December 2020
Volume 61, Issue 14
Open Access
Retina  |   December 2020
Decreased Vascular Patterning in the Retinas of Astronaut Crew Members as New Measure of Ocular Damage in Spaceflight-Associated Neuro-ocular Syndrome
Author Affiliations & Notes
  • Ruchi J. Vyas
    SGT Incorporated, NASA Ames Research Center, Mountain View, California, United States
  • Millennia Young
    NASA Johnson Space Center, Houston, Texas, United States
  • Matthew C. Murray
    Ames Blue Marble Space Institute of Science, NASA Ames Research Center, Mountain View, California, United States
  • Marina Predovic
    Ames Blue Marble Space Institute of Science, NASA Ames Research Center, Mountain View, California, United States
  • Shiyin Lim
    Ames Blue Marble Space Institute of Science, NASA Ames Research Center, Mountain View, California, United States
  • Nicole M. Jacobs
    Ames Blue Marble Space Institute of Science, NASA Ames Research Center, Mountain View, California, United States
  • Sara S. Mason
    MEI Technologies, NASA Johnson Space Center, Houston, Texas, United States
  • Susana B. Zanello
    KBR, NASA Johnson Space Center, Houston, Texas, United States
  • Giovanni Taibbi
    Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
  • Gianmarco Vizzeri
    Department of Ophthalmology and Visual Sciences, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
  • Patricia Parsons-Wingerter
    Low Gravity Exploration Technology, NASA, Glenn Research Center, Cleveland, Ohio, United States
Investigative Ophthalmology & Visual Science December 2020, Vol.61, 34. doi:https://doi.org/10.1167/iovs.61.14.34
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      Ruchi J. Vyas, Millennia Young, Matthew C. Murray, Marina Predovic, Shiyin Lim, Nicole M. Jacobs, Sara S. Mason, Susana B. Zanello, Giovanni Taibbi, Gianmarco Vizzeri, Patricia Parsons-Wingerter; Decreased Vascular Patterning in the Retinas of Astronaut Crew Members as New Measure of Ocular Damage in Spaceflight-Associated Neuro-ocular Syndrome. Invest. Ophthalmol. Vis. Sci. 2020;61(14):34. doi: https://doi.org/10.1167/iovs.61.14.34.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Ocular structural and functional changes, collectively termed spaceflight-associated neuro-ocular syndrome (SANS), have been described in astronauts undergoing long-duration missions in the microgravity environment of the International Space Station. We tested the hypothesis that retinal vascular remodeling, particularly by smaller vessels, mediates the chronic headward fluid shifts associated with SANS.

Methods: As a retrospective study, arterial and venous patterns extracted from 30° infrared Heidelberg Spectralis retinal images of eight crew members acquired before and after six-month missions were analyzed with NASA's recently released VESsel GENeration Analysis (VESGEN) software. Output parameters included the fractal dimension (Df) and overall length density (Lv) that was further classified into large and small vascular branching generations. Vascular results were compared with SANS-associated clinical ocular measures.

Results: Significant postflight decreases in Df, Lv, and in smaller but not larger vessels were quantified in 11 of 16 retinas for arteries and veins (P value for Df, Lv, and smaller vessels in all 16 retinas were ≤0.033). The greatest vascular decreases occurred in the only retina displaying clinical evidence of SANS by choroidal folds and optic disc edema. In the remaining 15 retinas, decreases in vascular density from Df and Lv ranged from minimal to high by a custom Subclinical Vascular Pathology Index.

Conclusions: Together with VESGEN, the Subclinical Vascular Pathology Index may represent a new, useful SANS biomarker for advancing the understanding of SANS etiology and developing successful countermeasures for long duration space exploration in microgravity, although further research is required to better characterize retinal microvascular adaptations.

