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NASA NTRS2005

DEVELOPMENT OF AN INFLIGHT COUNTERMEASURE TO MITIGATE POSTFLIGHT GAIT DYSFUNCTION

Following spaceflight crewmembers experience gait and postural instabilities due to inflight adaptive alterations in sensorimotor function. These changes can pose a risk to crew safety if nominal or emergency vehicle egress is required immediately following long-duration spaceflight. At present, no operational countermeasure is available to mitigate postflight locomotor disturbances. Therefore, the goal of this study is to develop an inflight training regimen that facilitates the recovery of locomotor function after long-duration spaceflight. The countermeasure we are developing is based on the concept of variable practice. During this type of training the subject gains experience producing the appropriate adaptive motor behavior under a variety of sensory conditions and response constraints. This countermeasure is built around current ISS treadmill exercise activities. Crewmembers will conduct their nominal inflight treadmill exercise while being exposed to variations in visual flow patterns. These variations will challenge the postural and locomotor systems repeatedly, thereby promoting adaptive reorganization in locomotor behavior. As a result of this training a subject learns to solve a class of motor problems, rather than a specific motor solution to one problem, Le., the subject learns response generalizability or the ability to "learn to learn" under a variety of environmental constraints. We anticipate that this training will accelerate recovery of postural and locomotor function during readaptation to gravitational environments following spaceflight facilitating neural adaptation to unit (Earth) and partial (Mars) gravity after long-duration spaceflight. The study calls for one group of subjects to perform the inflight treadmill training regimen while a control group of subjects performs only the nominal exercise procedures. Locomotor function in both groups is assessed before and after spaceflight using two tests of gait function: The Integrated Treadmill Locomotion Test (ITLT) and the Functional Mobility Test (FMT). The ITLT characterizes alterations in the integrated function of multiple sensorimotor subsystems responsible for the control of locomotion. This test calls for subjects to walk on a motorized treadmill while we assess changes in dynamic postural stability, head-trunk coordination, short-latency head stabilization responses, dynamic visual acuity, lower limb coordination strategies and gait cycle timing. To make these assessments we measure the following parameters while subjects walk on the treadmill: 1) full body 3-dimensional kinematics using a motion capture system (Motion Analysis Corp., Santa Rosa, CA); 2) the shock-wave transmitted from heel-strike to the head using triaxial accelerometers placed on the tibia and head (Entran, Fairfield, NJ); 3) vertical forces using an instrumented treadmill (Kistler Instrument Corp., Amherst, NY); 4) Dynamic visual acuity using Landolt Cs presented on a laptop computer located 4m from the eyes and 5) Gait cycle timing using foot-switches (Motion Lab Systems, Inc., Baton Rouge, LA) attached to the plantar surface of each shoe at the heel and toe. The FMT evaluates a subject's ability to perform challenging locomotor maneuvers similar to those encountered during an egress from a space vehicle. Subjects step over and duck under obstacles along with negotiating a series of pylons set up on a base of 10 cm thick medium density foam. The dependent measures for the FMT are time to complete the course and the number of obstacles touched. To date, we have collected pre and postflight locomotion data from Expeditions 5-9 who will serve as part of the control group for this study. Preliminary results comparing the recovery rates in gait control sub-systems obtained from the ITLT and FMT performance showed two recovery patterns: 1) a concordant recovery trend between gait control parameters and FMT performance indicating a restitution pattern of recovery and 2) gait controecovery that lagged recovery in FMT performance suggesting that improvement in locomotor function was attained through a pattern of substitution. These data suggest that recovery of postflight locomotor function may occur through adaptive mechanisms that lead to either restitution or substitution of function. Understanding the modes of postflight readaptation has implications for countermeasure development and testing and in astronaut postflight rehabilitation.

