Anterior ocular globe shift observed in astronauts after long-duration spaceflight

Anterior ocular globe shift observed in astronauts after long-duration spaceflight | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Anterior ocular globe shift observed in astronauts after long-duration spaceflight Bryn Martin, Katherine Warthen, Stuart Sater, Cynthia Roberts, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8912940/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background/Objectives Long-duration spaceflight is associated with ophthalmic effects such as optic disc edema, hyperopic shift, ocular globe flattening, and choroidal folds, collectively known as Spaceflight Associated Neuro-ocular Syndrome, or SANS. While the mechanism of SANS remains unknown, modeling of orbital congestion has predicted anterior shift of the eye which has not yet been evaluated. The goal of this study was to develop and apply a non-invasive MRI-based method for quantification of eye shift in long-duration spaceflight astronauts. Subjects/Methods Preflight and postflight 3D T1-weighted MR images of the head were analyzed from 18 astronauts after approximately 6 months of spaceflight, and in 10 terrestrial controls at baseline, 2, 6, and 12-month follow-up. A semi-automated method was developed to quantify 3-dimensional eye movement, in the x, y, and z direction, with respect to the skull at follow-up versus baseline based on ocular globe center-of-mass (eye shift). Association between eye shift and posterior globe flattening was tested with a Pearson correlation. Results Eye shift in the x, y, and z direction (-medial/+lateral, -posterior/+anterior, -inferior/+superior) was 0.34 ± 0.27 mm (p = 0.013), 0.73 ± 0.40 mm (p < 0.0001), -0.21 ± 0.35 mm (p = 0.14), in astronauts compared to -0.10 ± 0.14 mm, 0.12 ± 0.33 mm, and − 0.037 ± 0.35 mm in controls. Correlations between posterior globe flattening and eye shift were not significant in any x, y, or z direction. Conclusions A novel semi-automated MRI-based pipeline was developed to quantify anterior eye shift in astronauts and terrestrial controls. There were statistically significant shifts in eye center of mass in the anterior and lateral directions in astronauts compared to terrestrial controls. Health sciences/Medical research Biological sciences/Biological techniques Biological sciences/Neuroscience/Visual system Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Long-duration spaceflight (LDSF) astronauts are at risk for a myriad of ocular phenomena including optic disc edema, choroidal folds, posterior globe flattening, and hyperopic shift 1 – 5 . Together these are known as Spaceflight Associated Neuro-ocular Syndrome, or SANS 4 , one of the major NASA Human Research Roadmap risks 6 . The exact mechanism of SANS is unclear 5 , 7 – 10 , although it is thought to be related to headward fluid shift experienced during LDSF due to the prolonged loss of the hydrostatic pressure gradient driven by gravity. It remains unknown if there are individual biological risk factors that contribute to SANS, and why only some astronauts develop SANS 1 , 4 . SANS was initially attributed to a potential increase in intracranial pressure (ICP) during spaceflight due to the observation of optic disc edema present in some LDSF astronauts and mildly elevated postflight lumbar puncture opening pressures in some astronauts who presented with optic disc edema 3 , 9 , 11 . However, noninvasive ICP measurements collected during spaceflight 12 have not been observed to be pathologically elevated and direct ICP measures made via lumbar puncture in astronauts presenting with optic disc edema immediately following return from space were not pathologically elevated 13 . Additional theories of modifying factors that influence SANS include anatomic factors such as optic cup volume 14 and genetic polymorphisms such as alterations in the one-carbon pathway 15 – 17 . A novel theory for SANS development, supported by modeling data 18 , puts forth that headward fluid shift in microgravity may cause posterior orbital fat pad swelling. The bony orbit cone encases the eye, optic nerve, blood vessels, ocular muscles, and orbital fat 19 . Orbital fat swelling behind the eye may place a forward force on the eye, potentially contributing to SANS findings such as globe flattening and axial length reduction 20 . Reilly et al. employed finite element modeling to simulate orbital biomechanics under fluid shift and found that orbital fat swelling driven by this fluid shift may produce proptosis, or anterior eye shift within the orbit. In this model, eye shift during the subsequent fluid shift due to the loss of hydrostatic gradient was affected by a complex force balance including intracranial and intraocular pressures, orbital fat swelling, extraocular muscle tension, and optic nerve stretching 20 . In principle, this force balance would also be impacted by inter-individual differences in tissue compliance 21 – 23 . Orbital fat swelling and potential for anterior eye shift have not been quantified in astronauts, and it is unknown if they are related, relevant, or occur at all. If anterior eye shift occurs in spaceflight, it may indicate orbital fat swelling and an increased outward force on the back of the eye that may play a role in early SANS pathogenesis. Anterior eye shift has never been quantified after LDSF, representing a potentially important knowledge gap in SANS research. To examine this question, we developed and applied a semi-automated method to quantify anterior eye shift within the orbit based on MRI measurements collected longitudinally in LDSF astronauts and compared to ground-based controls. We hypothesized that anterior eye shift would be greater in LDSF astronauts compared to ground-based controls and inversely associated with posterior globe flattening 24 . Methods Participants This longitudinal case-control study included 26 LDSF astronauts and 10 ground-based control participants with baseline health similar to the astronaut group imaged on the same MRI scanner, as described by Carter et al 25 . Written informed consent was obtained for all participants in accordance with NASA IRB guidelines and data were collated across multiple studies (PRO0701, PRO0285, and STUDY00000277). Magnetic Resonance Imaging (MRI) MR Images were collected on a 3-Tesla Siemens MRI (Verio 3T; vB19; Siemens Healthineers, Erlangen, Germany) at baseline, 2-, 6-, and 12-month follow-up time points for controls and baseline and post-flight (R + 1:3) for LDSF astronauts. All data was collected on the same MR scanner. In the astronaut cohort, mean (SD) flight duration was 187 (58) days. Whole-head structural T1-weighted images were collected with a 3D Turbo-FLASH sequence and key sequence parameters: replication time (TR) = 1900 ms, echo time (TE) = 2.26ms, flip angle = 9°, field-of-view (FOV) = 256 mm x 256 mm, and voxel size (0.49mm, 0.49mm, 0.9mm) as described in Warthen et al. 26 and Carter et al. 25 . Image Processing We developed and applied a novel semi-automated technique to quantify eye center of mass shift (“eye shift”) within the orbits adapted from the brain-shift methods described by Warthen et al. 26 (Fig. 1 ). Whole-head structural T1 images were segmented with Simnibs Charm 27 to obtain tissues of interest including bone and eye (Fig. 1 a). Bone segmentations for follow-up timepoints were registered to baseline bone segmentations in