Astronauts experience ocular structural and visual impairments when exposed to microgravity on board the International Space Station (ISS), especially during the new long duration missions of six months or more.19 Of variable severity, these changes are denoted collectively by NASA as the spaceflight-associated neuro-ocular syndrome (SANS; previously visual impairments associated with increased intracranial pressure). Risks documented by established clinical methods include optic disc edema (ODE), optic nerve sheath distension, increased total retinal thickness, and choroid thickness, cotton wool spots, and posterior globe flattening with secondary hyperopic shift, accompanied by decreased near visual acuity.8 Estimations of the incidence of SANS have varied considerably, depending on the clinical measures and cutoff values for SANS. Research on the etiology of this complex syndrome has resulted in several explanations that continue to be actively investigated and focus on the headward fluid shifts incurred in the microgravity environment.8 After long duration missions, approximately 15% of astronauts have displayed clinically significant (Frisén grade 1–3) ODE, with choroidal folds observed in 20% of astronauts, and subclinical levels of increased ODE, TRT, and choroid thickness documented for the remainder of most crew members.6,8 For this study, we tested the hypothesis that blood vessels in the retinas of crew members, particularly the smaller vessels, necessarily remodel to mediate and accommodate the chronic headward fluid shifts believed to be associated with the cardiovascular stresses of prolonged microgravity.5,6,10,11 A fundamental function of the microvascular endothelium throughout the body is to regulate overall fluid balances within each tissue.12 
For this investigation, vascular patterns extracted from retinal images of eight astronauts acquired before and after 6-month missions to the ISS were mapped and quantified using NASA's VESsel GENeration Analysis (VESGEN) software.1315 Previous research demonstrated the ability of VESGEN to identify oscillatory (alternating), homeostatic-like changes in the vascular patterning of retinas at progressive stages of diabetic retinopathy.13,16,17 Results for retinas from early to late stages of diabetic retinopathy revealed that vascular remodeling alternated between patterns of increased and decreased vessel density, primarily because of successive alternations between low and high densities of the small vessels. For early in vivo studies on the regulation of angiogenesis and antiangiogenesis by numerous cytokines such as vascular endothelial growth factor (VEGF)-A1823 and anti-inflammatory agents,13,24,25 analysis by VESGEN demonstrated that each molecular regulator induced a unique “fingerprint” or “signature” pattern of vascular response. For example, as a complex cytokine of pluripotent activity, VEGF-A (also termed vascular permeability factor) displayed a phenotypic switch between the stimulation of physiologic angiogenesis at a low concentration to a nonangiogenic pathologic stimulation of vessel dilation and leakage at high concentration.21 In contrast, basic fibroblast growth factor exerted only a dose-dependent stimulation of robust angiogenesis.26 The angiogenesis inhibitor angiostatin induced an ill-formed, pathologic response of vascular patterning,18 whereas the anti-inflammatory clinical steroid triamcinolone acetonide inhibited angiogenesis by not only selectively inhibiting the growth of new small vessels, but also thinning the diameters of all vessels throughout the vascular tree.24 
The aim of this study was to test whether changes in arterial and venous patterning within crew member retinas during long duration missions offer a useful early-stage predictor, monitor, and new measure of SANS. Based on vascular branching rules such as vessel connectivity and fractal bifurcational branching, the automated vascular mapping and quantification by VESGEN assigns vessels to branching generations for site-specific analysis of changes within complex branching vascular trees.13 Software output includes informative vascular maps and parameters such as vessel length, diameter, branchpoints and the fractal dimension (Df). This analytical approach has consistently validated the important role of small vessels in vascular remodeling.13,17,19,20,24,25,2729 As developed by Mandelbrot and others,30,31 fractal geometry describes the complex space-filling patterns observed frequently in nature and in the transport phenomena of physics that include vascular and neuronal branching, arterial river systems, botanical trees, and retinal vascular remodeling.13,17 As a useful measure of overall vascular space-filling capacity, Df is of fractional value, unlike the dimensional integers of Euclidean geometry. Branching patterns in human and other vertebrate vascular systems are based to some extent on the fractal property of self-similarity, by which the characteristic vascular bifurcational branching pattern is repeated at decreasing length scales.31,32 
Methods
Participants
The retrospective cohort study design of eight U.S. astronaut crew members conformed to the tenets of the Declaration of Helsinki, epidemiological guidelines,33 and was approved by the Institutional Review Board and Lifetime Surveillance of Astronaut Health (LSAH) at the NASA Johnson Space Center, Houston, Texas, after informed consent by the participants. Because of astronaut privacy rights, only limited and pooled information on characteristics of the study participants is available from LSAH (Table 1). All crew members completed missions of approximately six months aboard the ISS, with preflight and postflight medical exams that included fundoscopy and/or optical coherence tomography (OCT). Crew members were required to meet defined NASA medical standards at crew selection and flight selection, with specific requirements defined for all body systems that include standards for visual/ocular, neurologic, and cardiovascular fitness.8,3436 Preflight and postflight exams were performed in the upright position. Exercise prescriptions (especially for resistive exercise) were highly similar for ISS crew members after adjusting for size and gender of the crew member. 
Table 1.
 
Characteristics of Study Participants (Most Astronauts Were Repeat Flyers)8
Table 1.
 
Characteristics of Study Participants (Most Astronauts Were Repeat Flyers)8
Study Design
The study consisted of two phases. First, vascular images of the retinas of eight crew members (de-identified as A–G) acquired preflight and postflight flight by Medical Operations, Johnson Space Center (n = 8; 16 retinas; 32 pre/post images) were analyzed with VESGEN by vascular analysts in a blinded manner (i.e., participant identity and pre/post ISS image status were masked to the vascular analysis team). Second, the pre/post status of the images was unmasked to assess vascular changes. Retinal vascular results were compared with ocular and visual measures from clinical findings such as axial length (IOL Master 500, Carl Zeiss Meditec, Dublin, CA), ODE identified during dilated fundus examination from retinal images using a TRC 50EX retinal mydriatic camera (Topcon, Oakland, NJ), and TRT and peripapillary choroidal thickness measured by Heidelberg Spectralis OCT (Heidelberg Engineering GmbH, Heidelberg, Germany).9 
Image Acquisition and Post Processing
Retinal vascular images (1536 × 1536 pixels2) acquired by Spectralis infrared (IR) 30° imaging (Heidelberg Engineering) at Medical Operations, Johnson Space Center were centered on the optic disc (average resolution, 6.03 µm/pixel). The track mode of the OCT was used to scan the identical retinal area in postflight images from baseline preflight images for exact comparisons of vascular differences. Because the original 1536 × 1536 pixel2 images were converted during transmission of crew member data to a bitmap (bmp) image format at 496 × 496 pixel2, a scaling factor of 0.3229 was applied to recover the original 1536 × 1536 pixel2 image resolution for correct calculation of the physical dimensions of parameters for total vessel length density (Lv). 
In brief,13,17 a binary vascular pattern of overlapping arterial and venous trees was extracted from grayscale IR images by semi-automatic computer processing with Photoshop (Adobe, Mountain View, CA) using large high-resolution Apple monitors (Cupertino, CA). The binary vascular pattern was manually separated into images of arterial and venous trees by comparison with color fundus images (when available) and by basic physiologic principles of vascular tree connectivity, branching, vessel tapering, and arteriovenous pairing. Vessel interpretation was subject to agreement by at least two experienced vascular image analysts (with reviews and final decision by senior analyst). 
This report is the first on the application of the VESGEN analysis to a longitudinal study of human retinal images (Tables 14). For previous13,16,17 and concluding studies of diabetic retinopathy, only single images of patients were analyzed as cross-sectional study designs. Consequently, an important new method for this study was the straightforward reconciliation of first the segmented pre/post vascular patterns, and then of the separated arterial and venous trees, described in detail in the Supplementary Data. This process was undertaken to ensure that any differences in the blinded results of the vascular analysis could be attributed to actual differences of vascular response to microgravity, and not to artifacts of the vessel segmentation. Although the quality of the pre/post IR images appeared quite uniform, minor differences in the detection of smaller vessels also probably resulted from inevitable imaging limitations. 
Table 2.
 
