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Background Context For chronic low back pain, the causal mechanisms between pathological features from imaging and patient symptoms are unclear. For instance, disc herniations can often be present without symptoms. There remains a need for improved knowledge of the pathophysiological mechanisms that explore spinal tissue damage and clinical manifestations of pain and disability. Spaceflight and astronaut health provides a rare opportunity to study potential low back pain mechanisms longitudinally. Spaceflight disrupts diurnal loading on the spine and several lines of evidence indicate that astronauts are at a heightened risk for low back pain and disc herniation following spaceflight. Purpose To examine the relationship between prolonged exposure to microgravity and the elevated incidence of postflight disc herniation, we conducted a longitudinal study to track the spinal health of twelve NASA astronauts before and after approximately 6-months in space. We hypothesize that the incidence of postflight disc herniation and low back complaints associates with spaceflight-included muscle atrophy and pre-existing spinal pathology. Study Design This is a prospective longitudinal study. Patient Sample Our sample included a cohort of twelve astronaut crewmembers. Outcome Measures From 3T MRI, we quantified disc water content (ms), disc degeneration (Pfirrmann grade), vertebral end plate irregularities, facet arthropathy and/ fluid, high intensity zones, disc herniation, multifidus total cross-sectional area (cm2), multifidus lean muscle cross-sectional area (cm2), and muscle quality/composition (%). From quantitative fluoroscopy we quantified, maximum flexion-extension ROM (°), maximum lateral bending ROM (°), and maximum translation (%). Lastly, patient outcomes and clinical notes were used for identifying postflight symptoms associated with disc herniations from 3T MRI. Methods Advanced imaging data from 3T MRI were collected at three separate time points in relation to spending 6-months in space: (1) within a year before launch (“pre-flight”), (2) within a week after return to Earth (“post-flight”), and (3) between 1- and 2-months after return to Earth (“recovery”). Fluoroscopy of segmental kinematics was collected at preflight and postflight timepoints. We assessed the effect of spaceflight and postflight recovery on longitudinal changes in spinal structure and function, as well as differences between crew members who did and did not present a symptomatic disc herniation following spaceflight. Results Half of our astronauts (n=6) experienced new symptoms associated with a new or previously asymptomatic lumbar disc protrusion or extrusion following spaceflight. We observed decreased multifidus muscle quality following spaceflight in the lower lumbar spine, with a reduced percentage of lean muscle at L4L5(-6.2%, p=.009) and L5S1 (-7.0%, p=.006) associated with the incidence of new disc herniation. Additionally, we observed reduced lumbar segment flexion-extension ROM for L2L3 (-17.2%, p=.006) and L3L4 (-20.5%, p=.02) following spaceflight, and furthermore that reduced ROM among the upper three lumbar segments (-24.1%, p=.01) associated with the incidence of disc herniation. Existing end plate pathology was most prevalent in the upper lumbar spine and associated with reduced segmental ROM (-20.5%, p=.02). Conclusions In conclusion from a 10-year study investigating the effects of spaceflight on the lumbar spine and risk for disc herniation, we found the incidence of lumbar disc herniation following spaceflight associates with compromised multifidus muscle quality and spinal segment kinematics, as well as pre-existing spinal end plate irregularities. These findings suggest differential effects of spinal stiffness and muscle loss in the upper versus lower lumbar spine regions that may specifically provoke risk for symptomatic disc herniation in the lower lumbar spine following spaceflight. Results from this study provide a unique longitudinal assessment of mechanisms and possible risk factors for developing disc herniations and related low back pain. Furthermore, these findings will help inform physiologic countermeasures to maintain spinal health in astronauts during long-duration missions in space.

Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.

Bone loss is one of the highest risk factors during long spaceflight for astronauts which can lead to health problems and increase fracture risk, but the mechanisms are still unclear. Bone is highly vascularized tissue, the vascular system in bone plays an important role in the development, regeneration and remodeling of bone. However, little is known about how the blood vessels in bones change and its effect on microgravity-induced osteoporosis, we investigated the above issues with tail-suspended rat model in this study. The result showed that the blood vessel volume and vessel number in long bones increased and H-type blood vessels (CD31hiEmcnhi vessels) reduced; moreover, exercise could alleviate the decrease of H-type blood vessels and osteogenesis in tail-suspended rats. These results revealed that changes of bone blood vessels may be a main reason for microgravity-induced bone mass rapid loss.