SPM12 28 (Fig. 1 b). The resulting registration matrix was then applied to align optic globe segmentations from follow-up scans into the baseline space. Cranial bone registrations were considered acceptable with Dice coefficient > 0.8 29 . Bone and eye segmentations were also visually inspected by an expert operator and excluded if they did not meet visual quality checks or were anatomically inaccurate. Change in the 3D center-of-mass for each eye at follow-up vs baseline (eye shift) in the x, y, and z direction (-medial/+lateral, -inferior/+superior, -posterior/-anterior) was calculated by FSL 30 (Fig. 1 c). The coordinate system with eye and skull for reference is depicted in Fig. 2 . Posterior globe flattening near the optic nerve head, also defined as posterior globe volume displacement, was obtained for the LDSF astronauts based on the previously published values of Sater et al. for the same astronaut cohort 24 . In brief, the optic globe was imaged for astronauts at baseline and post-flight using T2 MRI with full coverage of the left and right eye. Automated segmentations were converted to 3D globe surface point clouds with uniform point spacing, and follow-up globe point clouds were registered to baseline. Posterior optic globe volume displacement was calculated based on the posterior globe surface displacement measured within a 4 mm radius around the optic nerve head for each follow-up time point compared to baseline. Data Analysis and Statistics Shift of the eye was analyzed in a linear mixed effects model in R (version 4.2.0, lmer function). The dependent variable was the eye center-of-mass shift from baseline in the x, y, and z, directions. To account for mirrored movement of the left and right eye, x-direction medial shift was expressed as negative, and lateral shift was expressed as positive. Fixed effects included group (astronaut or control), direction, timepoint, and interactions between participant group and direction. Group was included as a random intercept to account for repeated measures. Estimated marginal means (EMMs) were calculated in R (4.5.1) based on parameters from the linear mixed effects model (emmeans package) to obtain group level adjusted means for each direction and participant group, with results averaged across timepoints. EMMs indicate adjusted means for each group and condition representing predicted values averaged over the covariates included in the model, reflecting expected eye shift values if all groups were compared under equivalent conditions. Pairwise comparisons were used to test for differences in eye shift from baseline between astronauts and controls within each direction, with 95% confidence intervals and Kenward-Rogers degrees-of-freedom adjustment 31 . Normality of each directional variable within each group was tested with a Shapiro-Wilk test in R. In an exploratory analysis, associations between measures were tested with Pearson correlations for eye shift versus globe flattening. Adjusted R 2 is reported to account for the number of predictors in the model. Results After data processing and quality checks, data from 35 astronaut eyes (17 left and 18 right eyes) at baseline and follow-up and 5–7 controls over 4 timepoints were included (n = 14 eyes at baseline; n = 10 eyes: 5 left and 5 right at 2 months; n = 12 eyes: 6 left and 6 right at 6 months; n = 14 eyes: 7 left and 7 right at 12 months follow-up) (Fig. 3 ). Eyes from astronauts shifted anteriorly to a greater degree than controls (+ 0.73 ± 0.40 mm versus + 0.12 ± 0.33 mm, mean ± STD, p < 0.0001) (Fig. 4 and Table 1 ). Astronaut eyes also shifted laterally (X-direction) compared to control participants (+ 0.34 ± 0.27 mm versus − 0.10 ± 0.14 mm, p = 0.013) (Fig. 4 and Table 1 ). In astronauts, the left and right eye tended to both move laterally, away from the midline (see L and R eye values in Fig. 3 ). Z-direction eye shift was not different between astronauts and controls (-0.21 ± 0.35 mm, + 0.10 ± 0.14, p = 0.14). Corresponding EMMs and 95% confidence intervals for each group are provided in Fig. 4 and Table 1 . A representative example of eye shift in an LDSF astronaut is visualized in Fig. 5 . The change in Y-direction eye shift of astronauts in COM was not correlated with the magnitude of posterior globe volume displacement (Fig. 6 , adjusted r 2 =-0.035, p = 0.64). Y shift of the left and right eye was strongly correlated when tested in all subjects (adjusted r 2 = 0.69, p = 4.13 x 10 − 5 ). Discussion A novel non-invasive MRI-based method was developed and applied to quantify eye center of mass shift in astronauts following ~ 6 months on the International Space Station compared to terrestrial controls scanned on the same MRI magnet measured at several follow-up time points up to 1-year from baseline. For the first time, we demonstrate that MRI obtained after LDSF revealed that eyes in astronauts shifted anteriorly compared to preflight, and this was absent in control participants imaged over a similar time frame. We did not observe an association between the magnitude of anterior shift and the magnitude of globe volume displacement, a marker of globe flattening at the optic nerve head. Further characterization is needed to determine if eye shift represents an additional independent effect of spaceflight or is a physiologic precursor to SANS. Anterior eye shift presented with a strong effect size and was observed in nearly all 18 astronauts analyzed (Fig. 3 and Fig. 4 ). The lack of eye shift in terrestrial controls (Fig. 3 and Fig. 4 ), not exposed to spaceflight, supports that the presented eye shift method has a small degree of normal variation over time and can be applied consistently. Visual inspection of eye shift (Fig. 1 c and Fig. 5 ) showed the entire eye surface moving anteriorly, outward from the apex of the orbit, with little change in the overall eye shape. Alongside anterior eye shift, the left and right eyes in astronauts moved laterally away from the mid-sagittal plane. This may occur because the human bony orbit is oriented with an approximately 45° lateral angle 32 , 33 . As the eye moves forward, it would also move slightly laterally given the orbital geometry orientation, adding confidence in the sensitivity of eye shift quantification. In contrast, these anterior and lateral shifts did not occur in controls, and no superior or inferior shifts were observed in either astronauts or controls (Fig. 3 and Fig. 4 ). Our findings of an anterior eye shift support previously published models of post-spaceflight orbital congestion 20 . Our data do not directly implicate orbital fat swelling or congestion but may provide a mechanistic explanation for the underlying cause of the eye shift. The pathophysiological significance, or possible benefit, of this eye movement is completely unknown. While anterior eye shift was present in nearly all astronauts, the degree of shift lacked correlation with posterior ocular globe volume displacement (Fig. 6 ). Globe volume displacement has previously been associated with development of optic disc edema in astronauts after spaceflight 24 . Additionally, optic nerve length has been shown to lengthen, which could be related to our globe shift finding 34 . The lack of correlation between anterior eye shift and globe flattening can be interpreted to mean these factors are unrelated, or that the eye shift is limiting the magnitude of globe flattening up to a certain point, before