Arterial and Venous Density in 16 Retinas of Eight Crew Members Before and After 6-Month Missions to the ISS.
Table 2.
 
Arterial and Venous Density in 16 Retinas of Eight Crew Members Before and After 6-Month Missions to the ISS.
Table 3.
 
Case Study of Crew Member A Diagnosed With SANS
Table 3.
 
Case Study of Crew Member A Diagnosed With SANS
Table 4.
 
SVPI for SANS From Preflight to Postflight Changes
Table 4.
 
SVPI for SANS From Preflight to Postflight Changes
Vascular Mapping and Quantification
Each binary arterial or venous image served as the single input image to VESGEN (version 1.0) for automated mapping and quantification (Fig. 1). The software, publicly available with a comprehensive user guide upon request to NASA,37 is written as a complex plug-in to ImageJ (U.S. National Institutes of Health, Bethesda, MD)38 and has been validated for the following operating systems: Microsoft Windows and MacOS through Mojave (Catalina is currently being tested). Output calculated by the software includes various arterial and venous maps, Df and Lv that is further divided into specific branching generations G1, G2,…G6 as Lv14 and Lv≥5 (Fig. 1).13 For a two-dimensional binary image, Df varies as a fractional value between 1 and 2 and for skeletonized vascular images, typically from 1.22 to 1.48. As further examples, Lv14 denotes Lv with respect to branching generations G1 to G4 (Fig. 1). Physical dimensions such as Lv = 0.000775 µm/µm2 are notated as 7.75 × 10–4 µm/µm2. The terms “vascular increase” and “vascular decrease” are used to summarize the increase or decrease in vascular density as measured by Df, Lv, Lv14, and Lv≥5
Figure 1.
 
Mapping and quantification of vascular branching trees. Binary images of arterial and venous trees extracted from the grayscale Spectralis IR image of the left retina of astronaut crew member E acquired before a 6-month mission to the ISS (AC) served as sole inputs for the vascular maps (DI). Specialized algorithms in VESGEN first calculate a skeleton (centerline) of the trees (D, G) that together with the input binary image generate further mappings such as the branching generations maps (E, H).13 The arterial and venous branching generations denoted in the legend were grouped by the software into large (red, Lv14) and small (yellow, Lv≥5) vessels using a VESGEN user-interactive option (F, I). This retina experienced the lowest vascular decrease of the 11 retinas for which postflight vascular decreases were measured. By VESGEN quantification of these and other vascular maps, arterial and venous Df are 1.354 and 1.329, and overall arterial and venous length densities (Lv), 12.1 × 10–4 µm/µm2 and 10.7 × 10–4 µm/µm2. For the postflight image, arterial and venous Df are 1.349 and 1.343, and overall arterial and venous length densities (Lv), 11.88 × 10–4 µm/µm2 and 11.37 × 10–4 µm/µm2.
Figure 1.
 