Introduction Experiments during spaceflight and simulated microgravity as head-down tilt bedrest, demonstrated the role of arterial stiffness among others, in microgravity induced cardiovascular pathologies and emphasized the need for a robust countermeasure. Aim The purpose of the present study was to evaluate the use of a new countermeasure, consisting of a high intensity Reactive Sledge (RSL) jumps training protocol, to counteract changes in arterial stiffness during long term head down tilt bedrest (LTBR). Methods The participants enrolled in the study were 23 male, healthy volunteers, aged between 20 and 45 years, subjected to LTBR for 60 days and randomly assigned either to a control (11) or to a training sledge (12) group using RSL 3-4 times per week, as a countermeasure. Recorded values were systolic and diastolic blood pressure, heart rate and the user's arterial stiffness index. Results Compared to baseline measurements, there was a deterioration in the values of arterial stiffness, systolic and diastolic blood pressure and heart rate, in both groups until day 35 of LTBR, interpreted as adaptation to the microgravity environment. From this day until the end of the experiment, arterial stiffness of the control group was constantly fluctuating, while constantly improving for the training group. During the recovery period, arterial stiffness values returned to the pre-experimental levels in both groups. Conclusions Overall, arterial stiffness increased the longer the time spent in LTBR and the countermeasure was partially effective in preventing the observed phenomenon. German Clinical Trials Register (DRKS), DRKS00012946, September 18, 2017, retrospectively registered.

Introduction: In the spaceflight, during launch and re-entry, the crew is exposed to acceleration ranging from +4Gx to +8Gx in nominal conditions. This study was conducted to assess the changes in cardiorespiratory parameters, namely, heart rate (HR), electrocardiogram (ECG), respiratory rate (RR), and SpO2 on exposure to simulated +Gx acceleration. Material and Methods: Fifteen randomly selected healthy male volunteers participated in the study. They were exposed to a simulated acceleration profile consisting of two peaks in the high-performance human centrifuge; first peak of +4Gx for 30 s and second peak of+8Gx for 30 s. The cardiorespiratory parameters were monitored and recorded during the acceleration exposure. The data were compiled and analyzed using one-way repeated measures ANOVA. Results: Significant increase in HR was observed on exposure to +4Gx (110.4 ± 16.7 bpm; P < 0.001) in comparison to the baseline value (80.5 ± 7.5 bpm). However, the changes in the HR at +8Gx were not significant in comparison to baseline as well as +4Gx values. On the other hand, RR indicated a significant increase on exposure to +8Gx (25.2 ± 5.8 breaths/min) in comparison to the baseline (15.1 ± 1.6 breaths/min; P = 0.001) and +4Gx (19.0 ± 6.1 breaths/min; P = 0.009) values. SpO2 showed a significant reduction at +8Gx (94.2 ± 3.8%) in comparison to baseline (98.9 ± 0.3%; P = 0.004) and +4Gx (96.9 ± 1.5%; P = 0.003). ECG did not show any evidence of arrhythmia during the exposure to +Gx acceleration. Conclusion: The insignificant changes in the HR at peak of +8Gx indicate less pronounced effects on the smaller hydrostatic gradient in +Gx acceleration unlike +Gz acceleration. However, the findings of the study point towards a significant increase in respiratory rate and reduction in SpO2 at +8Gx.

The objectives of this study were to determine whether 4 days of dry immersion (DI) induced similar arterial aging as spaceflight and to test the impact of thigh cuffs. Eighteen subjects underwent DI; nine wore thigh cuffs. Cardiac and arterial targets were assessed by ultrasound. No significant differences were found between the groups. The left ventricle volume, stroke volume (SV), and ejection fraction decreased with DI (p p p

During spaceflight, astronauts experience 1–1.5% bone loss per month, especially in the lumbar spine, pelvis and lower limbs. The bone loss leads to osteoporosis and increased the risk of fracture. Current researches focus on anti-osteoporosis under microgravity mainly by inhibiting bone resorption of osteoclasts and / or increasing bone formation of osteoblasts. However, studies on the effects of mass transfer in the bone lacunar-canalicular system (LCS) on osteoporosis are lacking. Osteocytes reside in the lacunae and communicate with other osteocytes, osteoblasts and osteoclasts through the LCS in the bone matrix. Osteocytes are mainly responsible for mechanosensing and signal regulation in bone, and the LCS is the basic structure for signaling, mass transfer and mechanical stimulation. Microgravity causes deficient mass transfer in the LCS, especially in the outer layer of osteon. Osteocytes far away from the Haversian canals are inhibited or accelerated apoptosis to stimulate osteoclasts which result in bone loss. Deficient mass transfer in the LCS may be a determinant of human osteoporosis under microgravity, which will open up a new way to treat osteoporosis in space.