flattening ensues. The latter possibility suggesting that anterior eye movement may be beneficial by accommodating changes in forces developing posterior to the eye before structural flattening occurs. Eye shift may also be related to globe flattening through a chain of other factors exhibiting inter-subject variability such as ocular globe compliance, orbital geometry, and muscle properties. In previous research conducted by our team 24 , globe volume displacement, was statistically significant in astronauts and greatest in a single astronaut with clinical SANS findings. Globe volume displacement also had positive association with globe axial length decreases. In the present study, the astronaut with clinical SANS findings presented with an anterior shift that was relatively average among the crew tested here (0.64 mm anterior Y-shift, see red triangle data point for SANS astronaut in Fig. 6 ). In principle, the astronaut globe flattening would result in an anterior center of mass shift of the eye, however in much smaller amounts than what are observed here. Thus, any eye center of mass change due to globe flattening would be overshadowed by shift of the entire eye as visualized in Fig. 1 c and Fig. 5 . It should be noted that the eye shift measured in this study came from data collected 1–3 days after the crewmembers returned to Earth and therefore may represent a partial recovery from the eye center of mass shift that was present during spaceflight. If recovery occurs rapidly, the values shown would represent an underestimation of the effect during spaceflight. Measurement devices to quantify eye shift non-invasively at the International Space Station may provide additional insight into the magnitude of eye shift that occurs before any recovery can occur. Forward movement, or shift, of the eye is clinically defined as proptosis. On Earth, it is determined by measuring the distance from the posterior surface of the cornea relative to the orbit rim at the interzygomatic line 35 . Clinical proptosis can be a potential complication of thyroid eye disease 36 on Earth, a factor which can also be associated with orbital fat swelling 37 , 38 , optic nerve head swelling 39 and changes in axial length following orbital decompression 40 . Because these standard clinical proptosis measurements do not use MRI, or measure eye shift from true baseline to evaluate proptosis, we are not able to directly compare the degree of eye shift in our study to proptosis measured in disease states on Earth. In cases of unilateral proptosis, an asymmetry of the protrusion between eyes of ~ 2 mm is considered clinically abnormal 41 . The greatest anterior shift we quantified in astronauts as measured by center of mass was 2.1 mm in our study, but this astronaut did not present with clinical SANS findings. Astronaut eye shift in the anterior y-direction was evenly distributed and did not appear to present in a grouped manner. The method described here may be useful to help quantify the degree of proptosis in terms of its change from baseline and 3-dimensional changes in x, y, and z over time. We detect no superior or inferior movement, and the lateral movement shown likely follows the anatomy with anterior movement as a primary outcome. Movement specific to one direction demonstrates that this technique is sensitive enough to detect eye movement without being overwhelmed by noise in each direction. The degree of eye shift documented in astronauts in our study, ranging from 0 to 2 mm, may not be visually apparent to the unaided eye particularly given the amount of facial swelling experienced in LDSF 42 . Swelling of orbital fat behind the eye could place slowly increasing, chronic pressure on the ocular globe and contribute to a forward eye shift. According to previous simulations, the extent of eye shift noted here would correspond to approximately 1.5% increase in orbital tissue volume, including fat, blood, and connective tissue swelling 20 . Differences in individual ocular globe tissue compliance may also play a role in the extent of observed shift and flattening. Globe compliance is known to vary due to several factors including age 23 , 43 , inflammation 44 , and diabetic status 21 , 22 . The chronic forward pressure placed on the eye by fat swelling would also be opposed by the muscles surrounding the eyes 45 , the strength of which in this data set is yet to be measured and may also explain some of the variation in eye shift. A stiffer globe may resist flattening and therefore be pushed forward more by orbital fat swelling, resulting in a greater degree of anterior shift. Conversely, a more compliant globe may flatten more immediately, and not show as much anterior shift. It is notable that we did not observe a relationship between the degree of shift and the magnitude of globe flattening at the ONH, which can be explained for a variety of reasons. First, it is possible that the anterior shift is attenuating the forces applied by the swelling fat pad, effectively limiting the magnitude of globe deformation. This explanation would suggest that anterior eye movement represents a protective effect during spaceflight. Second, it may be that the magnitude of both globe shift and globe deformation was too small for an interactive relationship to emerge. It would be valuable to investigate the magnitude of globe shift that occurs in a greater number of individuals with larger known changes in both globe deformation and optic disc edema. Limitations and future directions It should be noted that 26 astronauts and 10 controls were enrolled in the study, but only 18 astronauts (35 eyes) and 5–7 controls (36 eyes across all timepoints) satisfied quality checks for comparison to baseline. Thus, methods should be adapted to improve rate of success of skull registration, optimize MR image collection for more robust eye segmentation, and contrast for orbital tissues including muscle and fat, and correct for eye gaze angle changes. Direct quantification of orbital fat volume and ocular tissue compliance will be beneficial in future mechanical modeling 20 . Finally, these results should be reproduced in a larger cohort of and controls and tracked post-flight over time. Conclusions A novel method was developed to quantify eye center of mass shift in astronauts and controls. Applying this method, we report statistically significant anterior and lateral eye shift in astronauts after ~ 6 months in space. We did not find a correlation between eye shift and globe flattening. Eye shift may reflect a potential role of orbital fat swelling and the consequence, or benefit, of this structural change requires further investigation. Declarations Conflict of Interest The authors declare no conflict of interest. BAM has received research support from NASA and KBR. BAM is an employee of Neela Therapeutics and consultant to Flux Neuroscience, LLC. Author Contributions Methods and Idea origination: KGW, SHS, CJR, MAR, BAM, MAW Acknowledgements This study was supported by grant 80NSSC22K0023 and a Postdoctoral Grant Augmentation Award for KGW through the Human Research Program of the National Aeronautics and Space Administration (NASA). KJC, SSL, and BRM were also supported by the NASA Human Research Program. References Martin Paez Y, Mudie LI, Subramanian PS. Spaceflight Associated Neuro-Ocular Syndrome (SANS): A Systematic Review and Future Directions. Eye Brain. 2020; 12: 105–117. 