Mapping and quantification of vascular branching trees. Binary images of arterial and venous trees extracted from the grayscale Spectralis IR image of the left retina of astronaut crew member E acquired before a 6-month mission to the ISS (AC) served as sole inputs for the vascular maps (DI). Specialized algorithms in VESGEN first calculate a skeleton (centerline) of the trees (D, G) that together with the input binary image generate further mappings such as the branching generations maps (E, H).13 The arterial and venous branching generations denoted in the legend were grouped by the software into large (red, Lv14) and small (yellow, Lv≥5) vessels using a VESGEN user-interactive option (F, I). This retina experienced the lowest vascular decrease of the 11 retinas for which postflight vascular decreases were measured. By VESGEN quantification of these and other vascular maps, arterial and venous Df are 1.354 and 1.329, and overall arterial and venous length densities (Lv), 12.1 × 10–4 µm/µm2 and 10.7 × 10–4 µm/µm2. For the postflight image, arterial and venous Df are 1.349 and 1.343, and overall arterial and venous length densities (Lv), 11.88 × 10–4 µm/µm2 and 11.37 × 10–4 µm/µm2.
Relative decreases in vessel diameter and other considerations of vessel branching and tapering are used to classify the vessel branching generations (G1Gx), based on previous experimental results for heart and lung vascular branching3941 and the conservation of laminar blood flow.10 At a symmetric vessel bifurcation, the diameter of the offspring vessels decreases to 71% (1/√2) of the diameter of the parent vessel. The averaged decrease in vessel diameter to 71%, together with an (adjustable) tolerance factor of ±15% that accounts for the realistic asymmetry of biological vascular branching (Fig. 1), is used by VESGEN as the primary determinant of a new branching generation. 
Statistics
Analyses were conducted using linear mixed models that included subject-specific random effects to account for repeated measures of the left and right eyes within individuals. Primary VESGEN measures included Df, Lv, Lv14, and Lv≥5 measured for each vascular tree (arteries or veins). Time (pre or post) was included as a categorical fixed effect. Models were fit in SAS v9.4 using PROC GLIMMIX. The LSMEANS and LSMESTIMATE statements were used to estimate means and standard errors of the time-specific response and the premission to postmission change in VESGEN measures (threshold for confidence, P < 0.05). Additional models included axial length as a covariate to assess the association with VESGEN parameters. 
Changes in the VESGEN parameters were compared with the axial length as described elsewhere in this article and observationally compared with a fundoscopic diagnosis of ODE, changes in axial length, and changes in TRT and peripapillary choroidal thickness. There was only one instance of fundoscopy-identified ODE, leading to a minimal statistical resolution of P = 0.0625 (1/16). All possible permutations of the one diagnosis of ODE by fundoscopy compared with the other 15 retinas were used to estimate an empirical P value for the association. Because this single ODE was identified in the retina that also had the largest vascular changes measured by VESGEN, the empirical P value matched the minimal resolution (P = 0.0625). Change in TRT is considered as one of the earliest signs of the development of ODE. Unfortunately, premission to postmission TRT change measures were not available for two of the three subjects (four retinas) displaying the largest changes in vascular parameters, as well as for axial length and peripapillary choroidal thickness in several subjects. Therefore, the association between changes in VESGEN parameters and TRT, axial length and peripapillary choroidal thickness could only be reported individually. 
Results
Summary of Approach
The study comprised 32 preflight and postflight images collected by the Heidelberg OCT 30° IR mode from the two eyes of eight crew members. Post-ISS changes in overall arterial and venous patterning were quantified by Df and Lv. In addition, length densities of large and small vessels by Lv14 and Lv≥5 were calculated for branching generations of Gv14 and Gv≥5. Results are reported as (1) post-ISS trends of vascular patterning in the retinas of all crew members, (2) vascular response in the retinas of individual crew members, (3) association of trends in vascular patterning with clinical ocular measures, and (4) a subclinical vascular pathology index (SVPI) calculated from clinical incidence of SANS. 
Post-ISS Trends of Vascular Patterning in Retinas of All Crew Members
The overall vascular space-filling capacity by Df decreased in both arterial and venous trees after 6 months in microgravity, when averaged for all 16 crew member retinas (from Table 2, arterial mean change in Df, –0.02; standard error (SE), 0.006; P = 0.027; and venous mean change; –0.015; SE, 0.005; P = 0.009; see also Supplementary Table S1). As predicted, the length density of larger vessels in the first four branching generations, Lv14, was relatively unchanged. However, significant decreases were measured in Lv≥5 (arterial mean change, –0.92; SE, 0.30; P = 0.005; and venous mean change, –0.75; SE, 0.31; P = 0.019). Results indicate that vascular adaptations to microgravity occurred primarily in the smaller vessels. In general, decreases in the density of these smaller vessels were greater for small arteries than for small veins. As indicated by the low variability, Df is a sensitive measure of change in vascular space-filling capacity, although absolute numerical changes in Df are not large (Table 1, Supplementary Table S1).16,1821,24 
Vascular Response in Retinas of Individual Crew Members
Of the eight crew members, only the right eye of crew member A was diagnosed by NASA with SANS. Abnormal, degenerative postflight changes by several clinical measures established for SANS by NASA included the largest increase in TRT, ODE, and choroidal folds by fundoscopy imaging (Fig. 2). This retina displayed the largest decreases in both arterial and venous space-filling density by Df and Lv (Tables 234, and Supplementary Table S1). Postflight decreases in the patterning of small vessels by Lv≥5 (yellow vessels, Fig. 2, J, R) are apparent by visual inspection in comparison with the preflight retina (yellow vessels, Fig. 2, I, Q). In contrast, arterial and venous patterning within the left retina of crew member A remained relatively unchanged (Tables 23, and Supplementary Table S1Fig. 2). 
Figure 2.
 
Decreased vascular patterning in the right retina of ISS crew member A diagnosed with SANS. Arterial and venous postflight decreases in the right retina, but not left retina, are clearly visible in several vascular maps. The right retina was the only retina in this cohort diagnosed with SANS by fundoscopy examination from ODE and choroidal folds, visible in the postflight image at higher zoom. Binary vascular trees extracted from Spectralis IR grayscale images of the (A, B) right and (C, D) left retinas were automatically analyzed by the VESGEN software as (EH, MP) vascular skeletons and (IL, QT) vessel branching grouped into large (Gv14, red) and small (Gv56, yellow) generations. The arterial and venous Df and overall length densities (Lv) for this crew member are reported as an individual case study in Table 3. For visual comparison of vascular patterns, all images were aligned with optic nerve to left (image of right retina rotated 180°).
Figure 2.
 
