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Figure 1.
Bruch Membrane Opening (BMO)
Bruch Membrane Opening (BMO)

A, Marking of the BMO (orange marker) is shown on 1 radial section through the optic nerve head. The BMO center (red dashed line) was used to determine the location for a reference plane at 2 mm (white line), from which the BMO height was quantified (blue line). B, The BMO height is recessed in preflight optical coherence tomographic (OCT) scans compared with healthy controls. This difference increases after long-duration microgravity exposure.

Figure 2.
Optical Coherence Tomography
Optical Coherence Tomography

A, The Bruch membrane opening marked on each radial scan (Figure 1A) was used to fit a best-fit ellipse (blue ellipse), from which annular zones were constructed at 250, 500, 1000, and 1500 μm (black ellipses). The red circle shows the location of the standard retinal nerve fiber layer circular scan, and yellow dashed lines show the separation of the 4 quadrants. I indicates inferior; N, nasal; S, superior; and T, temporal. B, B-scan from standard retinal nerve fiber layer circular scan path (1.73-mm radius) with inner limiting membrane (ILM), nerve fiber layer/ganglion cell (NFL/GC), Bruch membrane (BM), and choroid segmentation is shown.

Figure 3.
Control, Preflight, and Postflight Optical Coherence Tomographic Scans
Control, Preflight, and Postflight Optical Coherence Tomographic Scans

Box and whiskers at each eccentricity show the 10th, 25th, 75th, and 90th percentiles, and the horizontal line shows the median of the global annular total retinal thickness (TRT) and retinal nerve fiber layer (RNFL) thickness. A and B, Control and preflight eyes. C and D, Preflight and postflight eyes. All outliers are plotted as hollow circles. BMO indicates Bruch membrane opening.

a Significant at P < .01 by Mann-Whitney test.

b Significant at P < .01 by Wilcoxon matched-pairs signed rank test.

Table 1.  
Circumpapillary Retinal Nerve Fiber Layer (RNFL) and Choroidal Thickness for Astronauts Preflight vs Postflight
Circumpapillary Retinal Nerve Fiber Layer (RNFL) and Choroidal Thickness for Astronauts Preflight vs Postflight
Table 2.  
Global Total Retinal Thickness (TRT) and Retinal Nerve Fiber Layer (RNFL) Thickness Measures of Annular Zones for Astronauts Preflight and Postflight
Global Total Retinal Thickness (TRT) and Retinal Nerve Fiber Layer (RNFL) Thickness Measures of Annular Zones for Astronauts Preflight and Postflight
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Original Investigation
February 2018

Optical Coherence Tomography Analysis of the Optic Nerve Head and Surrounding Structures in Long-Duration International Space Station Astronauts

Author Affiliations
  • 1University of Houston College of Optometry, Houston, Texas
  • 2MEI Technologies, Inc, Houston, Texas
  • 3Coastal Eye Associates, Webster, Texas
  • 4Universities Space Research Association, Houston, Texas
  • 5Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Ophthalmol. 2018;136(2):193-200. doi:10.1001/jamaophthalmol.2017.6226
Key Points

Question  Can optical coherence tomography technology be used to quantify changes in the posterior segment after spaceflight?

Findings  In this study comparing 15 preflight and postflight optical coherence tomographic scans, there was an increase in total retinal thickness and retinal nerve fiber layer thickness up to 1000 μm from the Bruch membrane opening. There was a downward deflection of the Bruch membrane opening and an increase in choroidal folds after spaceflight.

Meaning  While some postflight changes are similar to those with elevated intracranial pressure, the downward deflection of the Bruch membrane opening height and substantial increase in choroidal folds is not, suggesting an alternate hypothesis for spaceflight-associated neuro-ocular syndrome.

Abstract

Importance  After long-duration spaceflight, morphological changes in the optic nerve head (ONH) and surrounding tissues have been reported.

Objective  To develop methods to quantify ONH and surrounding tissue changes using preflight and postflight optical coherence tomographic scans of the ONH region.