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Extraocular muscle index as a novel indicator of inflammatory condition in graves’ ophthalmopathy patients. Front Endocrinol (Lausanne). 2025; 16: 1594828. Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations There is no conflict of interest Supplementary Files Table1.xlsx Table 1. Summary of astronaut and control eye shift in the x, y, and z-direction. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8912940","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":604229232,"identity":"6259b585-f496-4587-9541-95f7a40a3035","order_by":0,"name":"Bryn Martin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYFACxsYDH2wsEHw2IrQ0HJyRJkGSFgaGwzzIWggC3fbDDYdtEiQSN9xuPiZdUVEnz8fee/DDBwY7Od0G7FrMziQ2HM4Bapk551ia5Jkzhw3beM4lS85gSDY2O4BDywGgltwfEon9Ejlmko1tBxLYgAxmHoYDidtwaTn/sOGwBdCWNon8b0AtdQls8m/MmP/g03IDaAtDAtgWNqAWZqAtPGbMDHi1PGw42JMgYTxzRpqxZQPYLznGkj0GePxyPv3hgx8JNrIbbiQ/vNkADDH59jOGH35U2Mnh0oILGJCmfBSMglEwCkYBKgAAwlRdWR9cZMgAAAAASUVORK5CYII=","orcid":"","institution":"Flux Neuroscience, LLC","correspondingAuthor":true,"prefix":"","firstName":"Bryn","middleName":"","lastName":"Martin","suffix":""},{"id":604229233,"identity":"c247a3a0-3c5f-44e5-a2a5-20fec9309dd9","order_by":1,"name":"Katherine Warthen","email":"","orcid":"https://orcid.org/0000-0003-4169-8073","institution":"Stoneleaf Neuroscience","correspondingAuthor":false,"prefix":"","firstName":"Katherine","middleName":"","lastName":"Warthen","suffix":""},{"id":604229234,"identity":"db19f104-6541-4b29-abe9-16d7f4a77dbd","order_by":2,"name":"Stuart Sater","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Stuart","middleName":"","lastName":"Sater","suffix":""},{"id":604229235,"identity":"a882b215-6576-49c6-bf46-afa0027101ac","order_by":3,"name":"Cynthia Roberts","email":"","orcid":"https://orcid.org/0000-0002-0483-4163","institution":"The Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Cynthia","middleName":"","lastName":"Roberts","suffix":""},{"id":604229236,"identity":"46f02c9c-7998-4f64-8ddc-a8e64ad8af1b","order_by":4,"name":"Matthew Reilly","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Reilly","suffix":""},{"id":604229237,"identity":"e71d7466-27f8-4935-9584-2afc470cdb5a","order_by":5,"name":"Steven Katz","email":"","orcid":"","institution":"Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Steven","middleName":"","lastName":"Katz","suffix":""},{"id":604229238,"identity":"a33fe576-e5fb-4eff-acdb-539aa8affc96","order_by":6,"name":"Larry Kramer","email":"","orcid":"https://orcid.org/0000-0002-1450-9479","institution":"University of Texas Health Science Center at Houston, McGovern Medical School","correspondingAuthor":false,"prefix":"","firstName":"Larry","middleName":"","lastName":"Kramer","suffix":""},{"id":604229239,"identity":"b3ca4320-1a3c-4bf3-b8ba-e48db9256907","order_by":7,"name":"Khader Hasan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Khader","middleName":"","lastName":"Hasan","suffix":""},{"id":604229240,"identity":"c3df24e7-5cc6-4553-a53d-07164ec166a8","order_by":8,"name":"Katrina Carter","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Katrina","middleName":"","lastName":"Carter","suffix":""},{"id":604229241,"identity":"0a534f7f-7a1c-454a-b23b-901e3efb780b","order_by":9,"name":"Michael Williams","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Williams","suffix":""},{"id":604229242,"identity":"2f71714c-9e3d-4a71-881b-1bb8494a933a","order_by":10,"name":"Brandon Macias","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Brandon","middleName":"","lastName":"Macias","suffix":""},{"id":604229243,"identity":"c1264eaa-6958-465a-a4e9-56d31ffed90a","order_by":11,"name":"Steven Laurie","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Steven","middleName":"","lastName":"Laurie","suffix":""}],"badges":[],"createdAt":"2026-02-19 00:40:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8912940/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8912940/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104782399,"identity":"062463e8-2b4e-4018-84e0-999129e069e4","added_by":"auto","created_at":"2026-03-17 07:57:15","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1099851,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethod for 3D skull registration and eye shift quantification.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e A. Coronal, sagittal, and a 3D view of pre (blue) and post unregistered skull (orange). B. The same views with the post-skull registered to the pre-skull. C. Registered skulls with pre (pink) and post (green) ocular globe position with detail showing segmentation cross-sectional view through the eye.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/1cbcbf45eb925547091d5293.jpg"},{"id":104668820,"identity":"57e8d876-d76d-4667-ad22-6e0127a6fdc1","added_by":"auto","created_at":"2026-03-15 16:56:35","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":458827,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eCoordinate system for eye center of mass change from baseline.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Shift from baseline in the posterior direction are -Y, anterior +Y, lateral +X, medial -X, superior +Z, and inferior -Z.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/9e09ac1ac35026b94132be3b.jpg"},{"id":104781880,"identity":"82331dfb-335d-4116-a18d-8600eb50f1e3","added_by":"auto","created_at":"2026-03-17 07:56:31","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":229587,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEye center of mass (COM) shift in the X (-medial/+lateral) and Y (-posterior/+anterior) direction is different in astronauts (blue) compared to controls (purple = 2mo, green = 6mo, orange = 12mo follow-up).\u003c/strong\u003e 95% confidence interval bounds are demarcated with ellipses (blue = astronaut, black = controls), left eyes are represented with circles, and right eyes are represented with triangles. Blue dotted lines represent linear fit of L- and R-eye results for astronauts, showing lateral shift in both eyes.\u003c/p\u003e","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/cb433b4b7439d63c2d51bcda.jpg"},{"id":104668823,"identity":"f30cb2c3-3483-4971-92d2-a5ad277dbce5","added_by":"auto","created_at":"2026-03-15 16:56:35","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":118016,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eEye center of mass (COM) shift in terms of estimated marginal means adjusted for each group and direction.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Black dot is the estimated marginal mean and violet bar is the 95% confidence interval (*p=0.013, ***p\u0026lt;0.0001)\u003c/em\u003e\u003c/p\u003e","description":"","filename":"fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/2975d6c702729b78fe558b59.jpg"},{"id":104668824,"identity":"5fe3370a-e49b-4906-84ca-662dbd22caf9","added_by":"auto","created_at":"2026-03-15 16:56:35","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":179871,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExample of astronaut anterior eye shift.\u003c/strong\u003e Original eye position from an astronaut segmentation is shown in opaque gray, and post-spaceflight eye position is visualized in blue dots indicating a primarily anterior eye shift (+y).