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NASA NTRS2010

Human System Drivers for Exploration Missions

Evaluation of DRM4 in terms of the human system includes the ability to meet NASA standards, the inclusion of the human system in the design trade space, preparation for future missions and consideration of a robotic precursor mission. Ensuring both the safety and the performance capability of the human system depends upon satisfying NASA Space Flight Human System Standards.1 These standards in turn drive the development of program-specific requirements for Near-earth Object (NEO) missions. In evaluating DRM4 in terms of these human system standards, the currently existing risk models, technologies and biological countermeasures were used. A summary of this evaluation is provided below in a structure that supports a mission architecture planning activities. 1. Unacceptable Level of Risk The duration of the DRM4 mission leads to an unacceptable level of risk for two aspects of human system health: A. The permissible exposure limit for space flight radiation exposure (a human system standard) would be exceeded by DRM4. B. The risk of visual alterations and abnormally high intracranial pressure would be too high. 1

Kundrot, Craig E.↗
NASA NTRS2011

Effects and Responses to Spaceflight in the Mouse Retina

Several stress environmental factors are combined in a unique fashion during spaceflight, affecting living beings widely across their physiological systems. Recently, attention has been placed on vision changes in astronauts returning from long duration missions. Alterations include hyperoptic shift, globe flattening, choroidal folds and optic disc edema, which are probably associated with increased intracranial pressure. These observations justify a better characterization of the ocular health risks associated with spaceflight. This study investigates the impact of spaceflight on the biology of the mouse retina. Within a successful tissue sharing effort, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (Animal Enclosure Module) mice were used as ground controls. Oxidative stress-induced DNA damage was higher in the flight samples compared to controls on R+1, and decreased on R+7. A trend toward higher oxidative and cellular stress response gene expression was also observed on R+1 compared to AEM controls, and these levels decreased on R+7. Several genes coding for key antioxidant enzymes, namely, heme-oxygenase-1, peroxiredoxin, and catalase, were among those upregulated after flight. Likewise, NF B and TGFbeta1, were upregulated in one flight specimen that overall showed the most elevated oxidative stress markers on R+1. In addition, retinas from vivarium control mice evidenced higher oxidative stress markers, NF B and TGFbeta1, likely due to the more intense illumination in vivarium cages versus the AEM. These preliminary data suggest that spaceflight represents a source of environmental stress that translates into oxidative and cellular stress in the retina, which is partially reversible upon return to Earth. Further work is needed to dissect the contribution of the various spaceflight factors (microgravity, radiation) and to evaluate the impact of the stress response on retinal health.

Zanello, Susana B.↗
NASA NTRS2011

Contribution of Spaceflight Environmental Factors to Vision Risks

The risk of visual impairment and elevated intracranial pressure as a result of low-earth orbit microgravity exposure has directed our attention and research efforts to the eye. While the alterations observed in astronauts returning from long duration missions include vision and neuroanatomical changes observed by non-invasive methods, other effects and subsequent tissue responses at the molecular and cellular level can only be studied by accessing the tissue itself. As a result of this need, several studies are currently taking place within the Human and Health Countermeasures Element (HHC) that use animal models for eye research. The rodent eye has many similarities to the human eye, and both rats and mice have historically been used as models of human eye disease, aiding in the identification of the disease genes, elucidation of mechanisms of disease, as well as in the assessment of therapeutic treatments. These studies attempt to answer two central questions in the etiology of possible vision alterations in the environment of space exploration missions. The first is: what effects and response mechanisms take place in the different eye structures at the cellular and molecular level? The second question is directed to elucidate the contribution of the various environmental stressors (radiation, nutrition, fluid shift) to these effects. Collaborative approaches with internal and external investigators have allowed performing these studies in a most cost-effective fashion, providing preliminary data and laying the bases for testing further hypotheses in future and specifically designed animal experiments. From a study centered on the radioadaptive response in mice, we have learned that the retina responds to low and high dose gamma radiation by elevating antioxidant-related genes at early time points (4hrs) and that this response returns to control levels after 1 day post-irradiation. We are expanding this research with another collaborative study that investigates the combined effects of radiation exposure and iron overload on sensitivity to radiation injury in rat eyes. All main eye structures will be analyzed in this study: retina, lens and cornea. A study in collaboration with the Space Human Factors and Habitability Element (SHFH) investigates the effects of lunar dust exposure on the rat cornea. It is anticipated that common underlying oxidative stress mechanisms of damage may be observed as a result of these three stressors: radiation, nutritional iron and lunar dust. The contribution of fluid shift is addressed by a study using rats subjected to hindlimb suspension. The hypothesis to be tested in this study is that the mechanical stress imparted by the pressure differential across the optic disc and lamina cribosa will impact oxygenation (therefore causing oxidative stress and hypoxia) and cell survival. This study also includes the assessment of two nutritional antioxidant countermeasures: epigallocatechin gallate (green tea) and resveratrol. Finally, as a result of two successful tissue sharing efforts, we are proceeding with the analysis of eye samples of mice aboard two shuttle missions: STS-133 and STS-135. Results from the STS-133 study are presented in an independent abstract. Briefly, the results show that spaceflight represents a source of environmental stress that directly translates into oxidative and cellular stress in the retina. Similar analysis is also planned for the cornea. These samples add large value to our current vision research as they provide data on the direct effects of low-earth orbit spaceflight on eye structures and physiology.

