Opposite response of blood vessels in the retina to 6° head-down tilt and long-duration microgravity.

The Spaceflight Associated Neuro-ocular Syndrome (SANS), associated with the headward fluid shifts incurred in microgravity during long-duration missions, remains a high-priority health and performance risk for human space exploration. To help characterize the pathophysiology of SANS, NASA's VESsel GENeration Analysis (VESGEN) software was used to map and quantify vascular adaptations in the retina before and after 70 days of bed rest at 6-degree Head-Down Tilt (HDT), a well-studied microgravity analog. Results were compared to the retinal vascular response of astronauts following 6-month missions to the International Space Station (ISS). By mixed effects modeling, the trends of vascular response were opposite. Vascular density decreased significantly in the 16 retinas of eight astronauts and in contrast, increased slightly in the ten retinas of five subjects after HDT (although with limited significance). The one astronaut retina diagnosed with SANS displayed the greatest vascular loss. Results suggest that microgravity is a major variable in the retinal mediation of fluid shifts that is not reproduced in this HDT bed rest model.

Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis.

The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.

Decreased Vascular Patterning in the Retinas of Astronaut Crew Members as New Measure of Ocular Damage in Spaceflight-Associated Neuro-ocular Syndrome.

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 and overall vessel length density 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.

Ophthalmological Evaluation of Integrated Resistance and Aerobic Training During 70-Day Bed Rest.

INTRODUCTION: We evaluated ophthalmic changes in healthy individuals who underwent integrated resistance and aerobic training (iRAT) during 70-d 6° head-down tilt (HDT) bed rest (BR). METHODS: Participants were selected using NASA standard screening procedures. Standardized NASA BR conditions were implemented. Subjects were randomly assigned to the iRAT protocol or no exercise during HDTBR. Weekly ophthalmic examinations were performed in the sitting (pre/post-BR only) and HDT (BR only) positions. Mixed-effects linear models compared pre- and post-HDTBR intraocular pressure (IOP), Spectralis OCT circumpapillary retinal nerve fiber layer (cpRNFL) thickness, and peripapillary retinal thickness observations between groups. RESULTS: Six controls and nine exercisers completed the study. There was an overall effect of BR on our outcomes. Except Goldmann IOP (mean pre/post difference in controls and exercisers: -0.47 mmHg vs. +1.14 mmHg), the magnitude of changes from baseline was not significantly different between groups. There was a +1.38 mmHg and a +1.63 mmHg iCare IOP increase during BR in controls and exercisers, respectively. Spectralis OCT detected a +1.33 µm average cpRNFL thickness increase in both groups, and a +9.77 µm and a +6.65 µm peripapillary retinal thickening post-BR in controls and exercisers, respectively. Modified Amsler grid, red dot test, confrontational visual field, color vision, and stereoscopic fundus photography were unremarkable. CONCLUSIONS: HDTBR for 70 d induced peripapillary retinal thickening and cpRNFL thickening without visible signs of optic disc edema. The magnitude of such changes was not different between controls and exercisers. A slight IOP increase during BR subsided post-BR. Further study should evaluate whether different physical exercise paradigms may prevent/mitigate the risk of space-related visual impairment.Taibbi G, Cromwell RL, Zanello SB, Yarbough PO, Ploutz-Snyder RJ, Godley BF, Vizzeri G. Ophthalmological evaluation of integrated resistance and aerobic training during 70-day bed rest. Aerosp Med Hum Perform. 2017; 88(7):633-640.

Effects of short-term mild hypercapnia during head-down tilt on intracranial pressure and ocular structures in healthy human subjects.