\u003c/p\u003e","description":"","filename":"fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/34abb51e308d5f88fea7ce33.jpg"},{"id":104668825,"identity":"519efbb7-e434-48d3-9d79-2216e52f614b","added_by":"auto","created_at":"2026-03-15 16:56:35","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":163287,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eY-direction eye shift lacked correlation with posterior globe volume displacement (globe flattening) in astronauts \u003c/strong\u003e\u003c/em\u003e\u003cem\u003e(n=15). Several astronauts had notable posterior globe volume displacement (~20-30 mm\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e) and yet had relatively little eye shift. Blue line represents linear fit, gray band represents 95% confidence interval, le\u003c/em\u003eft eyes are represented with circles, and right eyes are represented with triangles. Red triangle indicates an astronaut with a high level of globe flattening as a SANS indicator (left eye not available in both measures). Ocular globe volume displacement values from Sater et al., 2021\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e","description":"","filename":"fig6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/b074bc61438a148ee46777ab.jpg"},{"id":108491668,"identity":"33c313d8-d4cf-4534-b60d-84b08a5b9ab1","added_by":"auto","created_at":"2026-05-05 09:55:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2497959,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/74a8c4a9-9675-4a21-a284-7b90b65eb9c4.pdf"},{"id":104668819,"identity":"8eb1f031-da05-4b4f-bd7c-09f574b74ec5","added_by":"auto","created_at":"2026-03-15 16:56:35","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11318,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Summary of astronaut and control eye shift in the x, y, and z-direction.\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8912940/v1/86b07976bb17a73347926a76.xlsx"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Anterior ocular globe shift observed in astronauts after long-duration spaceflight","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLong-duration spaceflight (LDSF) astronauts are at risk for a myriad of ocular phenomena including optic disc edema, choroidal folds, posterior globe flattening, and hyperopic shift\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Together these are known as Spaceflight Associated Neuro-ocular Syndrome, or SANS\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, one of the major NASA Human Research Roadmap risks\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The exact mechanism of SANS is unclear\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, although it is thought to be related to headward fluid shift experienced during LDSF due to the prolonged loss of the hydrostatic pressure gradient driven by gravity. It remains unknown if there are individual biological risk factors that contribute to SANS, and why only some astronauts develop SANS\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. SANS was initially attributed to a potential increase in intracranial pressure (ICP) during spaceflight due to the observation of optic disc edema present in some LDSF astronauts and mildly elevated postflight lumbar puncture opening pressures in some astronauts who presented with optic disc edema\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, noninvasive ICP measurements collected during spaceflight\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e have not been observed to be pathologically elevated and direct ICP measures made via lumbar puncture in astronauts presenting with optic disc edema immediately following return from space were not pathologically elevated\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Additional theories of modifying factors that influence SANS include anatomic factors such as optic cup volume\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e and genetic polymorphisms such as alterations in the one-carbon pathway\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA novel theory for SANS development, supported by modeling data\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, puts forth that headward fluid shift in microgravity may cause posterior orbital fat pad swelling. The bony orbit cone encases the eye, optic nerve, blood vessels, ocular muscles, and orbital fat\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Orbital fat swelling behind the eye may place a forward force on the eye, potentially contributing to SANS findings such as globe flattening and axial length reduction\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Reilly et al. employed finite element modeling to simulate orbital biomechanics under fluid shift and found that orbital fat swelling driven by this fluid shift may produce proptosis, or anterior eye shift within the orbit. In this model, eye shift during the subsequent fluid shift due to the loss of hydrostatic gradient was affected by a complex force balance including intracranial and intraocular pressures, orbital fat swelling, extraocular muscle tension, and optic nerve stretching\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In principle, this force balance would also be impacted by inter-individual differences in tissue compliance\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Orbital fat swelling and potential for anterior eye shift have not been quantified in astronauts, and it is unknown if they are related, relevant, or occur at all. If anterior eye shift occurs in spaceflight, it may indicate orbital fat swelling and an increased outward force on the back of the eye that may play a role in early SANS pathogenesis. Anterior eye shift has never been quantified after LDSF, representing a potentially important knowledge gap in SANS research.\u003c/p\u003e \u003cp\u003eTo examine this question, we developed and applied a semi-automated method to quantify anterior eye shift within the orbit based on MRI measurements collected longitudinally in LDSF astronauts and compared to ground-based controls. We hypothesized that anterior eye shift would be greater in LDSF astronauts compared to ground-based controls and inversely associated with posterior globe flattening\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThis longitudinal case-control study included 26 LDSF astronauts and 10 ground-based control participants with baseline health similar to the astronaut group imaged on the same MRI scanner, as described by Carter et al\u003csup\u003e25\u003c/sup\u003e. Written informed consent was obtained for all participants in accordance with NASA IRB guidelines and data were collated across multiple studies (PRO0701, PRO0285, and STUDY00000277).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMagnetic Resonance Imaging (MRI)\u003c/h3\u003e\n\u003cp\u003eMR Images were collected on a 3-Tesla Siemens MRI (Verio 3T; vB19; Siemens Healthineers, Erlangen, Germany) at baseline, 2-, 6-, and 12-month follow-up time points for controls and baseline and post-flight (R\u0026thinsp;+\u0026thinsp;1:3) for LDSF astronauts. All data was collected on the same MR scanner. In the astronaut cohort, mean (SD) flight duration was 187 (58) days.\u003c/p\u003e \u003cp\u003eWhole-head structural T1-weighted images were collected with a 3D Turbo-FLASH sequence and key sequence parameters: replication time (TR)\u0026thinsp;=\u0026thinsp;1900 ms, echo time (TE)\u0026thinsp;=\u0026thinsp;2.26ms, flip angle\u0026thinsp;=\u0026thinsp;9\u0026deg;, field-of-view (FOV)\u0026thinsp;=\u0026thinsp;256 mm x 256 mm, and voxel size (0.49mm, 0.49mm, 0.9mm) as described in Warthen et al.