Susana B. Zanello

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.

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.

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.

Analysis by NASA's VESGEN Software of Vascular Branching in the Human Retina with a Ground-Based Microgravity Analog

PURPOSE Targeted drug delivery to the ocular tissues remains a challenge. Biodegradable intraocular implants allow prolonged controlled release of drugs directly into the eye. In this study, we evaluated an anterior suprachoroidal polyurethane implant containing dexamethasone polyurethane dispersions (DX-PUD) as a drug delivery system in the rat model of endotoxin-induced uveitis (EIU). METHODS In vitro drug release was studied using PUD implants containing 8%, 20%, and 30% (wt/wt) DX. Cytotoxicity of the degradation products of DX-PUD was assessed on human ARPE-19 cells using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) test. Short-term ocular biocompatibility of suprachoroidal DX-PUD implants was evaluated in normal rat eyes. Endotoxin-induced uveitis was then induced in rat eyes preimplanted with DX-PUD. Clinical examination was performed at 24 hours; eyes were used to assess inflammatory cell infiltration and macrophage/microglial activation. Cytokine and chemokine expression in the iris/ciliary body and in the retina was investigated using quantitative PCR. Feasibility of anterior suprachoroidal PUD implantation was also tested using postmortem human eyes. RESULTS A burst release was followed by a sustained controlled release of DX from PUD implants. By-products of the DX-PUD were not toxic to human ARPE-19 cells or to rat ocular tissues. Dexamethasone-PUD implants prevented EIU in rat eyes, reducing inflammatory cell infiltration and inhibiting macrophage/microglial activation. Dexamethasone-PUD downregulated proinflammatory cytokines/chemokines (IL-1β, IL-6, cytokine-induced neutrophil chemoattractant [CINC]) and inducible nitric oxide synthase (iNOS) and upregulated IL-10 anti-inflammatory cytokine. Polyurethane dispersion was successfully implanted into postmortem human eyes. CONCLUSIONS Dexamethasone-PUD implanted in the anterior suprachoroidal space may be of interest in the treatment of intraocular inflammation.

Retinal non-visual photoreception in space

BACKGROUND Circadian rhythm disruption occurs during spaceflight, leading to crew health and performance decrements. Spaceflight-related retinal changes, including oxidative stress and neuronal loss, have been previously reported in mice. METHODS Animal tissue from experiments aboard shuttle missions STS-133 (BALB/cJ mice, albino strain) and STS-135 (C57BL mice, pigmented strain), along with ground controls, was examined to determine survival of intrinsically photosensitive retinal ganglion cells (ipRGC) and melanopsin expression in retinas of mice exposed to the spaceflight environment. Real-time qPCR (RTqPCT) and microarray approaches were used to analyze Opn4 (melanopsin) gene expression, while immunohistologic studies were conducted to detect melanopsin localization in the retina. RESULTS Opn4 expression was decreased in albino BALB/cJ mice exposed to spaceflight, as measured by RTqPCR, but not in C57BL mice samples as analyzed by microarray. Opn4 expression returned to control levels at 7 d postreturn in the BALB/cJ samples. Melanopsin positive RGCs were found in the expected proportion in all samples, except for the BALB/cJ samples at 1 d after flight, where virtually no immunoreactive cells were found. DISCUSSION Spaceflight environmental factors may affect the nonvisual function of the retina, mediated by a reduction in melanopsin expression and ipRGC survival, contributing to circadian disruption.

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.

High dietary iron increases oxidative stress and radiosensitivity in the rat retina and vasculature after exposure to fractionated gamma radiation

Radiation exposure in combination with other space environmental factors including microgravity, nutritional status, and deconditioning is a concern for long-duration space exploration missions. Astronauts experience altered iron homeostasis due to adaptations to microgravity and an iron-rich food system. Iron intake reaches three to six times the recommended daily allowance due to the use of fortified foods on the International Space Station. Iron is associated with certain optic neuropathies and can potentiate oxidative stress. This study examined the response of eye and vascular tissue to gamma radiation exposure (3 Gy fractionated at 37.5 cGy per day every other day for 8 fractions) in rats fed an adequate-iron diet or a high-iron diet. Twelve-week-old Sprague-Dawley rats were assigned to one of four experimental groups: adequate-iron diet/no radiation (CON), high-iron diet/no radiation (IRON), adequate-iron diet/radiation (RAD), and high-iron diet/radiation (IRON+RAD). Animals were maintained on the corresponding iron diet for 2 weeks before radiation exposure. As previously published, the high-iron diet resulted in elevated blood and liver iron levels. Dietary iron overload altered the radiation response observed in serum analytes, as evidenced by a significant increase in catalase levels and smaller decrease in glutathione peroxidase and total antioxidant capacity levels. 8-OHdG immunostaining, showed increased intensity in the retina after radiation exposure. Gene expression profiles of retinal and aortic vascular samples suggested an interaction between the response to radiation and high dietary iron. This study suggests that the combination of gamma radiation and high dietary iron has deleterious effects on retinal and vascular health and physiology.

Outcome measure to assess head-down bed rest subject performance.

BACKGROUND The purpose of the present study was to develop an objective outcome measure to assess the performance of head-down bed rest subjects. The rationale behind the development was that the current outcome measure is subjective and dependent upon how much the clinical psychologist knows about subject behaviors during the study to rate them accurately. METHODS The behaviorally anchored rating scales (BARS) were developed through the use of the critical incident technique, along with traditional BARS development procedures, and the use of focus groups. RESULTS Use of these methodologies yielded 86 usable critical incidents, which were used as anchors for the scales. DISCUSSION Further research will be necessary to determine whether or not associations exist between data from the BARS and psychological screening data.