Bloomberg, J. J.↗

NASA NTRS2006

A Countermeasure for Space Motion Sickness

Overall, the results obtained in both the U.S. and the Russian space programs indicate that most space crews will experience some symptoms of motion sickness (MS) causing significant impact on the operational objectives that must be accomplished to assure mission success. At this time the primary countermeasure for MS requires the administration of Promethazine. Promethazine is not a benign drug, and is most frequently administered just prior to the sleep cycle to prevent its side effects from further compromising mission objectives. Clearly other countermeasures for SMS must be developed. Currently the primary focus is on two different technologies: (1) developing new and different pharmacological compounds with less significant side effects, (2) preflight training. The primary problem with all of these methods for controlling MS is time. New drugs that may be beneficial are years from testing and development, and preflight training requires a significant investment of crew time during an already intensive pre-launch schedule. Granted, motion sickness symptoms can be minimized with either of the two methods detailed above, however, it may be possible to develop a countermeasure that does not require either extensive adaptation time or exposure to motion sickness. Approximately 25 years ago Professor Geoffrey Melvill Jones presented his work on adaptation of the vestibuloocular reflex (VOR) using optically reversed vision (left-right prisms) during head rotations in the horizontal plane. It was of no surprise that most subjects experienced motion sickness while wearing the optically reversing prisms. However, a serendipitous finding emerged during this research showing that the same subjects did not experience motion sickness symptoms when wearing the reversing prisms under stroboscopic illumination. The mechanism, by which this side-effect was believed to have occurred, is not clearly understood. However, the fact that no motion sickness was ever noted, suggests the possibility of producing functionally useful adaptation during space flight without the penalty of disabling motion sickness by controlling the rate of the adaptive process by means of an appropriate stroboscopically presented environment. After several recent meetings with Professor Melvill Jones, we were encouraged to repeat the motion sickness portions of his and Mandl's 1981 stroboscopic experiment. In conducting this experiment we used a randomized cross-over design where subjects were randomly assigned to either a stroboscopic flash or no strobe for their first exposure in the experimental design. Twenty subjects (19 subjects completed the study) read a short passage from Treasure Island mounted on the wall approximately 1 m from their eyes while wearing left-right reversing prisms. The strobe on time of 3 microseconds and flash frequency of 4 Hz was set to equal that used in the original study. Motion sickness was scored using a modified Miller and Graybiel scale that we constructed to include symptoms that may be elicited under conditions where reversing prisms are worn. On this scale a score of 5 represented Malaise IIa (mild motion sickness) and a score of 8 or above is approaching frank sickness. Symptoms were tracked and recorded every 5 min during the task. Testing was limited to 30 min unless the subject had reached the MIIa score, at which time the test was terminated. Performance under stroboscopic illumination was significantly better than when the subjects read under normal room illumination while wearing the left-right reversing prisms. Based on these results we developed a goggle system using LCD material that can be strobed. To evaluate the effectiveness of stroboscopic goggles we tested an additional 9 subjects in addition to retesting 10 used in the stroboscopic pilot study described above. These 19 subjects wore a pair of strobing LCD goggles that could be cycled at 4 Hz. These subjects wore the goggles while also wearing left-right reversg prisms. Results while wearing the goggles showed that none of the 19 subjects scored at the MIIa level on the motion sickness rating scale. When the goggles did not flash (no strobe), 11 of the 19 developed symptoms above the MIIa criteria. As a countermeasure the goggles seem to be effective, even with an on time of 10 msec (time the goggles are clear). We have also collected anecdotal data, from our personnel in the Neuroscience Laboratory at the Johnson Space Center, suggesting that the goggles may effective in preventing carsickness.

Reschke, M. F.↗

NASA NTRS2005

Development of an Inflight Countermeasure to Mitigate Postflight Gait Dysfunction

Following spaceflight crewmembers experience gait and postural instabilities due to inflight adaptive alterations in sensorimotor function. These changes can pose a risk to crew safety if nominal or emergency vehicle egress is required immediately following long-duration spaceflight. At present, no operational countermeasure is available to mitigate postflight locomotor disturbances. Therefore, the goal of this study is to develop an inflight training regimen that facilitates the recovery of locomotor function after long-duration spaceflight. The countermeasure we are developing is based on the concept of variable practice. During this type of training the subject gains experience producing the appropriate adaptive motor behavior under a variety of sensory conditions and response constraints. This countermeasure is built around current ISS treadmill exercise activities. Crewmembers will conduct their nominal inflight treadmill exercise while being exposed to variations in visual flow patterns. These variations will challenge the postural and locomotor systems repeatedly, thereby promoting adaptive reorganization in locomotor behavior. As a result of this training a subject learns to solve a class of motor problems, rather than a specific motor solution to one problem, Le., the subject learns response generalizability or the ability to "learn to learn" under a variety of environmental constraints. We anticipate that this training will accelerate recovery of postural and locomotor function during readaptation to gravitational environments following spaceflight facilitating neural adaptation to unit (Earth) and partial (Mars) gravity after long-duration spaceflight. The study calls for one group of subjects to perform the inflight treadmill training regimen while a control group of subjects performs only the nominal exercise procedures. Locomotor function in both groups is assessed before and after spaceflight using two tests of gait function: The Integrated Treadmill Locomotion Test (ITLT) and the Functional Mobility Test (FMT). The ITLT characterizes alterations in the integrated function of multiple sensorimotor subsystems responsible for the control of locomotion. This test calls for subjects to walk on a motorized treadmill while we assess changes in dynamic postural stability, head-trunk coordination, short-latency head stabilization responses, dynamic visual acuity, lower limb coordination strategies and gait cycle timing. To make these assessments we measure the following parameters while subjects walk on the treadmill: 1) full body 3-dimensional kinematics using a motion capture system (Motion Analysis Corp., Santa Rosa, CA); 2) the shock-wave transmitted from heel-strike to the head using triaxial accelerometers placed on the tibia and head (Entran, Fairfield, NJ); 3) vertical forces using an instumented treadmill (Kistler Instrument Corp., Amherst, NY); 4) Dynamic visual acuity using Landolt Cs presented on a laptop computer located 4m from the eyes and 5) Gait cycle timing using foot-switches (Motion Lab Systems, Inc., Baton Rouge, LA) attached to the plantar surface of each shoe at the heel and toe. The FMT evaluates s. subject's ability to perform challenging locomotor maneuvers similar to those encountered during an egress from a space vehicle. Subjects step over and duck under obstacles along with negotiating a series of pylons set up on a base of 10 cm thick medium density foam. The dependent measures for the FMT are time to complete the course and the number of obstacles touched. To date, we have collected pre and postflight locomotion data from Expeditions 5-9 who will serve as part of the control group for this study. Preliminary results comparing the recovery rates in gait control sub-systems obtained from the ITLT and FMT performance showed two recovery patterns: 1) a concordant recovery trend between gait control parameters and FMT performance indicating a restitution pattern of recovery and 2) gait controecovery that lagged recovery in FMT performance suggesting that improvement in locomotor function was attained through a pattern of substitution. These data suggest that recovery of postflight locomotor function may occur through adaptive mechanisms that lead to either restitution or substitution of function. Understanding the modes of postflight readaptation has implications for countermeasure development and testing and in astronaut postflight rehabilitation.