Spaceflight induces hepatic damage, partially owing to oxidative stress caused by the space environment such as microgravity and space radiation. We examined the roles of anti-oxidative sulfur-containing compounds on hepatic damage after spaceflight. We analyzed the livers of mice on board the International Space Station for 30 days. During spaceflight, half of the mice were exposed to artificial earth gravity (1 g) using centrifugation cages. Sulfur-metabolomics of the livers of mice after spaceflight revealed a decrease in sulfur antioxidants (ergothioneine, glutathione, cysteine, taurine, thiamine, etc.) and their intermediates (cysteine sulfonic acid, hercynine, N-acethylserine, serine, etc.) compared to the controls on the ground. Furthermore, RNA-sequencing showed upregulation of gene sets related to oxidative stress and sulfur metabolism, and downregulation of gene sets related to glutathione reducibility in the livers of mice after spaceflight, compared to controls on the ground. These changes were partially mitigated by exposure to 1 g centrifugation. For the first time, we observed a decrease in sulfur antioxidants based on a comprehensive analysis of the livers of mice after spaceflight. Our data suggest that a decrease in sulfur-containing compounds owing to both microgravity and other spaceflight environments (radiation and stressors) contributes to liver damage after spaceflight.

Altered gravity environments introduce cardiovascular changes that may require continuous hemodynamic monitoring in both spaceflight and terrestrial analogs. Conditions in such environments are often prohibitive to direct/invasive methods and therefore, indirect measurement techniques must be used. This study compares two common cardiac measurement techniques used in the human spaceflight domain, pulse contour analysis (PCA—Nexfin) and inert gas rebreathing (IGR—Innocor), in subjects completing ergometer exercise under altered gravity conditions simulated using a tilt paradigm. Seven subjects were tilted to three different angles representing Martian, Lunar, and microgravity conditions in the rostrocaudal direction. They completed a 36-min submaximal cardiovascular exercise protocol in each condition. Hemodynamics were continuously monitored using Nexfin and Innocor. Linear mixed-effects models revealed a significant bias of $$25.7\pm 1.7$$ ml ( $$p

In earlier studies, blindfolded participants used a joystick to orient themselves to the direction of balance in the horizontal roll plane while in a device programmed to behave like an inverted pendulum. In this spaceflight analog situation, position relevant gravitational cues are absent. Most participants show minimal learning, positional drifting, and failure of path integration. However, individual differences are substantial, some participants show learning and others become progressively worse. In Experiment 1, our goal was to determine whether spatial acuity could explain these individual differences in active balancing. We exposed blindfolded participants to passive movement profiles, with different frequency components, in the vertical and horizontal roll planes. They pressed a joystick trigger to indicate every time they passed the start point. We found greater spatial acuity for higher frequencies but no relation between passive spatial accuracy and active balance control in the horizontal roll plane, suggesting that spatial acuity in the horizontal roll plane does not predict performance in a disorienting spaceflight condition. In Experiment 2, we found significant correlations between passive spatial acuity in the vertical roll plane, where participants have task relevant gravitational cues, and early active balancing in the horizontal roll plane. These correlations appeared after participants underwent brief provocative vestibular stimulation by making a pitch head movement during vertical yaw rotation. Our findings suggest that vestibular stimulation may be a valuable part of assessments of individual differences in performance during initial exposure to disorienting spaceflight conditions where there are no reliable gravity dependent positional cues.

著者人数: 13名, 形態: カラー図版あり, Number of authors: 13, Physical characteristics: Original contains color illustrations, Accepted: 2021-08-26, 資料番号: PA2210082000

Cephalad fluid shifts in space have been hypothesized to cause the spaceflight-associated neuro-ocular syndrome (SANS) by increasing the intracranial-ocular translaminal pressure gradient. Lower body negative pressure (LBNP) can be used to shift upper-body blood and other fluids toward the legs during spaceflight. We hypothesized that microgravity would increase jugular vein volume (JVvol), portal vein cross-sectional area (PV), and intracranial venous blood velocity (MCV) and that LBNP application would return these variables toward preflight levels. Data were collected from 14 subjects (11 males) before and during long-duration International Space Station (ISS) spaceflights. Ultrasound measures of JVvol, PV, and MCV were acquired while seated and supine before flight and early during spaceflight at day 45 (FD45) and late at day 150 (FD150) with and without LBNP. JVvol increased from preflight supine and seated postures (46 ± 48% and 646 ± 595% on FD45 and 43 ± 43% and 702 ± 631% on FD150, P < 0.05), MCV increased from preflight supine (44 ± 31% on FD45 and 115 ± 116% on FD150, P < 0.05), and PV increased from preflight supine and seated (51 ± 56% on FD45 and 100 ± 74% on FD150, P < 0.05). Inflight LBNP of −25 mmHg restored JVvol and MCV to preflight supine level and PV to preflight seated level. Elevated JVvol confirms the sustained neck-head blood engorgement inflight, whereas increased PV area supports the fluid shift at the splanchnic level. Also, MCV increased potentially due to reduced lumen diameter. LBNP, returning variables to preflight levels, may be an effective countermeasure. NEW & NOTEWORTHY Microgravity-induced fluid shifts markedly enlarge jugular and portal veins and increase cerebral vein velocity. These findings demonstrate a marked flow engorgement at neck and splanchnic levels and may suggest compression of the cerebral veins by the brain tissue in space. LBNP (−25 mmHg for 30 min) returns these changes to preflight levels and, thus, reduces the associated flow and tissue disturbances.

