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Introduction. NASA's Human Research Program is focused on addressing health risks associated with long-duration missions on the International Space Station (ISS) and future exploration-class missions beyond low Earth orbit. Visual acuity changes observed after short-duration missions were largely transient, but now more than 50 percent of ISS astronauts have experienced more profound, chronic changes with objective structural findings such as optic disc edema, globe flattening and choroidal folds. These structural and functional changes are referred to as the visual impairment and intracranial pressure (VIIP) syndrome. Development of VIIP symptoms may be related to elevated intracranial pressure (ICP) secondary to spaceflight-induced cephalad fluid shifts, but this hypothesis has not been tested. The purpose of this study is to characterize fluid distribution and compartmentalization associated with long-duration spaceflight and to determine if a relation exists with vision changes and other elements of the VIIP syndrome. We also seek to determine whether the magnitude of fluid shifts during spaceflight, as well as any VIIP-related effects of those shifts, are predicted by the crewmember's pre-flight status and responses to acute hemodynamic manipulations, specifically posture changes and lower body negative pressure. Methods. We will examine a variety of physiologic variables in 10 long-duration ISS crewmembers using the test conditions and timeline presented in the figure below. Measures include: (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by CO rebreathe, interstitial fluid by calculation); (2) forehead/eyelids, tibia, and calcaneus tissue thickness (by ultrasound); (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography; intraocular pressure; 2-dimensional ultrasound including optic nerve sheath diameter, globe flattening, and retina-choroid thickness; Doppler ultrasound of ophthalmic and retinal arteries and veins); (6) cardiac variables by ultrasound (inferior vena cava, tricuspid flow and tissue Doppler, pulmonic valve, stroke volume, right heart dimensions and function, four-chamber views); and (7) ICP measures (tympanic membrane displacement, otoacoustic emissions). Pre- and post-flight, acute head-down tilt will induce cephalad fluid shifts, whereas lower body negative pressure will oppose these shifts. Controlled Mueller maneuvers will manipulate cardiovascular variables. Through interventions applied before, during, and after flight, we intend to fully evaluate the relationship between fluid shifts and the VIIP syndrome. Discussion. Ten subjects have consented to participate in this experiment, including the recent One-Year Mission crewmembers, who have recently completed R plus180 testing; all other subjects have completed pre-flight testing. Preliminary results from the One-Year Mission crewmembers will be presented, including measures of ocular structure and function, vascular dimensions, fluid distribution, and non-invasive estimates of intracranial pressure.

The visual impairment and intracranial pressure (VIIP) syndrome is a spaceflight-associated set of symptoms affecting more than 50% of American astronauts who have flown International Space Station (ISS) missions. VIIP is defined primarily by visual acuity deficits and anatomical changes to eye structures (e.g. optic disc edema, choroidal folds, and globe flattening) and is hypothesized to be related to elevated intracranial pressure secondary to a cephalad fluid shift. However, ocular symptoms have not been replicated in subjects completing prolonged bed rest, a well-accepted spaceflight analog. Altered vascular compliance along with spaceflight factors such as diet, radiation exposure, or environmental factors may cause alterations in the cardiovascular system that contribute to the manifestation of ocular changes. Loss of visual acuity could be a significant threat to crew health and performance during and after an exploration mission and may have implications for years post-flight. The overall objective of this project is to determine if spaceflight alters vascular compliance and whether such an adaptation is related to the incidence of VIIP. This objective will be met by completing three separate but related projects.

Background: Moderate and high intensity aerobic or resistance exercise has clearly identified benefits for cardiac, muscle, and bone health. However, the impact of such exercise - either as a mitigating or an exacerbating factor - on the development of the visual impairment and intracranial pressure syndrome (VIIP) is unknown. Accordingly, our aim was to characterize the effect of an acute bout of resistance (RE), moderate-intensity continuous (CE), and high-intensity interval exercise (IE) during a cephalad fluid shift on cerebral-ocular hemodynamics and pressures. Methods: 10 male subjects (36 plus or minus 9 years) completed 4 testing days in a 15 degree head-down tilt (HDT): (1) assessment of maximum volume of O (sub 2), (2) RE session (4 sets of 12 repetition maximum leg press exercise), (3) CE session (30 minutes of cycling at 60 percent maximum volume of O (sub 2)), and (4) IE session (4 by 4-minute intervals of exercise at 85 percent maximum volume of O (sub 2) with 3-minute active rest periods). During each session, blood flow (Vivid-e, GE Healthcare) in extracranial arteries (common carotid artery, CCA; internal carotid artery, ICA; external carotid artery, ECA and vertebral artery, VA), and mean blood flow velocity in middle cerebral artery (MCA), internal jugular pressure (IJP; VeinPress), and intraocular pressure (IOP; Icare PRO) were measured at rest, at the end of each resistance or interval set, and every 5 minutes during continuous exercise. Translaminar pressure gradient (TLPG) was estimated by subtracting IJP from IOP. Results: There were no differences across days in pre-exercise resting blood flows or pressures. IOP decreased slightly from HDT rest (20.2 plus or minus 2.3 millimeters of mercury) to exercise (RE: 19.2 plus or minus 2.8 millimeters of mercury; CE: 18.9 plus or minus 3.2 millimeters of mercury; IE: 20.1 plus or minus 2.8 millimeters of mercury), while IJP decreased during CE (31.6 plus or minus 9.5 millimeters of mercury) and RE (32.0 plus or minus 8.1 millimeters of mercury), and increased during IE (35.1 plus or minus 9.5 millimeters of mercury) from HDT rest (33.3 plus or minus 6.5 millimeters of mercury). Estimated TLPG was increased during IE only. Compared to RE and CE, IE resulted in the greatest increase in MCA blood flow velocity and extracranial artery blood flow. Conclusions: These preliminary results suggest that high-intensity IE acutely increases cerebral blood flow, IJP, and TLPG. Alterations in TLPG is one mechanism that may contribute to optic nerve sheath edema in astronauts. Accordingly, acutely raising IOP and/or orbital pressure during exercise could optimize cerebral-ocular pressures during spaceflight.