Bloomberg, J. J.↗

NASA NTRS2007

Artificial Gravity as a Multi-System Countermeasure to Bed Rest Deconditioning: Pilot Study Overview

Efficient, effective, multi-system countermeasures will likely be required to protect the health, safety, and performance of crews aboard planned exploration-class space flight missions to Mars and beyond. To that end, NASA, DLR, and IMBP initiated a multi-center international project to begin systematically exploring the utility of artificial gravity (AG) as a multi-system countermeasure in ground based venues using test subjects deconditioned by bed rest. The goal of this project is to explore the efficacy of short-radius, intermittent AG as a countermeasure to bone, muscle, cardiovascular, and sensory-motor adaptations to hypogravity. This session reports the results from a pilot study commissioned to validate a standardized protocol to be used by all centers involved in the project. Subject selection criteria, medical monitoring requirements, medical care procedures, experiment control procedures, and standardized dependent measures were established jointly. Testing was performed on 15 rigorously screened male volunteers subjected to 21 days of 6deg HDT bed rest. (All provided written consent to volunteer after the nature of the study and its hazards were clearly explained to them.) Eight were treated with daily 1hr AG exposures (2.5g at the feet decreasing to 1.0g at the heart) aboard a short radius (3m) centrifuge, while the other seven served as controls. Multiple tests of multiple dependent measures were made in each of the primary physiological systems of interest during a 10 day acclimatization period prior to HDT bed rest and again during an 8 day recovery period after the bed rest period was complete. Analyses of these data (presented in other papers in this session) suggest the AG prescription had salutary effects on aspects of the bone, muscle, and cardiovascular systems, with no untoward effects on the vestibular system, the immune system, or cognitive function. Furthermore, treatment subjects were able to tolerate 153/160 centrifuge sessions over the 21 day deconditioning protocol, suggesting that tolerance was unaffected by deconditioning. These positive results set the stage for full implementation of the planned multi-center international AG project. Future work will be devoted to developing optimization techniques for AG prescriptions (likely supplemented by exercise) to provide maximum physiological protection across all systems subject to space flight deconditioning in both men and women with minimum time and/or side effects. While a continuous AG solution (rotating vehicle) would likely be more efficient, this study suggests that intermittent AG could be an effective multi-system countermeasure.

Paloski, William H.↗

NASA NTRS2001

Alendronate and Resistive Exercise Countermeasures Against Bed Rest-Induced Bone Loss: Biochemical Markers of Bone and Calcium Metabolism

Weightlessness-induced bone loss must be counteracted to ensure crew health during extendedduration space missions. Studies were conducted to assess two bone loss countermeasures in a ground-based model: horizontal bed rest. Following a 3-wk ambulatory adaptation period, male and female subjects (aged 21-56 y) completed a 17-wk bed rest protocol. Subjects were assigned to one of three treatments: alendronate (ALEN; 10 mg/d, n=6), resistive exercise (RE; 1.5 h/d, 6 d/wk, n=8), or control (CN; no countermeasure, n=8). Dietary intake was adjusted to maintain body weight. Endocrine and biochemical indices were measured in blood and urine using standard laboratory methods. All data reported are expressed as percent change from individual pre-bedrest data. Serum calcium changed little during bed rest, and tended to decrease (4-8%) in ALEN subjects. In RE subjects, bone alkaline phosphatase and osteocalcin were increased >65 and >30%, respectively, during bed rest, while these were unchanged or decreased in ALEN and CN subjects. Urinary calcium was increased 50% in CN subjects, but was unchanged or decreased in both ALEN and RE groups. Urinary n-telopeptide excretion was increased 40-50% in CN and RE subjects, but decreased 20% in ALEN subjects. Pyridinium crosslink and deoxypyridinoline excretion were increased 20-50% during bed rest. These data suggest that RE countermeasures are effective at increasing markers of bone formation in an analog of weightlessness, while ALEN reduces markers of bone resorption. Counteracting the bone loss of space flight may require both pharmacologic and exercise countermeasures.