BACKGROUND: Glaucoma and ocular hypertension (OHT) are prevalent diseases with baseline intraocular pressure (IOP) elevations that future astronauts and spaceflight participants may suffer from. Preflight, in-flight, and postflight IOP measurements were collected aboard two U.S. Space Shuttle Program missions in normotensive control, OHT, and glaucomatous crewmembers. METHODS: Five subjects (three controls, one glaucomatous, one OHT) were studied aboard 2-wk Space Shuttle missions. Baseline IOP (triplicate; handheld tonometry) was recorded during training 12 mo preflight, in flight (114 d), and postflight (329 d). Subjective symptoms were recorded via questionnaires. Data were analyzed using a spreadsheet with two-sample t-tests. P-value < 0.05 determined significance. RESULTS: IOP increased for all in-flight vs. preflight measurements for controls (N 3, 48.9, 16.9, 5.85), OHT (N 1, 20.3), and glaucomatous (N 1, 32.2) groups. IOP eventually returned to baseline postflight [Return (R)35 d], except for the astronaut with OHT (R917). Subjective symptoms, likely multifactorial, included blurredvision, decreased visual acuity, and headaches. DISCUSSION: IOP increased during spaceflight and normalized upon return. Astronauts and commercial spaceflight participants may need screening for elevated IOP to potentially prevent sequelae related to glaucoma and OHT, the former which requires treatment in flight and the latter which may need prophylaxis. Previous studies have shown elevated IOP upon entry into microgravity with various normalization timeframes in flight and postflight. It is unclear how increased IOP relates to spaceflight-associated neuro-ocular syndrome (SANS); however, several hypotheses exist. Treatment strategies should be available for acute and chronic ocular pathology during spaceflight despite the unique challenges of eye-drop application in microgravity. Dalal SR, Ramachandran V, Khalid R, Manuel FK, Knowles JR, Jones JA. Increased intraocular pressure in glaucomatous, ocular hypertensive, and normotensive space shuttle crew. Aerosp Med Hum Perform. 2021; 92(9):728733.

The objective was to quantify the index of reflectivity of the common carotid artery and surrounding structures, before and after 6 mo of microgravity. Our hypothesis was that structural changes in the insonated target would increase its index of reflectivity. The neck anterior muscle and common carotid artery (walls and lumen) were visualized by echography (17 MHz linear probe), and the radiofrequency signal along each vertical line was displayed. The limits of the radiofrequency data corresponding to each target (muscle, vessel wall) were determined from the B-mode image and radiofrequency trace. Each target's index of reflectivity was calculated as the proportion of backscattered energy to the whole backscattered energy along the line. After 6 mo in flight, the index of reflectivity increased significantly for both common carotid walls, while it remained unchanged for the neck muscle, carotid intima and lumen. The index of reflectivity provided additional information beyond traditional B-mode imaging.

Long-duration space exploration missions will pose significant risks to the physical and behavioral health and performance of the crew. We documented the presence and frequency of (1) behavioral health and performance (BHP)-relevant symptoms for each condition in NASA's Exploration Medical Conditions List (EMCL), (2) the BHP-relevant effects of applicable medical treatments in the current International Space Station (ISS) On-Orbit Medication List, (3) the breadth of potential BHP impacts of spaceflight medical treatments, and (4) the likelihood of adverse BHP effects of treating spaceflight medical conditions. BHP symptoms and effects were categorized by the six neurobehavioral domains of the National Institute of Mental Health's Research Domain Criteria (RDoC) framework. Including the cognitive effects of acute and chronic pain (e.g., attention, memory), 94% of spaceflight medical conditions include symptoms relevant to Cognitive Systems (e.g., attention deficits, confusion, psychosis), 36% include symptoms relevant to Negative Valence Systems (e.g., anxiety), 32% include symptoms relevant to Arousal and Regulatory Systems (e.g., sleep disturbances), 22% include symptoms relevant to Sensorimotor Systems (e.g., dizziness), 19% include symptoms relevant to Positive Valence Systems (e.g., mania), and 11% include symptoms relevant to Social Processes (e.g., social withdrawal). Only 2% of spaceflight medical conditions have no documented BHP symptoms. Of the spaceflight medical treatments, 63% affect Arousal and Regulatory Systems, 60% affect Sensorimotor Systems, 59% affect Cognitive Systems, 53% affect Negative Valence Systems, 38% affect Positive Valence Systems, and 31% affect Social Processes. The breadth of potential BHP impacts was bimodal, in that 27% of spaceflight medical treatments had no documented BHP effects; however, 27% of treatments may produce adverse effects across all six neurobehavioral domains. Historical prevalence data on medical conditions, symptoms, and complaints from 14 years of International Space Station operations coupled with documented BHP effects of recommended treatments indicates the potential for up to 481 adverse BHP effects of spaceflight medical treatments per person-year. Assessing the potential BHP impacts of spaceflight medical conditions and their treatments highlights the interactive nature of operational risks, and can provide an enhanced evidence base to support integrated research and countermeasure development strategies for long-duration exploration missions.