Zanello, Susana B.↗
NASA NTRS2012

Contribution of Spaceflight Environmental Factors to Vision Risks

The recognition of a risk of visual impairment and intracranial pressure increase as a result of spaceflight has directed our attention and research efforts to the eye. While the alterations observed in astronauts returning from long duration missions include reportable vision and neuroanatomical changes observed by non-invasive methods, other effects and subsequent tissue responses at the molecular and cellular level can only be studied by accessing the tissue itself. As a result of this need, several studies are currently taking place that use animal models for eye research within the HHC Element. The implementation of these studies represents a significant addition to the capabilities of the biomedical research laboratories within the SK3 branch at JSC.

Zanello, Susana↗
NASA NTRS2012

Spaceflight Effects and Molecular Responses in the Mouse Eye: Observations after NASA Shuttle Mission STS-133

Background: Human space exploration implies a combination of stressors including microgravityinduced cephalad fluid shift and radiation exposure. Ocular changes in astronauts leading to visual impairment are of occupational health relevance. The effect of this complex environment on ocular morphology and function is poorly understood. Material and Methods: Mice were assigned to a Flight (FLT) group flown on shuttle mission STS133, Animal Enclosure Module (AEM), or vivarium (VIV) ground controls. Eyes were collected at 1, 5 and 7 days after landing, and were fixed for histological sectioning. The contralateral eye was used for gene expression profiling by qRT-PCR. Routine histology and immunohistochemistry using 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, glial fibrillary acidic protein (GFAP) and beta-amyloid were used to study the eyes. Results and Conclusions: 8-OHdG and caspase-3 immunoreactivity was increased in the retina in FLT samples at return from flight (R+1) compared to ground controls, and decreased at day 7 (R+7), suggesting an increase in oxidative stress and cell apoptosis. FLT mice showed evidence of retinal pigment epithelium (RPE) apoptosis possibly secondary to oxidative damage. Although attenuation of RPE has been related to retinal choroidal folds in astronauts, it is yet to be determined whether or not increased RPE apoptosis may contribute to the formation of choroidal folds or may increase the risk for other retinal pathologies, such as AMD. beta-amyloid was seen in the nerve fibers at the post-laminar region of the optic nerve in the flight samples (R+7). Deposition of beta-amyloid has a strong correlation with mechanical trauma. The coexpression of GFAP in astrocytes and oligodentrocytes in these same areas supports the possible mechanical origin probably secondary to intracranial pressure that is transmitted into the nerve, as a result of an increase in venous pressure associated to microgravity-induced cephalic fluid shift. However, there is the need to further investigate the nature of the changes through additional experimental work. Gene expression of oxidative and cellular stress response genes was unregulated in the retina of FLT samples upon landing followed by lower levels by R+7. These results suggest that reversible molecular damage occurs in the retina of mice exposed to spaceflight and that protective cellular and molecular pathways are induced in the retina in response to these changes.