Design, Setting, and Participants  Two separate analyses were done on retrospective data, with the first comparing a preflight group with a control group, followed by preflight to postflight analysis. All astronaut data were collected on the same instrument and maintained by the National Aeronautics and Space Administration (NASA) Lifetime Surveillance of Astronaut Health. Control data were all collected at the University of Houston. Participants were 15 astronauts who had previously been on an approximately 6-month long-duration mission and had associated preflight and postflight ONH scans. The control group consisted of 43 individuals with no history of ocular pathology or microgravity exposure. Development of algorithms and data analysis were performed between 2012 and 2015.

Main Outcomes and Measures  The optical coherence tomography data were analyzed using custom MATLAB programs (MathWorks) in which the Bruch membrane opening (BMO) was manually delineated and used as a reference for all morphological measures. The retinal pigment epithelium (RPE) position 2 mm from the center of the BMO was used to calculate the BMO height. Global and quadrant total retinal thickness and retinal nerve fiber layer (RNFL) thickness were calculated for elliptical annular regions referenced to the BMO. The standard circumpapillary circular scan was used to quantify RNFL and choroidal thickness.

Results  Among 15 astronauts (mean [SD] age at preflight evaluation, 48.7 [4.0] years) in this retrospective study, the BMO was recessed in preflight astronauts compared with healthy controls and deepened after long-duration microgravity exposure (median change, −9.9 μm; 95% CI of difference, −16.3 to 3.7 μm; P = .03). After long-duration missions, there was an increase in total retinal thickness to 1000 μm and RNFL to 500 μm from the BMO. Circumpapillary RNFL thickness increased by a median of 2.9 μm (95% CI of difference, 1.1-4.4 μm; P < .01), and there was no change in choroidal thickness (median change, 9.3 μm; 95% CI of difference, −12.1 to 19.6 μm; P = .66).

Conclusions and Relevance  After long-duration microgravity exposure, there are disc edema–like changes in the morphology of the ONH and surrounding tissue. The methods developed to analyze the ONH and surrounding tissue can be useful for assessing longitudinal changes and countermeasures in astronauts, as well as potentially for terrestrial disc edema causes.

Introduction

Several physiological changes and pathological risks are known to occur with space travel and prolonged exposure to microgravity environments. These include loss of bone and muscle mass and cardiovascular changes, such as fluid shifts, changes in total blood volume, heartbeat and heart rhythm irregularities, and diminished aerobic capacity 1-5 Because vision is important for both health and mission purposes, it has been investigated since the Gemini missions and has gained increased interest with longer-duration missions.6,7 Although significant vision changes are typically not noted with short-duration missions, longer-duration microgravity exposures have been associated with alterations in both visual acuity and ocular health.8,9 In a National Aeronautics and Space Administration (NASA) survey of 300 astronauts, 23% of short-flight and 49% of long-duration astronauts reported vision changes consistent with a hyperopic shift.8 Along with changes in refractive error, varying degrees of disc edema, globe flattening, choroidal folds, and cotton-wool spots have also been reported.8 In addition, a clinical case report suggests that some of these clinical findings might be recurrent in nature.10

Although the exact etiology remains unknown, it is hypothesized that the changes seen in astronauts are a result of microgravity-associated orbital and cranial cephalad fluid shifts. Because fluid shifts and venous stasis can result in elevated intracranial pressure (ICP) and because the clinical presentation has many similarities to that of pseudotumor cerebri, the ocular findings were previously described as visual impairment and ICP syndrome.11,12 However, as the role of ICP remains unclear, the syndrome has since been renamed spaceflight-associated neuro-ocular syndrome.13,14

Because optic nerve pathology could result in irreversible vision loss, it has been a concern for long-duration missions (eg, 6-month International Space Station missions). The clinical standard for assessing disc edema has been the modified Frisén grading system, either quantified from dilated indirect evaluation or fundus photography of the optic nerve head (ONH).15 Although an invaluable measure, this grading system is subjective and ordinal in nature.16 Optical coherence tomography (OCT) technology has had a significant influence on quantifying disc edema because it provides additional axial information from which retinal nerve fiber layer (RNFL) and total retinal thickness (TRT) measures can be quantified. In early studies using time-domain OCT, circumpapillary RNFL and TRT thickness was shown to relate well to the Frisén Scale.15 Subsequently, with spectral-domain volume scans, TRT measures at or proximal to the disc were shown to be sensitive to mild disc edema that had not reached the RNFL sampling at 1.73 mm from the disc center.17-19 In addition, OCT imaging has been used to visualize and quantify the deflection of the retinal pigment epithelium (RPE) that occurs with increased ICP and its resolution, thereby providing important information on the etiology of the disc edema.20,21 The objective of this study was to assess OCT-quantified morphological changes in astronauts who have been on long-duration missions, building on existing techniques used to assess the ONH.