Decreased vascular patterning in the right retina of ISS crew member A diagnosed with SANS. Arterial and venous postflight decreases in the right retina, but not left retina, are clearly visible in several vascular maps. The right retina was the only retina in this cohort diagnosed with SANS by fundoscopy examination from ODE and choroidal folds, visible in the postflight image at higher zoom. Binary vascular trees extracted from Spectralis IR grayscale images of the (A, B) right and (C, D) left retinas were automatically analyzed by the VESGEN software as (EH, MP) vascular skeletons and (IL, QT) vessel branching grouped into large (Gv14, red) and small (Gv56, yellow) generations. The arterial and venous Df and overall length densities (Lv) for this crew member are reported as an individual case study in Table 3. For visual comparison of vascular patterns, all images were aligned with optic nerve to left (image of right retina rotated 180°).
The largest vascular decreases associated with subclinical results for SANS by fundoscopy examination occurred bilaterally in the retinas of crew member B (Table 4Fig. 3). Overall, postflight vascular density decreased in 11 of 16 retinas by more than 0.02, a cutoff value for Df estimated from previous studies in which changes greater than 0.02 or 0.03 were meaningful for distinguishing between sampling or treatment groups (Supplementary Table S1).16,1821,24 
Figure 3.
 
Vascular decrease in the retinas of crew member B after 6 months on the ISS. Arterial and venous density decreased in the postflight left and right retinas to 76% and 75%, compared with a scale of 100% loss in the right retina of crew member A (Fig. 2Table 4). As for crew member A, binary arterial and venous trees extracted from grayscale images of the left and right retinas (AD) were analyzed by VESGEN as vascular skeletons (EH, MP) and generational branching grouped into large (Gv14, red) and small (Gv56, yellow) generations (IL, QT).
Figure 3.
 
Vascular decrease in the retinas of crew member B after 6 months on the ISS. Arterial and venous density decreased in the postflight left and right retinas to 76% and 75%, compared with a scale of 100% loss in the right retina of crew member A (Fig. 2Table 4). As for crew member A, binary arterial and venous trees extracted from grayscale images of the left and right retinas (AD) were analyzed by VESGEN as vascular skeletons (EH, MP) and generational branching grouped into large (Gv14, red) and small (Gv56, yellow) generations (IL, QT).
Association of Trends in Vascular Patterning with Clinical Ocular Measures for SANS and Other Ocular Response
Results from data visualization (Fig. 4) and permutation testing of the eight subjects indicate that vascular decreases in Df, Lv, and Lv≥5 appear to be positively associated with pre/post mission incidence of clinical measures that include ODE, choroidal folds identified through fundoscopy (by permutation testing, P = 0.0625), pre/post mission decreases in axial length, increased TRT, and, to some extent, increased peripapillary choroidal thickness. Measurements of TRT were lacking for two of the three crew members with the largest vascular pre/post vascular decreases, and of axial length and peripapillary choroidal thickness in a number of crew members. It is not known whether those retinas lacking TRT data experienced changes larger than the increase of 19.4 µm in TRT that recently is now viewed by NASA as the earliest signs of ODE leading to SANS. 
Figure 4.
 
Comparison of pre-to-post flight change in clinical ocular measures with Df, Lv, and Lv≥5. Subjects are ordered by increasing postmission decrease in Df. The largest increase in TRT and axial length, but not peripapillary choroidal thickness, occurred in the right retina of crew member A diagnosed with SANS by ODE and choroidal folds from fundoscopy examination.
Figure 4.
 
Comparison of pre-to-post flight change in clinical ocular measures with Df, Lv, and Lv≥5. Subjects are ordered by increasing postmission decrease in Df. The largest increase in TRT and axial length, but not peripapillary choroidal thickness, occurred in the right retina of crew member A diagnosed with SANS by ODE and choroidal folds from fundoscopy examination.
None of the participants reported visual changes. Subject A, who displayed the largest decrease in vascular density (Table 4), the largest ODE by OCT and fundoscopy, and the greatest change in globe flattening and refractive error (0.75 diopters), was also a myope, which may account for the lack of functional impact. Hyperopic refractive error shifts are the primary characteristics of functional change with spaceflight.8 By regression analysis, a greater axial length was associated with greater arterial and venous density by the space-filling measure of Df and density of smaller vessels (Lv≥5), but decreased the density of larger vessels (Lv14), whether in the preflight or postflight globe (n = 14; Table 5). When included in the mixed models as a covariate, Table 5 outlines the coefficient estimates and P values. 
Table 5.
 
Positive Association of Postflight Increases in Axial Length (per mm) of Ocular Globes With Postflight Change in Vascular Parameters
Table 5.
 