NASA is focusing on long-duration missions on the International Space Station (ISS) and future exploration-class missions beyond low-Earth orbit. Visual acuity changes observed after short-duration missions were largely transient, but more than 50% of ISS astronauts experienced more profound, chronic changes with objective structural and functional findings such as papilledema and choroidal folds. Globe flattening, optic nerve sheath dilation, and optic nerve tortuosity also are apparent. This pattern is referred to as the visual impairment and intracranial pressure (VIIP) syndrome. VIIP signs and symptoms, as well as postflight lumbar puncture data, suggest that elevated intracranial pressure (ICP) may be associated with the spaceflight-induced cephalad fluid shifts, but this hypothesis has not been tested. The purpose of this study is to characterize fluid distribution and compartmentalization associated with long-duration spaceflight, and to correlate these findings with vision changes and other elements of the VIIP syndrome. We also seek to determine whether the magnitude of fluid shifts during spaceflight, as well as the VIIP-related effects of those shifts, is predicted by the crewmember's preflight conditions and responses to acute hemodynamic manipulations (such as head-down tilt). Lastly, we will evaluate the patterns of fluid distribution in ISS astronauts during acute reversal of fluid shifts through application of lower body negative pressure (LBNP) interventions to characterize and explain general and individual responses. METHODS: We will examine a variety of physiologic variables in 10 long-duration ISS crewmembers using the test conditions and timeline presented in the Figure below. Measures include: (1) fluid compartmentalization (total body water by D2O, extracellular fluid by NaBr, intracellular fluid by calculation, plasma volume by CO rebreathe, interstitial fluid by calculation); (2) forehead/eyelids, tibia, calcaneus tissue thickness (by ultrasound); (3) vascular dimensions by ultrasound (jugular veins, cerebral and carotid arteries, vertebral arteries and veins, portal vein); (4) vascular dynamics by MRI (head/neck blood flow, cerebrospinal fluid pulsatility); (5) ocular measures (optical coherence tomography, intraocular pressure, 2-dimensional ultrasound including optic nerve sheath diameter, globe flattening, and retina-choroid thickness, Doppler ultrasound of ophthalmic and retinal arteries, and veins); (6) cardiac variables by ultrasound (inferior vena cava, tricuspid flow and tissue Doppler, pulmonic valve, stroke volume, right heart dimensions and function, four-chamber views); and (7) ICP measures (tympanic membrane displacement, distortion-product otoacoustic emissions, and ICP calculated by MRI). On the ground, acute head-down tilt will induce cephalad fluid shifts, whereas LBNP will oppose these shifts. Controlled Mueller maneuvers will manipulate cardiovascular variables. Through interventions applied before, during, and after flight, we intend to fully evaluate the relationship between fluid shifts and the VIIP syndrome.

The cephalad fluid shift induced by microgravity has been hypothesized to elevate intracranial pressure (ICP) and contribute to the development of the visual impairment/intracranial pressure (VIIP) syndrome experienced by many astronauts during and after long-duration space flight. In addition, elevated ambient partial pressure of carbon dioxide (PCO2) on the International Space Station (ISS) has also been hypothesized to contribute to the development of VIIP. We seek to determine if an acute, mild CO2 exposure, similar to that occurring on the ISS, combined with the cephalad fluid shift induced by head-down tilt will induce ophthalmic and ICP changes consistent with the VIIP syndrome.

