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NASA NTRSDate not supplied

Oculometric Surveillance of Neuro-Ocular Function

Future missions to the moon or Mars will require the crew to monitor and assess their health and performance more autonomously, with approaches easily useable and interpretable by non-clinicians. If an autonomous oculometric diagnostic-support system proves to be a reliable predictor of impending impairment of visual function in the case of primary ocular pathology on Earth, then it could also be applied in the future to the surveillance of crew to detect the potential progression of sensorimotor and neuro-ocular compromises during extended spaceflight missions, e.g., SANS, and thus guide earlier and more effective countermeasure intervention. Towards that goal, we intend to determine if a set of largely independent eye-movement metrics, called oculometrics, measured using a simple voluntary eye-tracking task that can be completed in just 5 minutes per eye, could provide clinically valid biomarkers of functional visual deficits due to primary ocular pathology. The premise is that oculometrics could be used to monitor slowly evolving ocular pathologies, potentially detecting them even before structural evidence appears in ocular imaging or other current state-of-the-art clinical measures. This study investigates how NASA’s patented oculometric assessment of visual and visuomotor function, shown to correlate with performance in a manual control task, will correlate with standard ophthalmological tests to confirm clinical and thus operational, validity.

eye movements↗
NASA NTRSDate not supplied

Correlated Changes in Retinal Thickness and Visuomotor Function in Asymptomatic Plaquenil Toxicity Patients

We have previously shown that a 5-minute eye-movement test can capture a number of largely independent “oculometric” parameters of human visual/visuomotor function (Liston & Stone, 2014). This test has been successfully used to characterize mild neural impairment due to traumatic brain injury, sleep and circadian disruption, and alcohol consumption (Liston et al., 2017; Stone et al, 2019; Tyson et al, 2021). Here, we extend this approach to study patients at risk of progressive posterior-segment illness to see how oculometrics relate to standard clinical ophthalmological measures. Five female patients (<20:40 BCVA, 34-60 years old) undergoing hydroxychloroquine treatment (2-7mg/kg/day for 10-23 years for rheumatologic illness) have participated thus far. Under monocular viewing conditions in randomized order, they tracked a moving spot undergoing radial step-ramp motion in one of 90 randomized directions, at one of 5 randomized speeds, starting at random times (for details, see Stone et al, 2019). We computed nine independent oculometrics (latency, initial acceleration, steady-state gain, proportion smooth, saccadic rate, saccadic amplitude, direction noise, speed responsiveness, and speed noise). Spectral-domain optical coherence tomography (Zeiss, Dublin, CA) was used to measure the average thickness of the nine Early Treatment Diabetic Retinopathy Study macular sectors from the internal limiting membrane to the retinal pigmented epithelium. We used Pearson’s correlation between retinal thickness and our oculometrics with t-statistics to test separate one-sided hypotheses across 10 retinae. Our preliminary analysis found significant changes in several different aspects of visuomotor performance. Most notably, latency increased, initial acceleration decreased, and steady-state pursuit gain decreased as retinal thickness decreased (r2 = 0.364, 0.579, and 0.692; one-tailed P = 0.032, 0.005, and 0.001, respectively). Speed responsiveness appeared to decrease, but this effect was marginal for our current sample (r2 = 0.253, P = 0.069). Lastly, direction discrimination and saccadic behavior appeared unchanged. We conclude that oculometrics may provide sensitive measures of changes in retinal thickness. More importantly, oculometrics have the potential to detect impairment before it becomes evident with standard clinical imaging tools, while also providing insight into the behavioral implications of any resulting deficits in visual/visuomotor function.