ProsperoPonce, Claudia Maria↗
NASA NTRS2012

Mechanical Stress and Antioxidant Protection in the Retina of Hindlimb Suspended Rats

It has been postulated that hindlimb suspension (HS) causes a cephalad fluid shift in quadrupeds similar to that occurring to humans in microgravity. Therefore, HS may provide a suitable animal model in which to recapitulate the ocular changes observed in the human Visual Impairment and Intracranial Pressure (VIIP) syndrome. This work reports preliminary results from a tissue sharing project using 34 week-old Brown Norway rats. Two different experiments compared normal posture controls and HS rats for 2 weeks and rats exposed to HS for 2 weeks but allowed to recover in normal posture for 2 additional weeks. The effects of two nutritional countermeasures, green tea extract (GT) and plant polyphenol resveratrol (Rv), were also evaluated. Green tea contains the antioxidant epigallocatechin gallate (EGCG). qPCR gene expression analysis of selected targets was performed on RNA from isolated retinas, and histologic analysis was done on one fixed eye per rat. The transcription factor early growth response protein 1 (Egr1) was upregulated almost 2-fold in HS retinas relative to controls (P = 0.059), and its expression returned to control levels after 2 weeks of recovery in normal posture (P = 0.023). HS-induced upregulation of Egr1 was attenuated (but not significantly) in retinas from rats fed an antioxidant rich (GT extract) diet. In rats fed the GT-enriched diet, antioxidant enzymes were induced, evidenced by the upregulation of the gene heme oxygenase 1 (Hmox1) (P = 0.042) and the gene superoxide dismutase 2 (Sod2) (P = 0.0001). Egr1 is a stretch-activated transcription factor, and the Egr1 mechanosensitive response to HS may have been caused by a change in the translaminal pressure and/or mechanical deformation of the eye globe. The observed histologic measurements of the various retinal layers in the HS rats were lower in value than those of the control animal (n = 1), however insufficient data were available for statistical analysis. Aquaporin 4, a water-selective channel involved in interstitial fluid homeostasis, showed an upregulated trend in HS retinas; however, these results are preliminary. Total retinal thickness increased significantly (P = 0.049) in HS rats fed a resveratrol enriched diet compared to HS rats on a normal diet. This change appeared to be reversed during the 2 weeks of recovery post HS, but no differences in retina thickness were observed between HS animals and HS recovered animals when both groups consumed a normal diet. The reversibility of the increase in retinal thickness induced by resveratrol during HS may therefore reflect an interaction between the stress provoked by HS and the cytoprotective mechanisms elicited by resveratrol

Glass, Aziza↗
NASA NTRS2012

New Therapeutic Window of Regenerative Opportunity in Diabetic Retinopathy by VESGEN Analysis

Vascular pattern may serve as a useful new biomarker principle of complex, multi-scale signaling in pathological, physiological angiogenesis and microvascular remodeling. Each angiogenesis stimulator or inhibitor we have analyzed, including VEGF, bFGF, TGF-beta1, angiostatin and triamcinolone acetonide, has induced a novel "fingerprint" or "signature" biomarker vascular pattern that is spatio-temporally unique. Remodeling vasculature thereby provides an informative read-out of dominant molecular signaling, when analyzed by innovative, fractal-based VESsel GENeration (VESGEN) Analysis software. Using VESGEN to analyze ophthalmic clinical vascular images, we recently introduced a potential paradigm shift to the understanding of early-stage progression that suggests new regenerative opportunities for human diabetic retinopathy (DR), the major blinding disease for working-aged adults. In a pilot study, we discovered that angiogenesis oscillates as a surprising, homeostatic-like regeneration of retinal vessels during early progression of DR (IOVS 51(1):498). Results suggest that the term non-proliferative DR may be a misnomer. In new studies, normalization of the vasculature will be determined from the response of vascular pattern to therapeutic monitoring and treatment. We have mapped and quantified in vivo experimental models of angiogenesis, lymphangiogenesis and intravital blood flow from cellular/molecular to higher systems levels that include a murine model of infant retinopathy of prematurity (ROP); developing and pathological coronary and placental-like vessel models; progressive intestinal inflammation, growing murine tumors, and other pathological, physiological and therapeutically treated tissues of transgenic mice and avian embryos. Vascular Alterations, Visual Impairments (VIIP) & Increased Intracranial Pressure (ICP), Immunosuppression & Bone Loss: NASA-defined risk categories for human space exploration and ISS Utilization