The capability to grow nutritious, palatable food for crew consumption during spaceflight has the potential to provide health-promoting, bioavailable nutrients, enhance the dietary experience, and reduce launch mass as we move toward longer-duration missions. However, studies of edible produce during spaceflight have been limited, leaving a significant knowledge gap in the methods required to grow safe, acceptable, nutritious crops for consumption in space. Researchers from Kennedy Space Center, Johnson Space Center, Purdue University and ORBITEC have teamed up to explore the potential for plant growth and food production on the International Space Station (ISS) and future exploration missions. KSC, Purdue, and ORBITEC bring a history of plant and plant-microbial interaction research for ISS and for future bioregenerative life support systems. JSC brings expertise in Advanced Food Technology (AFT), Behavioral Health and Performance (BHP), and statistics. The Veggie vegetable-production system on the ISS offers an opportunity to develop a pick-and-eat fresh vegetable component to the ISS food system as a first step to bioregenerative supplemental food production. We propose growing salad plants in the Veggie unit during spaceflight, focusing on the impact of light quality and fertilizer formulation on crop morphology, edible biomass yield, microbial food safety, organoleptic acceptability, nutritional value, and behavioral health benefits of the fresh produce. The first phase of the project will involve flight tests using leafy greens, with a small Chinese cabbage variety, Tokyo bekana, previously down selected through a series of research tests as a suitable candidate. The second phase will focus on dwarf tomato. Down selection of candidate varieties have been performed, and the dwarf cultivar Red Robin has been selected as the test crop. Four light treatments and three fertilizer treatments will be tested for each crop on the ground, to down select to two light treatments and one fertilizer treatment to test on ISS. Our work will help define light colors, levels, and horticultural best practices to achieve high yields of safe, nutritious leafy greens and tomatoes to supplement a space diet of prepackaged food. Our final deliverable will be the development of growth protocols for these crops in a spaceflight vegetable production system. With this work, and potentially with other pending joint projects, we will continue the synergistic research to help close gaps in the human research roadmap, and enable humans to venture to Mars and beyond. This research was co-funded by the Human Research Program and Space Biology (MTL1075) in the ILSRA 2015 NRA call.

NASA, in planning for long duration missions, has an imperative to provide a food system with the necessary nutrition, acceptability, and safety to ensure sustainment of crew health and performance. The Orion Multi-Purpose Crew Vehicle (MPCV) and future exploration missions are mass constrained; therefore we are challenged to reduce the mass of the food system by 10% while maintaining safety, nutrition, and acceptability for exploration missions. Food bars have previously been used to supplement meals in the Skylab food system, indicating that regular consumption of bars will be acceptable. However, commercially available products do not meet the requirements for a full meal replacement in the spaceflight food system. The purpose of this task is to develop a variety of nutritionally balanced breakfast replacement bars, which meet spaceflight nutritional, microbiological, sensorial, and shelf-life requirements, while enabling a 10% food mass savings. To date, six nutrient-dense meal replacement bars have been developed, using both traditional methods of compression as well as novel ultrasonic compression technologies developed by Creative Resonance Inc. (Phoenix, AZ). All bars will be prioritized based on acceptability and the four top candidates will be evaluated in the Human Exploration Research Analog (HERA) to assess the frequency with which actual meal replacement options may be implemented. Specifically, overall impact to mood, satiety, dietary discomfort, and satisfaction with food will be analyzed to inform successful implementation strategies. In addition, these bars will be evaluated based on final product sensory acceptability, nutritional stability, qualitative stability of analytical measurements (i.e. water activity and texture), and microbiological compliance over two years of storage at room temperature and potential temperature abuse conditions to predict long-term acceptability. It is expected that this work will enable a successful meal replacement strategy to be implemented that maintains crew food consumption and health, while informing exploration missions with appropriate mass savings expectations.

To compare structural and functional ocular outcomes between14-and 70-day HDTBR in healthy human subjects.

The visual impairment and intracranial pressure (VIIP) syndrome is a spaceflight-associated medical condition consisting of a constellation of symptoms affecting less than 70% of American astronauts who have flown International Space Station (ISS) missions. VIIP is defined primarily by visual acuity deficits and anatomical changes to eye structures and is hypothesized to be related to elevated intracranial pressure secondary to spaceflight-induced cephalad fluid shifts, although other space flight factors (e.g., diet, environmental factors) may contribute. Loss of visual acuity could be a significant threat to crew health and performance during and after an exploration mission and may have implications for years postflight.

Data from the Nutritional Status Assessment protocol provided biochemical evidence that the one-carbon metabolic pathway may be altered in individuals experiencing vision-related issues during and after space flight (1, 2). Briefly, serum concentrations of homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid were significantly (P<0.001) higher (25-45%) in astronauts with ophthalmic changes than in those without such changes (1). These differences existed before, during, and after flight. Serum folate was lower (P<0.01) during flight in individuals with ophthalmic changes. Preflight serum concentrations of cystathionine and 2-methylcitric acid, and mean in-flight serum folate, were significantly (P<0.05) correlated with postflight changes in refraction (1). A follow-up study was conducted to evaluate a small number of known polymorphisms of enzymes in the one-carbon pathway, and to evaluate how these relate to vision and other medical aspects of the eye. Specifically, we investigated 5 polymorphisms in MTRR, MTHFR, SHMT, and CBS genes and their association with ophthalmic changes after flight in 49 astronauts. The number of G alleles of MTRR 66 and C alleles of SHMT1 1420 both contributed to the odds of visual disturbances (3). Block regression showed that B-vitamin status at landing and genetics were significant predictors for many of the ophthalmic outcomes studied (3). In conclusion, we document an association between MTRR 66 and SHMT1 1420 polymorphisms and space flightinduced vision changes. These data document that individuals with an altered 1-carbon metabolic pathway may be predisposed to anatomic and/or physiologic changes that render them susceptible to ophthalmic damage during space flight.