Smith, Scott M.↗

NASA NTRS2011

Overview of Pre-Flight Physical Training, In-Flight Exercise Countermeasures and the Post-Flight Reconditioning Program for International Space Station Astronauts

International Space Station (ISS) astronauts receive supervised physical training pre-flight, utilize exercise countermeasures in-flight, and participate in a structured reconditioning program post-flight. Despite recent advances in exercise hardware and prescribed exercise countermeasures, ISS crewmembers are still found to have variable levels of deconditioning post-flight. This presentation provides an overview of the astronaut medical certification requirements, pre-flight physical training, in-flight exercise countermeasures, and the post-flight reconditioning program. Astronauts must meet medical certification requirements on selection, annually, and prior to ISS missions. In addition, extensive physical fitness testing and standardized medical assessments are performed on long duration crewmembers pre-flight. Limited physical fitness assessments and medical examinations are performed in-flight to develop exercise countermeasure prescriptions, ensure that the crewmembers are physically capable of performing mission tasks, and monitor astronaut health. Upon mission completion, long duration astronauts must re-adapt to the 1 G environment, and be certified as fit to return to space flight training and active duty. A structured, supervised postflight reconditioning program has been developed to prevent injuries, facilitate re-adaptation to the 1 G environment, and subsequently return astronauts to training and space flight. The NASA reconditioning program is implemented by the Astronaut Strength, Conditioning, and Rehabilitation (ASCR) team and supervised by NASA flight surgeons. This program has evolved over the past 10 years of the International Space Station (ISS) program and has been successful in ensuring that long duration astronauts safely re-adapt to the 1 g environment and return to active duty. Lessons learned from this approach to managing deconditioning can be applied to terrestrial medicine and future exploration space flight missions.

Kerstman, Eric↗

NASA NTRS2014

High Intensity Exercise Countermeasures does not Prevent Orthostatic Intolerance Following Prolonged Bed Rest

Approximately 20% of Space Shuttle astronauts became presyncopal during operational stand and 80deg head‐up tilt tests, and the prevalence of orthostatic intolerance increases after longer missions. Greater than 60% of the US astronauts participating in Mir and early International Space Station missions experienced presyncope during post‐flight tilt tests, perhaps related to limitations of the exercise hardware that prevented high intensity exercise training until later ISS missions. The objective of this study was to determine whether an intense resistive and aerobic exercise countermeasure program designed to prevent cardiovascular and musculoskeletal deconditioning during 70 d of bed rest (BR), a space flight analog, would protect against post‐BR orthostatic intolerance. METHODS Twenty‐six subjects were randomly assigned to one of three groups: non‐exercise controls (n=11) or one of two exercise groups (ExA, n=8; ExB, n=7). Both ExA and ExB groups performed the same resistive and aerobic exercise countermeasures during BR, but one exercise group received testosterone supplementation while the other received a placebo during BR in a double‐blinded fashion. On 3 d/wk, subjects performed lower body resistive exercise and 30 min of continuous aerobic exercise (≥75% max heart rate). On the other 3 d/wk, subjects performed only highintensity, interval‐style aerobic exercise. Orthostatic intolerance was assessed using a 15‐min 80 head‐up tilt test performed 2 d (BR‐2) before and on the last day of BR (BR70). Plasma volume was measured using carbon monoxide rebreathing on BR‐3 and before rising on the first recovery day (BR+0). The code for the exercise groups has not been broken, and results are reported here without group identification. RESULTS Only one subject became presyncopal during tilt testing on BR‐2, but 7 of 11 (63%) controls, 3 of 8 (38%) ExA, and 4 of 7 (57%) ExB subjects were presyncopal on BR70. Survival analysis of post‐BR tilt tests revealed no differences (p=0.77) between groups. Plasma volume (absolute or relative to body mass index) decreased (p<0.001) from pre to post‐BR, with no differences between groups. CONCLUSIONS These preliminary results corroborate previous reports that the performance of a vigorous exercise countermeasure protocol during BR, even with testosterone supplementation, does not protect against orthostatic intolerance or plasma volume loss. Preventing post‐BR orthostatic intolerance may require additional countermeasures, such as orthostatic stress during BR or end‐of‐BR fluid infusion.