eye movements↗
NASA NTRSDate not supplied

Spaceflight Associated Neuro-Ocular Syndrome: A Brief for Astronaut Candidates

INTRODUCTION: Spaceflight Associated Neuro-ocular Syndrome (SANS) was first described in 2011 as a clinical process involving degradation of visual acuity and structural changes of the eye when exposed to microgravity. This syndrome poses a risk to astronaut vision, safety, and mission performance, especially during extended-duration missions. The modern astronaut cohort is a diverse group of men and women including scientists, engineers, teachers, pilots, business professionals, and artists. Given their diverse backgrounds, it is imperative all crews are educated on SANS risks and potential countermeasures. This education must be comprehensive and easily understood, regardless of academic background or specific expertise. TOPIC: A PowerPoint was created to serve as a presentation and stand-alone educational aid for all astronaut candidates (ASCANS). This medium was chosen as it can be updated dynamically as new information emerges. The brief was split into sections to facilitate organized delivery of complex content in easy-to-understand components. Sections included descriptive statistics, signs and symptoms, outcomes, myths and ongoing research, countermeasures, ongoing surveillance, and unknown and future directions. More research is necessary in order to understand this syndrome, and without continued ASCAN participation in research, acquisition of data will not be possible. These efforts will become increasingly critical with deep space and exploration missions. APPLICATION: We recommend regular use of this brief for all ASCANS, and potentially veteran crewmembers, given the high risks and potentially poor outcomes associated with SANS. For ASCANS, recommendations include that this brief be provided at the start of their training, with a bi-annual refresher course for all astronauts. This ensures they are current on SANS information, given the dynamic nature of this syndrome. Additionally, this brief will be made available to all as a self-study aid, utilized as a refresher immediately prior to launch. It is anticipated that this brief will promote the health, safety, and wellbeing of professional and private crews alike, during and after long-duration spaceflight. RESOURCES: Brunstetter, T., Tarver, B., & Tsung, A. (2022, October). Spaceflight Associated Neuro-ocular Syndrome (Sans) and its Risk to Nasa Astronauts. JSC Aerospace Medicine Clerkship. Houston, TX; Lyndon B. Johnson Space Center. Laurie, S. S., Macias, B. R., Pardon, L. P., Brunstetter, T., Tarver, W. J., Gibson, C. R., Greenwald, S. H., Jasien, K. V., Mason, S., & Tsung, A. (2022). (rep.). Evidence Report: Risk of Spaceflight Associated Neuro-ocular Syndrome (SANS). Houston, TX: National Aeronautics and Space Administration. Mader, T. H., Gibson, C. R., Pass, A. F., Kramer, L. A., Lee, A. G., Fogarty, J., ... & Polk, J. D. (2011). Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmology, 118(10), 2058-2069. LEARNING OBJECTIVES: • The audience will be able to describe current Spaceflight Associated Neuro-ocular Syndrome (SANS) findings, significance, and countermeasures. • The audience will understand the importance of astronauts’ familiarity with SANS prior to flying and the large risks associated with this syndrome. CME QUESTIONS (3 QUESTIONS, MULTIPLE CHOICE A-D): 1. What is the approximate prevalence rate of SANS in astronauts? A. 22% B. 50% C. 66% D. 80% Answer: C. 2. Which of the ocular findings are NOT associated with SANS? A. Optic disc edema B. Retinal detachment C. Globe flattening D. Chorioretinal folds Answer: B. 3. Which of the following diagnostic technologies are NOT available in-flight? A. Ocular ultrasound B. Retinal photography C. MRI Orbit D. Optical Coherence Tomography (OCT) Answer: C.

Sara Stroble Mason↗
NASA NTRSDate not supplied

Oculometric Detection and Characterization of Sub-Clinical Visual/Visuomotor Impairment

It has long been known that qualitative abnormalities in eye movements can be used to diagnose overt brain pathologies (Diefendorf & Dodge, 1908; Fox & Holmes, 1926; Leigh & Zee, 2015). Here, we will examine the use of a set of quantitative measures of the human behavioral response (oculometrics) in a 5-minute radial ocular tracking task (Krukowski & Stone, 2005) with sufficient temporal, spatial, and directional uncertainty to minimize the contribution of a priori prediction or anticipation, and to emphasize the use of a posteriori visual processing of the stimulus trajectory (Liston & Stone, 2014). The derived oculometrics provide a largely independent, reliable set of metrics that are sensitive enough to detect mild sub-clinical impairment across a range of possible neural loci (Stone et al., 2019) with the pattern of impairment across the set providing specificity as to its nature (Tyson et al., 2023). We will review our earlier findings where oculometrics have been used to detect mild impairment due to traumatic brain injury, sleep loss, and low-dose alcohol (Liston et al., 2017; Stone et al., 2019; Tyson et al., 2021). We will also report on a recent clinical study of asymptomatic patients at risk of retinal pathology (Leung et al., 2022) and show that oculometrics can detect and characterize substantive loss of visual function in the absence of clinical indicators of pathology. We conclude that oculometric testing could be used as a routine non-invasive ophthalmological or neurological tool to aid in the early detection and diagnosis of neural injury, toxicity, or disease.

