Design of a magnetic field compatible, high-performance optical breast imaging system for MRI-guided optical spectroscopy A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy by Fadi El-Ghussein Thayer School of Engineering Dartmouth College Hanover, New Hampshire Date September 22nd 2014 Examining Committee: Chairman_______________________ Brian Pogue Member________________________ Shudong Jiang Member________________________ Keith Paulson Member________________________ Sergio Fantini ___________________ F. Jon Kull Dean of Graduate Studies iv Abstract Multimodality imaging is becoming the standard of care for research and clinical studies. Such an approach is able to provide complementary information which can detect and characterize tumors. Advancing instrumentation for diffuse near-infrared spectroscopy (NIRS) within a conventional magnetic resonance imaging (MRI) scanner requires careful choices to make a true hybrid imaging system. In this thesis, a series of system technology development studies were completed in order to analyze what was needed to prototype the next phase of this technology with detection being possible within the MRI. Initially in a breast imaging system, a set of parallel plates was used with a newly created frequency-domain and continuous wave source-detector array. The opto-electronic sub- system was created and deployed within a previously existing MRI-coupled spectroscopy approach, principally allowing incorporation of additional NIR wavelengths beyond 850nm, with interlaced channels of photomultiplier tubes and silicon photodiodes. This new sub-system improved the data quality and accuracy in recovery of all breast optical properties. While the current system is highly functional, and was deployed in a large clinical trial of over 60 subjects, the usability was found to be limited due to the cumbersome nature of the fiber-breast geometry and adaptability of the system. Furthermore, there is a severe penalty for the lack of full breast coverage as the sensitivity of DOT to tumors drops. Full coverage of the breast was found to be a critical. Adding more fibers for full breast coverage is impractical due to the size of the fibers as well as the significant cost that would be incurred. In order to solve this challenge, we have built a system which places detectors in direct contact with the patient’s tissue, thus, forgoing the long fiber optic ii cables used with the hybrid system and improving light throughput. The new modular design, which allows up to 64 detectors to be used, places the detectors’ frontend electronics outside the MRI room without sacrificing the detectors sensitivity or dynamic range. Characterization and calibration of the system is described in detail. iii Acknowledgements I would first like to thank my supervisor, Professor Brian Pogue for providing me with this incredible opportunity and allowing me to pursue my PhD degree with him. I am truly blessed to have been in his group. His driving force and support was a turning point when this work was overwhelming. I am sincerely grateful for his patience and for always finding the time to speak with me when I need his guidance. One can only be humbled to have met and been a student of such a great supervisor to whom I am deeply indebted. I would also like to thank Professor Shudong Jiang who showed her enormous support and encouragement throughout my PhD. She engaged me in discussions and guided me through my first years as a graduate student. She went out of her way and displayed so much kindness and offered a great amount of help during our clinical trial in Xi’an, China. The success of the clinical trial and the completion of this PhD would have not been possible without her It is hard to image where the optics in medicine group would have been if it wasn’t for the tireless efforts and long vision of Professor Keith Paulson. Professor Paulson, the driving force behind this group at Dartmouth College, also was the key reason for getting the clinical trial off the ground. I am very thankful for his efforts and for his dedication to this group. I would also like to thank Professor Sergio Fantini, a pioneer in his field, for being kind enough to serve as a member of my PhD committee. His work in this field played a key role in my understanding of optical tomography. I must also thank my original mentor Professor Michael Kruger who has shaped me to the person I am today. He has engaged me, challenged me, motivated me, and helped me find the potential in myself. am deeply indebted to him and will forever keep him in my thoughts. Finally, I would like to thank my parents and my siblings, Amani and Feras for their love and support and my wife Shaimah for her love and support as well. I dedicate this work to my mom and dad, Abeer and Mohammed. All the love of this world is not enough to repay them, but I will continue to love them more and more every day. iv Table of Contents Abstract (times, regular, 12, double spaced) ....................................................................... ii Acknowledgements ........................................................................................................... iv Table of Contents .................................................................................................................v List of Tables ................................................................................................................... viii List of Figures .................................................................................................................... ix List of Acronyms ........................................................................................................... xviii 1. Overview ..........................................................................................................................1 1.1 Introduction to optical tomography and functional imaging .................................................... 1 1.2 Aims of this thesis ......................................................................................................3 1.3 Organization of this thesis .........................................................................................4 2. Background ......................................................................................................................6 2.1 NIR tomography/spectroscopy .............................................................................................................. 6 2.2 Tissue Optics And Optical Contrast ...................................................................................................... 7 2.3 NIR Instrument Types ............................................................................................................................. 12 2.4 Light Modeling and the diffusion approximation ........................................................................ 17 2.5 Image Reconstruction ............................................................................................................................. 19 2.6 Photon Detectors ....................................................................................................................................... 23 2.6.1 Light ..............................................................................................................23 2.6.2 Photomultiplier tube (PMT) detectors ..........................................................25 2.6.3 Photodiodes/PIN photodiodes .......................................................................29 2.6.4 Silicon Photomultiplier .................................................................................32 2.6.5 Photon Counting ...........................................................................................36 2.6.6 Detectors Comparison ...................................................................................41 3. Time-domain Imaging ...................................................................................................44 3.1 Introduction ‐ Background and Importance .................................................................................. 44 3.1.1 TCSPC Building Blocks ...................................................................................48 3.1.1 Discriminators ...................................................................................................49 3.1.1 Time-to-Amplitude (TAC) ................................................................................51 3.1.1 TCSPC Data Type.............................................................................................52 3.2 Small‐Animal Time‐Domain System Characterization .............................................................. 53 3.2.1 Control Flow Improvements .............................................................................57 3.2.2 Calibration and Data Types ..............................................................................60 3.2.2.1 Laser Reference Calibration .......................................................................60 3.2.2.2 Inter-detectors Calibration and Time-Referencing ....................................62 3.3 Phantom/Animal Results ....................................................................................................................... 64 3.3.1 Phantom Imaging ..............................................................................................64 3.3.2 Animal Imaging ................................................................................................66