Methods
Participants

Two separate data sets were used for analysis, one from the current astronaut corps and the second from a healthy group of individuals who had not been exposed to microgravity. In this retrospective study, there were 15 NASA astronauts with preflight and postflight OCT ONH clinical scans after an approximately 6-month long-duration mission. To maintain confidentiality, the NASA Lifetime Surveillance of Astronaut Health provided us only deidentified OCT, postflight optical biometry data, as well as the number of days after landing that testing was done, which met NASA’s institutional review board requirement for waiver of consent. Mission length, age at testing, time before launch for preflight test, and previous time in space are attributable and were only provided in a summary format. To determine if there were any preexisting morphological changes from previous missions, the preflight data were compared with healthy eyes that had no microgravity exposure. This sample included 43 individuals (mean [SD] age, 33.4 [13.3] years) with no history of ocular pathology or microgravity exposure and less than 5 diopters of emmetropia who were recruited from the patients, students, or staff at the University of Houston University Eye Institute. All data were collected retrospectively. Development of algorithms and data analysis were performed between 2012 and 2015. The procedures for data collection and analysis were reviewed by the University of Houston committee for protection of human participants for the healthy nonastronaut sample and by NASA’s institutional review board for all aspects that included astronaut data.

Optical Coherence Tomography

The OCT scan analyzed was the 200 × 200 optic disc cube scan acquired using a Cirrus HD-OCT instrument (Carl Zeiss Meditec). Only scans with a quality exceeding 7 of 10 and that were complete with minimal instrument algorithm segmentation error were used for data analysis. The OCT reflectance data and corresponding instrument-determined TRT and RNFL thickness measures were exported (img and advanced export; Cirrus HD-OCT) and subsequently read into MATLAB (MathWorks). The OCT scans from healthy control and astronaut data were randomized, and we subjectively evaluated each volume for choroidal folds, graded as either being present or absent.

Before OCT thickness data were quantified, transverse scaling for each eye was computed using an individualized 3-surface schematic eye, incorporating optical biometry data collected with the IOL Master (Carl Zeiss Meditec). Methods for scaling have been described previously.22-24 There were 3 astronauts for whom optical biometry data were not available, and an emmetropic eye was assumed for these individuals. All B-scans had a total depth of 2 mm, corresponding to an axial scaling of 1.95 μm per pixel or 2 mm per 1024 pixels.

For peripapillary and ONH morphological quantification, the Bruch membrane opening (BMO) was used as a reference. The BMO was manually marked on each of 12 equally spaced radial scans through the center of the ONH that were interpolated from the 200 × 200 OCT volume data. The BMO area was quantified using a best-fit ellipse to the marked points on the radial scans. In addition, the position of the RPE, 2 mm from the center of the ONH, was marked and used to calculate the perpendicular BMO height (Figure 1).

Exported OCT data included .dat files containing A-scan–specific thickness measures for TRT and RNFL thickness for the 200 × 200 region scanned. Using the BMO as a reference, TRT and RNFL mean and quadrant thickness measures were calculated for the region within the BMO and for the following 4 elliptical annuli: (1) BMO to 250 μm, (2) 250 to 500 μm, (3) 500 to 1000 μm, and (4) 1000 to 1500 μm (Figure 2A). The mean and quadrant values calculated based on the clinical standard circular scan path, 1.73 mm in radius, centered on the ONH were also evaluated. An interpolated B-scan from this circular scan path was compensated25,26 to visualize the choroid sclera border, which was manually delineated and used to calculate the mean and quadrant choroidal thickness (Figure 2B and eFigure in the Supplement).

