SYMPTOM-FREE IN ZERO-G? NOVEL TECHNIQUES FOR RAPID ASSESSMENT OF VESTIBULO-OCULAR FUNCTION AND THEIR USE IN PREDICTING PERFORMANCE FROM BASELINE METRICS by Kara H. Beaton A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March 26, 2014 © 2014 Kara H. Beaton All Rights Reserved Abstract Spaceflight elicits adaptive changes in neurovestibular signaling to accommodate exposure to novel gravity levels. With the prospect of longer-duration missions to Mars and beyond, NASA is currently faced with two immediate needs, which form the founda- tion of this dissertation: (1) portable technologies to evaluate functional decrements in sensorimotor performance that can be quickly self-administered, and (2) countermeasures that can pre-adapt astronauts prior to spaceflight, accelerate adaptation inflight, or fore- cast performance (e.g., adaptive capabilities or space motion sickness susceptibility) from preflight metrics alone. In this dissertation, we focus specifically on the design, devel- opment, and implementation of three innovative approaches to quantify the vestibular control of eye movements using minimal hardware, and we use these techniques to pre- dict adaptive performance from baseline measures. Vertical and Torsional Alignment Nulling and Vestibulo-Ocular Nulling (VON) were developed to evaluate binocular positioning misalignments and the vestibulo-ocular reflex (VOR), respectively. These tests are embedded in a hand-held device, which in- corporates a tablet computer, small wireless motion sensors, and a pair of specialized eyeglasses, and employs various mobile-apps developed in-house. Through a series of experiments performed in the laboratory and in parabolic-flight, we validated these new assessment tests and explored gravity-level dependencies in vestibulo-ocular function. We found that ocular misalignments are gravity-dependent and developed a bilateral con- trol systems model to describe this dependency. Additionally, variability in baseline tor- sional misalignment strongly correlates with motion-sickness susceptibility in altered gravity environments. Our VON test provides a rapid measure of dynamic gaze stability ii that is more consistent than traditional measures of VOR gain. VON results vary system- atically with gravity levels, providing evidence for an otolith-modulating component of the angular VOR. Finally, the strength of baseline inter-trial correlations forecast adap- tive capacity in the VOR. The portable technologies developed in this dissertation have applications beyond spaceflight operations, including bedside clinical testing, remote field-testing, or any ap- plications limited by time constraints, resources, technical personnel, or clinical expertise. The ability to forecast performance from baseline metrics alone, without exposure to an adaptive stimulus, has important implications for the design of individualized interven- tions, such as rehabilitation protocols to expedite terrestrial compensation for vestibular pathologies, or preflight training and inflight countermeasures to facilitate adaptation to altered gravity environments. Thesis advisor: Dr. Mark Shelhamer Thesis committee: Drs. David S. Zee, Eric Young, Michael C. Schubert, Jacob Bloom- berg Primary reader: Dr. Mark Shelhamer Secondary Reader: Dr. David S. Zee iii Acknowledgements This dissertation is the direct result of the numerous faculty advisors, professional colleagues, family members, and friends who have mentored and supported me through- out this endeavor. I am forever grateful. Specifically, I would like to thank the following individuals: • My thesis committee Drs. Mark Shelhamer, David Zee, Eric Young, Michael Schubert, and Jacob Bloomberg, without which this body of work would not have been completed. You are true scientific pioneers, and I am honored to have had the opportunity to be your student. • My lab mates Aaron Wong, Dale Roberts, Adrian Lasker, Amir Kheradmand, Howard Ying, and Rebecca Scholz for their invaluable technical support, engag- ing and insightful conversations, and life-long friendships. • My professional colleagues and friends Drs. Scott Wood, Angus Rupert, and the late Fred Guedry for providing many opportunities for me to pursue my dreams. • My husband Jon and family members Cary, Gayle, Jonathan, Meg, and Min for their endless love and encouragement throughout this adventure. iv Dedication To Dad and Mom, For everything. v Table of Contents Abstract .............................................................................................................................. ii Acknowledgements .......................................................................................................... iv Dedication .......................................................................................................................... v Table of Contents ............................................................................................................. vi List of Tables .................................................................................................................... ix List of Figures .................................................................................................................... x 1 Introduction .............................................................................................................. 1 1.1 Motivation ......................................................................................................... 1 1.2 Vestibular physiology ....................................................................................... 6 1.3 Vestibular control of eye movements ............................................................... 9 1.3.1 Quantifying vestibulo-ocular reflexes ............................................... 11 1.3.2 Clear vision requires proper binocular positioning alignment .......... 13 1.3.3 The vestibulo-ocular reflex facilitates gaze stability during head motion ....................................................................................... 17 1.4 Vestibular adaptation to spaceflight ................................................................ 24 1.4.1 The otolith tilt-translation ambiguity and otolith tilt-translation reinterpretation hypothesis ................................................................ 26 1.4.2 Context-specific adaptation and adaptive generalization may facilitate preflight adaptation ............................................................. 28 2 Experimental design and methods ....................................................................... 33 2.1 Introduction ..................................................................................................... 33 2.2 Definition of terms .......................................................................................... 34 2.3 Test subjects .................................................................................................... 38 2.4 Test environments ........................................................................................... 40 2.4.1 Parabolic-flight testing ...................................................................... 41 2.5 VOR adaptation experiments .......................................................................... 43 2.5.1 VOR adaptation stimulus .................................................................. 43 2.5.2 VOR gain calculations ....................................................................... 46 3 Vertical and Torsional Alignment Nulling quantify binocular misalignments and forecast motion sickness susceptibility ................................ 51 3.1 Introduction ..................................................................................................... 51 vi 3.1.1 Overview ........................................................................................... 51 3.1.2 The CNS compensates for otolith asymmetries ................................ 52 3.1.3 Otolith asymmetries manifest as binocular positioning misalignments .................................................................................... 56 3.1.4 Altered g-levels elicit binocular misalignments and provide evidence for central compensation .................................................... 59 3.2 Objectives ....................................................................................................... 64 3.3 Materials and methods .................................................................................... 66 3.3.1 VAN and TAN design ....................................................................... 66 3.3.2 Prism validation experiments ............................................................ 71 3.3.3 Parabolic-flight experiments ............................................................. 75 3.4 Results ........................................................................................................... 78 3.4.1 VAN and TAN quantify visual disparities induced by prisms .......... 78 3.4.2 Variability in baseline torsional misalignment correlates with motion sickness susceptibility ................................................... 83 3.4.3 Binocular misalignments increase in novel g-levels ......................... 85 3.5 Discussion ....................................................................................................... 90 3.5.1 Prism experiments reveal test requirements .....................................