Platts, Steven H.↗

NASA NTRS2016

Evaluation of an Impedance Threshold Device as a VIIP Countermeasure

Visual Impairment /Intracranial Pressure (VIIP) is a top human spaceflight risk for which NASA does not currently have a proven mitigation strategy. Thigh cuffs (Braslets) and lower body negative pressure (LBNP; Chibis) devices have been or are currently being evaluated as a means to reduce VIIP signs and symptoms, but these methods alone may not provide sufficient relief of cephalic venous congestion and VIIP symptoms. Additionally, current LBNP devices are too large and cumbersome for their systematic use as a countermeasure. Therefore, a novel approach is needed that is easy to implement and provides specific relief of symptoms. This investigation will evaluate an impedance threshold device (ITD) as a VIIP countermeasure. The ITD works by providing up to 7 cm H2O (approximately 5 mmHg) resistance to inspiratory air flow, effectively turning the thorax into a vacuum pump upon each inhalation which lowers the intrathoracic pressure (ITP) and facilitates venous return to the heart. The ITD is FDA-approved and was developed to augment venous return to the central circulation and increase cardiac output during cardiopulmonary resuscitation (CPR) and in patients with hypotension. While the effect of ITD on CPR survival outcomes is controversial, the ITD's ability to lower ITP with a concomitant decrease in intracranial pressure (ICP) is well documented. A similar concept that creates negative ITP during exhalation (intrathoracic pressure regulator; ITPR) decreased ICP in 16 of 20 patients with elevated ICP in a hospital pilot study. ITP and central venous pressure (CVP) have been shown to decrease in microgravity however ITP drops more than CVP, indicating an increased transmural CVP. This could explain the paradoxical distention of jugular veins (JV) in microgravity despite lower absolute CVP and also suggests that JV transmural pressure is not dramatically elevated. Use of an ITD may lower JV pressure enough to remove or relieve cephalic venous congestion. During spaceflight experiments with Braslet thigh cuffs and modified (open-glottis) Mueller maneuvers, Braslets alone reduced cardiac preload but only reduced the internal JV (IJV) cross sectional area by 23%. The addition of Mueller maneuvers resulted in an IJV area reduction of 48%. This project will test if ITD essentially applies a Mueller maneuver with added negative ITP in every respiratory cycle, acting to: 1) reduce venous congestion in the neck and 2) potentially lower ICP. The expected mechanism of action is that in microgravity (or an analog) blood is relocated toward the heart from vasculature in the head and neck. Once validated, the ITD would be an exceptionally easy countermeasure to deploy and test on the ISS. Dosage could be altered though 1) duration of application and 2) inspiratory resistance set point. Effects could be additionally enhanced through co-application with other countermeasures such as thigh cuffs or LBNP.

Ebert, D.↗

NASA NTRS2016

Evaluation of an Impedance Threshold Device as a VIIP Countermeasure

Visual Impairment/Intracranial Pressure (VIIP) is a top human spaceflight risk for which NASA does not currently have a proven mitigation strategy. Thigh cuffs (Braslets) and lower body negative pressure (LBNP; Chibis) devices have been or are currently being evaluated as a means to reduce VIIP signs and symptoms, but these methods alone may not provide sufficient relief of cephalic venous congestion and VIIP symptoms. Additionally, current LBNP devices are too large and cumbersome for their systematic use as a countermeasure. Therefore, a novel approach is needed that is easy to implement and provides specific relief of symptoms. This investigation will evaluate an impedance threshold device (ITD) as a VIIP countermeasure. The ITD works by providing up to 7 cm H2O (approximately 5 mmHg) resistance to inspiratory air flow, effectively turning the thorax into a vacuum pump upon each inhalation which lowers the intrathoracic pressure (ITP) and facilitates venous return to the heart. The ITD is FDA-approved and was developed to augment venous return to the central circulation and increase cardiac output during cardiopulmonary resuscitation (CPR) and in patients with hypotension. While the effect of ITD on CPR survival outcomes is controversial, the ITD's ability to lower ITP with a concomitant decrease in intracranial pressure (ICP) is well documented. A similar concept that creates negative ITP during exhalation (intrathoracic pressure regulator; ITPR) decreased ICP in 16 of 20 patients with elevated ICP in a hospital pilot study. ITP and central venous pressure (CVP) have been shown to decrease in microgravity however ITP drops more than CVP, indicating an increased transmural CVP. This could explain the paradoxical distention of jugular veins (JV) in microgravity despite lower absolute CVP and also suggests that JV transmural pressure is not dramatically elevated. Use of an ITD may lower JV pressure enough to remove or relieve cephalic venous congestion. During spaceflight experiments with Braslet thigh cuffs and modified (open-glottis) Mueller maneuvers, Braslets alone reduced cardiac preload but only reduced the internal JV (IJV) cross sectional area by 23%. The addition of Mueller maneuvers resulted in an IJV area reduction of 48%. This project will test if ITD essentially applies a Mueller maneuver with added negative ITP in every respiratory cycle, acting to: 1) reduce venous congestion in the neck and 2) potentially lower ICP. The expected mechanism of action is that in microgravity (or an analog) blood is relocated toward the heart from vasculature in the head and neck. Once validated, the ITD would be an exceptionally easy countermeasure to deploy and test on the ISS. Dosage could be altered though 1) duration of application and 2) inspiratory resistance set point. Effects could be additionally enhanced through co-application with other countermeasures such as thigh cuffs or LBNP.