Parsons-Wingert, Patricia A.↗
NASA NTRS2013

An Evidence Base for Human Spaceflight Risks in Wikipedia

NASA's Human Research Program (HRP) is focused on understanding and mitigating thirty two risks to crew health and performance in exploration missions beyond low Earth orbit. The HRP has developed an evidence report for each of the risks. Most evidence reports are a brief review article describing the evidence related to a specified risk, written at a level appropriate for the scientifically educated, non‐specialist reader. Each evidence report captured the current state of knowledge from both research and operations. Two limitations of the evidence reports have become apparent: 1) they are updated infrequently and 2) they do not take full advantage of the expertise available in other space agencies and in related fields of terrestrial research. Therefore, the HRP is experimenting with the use of Wikipedia articles as a repository for evidence. Wikipedia's accessibility to the international space flight community and researchers in related terrestrial fields creates the opportunity to generate a more timely and comprehensive evidence base. Initial Wikipedia articles were populated for seven risks using a subset of the information in the HRP‐approved evidence reports: Fatigue and Sleep Loss, Treating An Ill or Injured Crew Member, Radiation Carcinogenesis, Visual Impairment and Intracranial Pressure, Renal Stone Formation, Team Cohesion, and Intervertebral Disc Damage. Since the initial articles were created, there have been additions to these Wikipedia articles, including content from sources outside the HRP, and editorial changes to the pages. We will report on the nature of the contributions made after the initial articles were created, the comprehensiveness of the resulting Wikipedia articles, and the effort required to maintain quality control of the content. The Wikipedia approach will also be compared to wiki efforts that exert more traditional editorial control of content prior to posting.

Kundrot, Craig↗
NASA NTRS2014

Hindlimb Suspension as a Model to Study Ophthalmic Complications in Microgravity Status Report: Optimization of Rat Retina Flat Mounts Staining to Study Vascular Remodeling

Preliminary data from a prior tissue‐sharing experiment has suggested that early growth response protein‐1 (Egr1), a transcription factor involved in various stress responses in the vasculature, is induced in the rat retina after 14 days of hindlimb suspension (HS) and may be evidence that mechanical stress is occurring secondary to the cephalad fluid shift. This mechanical stress could cause changes in oxygenation of the retina, and the subsequent ischemia‐ or inflammation‐driven hypoxia may lead to microvascular remodeling. This microvascular remodeling process can be studied using image analysis of retinal vessels and can be then be quantified by the VESsel GENeration Analysis (VESGEN) software, a computational tool that quantifies remodeling patterns of branching vascular trees and capillary or vasculogenic networks. Our project investigates whether rodent HS is a valid model to study the effects of simulated‐weightlessness on ocular structures and their relationship with intracranial pressure (ICP). One of the hypotheses to be tested is that HS‐induced cephalad fluid shift is accompanied by vascular engorgement that produces changes in retinal oxygenation, leading to oxidative stress, hypoxia, microvascular remodeling, and cellular degeneration. We have optimized the procedure to obtain flat mounts of rat retina, staining of the endothelial lining in vasculature and acquisition of high quality images suitable for VESGEN analysis. Briefly, eyes were fixed in 4% paraformaldehyde for 24 hours and retinas were detached and then mounted flat on microscope slides. The microvascular staining was done with endothelial cell‐specific isolectin binding, coupled to Alexa‐488 fluorophore. Image acquisition at low magnification and high resolution was performed using a new Leica SP8 confocal microscope in a tile pattern across the X,Y plane and multiple sections along the Z‐axis. This new confocal microscope has the added capability of dye separation using the Linear Unmixing method and allows us to remove the autofluorescence originating from the photoreceptor layer. In summary, we have an improved method for studying the retinal microvasculature that will provide an increase in the quality of images captured and will be applied throughout the various animal cohorts of the recentlyinitiated study that will evaluate rodent HS as a model to study ophthalmic complications in microgravity.