\u003csup\u003e26\u003c/sup\u003e and Carter et al.\u003csup\u003e25\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eImage Processing\u003c/h3\u003e\n\u003cp\u003eWe developed and applied a novel semi-automated technique to quantify eye center of mass shift (\u0026ldquo;eye shift\u0026rdquo;) within the orbits adapted from the brain-shift methods described by Warthen et al.\u003csup\u003e26\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Whole-head structural T1 images were segmented with Simnibs Charm\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e to obtain tissues of interest including bone and eye (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Bone segmentations for follow-up timepoints were registered to baseline bone segmentations in SPM12\u003csup\u003e28\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The resulting registration matrix was then applied to align optic globe segmentations from follow-up scans into the baseline space. Cranial bone registrations were considered acceptable with Dice coefficient\u0026thinsp;\u0026gt;\u0026thinsp;0.8\u003csup\u003e29\u003c/sup\u003e. Bone and eye segmentations were also visually inspected by an expert operator and excluded if they did not meet visual quality checks or were anatomically inaccurate. Change in the 3D center-of-mass for each eye at follow-up vs baseline (eye shift) in the x, y, and z direction (-medial/+lateral, -inferior/+superior, -posterior/-anterior) was calculated by FSL\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). The coordinate system with eye and skull for reference is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePosterior globe flattening near the optic nerve head, also defined as posterior globe volume displacement, was obtained for the LDSF astronauts based on the previously published values of Sater et al. for the same astronaut cohort\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. In brief, the optic globe was imaged for astronauts at baseline and post-flight using T2 MRI with full coverage of the left and right eye. Automated segmentations were converted to 3D globe surface point clouds with uniform point spacing, and follow-up globe point clouds were registered to baseline. Posterior optic globe volume displacement was calculated based on the posterior globe surface displacement measured within a 4 mm radius around the optic nerve head for each follow-up time point compared to baseline.\u003c/p\u003e\n\u003ch3\u003eData Analysis and Statistics\u003c/h3\u003e\n\u003cp\u003eShift of the eye was analyzed in a linear mixed effects model in R (version 4.2.0, lmer function). The dependent variable was the eye center-of-mass shift from baseline in the x, y, and z, directions. To account for mirrored movement of the left and right eye, x-direction medial shift was expressed as negative, and lateral shift was expressed as positive. Fixed effects included group (astronaut or control), direction, timepoint, and interactions between participant group and direction. Group was included as a random intercept to account for repeated measures. Estimated marginal means (EMMs) were calculated in R (4.5.1) based on parameters from the linear mixed effects model (emmeans package) to obtain group level adjusted means for each direction and participant group, with results averaged across timepoints. EMMs indicate adjusted means for each group and condition representing predicted values averaged over the covariates included in the model, reflecting expected eye shift values if all groups were compared under equivalent conditions. Pairwise comparisons were used to test for differences in eye shift from baseline between astronauts and controls within each direction, with 95% confidence intervals and Kenward-Rogers degrees-of-freedom adjustment\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Normality of each directional variable within each group was tested with a Shapiro-Wilk test in R. In an exploratory analysis, associations between measures were tested with Pearson correlations for eye shift versus globe flattening. Adjusted R\u003csup\u003e2\u003c/sup\u003e is reported to account for the number of predictors in the model.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAfter data processing and quality checks, data from 35 astronaut eyes (17 left and 18 right eyes) at baseline and follow-up and 5\u0026ndash;7 controls over 4 timepoints were included (n\u0026thinsp;=\u0026thinsp;14 eyes at baseline; n\u0026thinsp;=\u0026thinsp;10 eyes: 5 left and 5 right at 2 months; n\u0026thinsp;=\u0026thinsp;12 eyes: 6 left and 6 right at 6 months; n\u0026thinsp;=\u0026thinsp;14 eyes: 7 left and 7 right at 12 months follow-up) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Eyes from astronauts shifted anteriorly to a greater degree than controls (+\u0026thinsp;0.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.40 mm versus +\u0026thinsp;0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33 mm, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;STD, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e). Astronaut eyes also shifted laterally (X-direction) compared to control participants (+\u0026thinsp;0.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 mm versus \u0026minus;\u0026thinsp;0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 mm, p\u0026thinsp;=\u0026thinsp;0.013) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e). In astronauts, the left and right eye tended to both move laterally, away from the midline (see L and R eye values in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Z-direction eye shift was not different between astronauts and controls (-0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35 mm, +\u0026thinsp;0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14, p\u0026thinsp;=\u0026thinsp;0.14). Corresponding EMMs and 95% confidence intervals for each group are provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. A representative example of eye shift in an LDSF astronaut is visualized in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThe change in Y-direction eye shift of astronauts in COM was not correlated with the magnitude of\u003c/p\u003e \u003cp\u003eposterior globe volume displacement (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, adjusted r\u003csup\u003e2\u003c/sup\u003e=-0.035, p\u0026thinsp;=\u0026thinsp;0.64). Y shift of the left and right eye was strongly correlated when tested in all subjects (adjusted r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.69, p\u0026thinsp;=\u0026thinsp;4.13 x 10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA novel non-invasive MRI-based method was developed and applied to quantify eye center of mass shift in astronauts following\u0026thinsp;~\u0026thinsp;6 months on the International Space Station compared to terrestrial controls scanned on the same MRI magnet measured at several follow-up time points up to 1-year from baseline. For the first time, we demonstrate that MRI obtained after LDSF revealed that eyes in astronauts shifted anteriorly compared to preflight, and this was absent in control participants imaged over a similar time frame. We did not observe an association between the magnitude of anterior shift and the magnitude of globe volume displacement, a marker of globe flattening at the optic nerve head. Further characterization is needed to determine if eye shift represents an additional independent effect of spaceflight or is a physiologic precursor to SANS.