Ebert, Douglas↗

NASA NTRS2018

Prevention of Spaceflight-Induced Bone Loss: A Promising Dietary Countermeasure

Space radiation is one of the challenges for long-term spaceflight, especially for missions beyond low Earth Orbit. We have shown that a diet composed of 25% dried plum (DP) prevents radiation-induced bone loss. The DP diet fully protected the cancellous bone microarchitecture of mice exposed to ionizing radiation (gamma, proton, and HZE). In particular relevant to space radiation, we showed that the DP diet prevents bone loss due to 1Gy of sequential exposure of proton (1H, low linear energy transfer -LET-), and 1Gy of iron (56Fe, high-LET). In addition, total body exposure to 1Gy of HZE radiation (56Fe) impaired the osteoprogenitors in mice fed the control diet, as indicated by decreased osteoblast mineralization. In contrast, marrow stem cells from mice fed the DP did not exhibit these deficits. Based on these promising results supporting DP as a countermeasure to prevent space radiation induced-tissue damage, we conducted additional studies to combine radiation and simulated microgravity. We exposed skeletally mature male mice to simulated microgravity (using hindlimb unloading, HU) or total body irradiation (TBI, 2Gy 137Cs) or in combination (HU+TBI). We observed bone loss in the mice fed the control diet (CD) exposed to simulated spaceflight, as measured by cancellous bone microarchitecture parameters such as percent bone volume (BV/TV). In contrast, mice fed the DP diet did not exhibit similar bone loss with either treatments (HU or TBI) or combined (HU+TBI) as seen in most parameters. This was observed in both long bones (tibia) and axial bones (vertebrae). Furthermore, preliminary data shows that pre-feeding with the DP diet attenuates the HU-induced decrement in bone-forming osteoblasts colony counts and mineralization capacity of the osteoprogenitor cells. We also performed DP feeding at lower doses (5%, 10%) and found that these doses are less effective in preventing the radiation-induced bone loss. All our studies with the DP diet as a countermeasure were done with a period of pre-feeding ranging from 14 to 21 days before irradiation, and in order to test the capacity of the DP diet as a countermeasure provided after exposure to radiation, we exposed mice to 2Gy gamma radiation and then provided the DP diet 24 hours post-IR. Preliminary data indicates that DP mitigated the radiation-induced deficits in certain cancellous bone structural parameters. Finally, we showed that mice fed with the control diet (CD) increased oxidative damage in the serum after radiation exposure, whereas mice fed the DP diet do did not show such an increase. In summary, the DP diet is a promising countermeasure for spaceflight-induced tissue damage.

Schreurs, Ann-Sofie↗

NASA NTRS2020

Use of Otoacousticemission Phase Change to Evaluate Countermeasures for Spaceflight-Associated Neuro-Ocular Syndrome

Spaceflight-associated neuro-ocular syndrome (SANS) is a human spaceflight risk recognized by NASA. Elevated intracranial pressure (ICP) has been implicated as a root cause of many SANS signs and symptoms, yet there is no reliable noninvasive means of monitoring ICP. We have developed a noninvasive method of monitoring ICP change that exploits ear canal acoustic and otoacoustic emission (OAE) measurements. Changed ICP alters pressure in the inner ear, leading to changes in the tension and position of middle ear (ME) components; tension of these components determines the phase of the stimulus in the ear canal and the OAE response sound transmission back through the ME. The OAE method has been validated in several studies, including our own experiments as part of the NASA Fluid Shifts study. Systematic OAE phase changes demonstrating increased ME tension (an ICP indicator) are observed as posture is changed from seated to supine to head-down tilt (HDT). This effect can be substantially mitigated by lower body negative pressure (LBNP). The OAE technique has also been used on International Space Station (ISS) crewmembers, providing evidence that ICP in microgravity is similar to that seen on the ground in the supine position. The OAE method is also a rapid and noninvasive means of assessing the effectiveness of SANS countermeasures. Here we report results from two studies which used OAEs. In the most recent study (Venous Congestion Countermeasures - VCCM), three promising countermeasures [LBNP, an impedance threshold device (ITD), and veno-occlusive thigh cuffs (VTC)] were applied individually and in combination. In our previous ITD-only study, ITD was investigated for its ability to reduce ICP and cephalic venous congestion in supine and various HDT postures. Internal jugular vein (IJV) ultrasound showed a clear decongestive effect at all postures, however OAE data showed that ITD only caused a phase decrease (tension decrease) in HDT postures. In supine, ITD appeared to INCREASE tension. This paradox leads us to hypothesize that the OAE method is not accurately representing ICP changes with countermeasures (CM), which can alter ME tension through other means, such as ME pressure (MEP) changes. More generally, the exact mechanism for observed OAE response and stimulus phase shifts are not clearly understood, specifically with regard to the effects of MEP. The VCCM study examined the effects of externally-applied MEP on OAE recordings to document the relationship between these parameters. Analysis of these data provide new insights to these OAE mechanisms, in addition to results on CM effectiveness.