Theriot, Corey A.↗
NASA NTRS2014

The Relationship Between CO2 Levels and CO2 Related Symptoms Reported on the ISS

Medical Operations, Toxicology, and the Lifetime Surveillance of Astronaut Health collaborated to assess the association of CO2 levels on board the International Space Station and USOS crew reported symptoms inflight, i.e. headache and vision changes. Private Medical Conference (PMC) documents and the weekly Space Medicine Operations Team (SMOT) Notes were used to provide a robust data set of inflight medical events. All events and non‐events were documented independent of CO2 levels and other potential contributors. Average (arithmetic mean) and single point maximum ppCO2 was calculated for the 24 hours and 7 days prior to the PMC or SMOT date and time provided by LSAH. Observations falling within the first 7 days of flight (147) were removed from the datasets analyzed to avoid confounding with Space Adaptation Syndrome. The final analysis was based on 1716 observations. For headache, 46 headaches were observed. CO2 level, age at launch, time inflight, and data source were all significantly associated with headache. In particular, for each 1 mmHg increase in CO2, the odds of a crewmember reporting a headache doubled. For vision changes, 29 reports of vision changes were observed. These observations were not found to be statistically associated with CO2 levels as analyzed. While the incidence of headache has was not high (~3%), headaches may be an indicator of underlying increases in intracranial pressure, which may result likely from the synergy between CO2‐induced cerebral vasodilatation and decreased venous drainage in microgravity. Vision changes were inconsistently reported and as a result did not align appropriately with the CO2 levels. Further analysis is needed. Our results support ongoing efforts to lower the CO2 exposure limits in spacecraft.

VanBaalen, M.↗
NASA NTRS2014

Focal Gray Matter Plasticity as a Function of Long Duration Head-down Tilt Bed Rest

Long duration spaceflight (i.e., 22 days or longer) has been associated with changes in sensorimotor systems, resulting in difficulties that astronauts experience with posture control, locomotion, and manual control. The microgravity environment is an important causal factor for spaceflight induced sensorimotor changes. Whether these sensorimotor changes may be related to structural and functional brain changes is yet unknown. However, increased intracranial pressure that by itself has been related to microgravity-induced bodily fluid shifts: [1] has been associated with white matter microstructural damage, [2] Thus, it is possible that spaceflight may affect brain structure and thereby cognitive functioning. Long duration head-down tilt bed rest has been suggested as an exclusionary analog to study microgravity effects on the sensorimotor system, [3] Bed rest mimics microgravity in body unloading and bodily fluid shifts. In consideration of the health and performance of crewmembers both in- and post-flight, we are conducting a prospective longitudinal 70-day bed rest study as an analog to investigate the effects of microgravity on brain structure, and [4] Here we present results of the first eight subjects.

