INTRODUCTION To date, 559 humans have been flown into space, but long-duration (>300 days) missions are rare (n = 8 total). Long-duration missions that will take humans to Mars and beyond are planned by public and private entities for the 2020s and 2030s; therefore, comprehensive studies are needed now to assess the impact of long-duration spaceflight on the human body, brain, and overall physiology. The space environment is made harsh and challenging by multiple factors, including confinement, isolation, and exposure to environmental stressors such as microgravity, radiation, and noise. The selection of one of a pair of monozygotic (identical) twin astronauts for NASA’s first 1-year mission enabled us to compare the impact of the spaceflight environment on one twin to the simultaneous impact of the Earth environment on a genetically matched subject. RATIONALE The known impacts of the spaceflight environment on human health and performance, physiology, and cellular and molecular processes are numerous and include bone density loss, effects on cognitive performance, microbial shifts, and alterations in gene regulation. However, previous studies collected very limited data, did not integrate simultaneous effects on multiple systems and data types in the same subject, or were restricted to 6-month missions. Measurement of the same variables in an astronaut on a year-long mission and in his Earth-bound twin indicated the biological measures that might be used to determine the effects of spaceflight. Presented here is an integrated longitudinal, multidimensional description of the effects of a 340-day mission onboard the International Space Station. RESULTS Physiological, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data were collected over 25 months. Some biological functions were not significantly affected by spaceflight, including the immune response (T cell receptor repertoire) to the first test of a vaccination in flight. However, significant changes in multiple data types were observed in association with the spaceflight period; the majority of these eventually returned to a preflight state within the time period of the study. These included changes in telomere length, gene regulation measured in both epigenetic and transcriptional data, gut microbiome composition, body weight, carotid artery dimensions, subfoveal choroidal thickness and peripapillary total retinal thickness, and serum metabolites. In addition, some factors were significantly affected by the stress of returning to Earth, including inflammation cytokines and immune response gene networks, as well as cognitive performance. For a few measures, persistent changes were observed even after 6 months on Earth, including some genes’ expression levels, increased DNA damage from chromosomal inversions, increased numbers of short telomeres, and attenuated cognitive function. CONCLUSION Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight. The persistence of the molecular changes (e.g., gene expression) and the extrapolation of the identified risk factors for longer missions (>1 year) remain estimates and should be demonstrated with these measures in future astronauts. Finally, changes described in this study highlight pathways and mechanisms that may be vulnerable to spaceflight and may require safeguards for longer space missions; thus, they serve as a guide for targeted countermeasures or monitoring during future missions.

The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight.

The human gut microbiome can influence health through the brain-gut-microbiome axis. Growing evidence suggests that the gut microbiome can influence sleep quality. Previous studies that have examined sleep deprivation and the human gut microbiome have yielded conflicting results. A recent study found that sleep deprivation leads to changes in gut microbiome composition while a different study found that sleep deprivation does not lead to changes in gut microbiome. Accordingly, the relationship between sleep physiology and the gut microbiome remains unclear. To address this uncertainty, we used actigraphy to quantify sleep measures coupled with gut microbiome sampling to determine how the gut microbiome correlates with various measures of sleep physiology. We measured immune system biomarkers and carried out a neurobehavioral assessment as these variables might modify the relationship between sleep and gut microbiome composition. We found that total microbiome diversity was positively correlated with increased sleep efficiency and total sleep time, and was negatively correlated with wake after sleep onset. We found positive correlations between total microbiome diversity and interleukin-6, a cytokine previously noted for its effects on sleep. Analysis of microbiome composition revealed that within phyla richness of Bacteroidetes and Firmicutes were positively correlated with sleep efficiency, interleukin-6 concentrations and abstract thinking. Finally, we found that several taxa (Lachnospiraceae, Corynebacterium, and Blautia) were negatively correlated with sleep measures. Our findings initiate linkages between gut microbiome composition, sleep physiology, the immune system and cognition. They may lead to mechanisms to improve sleep through the manipulation of the gut microbiome.

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Gut Microbiome Diversity Is Associated with Sleep Physiology in Humans