\u003c/p\u003e \u003cp\u003eAnterior eye shift presented with a strong effect size and was observed in nearly all 18 astronauts analyzed (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The lack of eye shift in terrestrial controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), not exposed to spaceflight, supports that the presented eye shift method has a small degree of normal variation over time and can be applied consistently. Visual inspection of eye shift (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) showed the entire eye surface moving anteriorly, outward from the apex of the orbit, with little change in the overall eye shape. Alongside anterior eye shift, the left and right eyes in astronauts moved laterally away from the mid-sagittal plane. This may occur because the human bony orbit is oriented with an approximately 45\u0026deg; lateral angle\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. As the eye moves forward, it would also move slightly laterally given the orbital geometry orientation, adding confidence in the sensitivity of eye shift quantification. In contrast, these anterior and lateral shifts did not occur in controls, and no superior or inferior shifts were observed in either astronauts or controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur findings of an anterior eye shift support previously published models of post-spaceflight orbital congestion\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Our data do not directly implicate orbital fat swelling or congestion but may provide a mechanistic explanation for the underlying cause of the eye shift. The pathophysiological significance, or possible benefit, of this eye movement is completely unknown. While anterior eye shift was present in nearly all astronauts, the degree of shift lacked correlation with posterior ocular globe volume displacement (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Globe volume displacement has previously been associated with development of optic disc edema in astronauts after spaceflight\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Additionally, optic nerve length has been shown to lengthen, which could be related to our globe shift finding\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. The lack of correlation between anterior eye shift and globe flattening can be interpreted to mean these factors are unrelated, or that the eye shift is limiting the magnitude of globe flattening up to a certain point, before flattening ensues. The latter possibility suggesting that anterior eye movement may be beneficial by accommodating changes in forces developing posterior to the eye before structural flattening occurs. Eye shift may also be related to globe flattening through a chain of other factors exhibiting inter-subject variability such as ocular globe compliance, orbital geometry, and muscle properties.\u003c/p\u003e \u003cp\u003eIn previous research conducted by our team\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, globe volume displacement, was statistically significant in astronauts and greatest in a single astronaut with clinical SANS findings. Globe volume displacement also had positive association with globe axial length decreases. In the present study, the astronaut with clinical SANS findings presented with an anterior shift that was relatively average among the crew tested here (0.64 mm anterior Y-shift, see red triangle data point for SANS astronaut in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). In principle, the astronaut globe flattening would result in an anterior center of mass shift of the eye, however in much smaller amounts than what are observed here. Thus, any eye center of mass change due to globe flattening would be overshadowed by shift of the entire eye as visualized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. It should be noted that the eye shift measured in this study came from data collected 1\u0026ndash;3 days after the crewmembers returned to Earth and therefore may represent a partial recovery from the eye center of mass shift that was present during spaceflight. If recovery occurs rapidly, the values shown would represent an underestimation of the effect during spaceflight. Measurement devices to quantify eye shift non-invasively at the International Space Station may provide additional insight into the magnitude of eye shift that occurs before any recovery can occur.\u003c/p\u003e \u003cp\u003eForward movement, or shift, of the eye is clinically defined as proptosis. On Earth, it is determined by measuring the distance from the posterior surface of the cornea relative to the orbit rim at the interzygomatic line\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Clinical proptosis can be a potential complication of thyroid eye disease\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e on Earth, a factor which can also be associated with orbital fat swelling\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, optic nerve head swelling\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e and changes in axial length following orbital decompression\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Because these standard clinical proptosis measurements do not use MRI, or measure eye shift from true baseline to evaluate proptosis, we are not able to directly compare the degree of eye shift in our study to proptosis measured in disease states on Earth. In cases of unilateral proptosis, an asymmetry of the protrusion between eyes of ~\u0026thinsp;2 mm is considered clinically abnormal\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. The greatest anterior shift we quantified in astronauts as measured by center of mass was 2.1 mm in our study, but this astronaut did not present with clinical SANS findings. Astronaut eye shift in the anterior y-direction was evenly distributed and did not appear to present in a grouped manner. The method described here may be useful to help quantify the degree of proptosis in terms of its change from baseline and 3-dimensional changes in x, y, and z over time. We detect no superior or inferior movement, and the lateral movement shown likely follows the anatomy with anterior movement as a primary outcome. Movement specific to one direction demonstrates that this technique is sensitive enough to detect eye movement without being overwhelmed by noise in each direction. The degree of eye shift documented in astronauts in our study, ranging from 0 to 2 mm, may not be visually apparent to the unaided eye particularly given the amount of facial swelling experienced in LDSF\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSwelling of orbital fat behind the eye could place slowly increasing, chronic pressure on the ocular globe and contribute to a forward eye shift. According to previous simulations, the extent of eye shift noted here would correspond to approximately 1.5% increase in orbital tissue volume, including fat, blood, and connective tissue swelling\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Differences in individual ocular globe tissue compliance may also play a role in the extent of observed shift and flattening. Globe compliance is known to vary due to several factors including