Koppelmans, Vincent↗
NASA NTRS2014

Optic Nerve Sheath Mechanics and Permeability in VIIP Syndrome

Long-duration space flight carries the risk of developing Visual Impairment and Intracranial Pressure (VIIP) syndrome, a spectrum of ophthalmic changes including posterior globe flattening, choroidal folds, distension of the optic nerve sheath (ONS), optic nerve kinking and potentially permanent degradation of visual function. The slow onset of VIIP, its chronic nature, and certain clinical features strongly suggest that biomechanical factors acting on the ONS play a role in VIIP. Here we measure several relevant ONS properties needed to model VIIP biomechanics. The ONS (meninges) of fresh porcine eyes (n7) was reflected, the nerve proper was truncated near the sclera, and the meninges were repositioned to create a hollow cylinder of meningeal connective tissue attached to the posterior sclera. The distal end was cannulated, sealed, and pressure clamped (mimicking cerebrospinal fluid [CSF] pressure), while the eye was also cannulated for independent control of intraocular pressure (IOP). The meninges were inflated (CSF pressure cycling 7-50 mmHg) while ONS outer diameter was imaged. In another set of experiments (n4), fluid permeation rate across the meninges was recorded by observing the drainage of an elevated fluid reservoir (30 mmHg) connected to the meninges. The ONS showed behavior typical of soft tissues: viscoelasticity, with hysteresis in early preconditioning cycles and repeatable behavior after 4 cycles, and nonlinear stiffening, particularly at CSF pressures 15 mmHg (Figure). Tangent moduli measured from the loading curve were 372 101, 1199 358, and 2050 379 kPa (mean SEM) at CSF pressures of 7, 15 and 30 mmHg, respectively. Flow rate measurements through the intact meninges at 30mmHg gave a permeability of 1.34 0.46 lmincm2mmHg (mean SEM). The ONS is a tough, strain-stiffening connective tissue that is surprisingly permeable. The latter observation suggests that there could be significant CSF drainage through the ONS into the orbit, likely important for CSF transport in the optic nerve. These experimental measurements, extended to human eyes, are informing computational models of the pathophysiology and biomechanics of the ONS in VIIP syndrome.

biomechanics↗
NASA NTRS2014

NASA's Approach to Critical Risks for Extended Human Space Flight

Planetary Robotic and Human Spaceflight Exploration Humans are exposed to a great variety of hazards in the space environment. These include the effects of weightlessness, radiation, isolation and confinement, altered day-night cycles, and others. These inherent hazards have both physiological and behavioral consequences. The adaptive capabilities of humans in these situations is remarkable, and often exceed our expectations. However, the demanding environment and challenging operational pace can push some of these adaptive processes to their limits. The NASA Human Research Program (HRP) is tasked with mitigating the most serious of these effects on human health, safety, and performance, in long-duration space flight. This can involve the development and deployment of physiological countermeasures, better understanding of the physiological alterations and avoidance of exacerbating situations, inputs to the design of future spacecraft to minimize risks, and in some cases the awareness that some level of risk might have to be accepted based on the resulting consequences and their likelihood. HRP has identified a few areas that are of special concern due to their severity, lack of understanding of underlying causes, or potential for negative impact on health or performance. Some of these areas are visual impairment possibly due to increased intracranial pressure, behavioral and performance problems due to sleep deficits and isolation, and acute and chronic effects of radiation. These problems can, if not addressed, be expected to increase on longer and more distant missions. The evidence from spaceflight, laboratory, and analog studies that supports the selection of the most critical risks will be discussed. Current and planned research programs that address these risks, and their anticipated outcomes, will also be described.

Shelhamer, Mark↗
NASA NTRS2014

Changes in Near Visual Acuity of Over Time in the Astronaut Corps

We hypothesized that visual impairment due to intracranial pressure (VIIP) would increase the rate of which presbyopia would occur in the astronaut population, with long durations flyers at an especially high risk. Presbyopia is characterized as the gradual loss of near visual acuity overtime due to a loss in ability to accommodate. It generally develops in the mid‐40s and progresses until about age 65. This analysis considered annual vision exams conducted on active NASA astronauts with spaceflight experience currently between the ages of 40 to 60 years of age. Onset of presbyopia was characterized as a shift of at least 20 units on the standard Snellen test from one annual exam to the next. There were 236 short duration and 48 long duration flyers, the majority of whom did experience onset of presbyopia between age 40 and 60. This shift however, did not necessarily come after spaceflight. In comparing the short and long duration flyers the mean age of onset was 47 years old (SD+/-3.7). The mean of onset within the general population is 45 to 47 years old [1, 2]. The mean age of the onset of presbyopia as compared to the general population indicates that space flight does not induce early development of presbyopia.