eye movements↗
DOE OSTI2023

2022 Prentice Award Lecture: Advancing Retinal Imaging and Visual Function in Patient Management and Disease Mechanisms

Patient-based research plays a key role in probing basic visual mechanisms. Less-well recognized is the role of patient-based retinal imaging and visual function studies in elucidating disease mechanisms, which are accelerated by advances in imaging and function techniques and are most powerful when combined with the results from histology and animal models. A patient's visual complaints can be one key to patient management, but human data are also key to understanding disease mechanisms. Unfortunately, pathological changes can be difficult to detect. Before advanced retinal imaging, the measurement of visual function indicated the presence of pathological changes that were undetectable with existing clinical examination. Over the past few decades, advances in retinal imaging have increasingly revealed the unseen. This has led to great strides in the management of many diseases, particularly diabetic retinopathy and macular edema, and age-related macular degeneration. It is likely widely accepted that patient-based research, as in clinical trials, led to such positive outcomes. Both visual function measures and advanced retinal imaging have clearly demonstrated differences among retinal diseases. Contrary to initial thinking, sight-threatening damage in diabetes occurs to the outer retina and not only to the inner retina. This has been clearly indicated in patient results but has only gradually entered the clinical classifications and understanding of disease etiology. There is strikingly different pathophysiology for age-related macular degeneration compared with photoreceptor and retinal pigment epithelial genetic defects, yet research models and even some treatments confuse these. It is important to recognize the role that patient-based research plays in probing basic visual mechanisms and elucidating disease mechanisms, combining these findings with the concepts from histology and animal models. Thus, this article combines sample instrumentation from my laboratory and progress in the fields of retinal imaging and visual function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Adaptive Optical Two-Photon Fluorescence Microscopy Probes Cellular Organization of Ocular Lenses In Vivo

The mammalian ocular lens is an avascular multicellular organ that grows continuously throughout life. Traditionally, its cellular organization is investigated using dissected lenses, which eliminates in vivo environmental and structural support. Therefore, in vivo optical imaging methods for studying lenses in their native context in live animals are urgently needed. Here, we demonstrated that two-photon fluorescence microscopy can visualize lens cells in vivo. To maintain subcellular resolution at depth, we used adaptive optics to correct aberrations owing to ocular and lens tissues, which led to substantial signal and resolution improvements. Imaging lens cells up to 980 µm deep, we observed novel cellular organizations including suture-associated voids, enlarged vacuoles, and large cavities, contrary to the conventional view of a highly ordered organization. We tracked these features longitudinally over weeks and observed the incorporation of new cells during growth. Taken together, noninvasive longitudinal in vivo imaging of lens morphology using adaptive optics two-photon fluorescence microscopy will allow us to observe the development or alterations of lens cellular organization in living animals directly.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2024

Oculometric Biomarkers of Visuomotor Deficits in Clinically Asymptomatic Patients With Systemic Lupus Erythematosus Undergoing Long-Term Hydroxychloroquine Treatment

Introduction: This study examines a set of oculomotor measurements, or “oculometric” biomarkers, as potential early indicators of visual and visuomotor deficits due to retinal toxicity in asymptomatic Systemic Lupus Erythematosus (SLE) patients on long-term hydroxychloroquine (HCQ) treatment. The aim is to identify subclinical functional impairments that are otherwise undetectable by standard clinical tests and to link them to structural retinal changes. Methods: We measured oculomotor responses in a cohort of SLE patients on chronic HCQ therapy using a previously established behavioral task and analysis technique. We also examined the relationship between oculometrics, OCT measures of retinal thickness, and standard clinical perimetry measures of visual function in our patient group using Bivariate Pearson Correlation and a Linear Mixed-Effects Model (LMM). Results: Significant visual and visuomotor deficits were found in 12 asymptomatic SLE patients on long-term HCQ therapy compared to a cohort of 17 age-matched healthy controls. Notably, six oculometrics were significantly different. The median initial pursuit acceleration was 22%, steady-state pursuit gain 16%, proportion smooth 7%, and target speed responsiveness 31% lower, while catch-up saccade amplitude was 46% and fixation error 46% larger. Excluding the two patients with diagnosed mild toxicity, four oculometrics, all but fixation error and proportion smooth, remained significantly impaired compared to controls. Across our population of 12 patients (24 retinae), we found that pursuit latency, initial acceleration, steady-state gain, and fixation error were linearly related to retinal thickness even when age was accounted for, while standard measures of clinical function (Mean Deviation and Pattern Standard Deviation) were not. Discussion: Our data show that specific oculometrics are sensitive early biomarkers of functional deficits in SLE patients on HCQ that could be harnessed to assist in the early detection of HCQ-induced retinal toxicity and other visual pathologies, potentially providing early diagnostic value beyond standard visual field and OCT evaluations.

eye movements↗