Many astronauts experience ocular structural and functional changes during long-duration spaceflight, including choroidal folds, optic disc edema, globe flattening, optic nerve sheath diameter (ONSD) distension, retinal nerve fiber layer thickening, and decreased visual acuity. The leading hypothesis suggests that weightlessness-induced cephalad fluid shifts increase intracranial pressure (ICP), which contributes to the ocular structural changes, but elevated ambient CO2 levels on the International Space Station may also be a factor. We used the spaceflight analog of 6° head-down tilt (HDT) to investigate possible mechanisms for ocular changes in eight male subjects during three 1-h conditions: Seated, HDT, and HDT with 1% inspired CO2 (HDT + CO2). Noninvasive ICP, intraocular pressure (IOP), translaminar pressure difference (TLPD = IOP-ICP), cerebral and ocular ultrasound, and optical coherence tomography (OCT) scans of the macula and the optic disc were obtained. Analysis of one-carbon pathway genetics previously associated with spaceflight-induced ocular changes was conducted. Relative to Seated, IOP and ICP increased and TLPD decreased during HDT During HDT + CO2 IOP increased relative to HDT, but there was no significant difference in TLPD between the HDT conditions. ONSD and subfoveal choroidal thickness increased during HDT relative to Seated, but there was no difference between HDT and HDT + CO2 Visual acuity and ocular structures assessed with OCT imaging did not change across conditions. Genetic polymorphisms were associated with differences in IOP, ICP, and end-tidal PCO2 In conclusion, acute exposure to mild hypercapnia during HDT did not augment cardiovascular outcomes, ICP, or TLPD relative to the HDT condition.

Ocular Outcomes Comparison Between 14- and 70-Day Head-Down-Tilt Bed Rest.

PURPOSE: To compare ocular outcomes in healthy subjects undergoing 14- and/or 70-day head-down-tilt (HDT) bed rest (BR). METHODS: Participants were selected by using NASA standard screening procedures. Standardized NASA BR conditions were implemented. Subjects maintained a 6° HDT position for 14 and/or 70 consecutive days. Weekly ophthalmologic examinations were performed in the sitting (pre/post-BR only) and HDT positions. Mixed-effects linear models compared pre- and post-HDT BR observations between 14- and 70-day HDT BR in best-corrected visual acuity, spherical equivalent, intraocular pressure (IOP), Spectralis OCT retinal nerve fiber layer thickness, peripapillary and macular retinal thicknesses. RESULTS: Sixteen and six subjects completed the 14- and 70-day HDT BR studies, respectively. The magnitude of HDT BR-induced changes was not significantly different between the two studies for all outcomes, except the superior (mean pre/post difference of 14- vs. 70-day HDT BR: +4.69 µm versus +11.50 µm), nasal (+4.63 µm versus +11.46 µm), and inferior (+4.34 µm versus +10.08 µm) peripapillary retinal thickness. A +1.42 mm Hg and a +1.79 mm Hg iCare IOP increase from baseline occurred during 14- and 70-day HDT BR, respectively. Modified Amsler grid, red dot test, confrontational visual field, color vision, and stereoscopic fundus photography were unremarkable. CONCLUSIONS: Seventy-day HDT BR induced greater peripapillary retinal thickening than 14-day HDT BR, suggesting that time may affect the amount of optic disc swelling. Spectralis OCT detected retinal nerve fiber layer thickening post BR, without clinical signs of optic disc edema. A small IOP increase during BR subsided post HDT BR. Such changes may have resulted from BR-induced cephalad fluids shift. The HDT BR duration may be critical for replicating microgravity-related ophthalmologic changes observed in astronauts on ≥6-month spaceflights.

Correlation and Agreement Between Cirrus HD-OCT "RNFL Thickness Map" and Scan Circle Retinal Nerve Fiber Layer Thickness Measurements.

PURPOSE: To evaluate the correlation and agreement between optical coherence tomography (Cirrus HD-OCT) retinal nerve fiber layer (RNFL) thickness map and scan circle RNFL thickness measurements. METHODS: ImageJ and custom Perl scripts were used to derive RNFL thickness measurements from RNFL thickness maps of optic disc scans of healthy and glaucomatous eyes. Average, quadrant, and clock-hour RNFL thickness of the map, and RNFL thickness of the areas inside/outside the scan circle were obtained. Correlation and agreement between RNFL thickness map and scan circle RNFL thickness measurements were evaluated using R and Bland-Altman plots, respectively. RESULTS: A total of 104 scans from 26 healthy eyes and 120 scans from 30 glaucomatous eyes were analyzed. RNFL thickness map and scan circle measurements were highly reproducible (eg, in healthy eyes, average RNFL thickness coefficients of variation were 2.14% and 2.52% for RNFL thickness map and scan circle, respectively) and highly correlated (0.55 ≤ R ≤ 0.98). In general, the scan circle provided greater RNFL thickness than the RNFL thickness map in corresponding sectors and the differences tended to increase as RNFL thickness increased. The width of the 95% limits of agreement ranged between 5.28 and 36.80 µm in healthy eyes, and between 11.69 and 42.89 µm in glaucomatous eyes. CONCLUSIONS: Despite good correlation between RNFL thickness map and scan circle measurements, agreement was generally poor, suggesting that RNFL thickness assessment over the entire scan area may provide additional clinically relevant information to the conventional scan circle analysis. In the absence of available measurements from the entire peripapillary region, the RNFL thickness maps can be used to investigate localized RNFL thinning in areas not intercepted by the scan circle.