Positive Association of Postflight Increases in Axial Length (per mm) of Ocular Globes With Postflight Change in Vascular Parameters
SVPI From the Clinical Incidence of SANS
To further examine postflight trends in decreased arterial and venous patterning, results from the VESGEN analysis within individual retinas were ranked from one to 16 by the SVPI according to greatest vascular loss for estimation of potential subclinical vascular pathology and risk for SANS. Briefly, magnitudes of arterial and venous changes by Df and Lv for each of the 15 retinas found to be clinically normal by fundoscopy were averaged and compared with changes in the right retina of crew member A as the SANS reference value (i.e., normalized to the SANS retina; Table 4). Negative values by SVPI indicate a postflight increase in vascular density. By the SVPI, 10 retinas experienced pre/post vascular decreases from 8% to 76% of the decrease in the SANS retina. The largest subclinical vascular decreases occurred bilaterally in the retinas of crew member B (Fig. 3). Smaller postflight decreases in vascular density within some retinas may indicate a vascular-protective adaptation against SANS ocular structural changes. Alternatively, these 10 retinas may represent varying levels of early stage subclinical microvascular injury incurred during prolonged microgravity. 
Retinas of five crew members with slight increases in vascular density from 1% to 25% were rendered in the SVPI as negative values (i.e., as gains in vascular density added to the total scale of vascular decrease from 0% to 100% established by the SANS retina). Vascular changes from –25% to +25% may represent the level of measurement error (background) in the IR images resulting from the limiting vascular resolution of Spectralis imaging. 
Discussion
After six months on the ISS, 70% of astronaut retinas (11/16) exhibited microvascular decreases by VESGEN vascular analysis (i.e., decreases in Lv≥5). Overall decreases in arterial and venous densities, and decreases in small but not large vessels, provide preliminary confirmation of the hypothesis that blood vessels in the retina, particularly the smaller vessels, remodel to accommodate the prolonged fluid shifts experienced in microgravity. A further important result is that the loss of vessel density appeared to be similar for both arteries and veins. 
To our knowledge, this is the first report on the decrease of retinal vascular patterning in response to long-duration microgravity. The trend toward vascular decrease, particularly of the small vessels, was confirmed by several approaches that include (1) statistical analysis of premission to postmission changes by several confirming measures (Df, Lv, and Lv≥5; all P ≤ 0.033); (2) association of greatest vascular loss with the one retina diagnosed with SANS from ODE and choroidal folds by fundoscopy, and greatest changes in TRT by OCT (from permutation testing; P = 0.0625) and axial length (but not with increased peripapillary thickness); (3) observational association of the range of vascular decrease in the 16 retinas with TRT, and (4) calculation of the range of subclinical vascular loss (SVPI) in 15 retinas compared with the maximal loss in the single SANS retina. Vascular decreases determined by this study ranged from none to considerable, as could be predicted from the variable incidence reported for SANS.13,5,6,8 Significant decreases in vascular density occurred both unilaterally and bilaterally, as reported previously for other ocular measures associated with SANS.1,2 
Results of this investigation suggest that vascular patterning may offer an early stage predictor and biomarker of future susceptibility to SANS ocular structural changes. Further investigations on the role of the microvasculature in the retina are important for a more complete understanding of SANS etiology and the development of successful countermeasures. Results demonstrate that the VESGEN analysis, if validated by future studies on early stage detection of vascular loss, could potentially be adapted for flight monitoring of SANS susceptibility using ISS OCT data. 
Investigations on SANS by other approaches propose potential causes resulting in fluid changes within the eye5,6,10,42 that may be multifactorial, such as systemic cardiovascular disturbances, increased intracranial pressure and structural changes in the brain leading to transduction of fluid through the optic nerve to the eye,4346 and nutritional, hypercapnic, genetic, and inflammatory status.6,43,44,4749 From terrestrial measurements of sequential peripapillary TRT measures within the same subjects across multiple days, in multiple postures and with multiple analysts, a change of 19.4 µm was determined to have less than a 5% chance of being due to these sources of measurement variability, offering a potential cutoff value for the earliest sign of ODE.6 As reported recently, an increased IOP has not been shown to be strongly associated with SANS, and IOP normalizes to preflight values after 4 days of spaceflight.50 
Crucial to the understanding of how these vascular decreases influence the development of SANS during long duration microgravity is whether the small vessels underwent vaso-obliteration (vessel dropout or loss), or the diameters of small vessels in the retina simply decreased below the limit of image resolution, or both. We speculate that the vascular decreases most likely resulted from decreased vessel diameter (caliber). Potential etiologic mechanisms of decreased vessel diameter include systemic losses in blood volume as reported previously.42,51 Spaceflight hypovolemia of approximately 10% is ascribed to several causes that include reduced fluid intake, loss of erythrocytes, and potentially faster fluid shifts from intravascular to interstitial spaces, resulting from lower transmural pressures because of decreased compression of tissues in microgravity, especially within the thorax.42,51 Alternatively, vascular decreases may be secondary to vascular compression from optic disc/peripapillary swelling.5254 