Study objectives The Psychomotor Vigilance Test (PVT) is reported to be free of practice effects that can otherwise confound the effects of sleep loss and circadian misalignment on performance. This differentiates the PVT from more complex cognitive tests. To the best of our knowledge, no study has systematically investigated practice effects on the PVT across multiple outcome domains, depending on administration interval, and in ecologically more valid settings. Methods We administered a validated 3-minute PVT (PVT-B) 16 times in 45 participants (23 male, mean ± SD age 32.6 ± 7.3 years, range 25-54 years) with administration intervals of ≥10 days, ≤5 days, or 4 times per day. We investigated linear and logarithmic trends across repeated administrations in 10 PVT-B outcome variables. Results The fastest 10% of response times (RT; plin = .0002), minimum RT (plog = .0010), and the slowest 10% of reciprocal RT (plog = .0124) increased while false starts (plog = 0.0050) decreased with repeated administration, collectively decreasing RT variability (plog = .0010) across administrations. However, the observed absolute changes were small (e.g., -0.03 false starts per administration, linear fit) and are probably irrelevant in practice. Test administration interval did not modify the effects of repeated administration on PVT-B performance (all p > .13 for interaction). Importantly, mean and median RT, response speed, and lapses, which are among the most frequently used PVT outcomes, did not change systematically with repeated administration. Conclusions PVT-B showed stable performance across repeated administrations. Combined with its high sensitivity, this corroborates the status of the PVT as the de facto gold standard measure of the neurobehavioral effects of sleep loss and circadian misalignment.

Repeated Administration Effects on Psychomotor Vigilance Test Performance.

BACKGROUND AND PURPOSE: Widespread brain structural changes are seen following extended spaceflight missions. The purpose of this study was to investigate whether these structural changes are associated with alterations in motor or cognitive function. MATERIALS AND METHODS: Brain MR imaging scans of National Aeronautics and Space Administration astronauts were retrospectively analyzed to quantify pre- to postflight changes in brain structure. Local structural changes were assessed using the Jacobian determinant. Structural changes were compared with clinical findings and cognitive and motor function. RESULTS: Long-duration spaceflights aboard the International Space Station, but not short-duration Space Shuttle flights, resulted in a significant increase in total ventricular volume (10.7% versus 0%, P CONCLUSIONS: While cautious interpretation is appropriate given the small sample size and number of comparisons, these findings suggest that brain structural changes are associated with changes in cognitive and motor test scores and with the development of spaceflight-associated neuro-optic syndrome.

http://www.ajnr.org/content/ajnr/40/11/1878.full.pdf

Prolonged Microgravity Affects Human Brain Structure and Function.

Acute exposure to carbon dioxide (CO2) concentrations below those found on the International Space Station are reported to deteriorate complex decision-making. Effective decision-making is critical to human spaceflight, especially during an emergency response. Therefore, effects of acutely elevated CO2 on decision-making competency and various cognitive domains were assessed in astronaut-like subjects by the Strategic Management Simulation (SMS) and Cognition test batteries. The double-blind cross-over study included 22 participants at the Johnson Space Center randomly assigned to one of four groups. Each group was exposed to a different sequence of four concentrations of CO2 (600, 1200, 2500, 5000 ppm). Subjects performed Cognition before entering the chamber, 15 min and 2.5 h after entering the chamber, and 15 min after exiting the chamber. The SMS was administered 30 min after subjects entered the chamber. There were no clear dose–response patterns for performance on either SMS or Cognition. Performance on most SMS measures and aggregate speed, accuracy, and efficiency scores across Cognition tests were lower at 1200 ppm than at baseline (600 ppm); however, at higher CO2 concentrations performance was similar to or exceeded baseline for most measures. These outcomes, which conflict with those of other studies, likely indicate differing characteristics of the various subject populations and differences in the aggregation of unrecognized stressors, in addition to CO2, are responsible for disparate outcomes among studies. Studies with longer exposure durations are needed to verify that cognitive impairment does not develop over time in crew-like subjects.

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Effects of acute exposures to carbon dioxide on decision making and cognition in astronaut-like subjects

BACKGROUND: Sustained high-level cognitive performance is of paramount importance for the success of space missions, which involve environmental, physiological, and psychological stressors that may aff ect brain functions. Despite subjective symptom reports of cognitive fl uctuations in spacefl ight, the nature of neurobehavioral functioning in space has not been clarifi ed. METHODS: We developed a computerized cognitive test battery ( Cognition ) that has sensitivity to multiple cognitive domains and was specifi cally designed for the high-performing astronaut population. Cognition consists of 15 unique forms of 10 neuropsychological tests that cover a range of cognitive domains, including emotion processing, spatial orientation, and risk decision making. Cognition is based on tests known to engage specifi c brain regions as evidenced by functional neuroimaging. Here we describe the fi rst normative and acute total sleep deprivation data on the Cognition test battery as well as several eff orts underway to establish the validity, sensitivity, feasibility, and acceptability of Cognition . RESULTS: Practice eff ects and test-retest variability diff ered substantially between the 10 Cognition tests, illustrating the importance of normative data that both refl ect practice eff ects and diff erences in stimulus set diffi culty in the population of interest. After one night without sleep, medium to large eff ect sizes were observed for 3 of the 10 tests addressing vigilant attention (Cohen ’ s d 5 1.00), cognitive throughput (d 5 0.68), and abstract reasoning (d 5 0.65). CONCLUSIONS: In addition to providing neuroimaging-based novel information on the eff ects of spacefl ight on a range of cognitive functions, Cognition will facilitate comparing the eff ects of ground-based analogues to spacefl ight, increase consistency across projects, and thus enable meta-analyses.