Factors Affecting Cirrus-HD OCT Optic Disc Scan Quality: A Review with Case Examples.

Spectral-domain OCT is an established tool to assist clinicians in detecting glaucoma and monitor disease progression. The widespread use of this imaging modality is due, at least in part, to continuous hardware and software advancements. However, recent evidence indicates that OCT scan artifacts are frequently encountered in clinical practice. Poor image quality invariably challenges the interpretation of test results, with potential implications for the care of glaucoma patients. Therefore, adequate knowledge of various imaging artifacts is necessary. In this work, we describe several factors affecting Cirrus HD-OCT optic disc scan quality and their effects on measurement variability.

Ocular outcomes evaluation in a 14-day head-down bed rest study.

INTRODUCTION: We evaluated ocular outcomes in a 14-d head-down tilt (HDT) bed rest (BR) study designed to simulate the effects of microgravity on the human body. METHODS: Healthy subjects were selected using NASA standard screening procedures. Standardized NASA BR conditions were implemented (e.g., strict sleep-wake cycle, standardized diet, 24-hour-a-day BR, continuous video monitoring). Subjects maintained a 6° HDT position for 14 consecutive days. Weekly ophthalmological examinations were performed in the sitting (pre/post-BR) and HDT (in-bed phase) positions. Equivalency tests with optimal-alpha techniques evaluated pre/post-BR differences in best-corrected visual acuity (BCVA), spherical equivalent, intraocular pressure (IOP), Spectral-domain OCT retinal nerve fiber layer thickness (RNFLT), optic disc and macular parameters. RESULTS: 16 subjects (12 men and 4 women) were enrolled. Nearly all ocular outcomes were within our predefined clinically relevant thresholds following HDTBR, except near BCVA (pre/post-BR mean difference: -0.06 logMAR), spherical equivalent (-0.30 D), Tonopen XL IOP (+3.03 mmHg) and Spectralis OCT average (+1.14 µm), temporal-inferior (+1.58 µm) and nasal-inferior RNFLT (+3.48 µm). Modified Amsler grid, red dot test, confrontational visual field, and color vision were within normal limits throughout. No changes were detected on stereoscopic color fundus photography. DISCUSSION: A few functional and structural changes were detected after 14-d HDTBR, notably an improved BCVA possibly due to learning effect and RNFL thickening without signs of optic disc edema. In general, 6° HDTBR determined a small nonprogressive IOP elevation, which returned to baseline levels post-BR. Further studies with different BR duration and/or tilt angle are warranted to investigate microgravity-induced ophthalmological changes.

Effect of motion artifacts and scan circle displacements on Cirrus HD-OCT retinal nerve fiber layer thickness measurements.