Statistical Analysis

Because microgravity-associated ocular changes are commonly asymmetric in nature and because there are differences in the shape, position, and size of the ONH of the 2 eyes, both eyes were included for data analysis.27 As there are a small number of astronauts and the measures are not normally distributed, nonparametric statistics were used (Mann-Whitney test) to compare the health controls and preflight astronaut groups. Paired t tests, with nonparametric assumptions (Wilcoxon matched-pairs signed rank test), were used for statistical analysis of preflight vs postflight astronaut data. For differences between groups, medians with 95% CIs are presented. The P value for significance was adjusted to 2-sided P < .01 for all TRT and RNFL statistics to account for multiple comparisons made for each annulus (global and 4 sectoral measures, equaling 5 comparisons). For all other measures (ie, BMO height and BMO area), 2-sided P < .05 was used.

Results

At the start of the study, there were 33 NASA International Space Station astronauts, 15 (mean [SD] age at preflight evaluation, 48.7 [4.0] years) of whom had preflight and postflight OCT scans after a long-duration mission. To maintain confidentiality of participants, we were provided only the raw scans as described in the Methods section, with certain aspects provided in summary format (eTable 1 in the Supplement). The preflight scans were collected between 277 and 28 days before launch (mean [SD], 151 [138] days; median, 106 days). The postflight scans were collected between 2 and 18 days after landing, with most scans acquired in the first week (mean, 5.87 days; median, 5 days). Scans from 43 healthy controls with no previous microgravity exposure were used. Of these, 36 right eyes and 33 left eyes met the inclusion criteria. Excluded eyes had either eye movement artifact or segmentation error.

Healthy Controls vs Preflight Astronaut Group

Eight of 30 preflight scans (27%) from 6 of 15 participants (40%) had signs of choroidal folds, while no folds were detected on the healthy control OCT volume scans. The median BMO area in the healthy controls was 1.71 mm2 and was not statistically different than that from preflight data (median, 1.69 mm2) (95% CI of difference, −0.31 to 0.01 mm2; P = .06). However, in the astronaut group, the BMO height was posteriorly positioned (median, −140.0 μm) compared with the control group (median, −113.7 μm) (95% CI of difference, −53.0 to 7.3 μm; P = .01) (Figure 1B).

The global RNFL thickness using a standard 1.73-mm-radius circular scan centered on the ONH was similar between the preflight group (median, 93.2 μm) and control group (median, 91.1 μm) (95% CI of difference, −4.1 to 4.8 μm; P = .90). Based on quadrant analysis, the nasal RNFL sector in the preflight group was thicker than that in healthy controls (95% CI of difference, 1.4-11.8 μm; P = .01) (eTable 2 in the Supplement). The global circumpapillary choroidal thickness was greater in the preflight astronaut group (median, 238.5 μm) but was not statistically different from that of the control group (median, 230.2 μm) (95% CI of difference, −6.1 to 46.0 μm; P = .15).

The mean preflight TRT confined to the BMO was not different compared with that of the healthy control group (median preflight, 229.2 μm and median control, 195.2 μm; P = .24). However, for the 2 annuli closest to the BMO (BMO to 250 μm and 250-500 μm), the mean thickness measure was significantly greater in the preflight scans (Figure 3A, eTable 3 in the Supplement for the mean annuli, and eTable 4 in the Supplement for the mean sectors). It was expected that the same pattern would be noted for RNFL annuli thickness analysis, but there was no statistical difference between global RNFL measures in any of the annuli between the 2 groups (Figure 3B and eTable 3 in the Supplement). The standard circumpapillary circular scan path will overlap 1 of the 2 outer annuli, depending on the size of the ONH; hence, these 2 analyses should have similar findings. For example, similar to circumpapillary scans, the RNFL thickness of the 500 to 1000 μm annulus nasal quadrant in the preflight data (median, 87.6 μm) was greater than that in the control group (median, 81.6 μm); however, this did not reach statistical significance (95% CI of difference, −12.4 to 0.1 μm; P = .049). Similarly, for the temporal sector, although the RNFL thickness was thinner in the preflight group compared with controls, it did not reach statistical significance (preflight median temporal thickness at 500-1000 μm annulus, 63.7 μm and control, 68.9 μm; P = .02).