INTRODUCTION: During active phases of manned spaceflight there is a possibility of a spacecraft landing at any point traversed by its orbital path on the Earth. Survival training after emergency landing is an important and vital part of pre-mission preparations. In this paper we analyze medical issues associated with winter survival training in marshy and forested terrain.METHODS: From 2011 to 2019, 50 International Space Station crews participated in winter survival training. Crewmembers included Roscosmos, NASA, CSA, ESA, and JAXA astronauts, spaceflight participants, and instructors. Medical protocols and training final reports were analyzed for conditions and medical events.RESULTS: The health status of crewmembers during training was nominal. Temperature sensation was reported as comfortable or moderately cold during daytime and moderately cold or cold during nighttime. SpO2 (blood oxygen saturation) and heart rate recorded during training did not exceed normal values. SpCO (blood carbon monoxide saturation) generally was within normal limits. All participating crewmembers lost some bodyweight, from 0.15.5 kg (average 2.1 kg). Over the course of winter survival training there were 32 medical and environmental events requiring medical intervention. For two of the crewmembers requiring medical intervention, training was subsequently canceled.DISCUSSION: Winter survival training has successfully prepared spaceflight crews for the possibility of off-nominal landings in challenging terrain under adverse conditions. As this training involves high fidelity flight-like survival equipment and assigned flight crewmembers, the medical problems described here should closely reflect type and prevalence of events during an actual contingency scenario.Kireev KS, Grishin AP, Dowell GL. Medical issues associated with winter survival training. Aerosp Med Hum Perform. 2021; 92(8):676680.

With the reignited push for manned spaceflight and the development of companies focused on commercializing spaceflight, increased human ventures into space are inevitable. However, this venture would not be without risk. The lower gravitational force, known as microgravity, that would be experienced during spaceflight significantly disrupts many physiological systems. One of the most notably affected systems is the musculoskeletal system, where exposure to microgravity causes both bone and skeletal muscle loss, both of which have significant clinical implications. In this review, we focus on recent advancements in our understanding of how exposure to microgravity affects the musculoskeletal system. We will focus on the catabolic effects microgravity exposure has on both bone and skeletal muscle cells, as well as their respective progenitor stem cells. Additionally, we report on the mechanisms that underlie bone and muscle tissue loss resulting from exposure to microgravity and then discuss current countermeasures being evaluated. We reveal the gaps in the current knowledge and expound upon how current research is filling these gaps while also identifying new avenues of study as we continue to pursue manned spaceflight.

BACKGROUND: The National Aeronautics and Space Administration (NASA) Flight Crew Health Stabilization Program (HSP) was historically implemented to minimize infectious disease transmission to astronauts in the immediate prelaunch period. The first ever commercial application and adaptation of the NASA HSP was implemented during the Crew Demo-2 mission in the time of the Coronavirus disease 2019 (COVID-19) pandemic. This article details and discusses the first commercial implementation and adaptation of the HSP prior to the Crew Demo-2 launch.METHODS: This is a retrospective descriptive analysis of the application of NASA disease prevention protocols for human spaceflight during the COVID-19 pandemic. In the context of the pandemic, extra precautions added to the HSP included daily symptom surveys completed by Primary Contacts of the crew, COVID-19 RT-PCR testing, and improved quarantine protocols.RESULTS: Of the 91 SpaceX Primary Contacts who completed a total of 2720 daily symptom surveys prior to launch, 22 individuals (24.2) and 198 surveys (7.3) returned positive for potential symptoms of COVID-19. Two individuals were removed due to symptoms indistinguishable from COVID-19. Through this survey, systematic quarantine, and PCR testing, the Crew Demo-2 mission was successful with no known infectious diseases transmitted.CONCLUSIONS: Overall, the commercial implementation of the NASA Health Stabilization Program by SpaceX with adjustments required during the COVID-19 pandemic was a success, with protocols allowing identification and removal of potentially infectious persons from the program. The principles of the HSP may provide an adequate infectious disease playbook for commercial spaceflight operations going forward.Petersen E, Pattarini JM, Mulcahy RA, Beger SB, Mitchell MR, Hu YD, Middleton KN, Frazier W, Mormann B, Esparza H, Asadi A, Musk ER, Alter G, Nilles E, Menon AS. Adapting disease prevention protocols for human spaceflight during COVID-19. Aerosp Med Hum Perform. 2021; 92(7):597602.