PURPOSE: To evaluate the effect of scan circle displacements on retinal nerve fiber layer thickness (RNFLT) measurements in Cirrus HD-OCT scans with motion artifacts affecting the optic disc. METHODS: In this cross-sectional study, 70 scans from 18 healthy eyes and 100 scans from 26 glaucomatous eyes were divided into 85 pairs, each composed by a scan with one motion artifact affecting the optic disc, and a scan from the same eye without motion artifacts. En face images underwent automated realignment, and horizontal/vertical scan circle displacements were determined. Multiple regression analysis evaluated the relationship between scan circle displacements and RNFLT change. RESULTS: Scans with motion artifacts showed similar displacements in healthy and glaucomatous eyes (P values ≥ 0.08). Average RNFLT and quadrants were relatively unchanged, while clock-hours showed more changes (e.g., in glaucomatous eyes, clock-hour-7 RNFLT was lower in scans with motion artifacts, P = 0.05). Scan circle displacements produced average RNFLT changes above test-retest variability in 3/85 cases (3.53%). Retinal nerve fiber layer thickness tended to decrease in sectors moved away from the disc and to increase in sectors closer to the disc (R(2) ≤ 0.40 and R(2) ≤ 0.22 in healthy and glaucomatous eyes, respectively). In healthy eyes, horizontal displacements ≥ 423 and 325 µm were associated with average and quadrant RNFLT changes above test-retest variability, respectively. CONCLUSIONS: Scan circle displacements occurred in all scans with motions artifacts affecting the optic disc. Average RNFLT and quadrants were more robust than clock-hours. Because motion artifacts may be difficult to detect, clinicians should carefully inspect en face OCT images for their presence and interpret clock-hour results cautiously.

Effects of 30-day head-down bed rest on ocular structures and visual function in a healthy subject.

INTRODUCTION: We report ocular changes occurring in a healthy human subject enrolled in a bed rest (BR) study designed to replicate the effects of a low-gravity environment. CASE REPORT: A 25-yr-old Caucasian man spent 30 consecutive days in a 6 degrees head-down tilt (HDT) position at the NASA Flight Analogs Research Unit. Comprehensive ophthalmologic exams, optic disc stereo-photography, standard automated perimetry (SAP), and optic disc Spectralis OCT scans were performed at baseline, immediately post-BR (BR+0), and 6 mo post-BR. MAIN OUTCOME MEASURES: changes in best-corrected visual acuity, intraocular pressure (IOP), cycloplegic refraction, SAP, and Spectralis OCT measures. At BR+0 KIOP was 11 and 10 mmHg in the right (OD) and left eye (OS), respectively (a bilateral 4-mmHg decrease compared to baseline); SAP documented a possible bilateral symmetrical inferior scotoma; Spectralis OCT showed an average 19.4 microm (+5.2%) increase in peripapillary retinal thickness, and an average 0.03 mm3 (+5.0%) increase in peripapillary retinal volume bilaterally. However, there were no clinically detectable signs of optic disc edema. At 6 mo post-BR, IOP was 13 and 14 mmHg in OD and OS, respectively, and the scotoma had resolved. Spectralis OCT measurements matched the ones recorded at baseline. DISCUSSION: In this subject, a reduction in IOP associated with subtle structural and functional changes compared to baseline were documented after prolonged head-down BR. These changes may be related to cephalad fluid shifts in response to tilt. Further studies should clarify whether decreased translaminar pressure (i.e., the difference between IOP and intracranial pressure) may be responsible for these findings.

The effect of microgravity on ocular structures and visual function: a review.

Ocular structural and functional changes, including optic disk edema and reduction of near visual acuity, have been recently described in some astronauts returning from long-duration space travels. It is hypothesized that ocular changes related to spaceflight may occur, in predisposed individuals, as a result of cephalad shift of body fluids, possibly leading to elevated intracranial pressure (ICP). Results from head-down bed-rest studies (used to simulate the effects of microgravity) and from parabolic flight experiments (used to produce transient periods of microgravity) indicate that ocular blood flow and intraocular pressure (IOP) may undergo changes in a low-gravity environment. Recent studies suggest that changes in translaminar pressure (i.e., IOP minus ICP) may be implicated in the pathophysiology of optic disk neuropathies. Because postural changes exert an effect on both IOP and ICP, the head-down bed-rest analog may also be used as a platform to characterize the relationship between IOP and ICP, and their reciprocal influence in the pathophysiology of conditions such as optic disk edema or glaucoma.

Diagnostic assessment of normal and pale optic nerve heads by confocal scanning laser ophthalmoscope and stereophotography.