Edematous fluid transfers by sources such as an increased intracranial pressure and ODE, in addition to the globe flattening reported here and in many other previous studies, may cause high extravascular fluid pressures within the eye to constrict vessels and impede blood flow, perhaps to the level of vessel dropout. Such extravascular tissue pressure may be analogous to the “compartment syndrome” described for injuries such as tibial fracture, abdominal organ failure, or surgery, in which tissue injury accompanied by excessive edema overcomes the ability of the microvascular endothelium to mediate the disturbed fluid balances, resulting in tissue damage or necrosis.5254 Or retinal and optic disc edemas may have obscured the vessels, which implies that changes reported here may in part or fully derive from vessel obscuration. 
New studies with higher resolution ophthalmic imaging such as Spectralis IR of unmodified resolution (see Methods) or OCT angiography are clearly necessary to determine whether these vascular changes are due to decreased vessel diameter, vaso-obliteration, vessel obscuration, or a combination of these factors. Although the diameters of smaller vessels may have decreased in microgravity, the diameters of larger vessels did not appear to change significantly (data not included because of limitations in the relatively low-resolution Spectralis IR vascular imaging for reliable determination of vessel diameter). Unsurprisingly, given the level of Spectralis IR resolution of 6.03 µm/pixel, the diameters of the smallest vessels detected in all images for our study were slightly less than 12 µm, or two pixels. Thus, postflight decreases in vessel diameter below this imaging cutoff value would not be detectable by the analysis. 
For now, we can only speculate on the significance of the negative values in the SVPI of 25% or less. Such negative values may represent a positive retinal vascular adaptation to long-duration microgravity that helps to accommodate the excess headward fluid shifts. An alternative, perhaps more plausible, explanation is that ±25% values of vascular change may represent the current level of noise in the VESGEN analysis. The limited resolution of OCT Spectralis IR vascular imaging mode, unlike that of OCT angiography or fluorescein angiography, is not optimal for the sensitive detection of smaller blood vessels. However, Spectralis IR was the only vascular imaging mode available for our study. It is possible but unlikely that postflight decreases in axial length altered the fidelity of OCT tracking for reproducible imaging of retinal vessels. 
The analysis of vascular patterning in the astronaut retina is the first longitudinal study of human subjects using the VESGEN software, following previous cross-sectional studies of diabetic retinopathy as a technology proof of principle.10,13,14 Limitations of this study include the small number of subjects and relatively low resolution of the vascular imaging by the modified Spectralis IR (see Methods). Currently, Spectralis IR is the only retinal vascular imaging available to NASA Medical Operations before, during, and after ISS missions. The quality of the scanning acquisition for all images appeared highly similar but not identical, differing only slightly in image sharpness, contrast, and retinal field of view. Despite these limitations, the pre/post mission results reveal a clear trend of vascular decrease for this cohort. In previous studies with VESGEN on other applications,13,1625,28,29 the significance of vascular trends was also of relatively strong statistical significance, perhaps because hundreds of vessels are captured in a typical clinical or microscopic microvascular image. 
Larger ocular globes were found to be positively associated with the increased density of small vessels and decreased density of large arteries. The decreased density of large, major arborizing vessels in larger eyes is understandable, as this vascular patterning is relatively fixed and constant among all eyes. The increased density of smaller vessels probably arises from the limiting Spectralis IR image resolution. Small vessels are perhaps proportionally larger in larger eyes and therefore more detectable at limits of resolution. Despite this methodological limitation, the vascular analysis nonetheless detected the trend toward postflight decreases in vascular patterning with strong statistical significance. 
New segmentation methods are being developed at NASA for the automated extraction of vascular pattern based on artificial intelligence and machine learning algorithms (VESGEN v1.11, scheduled for global release in 2020–2021).37 In addition to the vascular maps and parameters reported here (Df and Lv), additional output calculated by the software includes other vascular maps and options for vascular network analysis, vessel tortuosity, vessel diameter, and densities of vessel number, vessel area, and vessel branch point specified for branching generations G1, G2,…Gx.13 
In conclusion, the results of this proof-of-concept investigation demonstrate that vascular density decreased in the astronaut retinas after six-month missions to the ISS in microgravity. Vascular patterning may offer a valuable early stage predictor, ongoing monitor, and new diagnostic of retinal status for SANS, a high-priority risk defined by NASA for long duration space exploration missions such as Mars. From extensive international research on the ISS habitat, we are beginning to understand the significance of factors such as microgravity, hypobaria, hypoxia, and hypercapnia for future habitats of long-duration space exploration. Yet much remains to be learned. The effect of partial lunar gravity on vascular adaptations in the retina, for example, is not yet known. 
Acknowledgments
Supported by the National Aeronautics and Space Administration (NASA) with Grant NNJ12ZSA002N by the Human Research Program (HRP) and additional support by the HRP Space Radiation and Vascular Centennial Challenge Programs to P.P.W. We thank Robert Ploutz-Snyder, University of Michigan, for initial biostatistical and power analysis design of the study, and Peter Norsk (HRP, NASA) for suggesting the SVPI. 
Disclosure: R.J. Vyas, None; M. Young, None; M.C. Murray, None; M. Predovic, None; S. Lim, None; N.M. Jacobs, None; S.S. Mason, None; S.B. Zanello, None; G. Taibbi, None; G. Vizzeri, None; P. Parsons-Wingerter, None 
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Figure 1.
 