In humans and other vertebrates, the range of disturbances and behavioural changes induced by spaceflight conditions are well known. Sensory organs and the central nervous system (CNS) are forced to adapt to new environmental conditions of weightlessness. In comparison with peripheral vestibular organs and behavioural disturbances in weightlessness conditions, the CNS vestibular centres of vertebrates, including the cerebellum, have been poorly examined in orbital experiments, as well as in experimental micro- and hypergravity. However, the cerebellum serves as a critical control centre for learning and sensory system integration during space-flight. Thus, it is referred to as a principal brain structure for adaptation to gravity and the entire sensorimotor adaptation and learning during weightlessness. This paper is focused on the prolonged spaceflight effects on the vestibular cerebellum evidenced from animal models used in the Bion-M1 project. The changes in the peripheral vestibular apparatus and brainstem primary vestibular centres with appropriate behavioural disorders after altered gravity exposure are briefly reviewed. The cerebellum studies in space missions and altered gravity are discussed.

Following long‐duration spaceflight, some astronauts exhibit ophthalmic structural changes referred to as Spaceflight Associated Neuro‐ocular Syndrome (SANS). Optic disc edema is a common sign of SANS. The origin and effects of SANS are not understood as signs of SANS have not manifested in previous spaceflight analog studies. In the current spaceflight analog study, 11 subjects underwent 30 days of strict head down‐tilt bed rest in elevated ambient carbon dioxide (HDBR+CO2). Using functional magnetic resonance imaging (fMRI), we acquired resting‐state fMRI data at 6 time points: before (2), during (2), and after (2) the HDBR+CO2 intervention. Five participants developed optic disc edema during the intervention (SANS subgroup) and 6 did not (NoSANS group). This occurrence allowed us to explore whether development of signs of SANS during the spaceflight analog impacted resting‐state functional connectivity during HDBR+CO2. In light of previous work identifying genetic and biochemical predictors of SANS, we further assessed whether the SANS and NoSANS subgroups exhibited differential patterns of resting‐state functional connectivity prior to the HDBR+CO2 intervention. We found that the SANS and NoSANS subgroups exhibited distinct patterns of resting‐state functional connectivity changes during HDBR+CO2 within visual and vestibular‐related brain networks. The SANS and NoSANS subgroups also exhibited different resting‐state functional connectivity prior to HDBR+CO2 within a visual cortical network and within a large‐scale network of brain areas involved in multisensory integration. We further present associations between functional connectivity within the identified networks and previously identified genetic and biochemical predictors of SANS. Subgroup differences in resting‐state functional connectivity changes may reflect differential patterns of visual and vestibular reweighting as optic disc edema develops during the spaceflight analog. This finding suggests that SANS impacts not only neuro‐ocular structures, but also functional brain organization. Future prospective investigations incorporating sensory assessments are required to determine the functional significance of the observed connectivity differences., We investigated resting‐state functional connectivity (FC) during a spaceflight analog with elevated carbon dioxide. A subset of participants developed optic disc edema, a sign of spaceflight‐associated neuro‐ocular syndrome (SANS) during the spaceflight analog. Subjects who developed optic disc edema exhibited a distinct pattern of FC changes within visual and vestibular‐related networks during the intervention.

Exposure to microgravity affects human physiology in various ways, and astronauts frequently report skin-related problems. Skin rash and irritation are frequent complaints during space missions, and skin thinning has also been reported after returning to Earth. However, spaceflight missions for studying the physiological changes in microgravity are impractical. Thus, we used a previously developed 3D clinostat to simulate a microgravity environment and investigate whether physiological changes of the skin can be reproduced in a 3D in vitro setting. Our results showed that under time-averaged simulated microgravity (taSMG), the thickness of the endothelial cell arrangement increased by up to 59.75%, indicating skin irritation due to vasodilation, and that the diameter of keratinocytes and fibroblast co-cultured spheroids decreased by 6.66%, representing skin thinning. The α1 chain of type I collagen was upregulated, while the connective tissue growth factor was downregulated under taSMG. Cytokeratin-10 expression was significantly increased in the taSMG environment. The clinostat-based 3D culture system can reproduce physiological changes in the skin similar to those under microgravity, providing insight for understanding the effects of microgravity on human health before space exploration.