age\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e, inflammation\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e, and diabetic status\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The chronic forward pressure placed on the eye by fat swelling would also be opposed by the muscles surrounding the eyes\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, the strength of which in this data set is yet to be measured and may also explain some of the variation in eye shift. A stiffer globe may resist flattening and therefore be pushed forward more by orbital fat swelling, resulting in a greater degree of anterior shift. Conversely, a more compliant globe may flatten more immediately, and not show as much anterior shift. It is notable that we did not observe a relationship between the degree of shift and the magnitude of globe flattening at the ONH, which can be explained for a variety of reasons. First, it is possible that the anterior shift is attenuating the forces applied by the swelling fat pad, effectively limiting the magnitude of globe deformation. This explanation would suggest that anterior eye movement represents a protective effect during spaceflight. Second, it may be that the magnitude of both globe shift and globe deformation was too small for an interactive relationship to emerge. It would be valuable to investigate the magnitude of globe shift that occurs in a greater number of individuals with larger known changes in both globe deformation and optic disc edema.\u003c/p\u003e\n\u003ch3\u003eLimitations and future directions\u003c/h3\u003e\n\u003cp\u003eIt should be noted that 26 astronauts and 10 controls were enrolled in the study, but only 18 astronauts (35 eyes) and 5\u0026ndash;7 controls (36 eyes across all timepoints) satisfied quality checks for comparison to baseline. Thus, methods should be adapted to improve rate of success of skull registration, optimize MR image collection for more robust eye segmentation, and contrast for orbital tissues including muscle and fat, and correct for eye gaze angle changes. Direct quantification of orbital fat volume and ocular tissue compliance will be beneficial in future mechanical modeling\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Finally, these results should be reproduced in a larger cohort of and controls and tracked post-flight over time.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eA novel method was developed to quantify eye center of mass shift in astronauts and controls. Applying this method, we report statistically significant anterior and lateral eye shift in astronauts after ~\u0026thinsp;6 months in space. We did not find a correlation between eye shift and globe flattening. Eye shift may reflect a potential role of orbital fat swelling and the consequence, or benefit, of this structural change requires further investigation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest. BAM has received research support from NASA and KBR. BAM is an employee of Neela Therapeutics and consultant to Flux Neuroscience, LLC.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eMethods and Idea origination: KGW, SHS, CJR, MAR, BAM, MAW\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThis study was supported by grant 80NSSC22K0023 and a Postdoctoral Grant Augmentation Award for KGW through the Human Research Program of the National Aeronautics and Space Administration (NASA). KJC, SSL, and BRM were also supported by the NASA Human Research Program.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMartin Paez Y, Mudie LI, Subramanian PS. Spaceflight Associated Neuro-Ocular Syndrome (SANS): A Systematic Review and Future Directions. Eye Brain. 2020; 12: 105\u0026ndash;117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRohr JJ, Sater S, Sass AM, Marshall-Goebel K, Ploutz-Snyder RJ, Ethier CR, et al. 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Front Endocrinol (Lausanne). 2025; 16: 1594828.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8912940/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8912940/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground/Objectives\u003c/p\u003e \u003cp\u003eLong-duration spaceflight is associated with ophthalmic effects such as optic disc edema, hyperopic shift, ocular globe flattening, and choroidal folds, collectively known as Spaceflight Associated Neuro-ocular Syndrome, or SANS. While the mechanism of SANS remains unknown, modeling of orbital congestion has predicted anterior shift of the eye which has not yet been evaluated. The goal of this study was to develop and apply a non-invasive MRI-based method for quantification of eye shift in long-duration spaceflight astronauts.\u003c/p\u003e \u003cp\u003eSubjects/Methods\u003c/p\u003e \u003cp\u003ePreflight and postflight 3D T1-weighted MR images of the head were analyzed from 18 astronauts after approximately 6 months of spaceflight, and in 10 terrestrial controls at baseline, 2, 6, and 12-month follow-up. A semi-automated method was developed to quantify 3-dimensional eye movement, in the x, y, and z direction, with respect to the skull at follow-up versus baseline based on ocular globe center-of-mass (eye shift). Association between eye shift and posterior globe flattening was tested with a Pearson correlation.\u003c/p\u003e \u003cp\u003eResults\u003c/p\u003e \u003cp\u003eEye shift in the x, y, and z direction (-medial/+lateral, -posterior/+anterior, -inferior/+superior) was 0.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 mm (p\u0026thinsp;=\u0026thinsp;0.013), 0.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.40 mm (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), -0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35 mm (p\u0026thinsp;=\u0026thinsp;0.14), in astronauts compared to -0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 mm, 0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33 mm, and \u0026minus;\u0026thinsp;0.037\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35 mm in controls. Correlations between posterior globe flattening and eye shift were not significant in any x, y, or z direction.\u003c/p\u003e \u003cp\u003eConclusions\u003c/p\u003e \u003cp\u003eA novel semi-automated MRI-based pipeline was developed to quantify anterior eye shift in astronauts and terrestrial controls. There were statistically significant shifts in eye center of mass in the anterior and lateral directions in astronauts compared to terrestrial controls.\u003c/p\u003e","manuscriptTitle":"Anterior ocular globe shift observed in astronauts after long-duration spaceflight","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-15 16:56:30","doi":"10.21203/rs.3.rs-8912940/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"10f1f5d0-0fa9-4d1a-ad34-c9d528fda3b9","owner":[],"postedDate":"March 15th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Reject after peer review","date":"2026-05-01T15:22:38+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":64296517,"name":"Health sciences/Medical research"},{"id":64296518,"name":"Biological sciences/Biological techniques"},{"id":64296519,"name":"Biological sciences/Neuroscience/Visual system"}],"tags":[],"updatedAt":"2026-05-01T15:25:41+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-15 16:56:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8912940","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8912940","identity":"rs-8912940","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}