Kemp, D.↗

NASA NTRSDate not supplied

A Multi Targeted Dietary Supplement as a Potential Countermeasure for Prolonged, Deep Space Exploration

Deep space exploration, particularly to the Moon and Mars, are currently major goals of NASA and other international space agencies. Long-term space flight presents unique challenges to the human physiology from microgravity, social isolation, altered circadian rhythm and radiation. Oxidative stress has been implicated as a crucial factor in space environment induced injury. Elucidating these detrimental effects on the central nervous system and brain is a primary objective, as they may result in adverse changes in astronaut behavior, mood and performance of critical tasks. We were recently funded by HRP Human Factors Behavioral Performance (HFBP) Element to test the hypothesis that Galactic Cosmic Ray Simulation (GCRsim) Ionizing Radiation (IR), microgravity and social isolation combine synergistically to trigger an oxidative stress response that alters immune homeostasis, brain structure and function, and neurobehavioral and cognitive performance. This project will identify potential biomarkers for, and mechanisms underlying, structural and functional changes in the immune and nervous systems leading to behavioral/cognitive performance deficits, and its potential application to develop effective countermeasures to mitigate negative health effects of long duration space habitation. Countermeasures to offset neurological damaged and cognitive deficits are paramount for protecting astronauts during deep space transits, but many countermeasures have been found to be unsuitable in ground-based model studies. We have developed a multi targeted dietary supplement (MTDS) designed to simultaneously ameliorate oxidative stress, inflammatory processes, energetic shortfalls, and membrane and mitochondrial deterioration. Administration of this MTDS has improved cognition and longevity in age accelerated and normal aging mice. Specifically, the MTDS was found to prevent a decline in mitochondrial complex III activity and cell loss, as well as prevent an increase in protein carbonyls and mitochondrial 3-nitrotyrosine in the brain of these mice. Further, administration of the MTDS was also found to reduce bone marrow chromosomal aberrations, DNA damage, lymphocyte apoptosis after whole body exposure of 2 Gy γ radiation. Mice exposed to a high dose cranially (10 Gy) had decreased cognitive responses (seen as increased latency time to uncover buried food and decreased novel object recognition), increased plasma 8-OHdG levels, increased markers of cell stress in the brain, decreased hippocampal brain-derived neurotrophic factor (BDNF) protein and decreased plasma levels of cytokines, all of which were ameliorated with treatment of the MTDS. As we have shown the supplement is protective in models of cognitive damage similar space environment stressors, particularly increased oxidative stress, we propose it may be a suitable countermeasure for upcoming deep space exploration.

radiation↗

NASA NTRSDate not supplied

MicroRNA Based Countermeasure Rescue Health Risks Associated with Space Radiation and Microgravity

From our earlier work, we demonstrated a circulating microRNA (miRNA) signature that is present and involved with the general increased health risks during spaceflight. From this work we demonstrated that this miRNA signature impacted the overall biology and health with both the microgravity and space radiation components of the space environment. We showed that this miRNA signature can be an optimal biomarker for health risk and also has potential to be utilized as a countermeasure to mitigate the damage caused by the space environment by utilizing a human 3D microvascular tissue model. By applying a novel self-delivery system to target 3 miRNAs (i.e. antagomirs) from our spaceflight miRNA signature impacting cardiovascular health risks, we were able to completely mitigate damage caused by exposure to simulated Galactic Cosmic Ray (GCR) irradiation. Here we further expand on the countermeasure experiments to uncover the specific novel biology involved with this countermeasure and in vivo experiments that demonstrates that these antagomirs rescue damage caused to certain organs due to both microgravity and space radiation. Specifically, the miRNAs rescued damage to the heart and immune suppression that occurred in addition to other key biology. In addition, we have also observed with the 3D microvascular tissue model improved DNA double strand break repair machinery which can also contribute to improved recovery and protection against damage caused by space radiation. This work expands on our previous work and further uncovers how a potential minimally invasive countermeasure can be used to mitigate space environment effects.