Preflight vs Postflight OCT Analysis

Of the 30 postflight scans, 10 additional eyes to the 8 noted preflight (total of 18 eyes in 11 of 15 participants) had choroidal folds on OCT volume analysis. There was a median increase in BMO area of 0.09 mm2 (95% CI of difference, 0.03-0.23 mm2; P < .01) that was not related to changes in ocular magnification from refractive error change, as determined through methods of image registration.24 There was a posterior shift in BMO position as quantified by BMO height (median change, −9.9 μm; 95% CI of difference, −16.3 to 3.7 μm; P = .03), and this change in position was not related to the change in BMO size (slope, −35.1 μm BMO height/mm2 BMO area; R2 = 0.02, P = .42).

Global circumpapillary RNFL thickness was greater in the postflight scans (median change, 2.9 μm; 95% CI of difference, 1.1-4.4 μm; P < .01), with the inferior RNFL quadrant having the largest increase (median change, 5.3 μm; 95% CI of difference, 3.1-11.3 μm; P < .01) (Table 1). Although global choroidal thickness was greater postflight (median change, 9.3 μm; 95% CI of difference, −12.1 to 19.6 μm), it was not statistically significant (P = .66) (Table 1). Because fluid shifts are a proposed mechanism for ocular changes,28 the association between change in choroidal and RNFL thickness was also investigated. Although there is variability in these 2 measures, the preflight to postflight thickness difference for global choroidal thickness and RNFL thickness was linearly related (slope, 0.08 μm RNFL/μm choroid; R2 = 0.25, P < .01). Because a change in BMO area could be from ONH edema causing physical enlargement of this region or decreased visualization of the margins, the association between BMO area and RNFL thickness was also investigated. There was also an association between the change in BMO size and RNFL thickness (slope, 31.6 μm/mm2; R2 = 0.34, P < .01), but no association was found between change in choroidal thickness and BMO size (slope, 99.34 μm/mm2; R2 = 0.08, P = .13).

Global TRT measures within the BMO and for annuli up to 1000 μm were significantly thicker for postflight scans (Table 2 and Figure 3C), as were measures of the superior, inferior, and nasal quadrants (eTable 5 in the Supplement). The thickness change in the temporal quadrant was only significant for regions 500 μm from the BMO. Although instrument output provides RNFL data inside the region of the BMO, the ONH has no other retinal layers, and the TRT best describes the axonal content of this region. Unlike TRT, RNFL annular measures were only significant up to 500 μm from the BMO (Table 2 and Figure 3D). However, similar to TRT, the increase in these annular regions was significant in the superior, inferior, and nasal quadrants (eTable 6 in the Supplement).

Discussion

The findings of this study show that in individuals exposed to long-duration microgravity there is a change in the position of the BMO, an increase in retinal thickness that is more pronounced closer to the ONH rim margin, and an increase in the proportion of eyes with choroidal folds. Because most astronauts included in this study had previous spaceflight experience, the preflight data were first compared with healthy controls before comparisons with postflight scans. The results of these investigations suggest that, although there may be resolution of structural changes, there can be long-term ocular anatomical changes after extended-duration spaceflight.

In patients with disc edema, there is reported correspondence between RNFL and TRT from standard circular scans and Frisén Scale grade.15 However, in the astronauts studied, the preflight global circumpapillary RNFL thickness data were not different from those of healthy controls, and only a modest increase in global RNFL thickness was seen postflight. This is similar to mild cases of disc edema, where anatomical changes at the ONH might be visible, but edema has typically not spread to regions sampled by the circumpapillary RNFL scan.

For the Cirrus HD-OCT system, the circumpapillary RNFL thickness is derived from a volumetric scan. The instrument algorithm segments both the RNFL and TRT for the 200 × 200 A-scan volume; in fact, total volume data have been shown to relate well with disc edema severity.29 In addition, TRT measures at the ONH or in the immediate peripapillary retina have also been proposed.17,19,30 Hence, to gain a better understanding of the regional change in thickness, custom algorithms were developed to analyze the volume scans to quantify both RNFL thickness and TRT measures at and immediately adjacent to the ONH.