Animals in space exploration studies serve both as a model for human physiology and as a means to understand the physiological effects of microgravity. To quantify the microgravity-induced changes to bone health in animals, we systematically searched Medline, Embase, Web of Science, BIOSIS, and NASA Technical reports. We selected 40 papers focusing on the bone health of 95 rats, 61 mice, and 9 rhesus monkeys from 22 space missions. The percentage difference from ground control in rodents was –24.1% [Confidence interval: −43.4, −4.9] for trabecular bone volume fraction and –5.9% [−8.0, −3.8] for the cortical area. In primates, trabecular bone volume fraction was lower by –25.2% [−35.6, −14.7] in spaceflight animals compared to GC. Bone formation indices in rodent trabecular and cortical bone were significantly lower in microgravity. In contrast, osteoclast numbers were not affected in rats and were variably affected in mice. Thus, microgravity induces bone deficits in rodents and primates likely through the suppression of bone formation.

Vertebrates use weight-lending otoconia in the inner ear otolith organs to enable detection of their translation during self or imposed movements and a change in their orientation with respect to gravity. In spaceflight, otoconia are near weightless. It has been hypothesized that otoconia undergo structural remodeling after exposure to weightlessness to restore normal sensation. A structural remodeling is reasoned to occur for hypergravity but in the opposite sense. We explored these hypotheses in several strains of mice within a Biospecimen Sharing Program in separate space- and ground-based projects. Mice were housed 90 days on the International Space Station, 13 days on two Shuttle Orbiter missions, or exposed to 90 days of hindlimb unloading or net 2.38 g via centrifugation. Corresponding flight habitat and standard cage vivarium controls were used. Utricular otoliths were visually analyzed using scanning electron microscopy and in selected samples before and after focused ion beam (FIB) milling. Results suggest a possible mass addition to the otoconia outer shell might occur after exposure to longer-duration spaceflight, but not short ones or hindlimb unloading. A destructive process is clearly seen after centrifugation: an ablation or thinning of the outer shell and cavitation of the inner core. This study provides a purely descriptive account of otoconia remodeling after exposures to altered gravity. The mechanism(s) underlying these processes must be identified and quantitatively validated to develop countermeasures to altered gravity levels during exploration missions.

BACKGROUND: This study aimed to investigate the biomechanical effects of different interventions on astronauts lumbar intervertebral discs in a microgravity environment during spaceflight and in a gravity environment when the astronaut returns.METHODS: A finite element model of the L4L5 lumbar segment was developed with eight loading schemes representing different interventions. The loading schemes included no intervention, wearing a penguin suit, sleeping in a fetal position, wearing a penguin suit combined with sleeping in the fetal position, reclining for 4 or 16 h/d, and maintaining upright posture for 4 or 16 h/d.RESULTS: Without intervention, the microgravity environment led to increased central pore pressure, radial displacement, and water content in the lumbar intervertebral disc. Wearing a penguin suit combined with sleeping in the fetal position can reduce disc pore pressure, axial stress, radial displacement, and water content to 0.156 MPa, 11.50 kPa, 0.538 mm, and 1.390%, respectively. When astronauts return to the gravity environment, staying upright for 4 h can reduce the pore pressure, axial stress, radial displacement, and water content of the intervertebral disc to 0.222 MPa, 10.72 kPa, 0.373 mm, and 0.219%, respectively.CONCLUSION: This study showed that wearing a penguin suit and sleeping in the fetal position both have the potential to protect the lumbar intervertebral disc from the negative effects caused by microgravity. Remaining in the upright posture for 4 h per day may help squeeze out the water in the intervertebral disc safely when astronauts return to the gravity environment.Zhang S, Wang K, Zhu R, Jiang C, Niu W. Penguin suit and fetal position finite element model to prevent low back pain in spaceflight. Aerosp Med Hum Perform. 2021; 92(5):312318.

The purpose of this systematic review is twofold: 1) to identify, evaluate, and synthesize the heretofore disparate scientific literatures regarding the effects of direct exposure to microgravity on the musculoskeletal system, taking into account for the first time both bone and muscle systems of both humans and animals; and 2) to investigate the efficacy and limitations of exercise countermeasures on the musculoskeletal system under microgravity in humans. The Framework for Scoping Studies (Arksey and O'Malley 2005) and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins JPT 2011) were used to guide this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was utilized in obtaining the combined results (Moher, Liberati et al. 2009). Data sources, PubMed, Embase, Scopus, and Web of Science were searched for published articles through October 2019 using the Mesh terms of microgravity, musculoskeletal system, and exercise countermeasures. A total of 84 references were selected, including 40 animal studies and 44 studies with human participants. The heterogeneity in the study designs, methodologies, and outcomes deemed this review unsuitable for a meta-analysis. Thus, we present a narrative synthesis of the results for the key domains under five categories: 1) Skeletal muscle responses to microgravity in humans 2) Skeletal muscle responses to microgravity in animals 3) Adaptation of the skeletal system to microgravity in humans 4) Adaptation of the skeletal system to microgravity in animals 5) Effectiveness of exercise countermeasures on the human musculoskeletal system in microgravity. Existing studies have produced only limited data on the combined effects on bone and muscle of human spaceflight, despite the likelihood that the effects on these two systems are complicated due to the components of the musculoskeletal system being anatomically and functionally interconnected. Bone is directly affected by muscle atrophy as well as by changes in muscle strength, notably at muscle attachments. Given this interplay, the most effective exercise countermeasure is likely to be robust, individualized, resistive exercise, primarily targeting muscle mass and strength.