Taiym, Wafa↗
NASA NTRS2015

Evalution of a DE-Identification Process for Ocular Imaging

Medical privacy of NASA astronauts requires an organized and comprehensive approach when data are being made available outside NASA systems. A combination of factors, including the uniquely small patient population, the extensive medical testing done on these individuals, and the relative cultural popularity of the astronauts puts them at a far greater risk to potential exposure of personal information than the general public. Therefore, care must be taken to ensure that the astronauts' identities are concealed. Magnetic Resonance Imaging (MRI) medical data is a recent source of interest to researchers concerned with the development of Visual Impairment due to Intracranial Pressure (VIIP) in the astronaut population. Each vision MRI scan of an astronaut includes 176 separate sagittal images that are saved as an "image series" for clinical use. In addition to the medical information these image sets provide, they also inherently contain a substantial amount of non-medical personally identifiable information (PII) such as-name, date of birth, and date of exam. We have shown that an image set of this type can be rendered, using free software, to give an accurate representation of the patient's face. This currently restricts NASA from dispensing MRI data to researchers in a deidentified format. Automated software programs, such as the Brain Extraction Tool, are available to researchers who wish to de-identify MRI sagittal brain images by "erasing" identifying characteristics such as the nose and jaw on the image sets. However, this software is not useful to NASA for vision research because it removes the portion of the images around the eye orbits, which is the main area of interest to researchers studying the VIIP syndrome. The Lifetime Surveillance of Astronaut Health program has resolved this issue by developing a protocol to de-identify MRI sagittal brain images using Showcase Premier, a DICOM (Digital Imaging and Communications in Medicine) software package. The software allows manual editing of one image from a patient's image set to be automatically applied to the entire image series. This new approach would allow a new level of access to untapped medical imaging data relating to VIIP that can be utilized by researchers while protecting the privacy of the astronauts. In the next step toward finalizing this technique, NASA clinical radiology consultants will test the images to verify removal of all metadata and PII.

LaPelusa, Michael B.↗
NASA NTRS2014

Effects of Mild Hypercapnia During Head-Down Bed Rest on Ocular Structures, Cerebral Blood Flow, aud Visual Acuity in Healthy Human Subjects

The cephalad fluid shift induced by microgravity has been hypothesized to cause an elevation in intracranial pressure (ICP) and contribute to the development of the Visual Impairment/Intracranial Pressure (VIIP) syndrome, as experienced by some astronauts during long-duration space flight. Elevated ambient partial pressure of carbon dioxide (PCO2) on ISS may also raise ICP and contribute to VIIP development. We seek to determine if the combination of mild CO2 exposure, similar to that occurring on the International Space Station, with the cephalad fluid shift induced by head-down tilt, will induce ophthalmic and cerebral blood flow changes similar to those described in the VIIP syndrome. We hypothesize that mild hypercapnia in the head-down tilt position will increase choroidal blood volume and cerebral blood flow, raise intraocular pressure (IOP), and transiently reduce visual acuity as compared to the seated or the head-down tilt position without elevated CO2, respectively.

