130 8.7 Experimental Analysis. 131 8.8 Discussion. 138 IV Conclusions & Future perspectives 143 9 General Conclusions & Future Perspectives 145 Curriculum Vitæ 151 Bibliography 153 Acknowledgements t is said that having a good first boss (in my case, supervisors) is crucial since I one will end up looking like him. If this is true, I have been fortunate. Firstly for the high worth of my tutors, but also with the centre in which this thesis has been developed. Here, I want to thank all the people who have helped me in the developing of this thesis. Kevin I discovered who would later be my supervisor, in a television program of scientific divulgation. It was a program in which the researcher interviewed showed his work to the general public. I was still studying the degree, but I thought, ”I hope some- day I can do half the impressive things this guy does”. When I decided I wanted to do the thesis, I got up the courage (of course thinking he would not answer (because he was a superstar)), and sent an email to Kevin Warwick. But he did reply (I still sometimes flip with it), and he gave me an appointment in Reading, UK, and agreed to supervise my thesis! Kevin was collaborating with Tipu Aziz, from Oxford University, in the design of intelligent systems for the treatment of Parkinson’s disease. So he proposed to me to work on that in my thesis. At the time, I only had a master’s degree in Artificial Intelligence. Since then, I have also learned Bioengineering and some Neuroimag- ing and Neuroscience. It has been a thesis’s topic that has led me to learn a little bit of quite a few things. So it turned out to be the perfect research area for the thesis. Why isn’t this, in the end, the goal of a thesis, exploration and continuous learning?. So I have to thank you, Kevin, for choosing this topic for me, because it has taken me to wonderful places. I have not been lucky enough to have Kevin in the same lab as me, nor in the same building, not even in the same country. Despite this, his influence has been inspiring; his work will always be an inspiration to me. Thank you, Kevin, for giving me this opportunity, because everything I have learned, all this adventure, started on that visit to Reading. Thanks to Tipu as well for the time he has dedicated to me and the data he has kindly lent me. Ernesto I met Ernesto at a seminar he taught at the master’s in bioengineering at UPM. He is an excellent teacher, so I had no doubt that he would be an excellent thesis tutor as well. Ernesto started supervising me in the middle of the thesis. But it has been long enough to learn from him. Like Kevin, he was not in the same geographical place as me. Maybe we have been able to see each other only once or twice a year. iii iv Acknowledgements But on those occasions, Ernesto sat down and talk to me for a long time to define the work for the next few months. He always has excellent ideas, so talking to him is very motivating. Having a skype with him always serves to renew the desire to do many cool things, so I hope they never finish. I admire very much your ability to get so much work done and commit so much to the university. I don’t know how you get there you have time for so much, but I hope part of your future time may be to keep doing cool things together. Thanks, Ernesto. Center for Biomedical Technology ++ I knew the CTB during the master’s degree in bioengineering, and I decided it was the best place to enrol my thesis. Many students want to be there, and there is no place for everyone. For that reason, I have to thank here Fernando Maestú for giving the opportunity to me. The CTB is a place full of very talented people. It thus becomes an inspiring place, which encourages the desire to learn. This is thanks to the direction of Fernando, but also of all the members of the lab, so I want to thank here all the students I’ve coincided with there. I want to give special thanks to Ricardo Bruña. My teacher of ”signals and sys- tems” during the master, my master’s final project supervisor, and my friend since then. Talking to him is a little frustrating because you realise all you have left to learn. But he always has time to sit with you in front of a blank sheet of paper and paints you drawings and mathematical formulas so that you understand things at a low level (the way I like it). Everything that I know about signal processing has been taught to me by him. And I am sure he will teach me everything I still have to know. I hope we keep working together a lot; it is the best things about the CTB. Although he is not a CTB colleague, I would like to thank Narayan here as well. He taught me Chaos Theory and his thesis was part of the basic bibliography of my bedside table (I’ve read it more times than mine). Thank you for being so impres- sive and spend time with me, I’ll never forget your wonderful tutorials at Aalto. Finally, thanks to the European Institute of Innovation and Technology (EIT Digital) for choosing me to do my thesis within their elitist doctoral school. It has allowed me to do an infinitely more complete training, with a vision of entrepreneurship and digital world (almost as in silicon valley), which is not possible outside its program. Thanks to the colleagues chosen with me, for the time together during the long training courses. We had a great time, and it was a vital experience that I will never forget. This thesis has never been merely a goal for me, but the beginning of a path, that I have enjoyed so much (I know this is not what a thesis student typically says, but I swear it is real). I hope to keep learning and doing new, inspiring, challenging and wonderful things with all of you, Kevin, Ernesto and colleagues. Thank you all. Acknowledgements v vi Acknowledgements Mi querida familia Nada de lo que una persona es o logra es por mérito exclusivo, sino una combi- nación de toda la educación recibida y una pizca de suerte. Del primer ingrediente, los únicos responsables son mis padres. Siempre nos han dicho que teníamos el potencial para hacer lo que quisieramos y nos han animado a hacerlo desde pe- queñas. Convencieron a la directora de mi primer colegio de que podía ir a clases de informatica con 6 años, con estudiantes diez años mayores que yo (quizás porque yo también era muy testaruda). Finalmente pude ir y lo hice bastante bien.