PURPOSE: To evaluate the diagnostic assessment of optic nerve heads (ONH) by stereophotography (SP) and Heidelberg retina tomograph (HRT) in patients with retinitis pigmentosa (RP). METHODS: This study involved 53 consecutive patients with RP and 24 controls who underwent ONH examination by SP and HRT. On the basis of the appearance at SP, RP ONH were divided in normal-colored (24/53) and pale (29/53). The measurements of vertical ONH diameter and vertical cup/disc ratio (VCDR) by SP and HRT were compared between the groups by means of t test and Bland-Altman plots. Diagnosis, ONH pallor and size, HRT image quality (image standard deviation, SD) were also inspected as sources of differences in the results by means of a multivariate analysis. RESULTS: Vertical diameter measurements were similar using SP and HRT, respectively (1.93±0.50 and 1.80±0.62 for normal-colored ONH, P=0.43; 2.02±0.65 and 1.90±0.40 for pale ONH, P=0.27; and 1.98±0.55 and 1.84±0.52 for controls, P=0.33). In normal-colored ONH, VCDR was 0.30±0.11 at SP and 0.31±0.21 at HRT (P=0.90); in controls, it was 0.29±0.13 at SP and 0.30±0.18 at HRT (P=0.77). In the group with pale ONH, VCDR was 0.34±0.14 at SP and 0.53±0.24 at HRT (P<0.001). HRT image quality was the only parameter which influenced the difference in VCDR estimates between SP and HRT (P=0.02). In patients with pale ONH, this difference was significantly higher, when images of acceptable quality were used for analysis (0.36±0.15 vs. 0.15±0.21 for images with good quality or better, P=0.03). CONCLUSIONS: In ONH diseases other than glaucoma, HRT may give misleading information when images of acceptable quality are considered for analysis. We therefore recommend the use of images with good quality or better (SD ≤30 µm) in these cases.

Reproducibility of the Heidelberg Retina Tomograph III Glaucoma Probability Score.

PURPOSE: To evaluate the intrasession reproducibility of the Heidelberg Retina Tomograph III (HRT III) Glaucoma Probability Score (GPS) and analyze the factors that may affect it. PATIENTS AND METHODS: Twenty normal subjects and 20 glaucomatous patients underwent 10 HRT III examinations of 1 randomly selected eye during the same session. The reproducibility of the GPS and its parameters was assessed by calculating the intraclass correlation coefficients (ICCs) and 95% confidence intervals of the study population as a whole, and of the 2 subgroups. The factors influencing individual reproducibility were evaluated by means of regression analysis. RESULTS: The reproducibility of the GPS parameters (at a confidence level of 95%) was almost perfect in the population as a whole (ICCs 0.964-0.856) and in the normal subjects (ICCs 0.976-0.897), but decreased in the glaucoma patients in whom it ranged from almost perfect to substantial (ICCs 0.922-0.705). The parameters were mainly influenced by image quality, but also by diagnosis and age, although the probability of glaucoma did not seem to depend on these variables. CONCLUSIONS: GPS is a highly reproducible diagnostic tool, especially in the case of "good" or better quality images as evaluated by the HRT software; moreover, the reproducibility of the GPS parameters was significantly better in normal subjects than in glaucoma patients.

Infantile nystagmus syndrome: Broadening the high-foveation-quality field with contact lenses.

We investigated the effects of contact lenses in broadening and improving the high-foveation-quality field in a subject with infantile nystagmus syndrome (INS). A high-speed, digitized video system was used for the eye-movement recording. The subject was asked to fixate a far target at different horizontal gaze angles with contact lenses inserted. Data from the subject while fixating at far without refractive correction and at near (at a convergence angle of 60 PD), were used for comparison. The eXpanded Nystagmus Acuity Function (NAFX) was used to evaluate the foveation quality at each gaze angle. Contact lenses broadened the high-foveation-quality range of gaze angles in this subject. The broadening was comparable to that achieved during 60 PD of convergence although the NAFX values were lower. Contact lenses allowed the subject to see "more" (he had a wider range of high-foveation-quality gaze angles) and "better" (he had improved foveation at each gaze angle). Instead of being contraindicated by INS, contact lenses emerge as a potentially important therapeutic option. Contact lenses employ afferent feedback via the ophthalmic division of the V cranial nerve to damp INS slow phases over a broadened range of gaze angles. This supports the proprioceptive hypothesis of INS improvement.