Mapping and quantification of vascular branching trees. Binary images of arterial and venous trees extracted from the grayscale Spectralis IR image of the left retina of astronaut crew member E acquired before a 6-month mission to the ISS (AC) served as sole inputs for the vascular maps (DI). Specialized algorithms in VESGEN first calculate a skeleton (centerline) of the trees (D, G) that together with the input binary image generate further mappings such as the branching generations maps (E, H).13 The arterial and venous branching generations denoted in the legend were grouped by the software into large (red, Lv14) and small (yellow, Lv≥5) vessels using a VESGEN user-interactive option (F, I). This retina experienced the lowest vascular decrease of the 11 retinas for which postflight vascular decreases were measured. By VESGEN quantification of these and other vascular maps, arterial and venous Df are 1.354 and 1.329, and overall arterial and venous length densities (Lv), 12.1 × 10–4 µm/µm2 and 10.7 × 10–4 µm/µm2. For the postflight image, arterial and venous Df are 1.349 and 1.343, and overall arterial and venous length densities (Lv), 11.88 × 10–4 µm/µm2 and 11.37 × 10–4 µm/µm2.
Figure 1.
 
Mapping and quantification of vascular branching trees. Binary images of arterial and venous trees extracted from the grayscale Spectralis IR image of the left retina of astronaut crew member E acquired before a 6-month mission to the ISS (AC) served as sole inputs for the vascular maps (DI). Specialized algorithms in VESGEN first calculate a skeleton (centerline) of the trees (D, G) that together with the input binary image generate further mappings such as the branching generations maps (E, H).13 The arterial and venous branching generations denoted in the legend were grouped by the software into large (red, Lv14) and small (yellow, Lv≥5) vessels using a VESGEN user-interactive option (F, I). This retina experienced the lowest vascular decrease of the 11 retinas for which postflight vascular decreases were measured. By VESGEN quantification of these and other vascular maps, arterial and venous Df are 1.354 and 1.329, and overall arterial and venous length densities (Lv), 12.1 × 10–4 µm/µm2 and 10.7 × 10–4 µm/µm2. For the postflight image, arterial and venous Df are 1.349 and 1.343, and overall arterial and venous length densities (Lv), 11.88 × 10–4 µm/µm2 and 11.37 × 10–4 µm/µm2.
Figure 2.
 
Decreased vascular patterning in the right retina of ISS crew member A diagnosed with SANS. Arterial and venous postflight decreases in the right retina, but not left retina, are clearly visible in several vascular maps. The right retina was the only retina in this cohort diagnosed with SANS by fundoscopy examination from ODE and choroidal folds, visible in the postflight image at higher zoom. Binary vascular trees extracted from Spectralis IR grayscale images of the (A, B) right and (C, D) left retinas were automatically analyzed by the VESGEN software as (EH, MP) vascular skeletons and (IL, QT) vessel branching grouped into large (Gv14, red) and small (Gv56, yellow) generations. The arterial and venous Df and overall length densities (Lv) for this crew member are reported as an individual case study in Table 3. For visual comparison of vascular patterns, all images were aligned with optic nerve to left (image of right retina rotated 180°).
Figure 2.
 
Decreased vascular patterning in the right retina of ISS crew member A diagnosed with SANS. Arterial and venous postflight decreases in the right retina, but not left retina, are clearly visible in several vascular maps. The right retina was the only retina in this cohort diagnosed with SANS by fundoscopy examination from ODE and choroidal folds, visible in the postflight image at higher zoom. Binary vascular trees extracted from Spectralis IR grayscale images of the (A, B) right and (C, D) left retinas were automatically analyzed by the VESGEN software as (EH, MP) vascular skeletons and (IL, QT) vessel branching grouped into large (Gv14, red) and small (Gv56, yellow) generations. The arterial and venous Df and overall length densities (Lv) for this crew member are reported as an individual case study in Table 3. For visual comparison of vascular patterns, all images were aligned with optic nerve to left (image of right retina rotated 180°).
Figure 3.
 
Vascular decrease in the retinas of crew member B after 6 months on the ISS. Arterial and venous density decreased in the postflight left and right retinas to 76% and 75%, compared with a scale of 100% loss in the right retina of crew member A (Fig. 2Table 4). As for crew member A, binary arterial and venous trees extracted from grayscale images of the left and right retinas (AD) were analyzed by VESGEN as vascular skeletons (EH, MP) and generational branching grouped into large (Gv14, red) and small (Gv56, yellow) generations (IL, QT).
Figure 3.
 
Vascular decrease in the retinas of crew member B after 6 months on the ISS. Arterial and venous density decreased in the postflight left and right retinas to 76% and 75%, compared with a scale of 100% loss in the right retina of crew member A (Fig. 2Table 4). As for crew member A, binary arterial and venous trees extracted from grayscale images of the left and right retinas (AD) were analyzed by VESGEN as vascular skeletons (EH, MP) and generational branching grouped into large (Gv14, red) and small (Gv56, yellow) generations (IL, QT).
Figure 4.
 
Comparison of pre-to-post flight change in clinical ocular measures with Df, Lv, and Lv≥5. Subjects are ordered by increasing postmission decrease in Df. The largest increase in TRT and axial length, but not peripapillary choroidal thickness, occurred in the right retina of crew member A diagnosed with SANS by ODE and choroidal folds from fundoscopy examination.
Figure 4.
 
Comparison of pre-to-post flight change in clinical ocular measures with Df, Lv, and Lv≥5. Subjects are ordered by increasing postmission decrease in Df. The largest increase in TRT and axial length, but not peripapillary choroidal thickness, occurred in the right retina of crew member A diagnosed with SANS by ODE and choroidal folds from fundoscopy examination.
Table 1.
 
Characteristics of Study Participants (Most Astronauts Were Repeat Flyers)8
Table 1.
 
Characteristics of Study Participants (Most Astronauts Were Repeat Flyers)8
Table 2.
 
Arterial and Venous Density in 16 Retinas of Eight Crew Members Before and After 6-Month Missions to the ISS.
Table 2.
 
Arterial and Venous Density in 16 Retinas of Eight Crew Members Before and After 6-Month Missions to the ISS.
Table 3.
 
Case Study of Crew Member A Diagnosed With SANS
Table 3.
 
Case Study of Crew Member A Diagnosed With SANS
Table 4.
 
SVPI for SANS From Preflight to Postflight Changes
Table 4.
 
SVPI for SANS From Preflight to Postflight Changes
Table 5.
 
Positive Association of Postflight Increases in Axial Length (per mm) of Ocular Globes With Postflight Change in Vascular Parameters
Table 5.
 
Positive Association of Postflight Increases in Axial Length (per mm) of Ocular Globes With Postflight Change in Vascular Parameters
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