Using elliptical annular regions, the global RNFL thickness was not significantly different for preflight measures compared with controls at any eccentricity. Similar to circumpapillary scans, the nasal sector of the 500 to less than 1000 μm RNFL annulus was thicker in preflight than for healthy controls. Although statistical significance was not reached, this nasal sector for preflight data was thicker for each of the 3 annuli compared with healthy controls. Similarly, the median RNFL thickness for the temporal quadrant was thinner for preflight scans. These results suggest that there is possible residual edema of the RNFL, with potential thinning in astronauts who have previously been exposed to microgravity environments. This is also supported by TRT data from the same annuli, where global thickness measures are thicker up to 500 μm from the BMO, and the median thickness is greater than that of controls for all quadrants up to 1000 μm.

After long-duration microgravity exposure, there was an increase in circumpapillary RNFL and annular global RNFL thickness and TRT measures. Increases in tissue thickness were greater closer to the BMO than at more distal annular locations. In addition, there were more eyes with choroidal folds postflight. Although ICP was not provided for any individual in the present study, the findings correspond to those often seen in patients with papilledema, suggesting elevated ICP as a potential cause.31-33 However, there are also differences between disc edema from pseudotumor cerebri and what is seen in astronauts. Specifically, terrestrial patients often have reports of headaches, tinnitus, or diplopia; while astronauts report mild headaches, these are typically not severe enough to interrupt mission activities.9 In addition, there are anatomical OCT differences between these 2 groups.

In terrestrial patients with increased ICP, the translaminar pressure gradient results in a bowing of the RPE and Bruch membrane (BM) of the ONH toward the vitreous body. Hence, the RPE/BM angle is useful for both diagnosis and monitoring of therapeutic intervention.19,20,30 For the astronaut preflight scans, the BMO height, which corresponds to the height component of the BM angle, was recessed compared with controls and further decreased after microgravity exposure. This suggests that the optic nerve was exposed to a translaminar pressure gradient that favored increased cupping. However, while a transient increase in intraocular pressure is noted immediately after entry into microgravity, for most of the time in microgravity, intraocular pressure is similar to that on the ground.8,34,35 With return to the ground, hydrostatic draining would be regained fairly rapidly, as is supported by early fluid shift experiments, in which calf muscle circumference started to increase immediately after return.36 If ICP is a contributing factor, the rapid change in fluid shifts, and therefore ICP, could explain the observed changes in BMO height. Similarly, there was no difference between preflight and postflight choroidal thickness, which could be due to the regaining of hydrostatic pressure, although there were more eyes with choroidal folds. Overall, these observations warrant biomechanical modeling to understand the morphological changes seen.

Limitations

This study had several limitations. Although all available astronauts’ preflight and postflight Cirrus HD-OCT scans of the ONH were included, the sample size was small. Many of the astronauts had been on previous missions, and time from the previous mission or total microgravity exposure was not accounted for. In addition, factors like age, sex, diet, and metabolism were not investigated in the present study. Finally, while high-quality scans were typically obtained, they had not been optimized for choroid quantification at the time of capture.

Conclusions

Although there are some similarities of spaceflight-associated neuro-ocular syndrome with pseudotumor cerebri, the exact pathophysiology remains unknown.14 The changes in RNFL thickness and TRT are similar to those that would be expected with elevated ICP. However, the changes in BMO height and the disproportionate number of individuals with choroidal folds are not typical with increased ICP. Future and ongoing studies that include OCT imaging of the posterior segment on the International Space Station will provide additional information on the time course of structural changes that will be important not only for understanding the pathophysiology but also for developing countermeasures.

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Article Information

Accepted for Publication: November 19, 2017.

Corresponding Author: Nimesh Patel, OD, PhD, University of Houston College of Optometry, 4901 Calhoun Rd, Houston, TX 77204 (npatel@central.uh.edu).

Published Online: January 11, 2018. doi:10.1001/jamaophthalmol.2017.6226

Author Contributions: Dr Patel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Patel, Pass, Otto.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Patel, Mason, Gibson.

Statistical analysis: Patel, Mason.

Obtained funding: Patel, Pass, Otto.

Administrative, technical, or material support: Mason, Gibson.

Study supervision: All authors.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest, and none were reported.

Funding/Support: This study was supported by a KBRwyle subcontract. Drs Patel and Pass were supported by the University of Houston College of Optometry core facilities grant NIH P30 EY007551 from the National Institutes of Health.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The manuscript was reviewed by the National Aeronautics and Space Administration (NASA) Lifetime Surveillance of Astronaut Health for participant privacy before being submitted for publication.

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