Angela Kubik↗

NASA NTRSDate not supplied

A MULTI TARGETED DIETARY SUPPLEMENT AS A POTENTIAL COUNTERMEASURE FOR DEEP SPACE EXPLORATION

Future deep space exploration to the Moon and Mars and beyond are currently major goals of NASA. Space flight presents unique challenges to the human physiology from the combined effects of microgravity, social isolation, altered circadian rhythm and radiation. Oxidative stress has been implicated as a crucial factor in space environment induced injury. Elucidating these detrimental effects on the central nervous system and brain is a primary objective, as they may result in adverse changes in astronaut behavior, mood and performance of critical tasks. We were recently funded by HRP Human Factors Behavioral Performance (HFBP) Element to test the hypothesis that Galactic Cosmic Ray Simulation (GCRsim) Ionizing Radiation (IR), microgravity and social isolation combine synergistically to trigger an oxidative stress response that alters immune homeostasis, brain structure and function, and neurobehavioral and cognitive performance. This project will identify potential biomarkers for, and mechanisms underlying, structural and functional changes in the immune and nervous systems leading to behavioral/cognitive performance deficits, and its potential application to develop effective countermeasures to mitigate negative health effects of long duration space habitation. Countermeasures to offset neurological damaged and cognitive deficits are paramount for protecting astronauts during deep space transits, but many countermeasures have been found to be unsuitable in ground-based model studies. We have developed a multi targeted dietary supplement (MTDS) designed to simultaneously ameliorate oxidative stress, inflammatory processes, energetic shortfalls, and membrane and mitochondrial deterioration. Administration of this MTDS has improved cognition and longevity in age accelerated and normal aging mice. Specifically, the MTDS was found to prevent a decline in mitochondrial complex III activity and cell loss, as well as prevent an increase in protein carbonyls and mitochondrial 3-nitrotyrosine in the brain of these mice. Further, administration of the MTDS was also found to reduce bone marrow chromosomal aberrations, DNA damage, lymphocyte apoptosis after whole body exposure of 2 Gy γ radiation. Mice exposed to a high dose cranially (10 Gy) had decreased cognitive responses (seen as increased latency time to uncover buried food and decreased novel object recognition), increased plasma 8-OHdG levels, increased markers of cell stress in the brain, decreased hippocampal brain-derived neurotrophic factor (BDNF) protein and decreased plasma levels of cytokines, all of which were ameliorated with treatment of the MTDS. As we have shown the supplement is protective in models of cognitive damage similar space environment stressors, particularly increased oxidative stress, we propose it may be a suitable countermeasure for upcoming deep space exploration.

Stephanie Puukila↗

NASA NTRSDate not supplied

Pilot Assessment of Immune Dysregulation, Stress and Latent Herpesvirus Reactivation at Palmer, Antarctica - Platform for validation of Immune Countermeasures?

Recent studieshave characterized adverse health events potentially relatedto immune system dysregulation, latent herpesvirus reactivation, and clinical incidence for crewmembers onboard ISS. Both areview article describing potential spaceflight countermeasures related to immunityand a specific countermeasures protocol for deep space missions were recently published. An appropriate ground analogto enable spaceflight countermeasures has yet to be validated, although winterover in Antarctica (AWO) seems a highly relevant mission parallel to spaceflight. AWO consists of prolonged deployment, extreme environment, circadian misalignment, personal isolation, station lifestyle (varies by base), and personal risk. Through several studies, AWO at several European bases has beencharacterized, and to date the data has revealed that (immunologically) deployment to interior bases at elevation and with persistent hypobaric hypoxia possesses certaindissimilarities to spaceflight. This proposal seeks to collect low cost pilot data assessing stress, immunity and viral reactivation during AWOat thecoastalU.S. Palmer Station. Even among coastal bases, lifestyle, available crew time/workload and logistical access can vary considerably. Considering all factors, if validated, Palmer may be the most feasible location to evaluate NASA countermeasures. The goal of this pilot study is to ascertain if Palmer may serve as a spaceflight analog option for ground validation of immune countermeasures.The study initiatedwith the crew deployed for winterover at Palmer in 2020.A second crew participated in the recently concluded WO2021 season.All participatingcrew havecollectedand preservedsaliva, plasma and hair samples. On location, the crewmembers alsoperformeda fingerstick blood collection for immediate analysis of basic peripheral leukocyte subsets. Preserved biosamples have beenreturned for analysis, with the WO2020 samples received, and the WO2021 samples currently en-route to Houston. It should be noted that COVID-19 had significant impacts on operations, including training and the collection of pre-mission baseline samples. Preliminary data from the 2020 crewmembers indicate that a relatively mild but detectable immune dysregulation persists at Palmer Station, including alterations in concentration of some plasma cytokines and consistent increases in the incidence of EBV reactivation. Final study data will be tabulated upon receipt of the 2021 crew samples.

Stephanie Krieger↗

NASA NTRSDate not supplied

microRNA Based Countermeasure Mitigate Health Risks Associated with Space Radiation and Microgravity

Afshin Beheshti↗

NASA NTRSDate not supplied

MicroRNA Based Countermeasure Rescue Health Risks Associated with Space Radiation and Microgravity

Afshin Beheshti↗

DOE OSTI2022

The Evolution of Medical Countermeasures for Ebola Virus Disease: Lessons Learned and Next Steps

The Ebola virus disease outbreak that occurred in Western Africa from 2013–2016, and subsequent smaller but increasingly frequent outbreaks of Ebola virus disease in recent years, spurred an unprecedented effort to develop and deploy effective vaccines, therapeutics, and diagnostics. This effort led to the U.S. regulatory approval of a diagnostic test, two vaccines, and two therapeutics for Ebola virus disease indications. Moreover, the establishment of fieldable diagnostic tests improved the speed with which patients can be diagnosed and public health resources mobilized. The United States government has played and continues to play a key role in funding and coordinating these medical countermeasure efforts. Here, we describe the coordinated U.S. government response to develop medical countermeasures for Ebola virus disease and we identify lessons learned that may improve future efforts to develop and deploy effective countermeasures against other filoviruses, such as Sudan virus and Marburg virus.

59 BASIC BIOLOGICAL SCIENCES↗