Development and Validation of the Cognition Test Battery for Spaceflight

Astronauts are required to maintain optimal neurobehavioral functioning despite chronic exposure to the stressors and challenges of spaceflight. Sleep of adequate quality and duration is fundamental to neurobehavioral functioning, however astronauts commonly experience short sleep durations in spaceflight (<6 h). As humans embark on long-duration space exploration missions, there is an outstanding need to identify the consequences of sleep deficiency in spaceflight on neurobehavioral functions. Therefore, we conducted a longitudinal study that examined the sleep-wake behaviors, neurobehavioral functions, and ratings of stress and workload of N=24 astronauts before, during, and after 6-month missions aboard the International Space Station (ISS). The computerized, Reaction SelfTest (RST), gathered astronaut report of sleep-wake behaviors, stress, workload, and somatic behavioral states; the RST also objectively assessed vigilant attention (i.e., Psychomotor Vigilance Test-Brief). Data collection began 180 days before launch, continued every 4 days in-flight aboard the ISS, and up to 90 days post-landing, which produced N=2,856 RSTs. Consistent with previous ISS studies, astronauts reported sleeping ~6.5 h in-flight. The adverse consequences of short sleep were observed across neurobehavioral functions, where sleep durations <6 h were associated with significant reductions in psychomotor response speed, elevated stress, and higher workload. Sleep durations <5 h were associated with elevated negative somatic behavioral states. Furthermore, longer sleep durations had beneficial effects on astronaut neurobehavioral functions. Taken together, our findings highlight the importance of sleep for the maintenance of neurobehavioral functioning and as with humans on Earth, astronauts would likely benefit from interventions that promote sleep duration and quality.

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Sleep deficiency in spaceflight is associated with degraded neurobehavioral functions and elevated stress in astronauts on six-month missions aboard the International Space Station.

Cognition Test Battery

INTRODUCTION Astronauts on the International Space Station (ISS) must manage the stressors of space flight, which can include working at a high level for long periods, experiencing altered sleep, and coping with a range of physical and psychological reactions to living in microgravity. Because exploration spaceflight will require missions even longer than the current 6-month stays on ISS, there is a need to identify whether the chronic effects of stressors across time in mission produce cumulative or escalating behavioral and biomedical risks for astronauts. Recent findings from the Mars 500 analog study of isolation and confinement for 17 months indicated that time in mission was associated with cumulative increases in adverse neurobehavioral responses [1] and stress in some individuals [2]. To inform the question of the whether time in mission in microgravity is associated with increasing stress, we analyzed astronauts' ratings of their stress levels, and other indications of negative neurobehavioral reactions, as a function of time in mission during 6-month stays on ISS.

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Effects of time in mission: iss astronauts ratings of stress

Abstract Study Objectives This study evaluated the utility and ecological validity of the 3-minute psychomotor vigilance test (PVT) completed by safety-critical personnel in an air medical transport operation as part of a fatigue risk management program. Methods Crewmembers in an air medical transport operation self-administered an alertness assessment incorporating a 3-minute PVT at different time points during their duty schedule. The prevalence of alertness deficits was evaluated based on a failure threshold of 12 errors considering both lapses and false starts. To evaluate the ecological validity of the PVT, the relative frequency of failed assessments was evaluated relative to crewmember position, timing of the assessment within the duty schedule, time of day, and sleep quantity in the last 24 h. Results 2.1% of assessments were associated with a failing PVT score. Crewmember position, timing of assessment within the duty shift, time of day, and sleep quantity in the last 24 h were found to affect the relative frequency of failed assessments. Obtaining less than 7–9 h of sleep was associated with systematic increases in the failure rate (F[1, 54 612] = 168.1, p < .001). Obtaining less than 4 h of sleep was associated with a frequency of a failed assessment 2.99 times higher than the frequency of a failed assessment when obtaining 7–9 h of sleep. Conclusions Results provide evidence for the utility and ecological validity of the PVT as well as the suitability of the PVT failure threshold to support fatigue risk management in safety-critical operations.

Christopher M. Mott

Papers

Development and Validation of the Cognition Test Battery for Spaceflight

Sleep deficiency in spaceflight is associated with degraded neurobehavioral functions and elevated stress in astronauts on six-month missions aboard the International Space Station.

Cognition Test Battery

Effects of time in mission: iss astronauts ratings of stress

Use of the psychomotor vigilance test to aid in the selection of risk controls in an air medical transport operation