Laurie, S. S.↗
NASA NTRS2015

Ocular Outcomes Comparison Between 14- and 70-day Head-down Tilt Bed Rest

INTRODUCTION: Ophthalmological changes, including optic disc edema with optic nerve sheath distension, posterior globe flattening with hyperopic shift, choroidal folds and cotton wool spots have been detected in some astronauts involved in long-duration spaceflights. (sup 1) It is hypothesized that elevated intracranial pressure resulting from microgravity-induced cephalad fluid shifts may be responsible for most of these findings. Head-down tilt bed rest (HTDBR) is a ground-based microgravity analog which also produces cephalad fluid shifts. It is conceivable that prolonged HDTBR exposure may induce ocular changes similar to those experienced in microgravity. Therefore, the purpose of the present study was to compare structural and functional ocular outcomes between 14- and 70-day HDTBR in healthy human subjects. It is hypothesized that 70-d HDTBR induced ocular changes of greater magnitude as compared to 14-d HDTBR. METHODS: Two HDTBR studies were conducted at the NASA Flight Analogs Research Unit, located at The University of Texas Medical Branch at Galveston, TX. Identical NASA standard screening procedures and BR conditions (e.g., strict sleep-wake cycle, standardized diet, continuous video monitoring) were implemented in both studies. Participants spent 14 and/or 70 consecutive days in a 6deg HDT position and did not engage in exercise. Subjects received weekly ocular examinations before, during, and after HDTBR. Ocular testing included: distance and near best-corrected visual acuity (BCVA), cycloplegic refraction, intraocular pressure (IOP) measurement, color vision, red dot test, modified Amsler grid test, confrontational visual field, color fundus photography and Spectral-domain OCT scans of the macula and the optic disc. Pre/post HDTBR differences between the two studies will be evaluated for BCVA, spherical equivalent, IOP, retinal nerve fiber layer (RNFL) thickness and macular OCT parameters. RESULTS: 16 (12 males and 4 females) and 6 (5 males and 1 female) subjects participated in the 14 and 70-day HDTBR studies, respectively. One subject participated in both studies. The demographic and ophthalmological characteristics of the 14-day HDTBR study have been presented elsewhere.2 In the 70- day study, subjects age averaged 39.5 +/- 7.8 years; pre- and post-HDTBR Goldmann IOP were, on average, 15.4 and 14.6 mmHg in the right eye, and 15.3 and 14.4 mmHg in the left eye, respectively; preand post-HDTBR Spectralis OCT (Heidelberg Engineering, GmbH, Heidelberg, Germany) average RNFL thickness were 103.8 and 106 μm in the right eye, and 103 and 104.3 μm in the left eye, respectively. In both studies, color vision, red dot test, modified Amsler grid test and confrontational visual field were within normal limits at all time points; no changes were detected on stereoscopic color optic disc photography. For the above outcomes, preliminary results of the pre/post HDTBR differences between the two studies will be presented at the 2015 Human Research Program Investigators' Workshop. CONCLUSIONS: Although 14-day HDTBR did not seem to induce clinically relevant ocular changes, (sup 2) a systematic evaluation and comparison with the 70-day HDTBR study results will elucidate whether the magnitude of ocular structural and functional changes is affected by the time spent in the recumbent position. Further research will also address the effects of integrated resistance and aerobic training during HDTBR on the ocular outcomes. REFERENCES: 1. Mader TH et al. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmology. 2011;118(10):2058-69. 2. Taibbi G et al. Ocular outcomes evaluation in a 14-day head-down bed rest study. Aviat Space Environ Med. 2014;85(10):983-92.

Cromwell, R.L.↗
NASA NTRS2015

Fluid Shifts

INTRODUCTION: Mechanisms responsible for the ocular structural and functional changes that characterize the visual impairment and intracranial pressure (ICP) syndrome (VIIP) are unclear, but hypothesized to be secondary to the cephalad fluid shift experienced in spaceflight. This study will relate the fluid distribution and compartmentalization associated with long-duration spaceflight with VIIP symptoms. We also seek to determine whether the magnitude of fluid shifts during spaceflight, as well as the VIIP-related effects of those shifts, can be predicted preflight with acute hemodynamic manipulations, and also if lower body negative pressure (LBNP) can reverse the VIIP effects. METHODS: Physiologic variables will be examined pre-, in- and post-flight in 10 International Space Station crewmembers including: fluid compartmentalization (D2O and NaBr dilution); interstitial tissue thickness (ultrasound); vascular dimensions and dynamics (ultrasound and MRI (including cerebrospinal fluid pulsatility)); ocular measures (optical coherence tomography, intraocular pressure, ultrasound); and ICP measures (tympanic membrane displacement, otoacoustic emissions). Pre- and post-flight measures will be assessed while upright, supine and during 15 deg head-down tilt (HDT). In-flight measures will occur early and late during 6 or 12 month missions. LBNP will be evaluated as a countermeasure during HDT and during spaceflight. RESULTS: The first two crewmembers are in the preflight testing phase. Preliminary results characterize the acute fluid shifts experienced from upright, to supine and HDT postures (increased stroke volume, jugular dimensions and measures of ICP) which are reversed with 25 millimeters Hg LBNP. DISCUSSION: Initial results indicate that acute cephalad fluid shifts may be related to VIIP symptoms, but also may be reversible by LBNP. The effect of a chronic fluid shift has yet to be evaluated. Learning Objectives: Current spaceflight VIIP research is described, including novel hardware and countermeasures.

Stenger, M. B.↗