Both microgravity and radiation exposure in the spaceflight environment have been identified as hazards to astronaut health and performance. Substantial study has been focused on understanding the biology and risks associated with prolonged exposure to microgravity, and the hazards presented by radiation from galactic cosmic rays (GCR) and solar particle events (SPEs) outside of low earth orbit (LEO). To date, the majority of the ground-based analogues (e.g., rodent or cell culture studies) that investigate the biology of and risks associated with spaceflight hazards will focus on an individual hazard in isolation. However, astronauts will face these challenges simultaneously Combined hazard studies are necessary for understanding the risks astronauts face as they travel outside of LEO, and are also critical for countermeasure development. The focus of this review is to describe biologic and functional outcomes from ground-based analogue models for microgravity and radiation, specifically highlighting the combined effects of radiation and reduced weight-bearing from rodent ground-based tail suspension via hind limb unloading (HLU) and partial weight-bearing (PWB) models, although in vitro and spaceflight results are discussed as appropriate. The review focuses on the skeletal, ocular, central nervous system (CNS), cardiovascular, and stem cells responses.

Emerging plans for travel to Mars and other deep space destinations make it critical for us to understand how spaceflight affects the human brain and behavior. Research over the past decade has demonstrated two co-occurring patterns of spaceflight effects on the brain and behavior: dysfunction and adaptive plasticity. Evidence indicates the spaceflight environment induces adverse effects on the brain, including intracranial fluid shifts, gray matter changes, and white matter declines. Past work also suggests that the spaceflight environment induces adaptive neural effects such as sensory reweighting and neural compensation. Here, we introduce a new conceptual framework to synthesize spaceflight effects on the brain, S paceflight P erturbation A daptation C oupled with D ysfunction (SPACeD). We review the literature implicating neurobehavioral dysfunction and adaptation in response to spaceflight and microgravity analogues, and we consider pre-, during-, and post-flight factors that may interact with these processes. We draw several instructive parallels with the aging literature which also suggests co-occurring neurobehavioral dysfunction and adaptive processes. We close with recommendations for future spaceflight research, including: 1) increased efforts to distinguish between dysfunctional versus adaptive effects by testing brain-behavioral correlations, and 2) greater focus on tracking recovery time courses.

ObjectivesBone loss remains a primary health concern for astronauts, despite in-flight exercise. We examined changes in bone microarchitecture, density and strength before and after long-duration spaceflight in relation to biochemical markers of bone turnover and exercise.MethodsSeventeen astronauts had their distal tibiae and radii imaged before and after space missions to the International Space Station using high-resolution peripheral quantitative CT. We estimated bone strength using finite element analysis and acquired blood and urine biochemical markers of bone turnover before, during and after spaceflight. Pre-flight exercise history and in-flight exercise logs were obtained. Mixed effects models examined changes in bone and biochemical variables and their relationship with mission duration and exercise.ResultsAt the distal tibia, median cumulative losses after spaceflight were −2.9% to −4.3% for bone strength and total volumetric bone mineral density (vBMD) and −0.8% to −2.6% for trabecular vBMD, bone volume fraction, thickness and cortical vBMD. Mission duration (range 3.5–7 months) significantly predicted bone loss and crewmembers with higher concentrations of biomarkers of bone turnover before spaceflight experienced greater losses in tibia bone strength and density. Lower body resistance training volume (repetitions per week) increased 3–6 times in-flight compared with pre-spaceflight. Increases in training volume predicted preservation of tibia bone strength and trabecular vBMD and thickness.ConclusionsFindings highlight the fundamental relationship between mission duration and bone loss. Pre-flight markers of bone turnover and exercise history may identify crewmembers at greatest risk of bone loss due to unloading and may focus preventative measures.

Following prolonged stays on the International Space Station (ISS), some astronauts exhibit visual acuity changes, ophthalmological findings, and mildly elevated intracranial pressures as part of a novel process called spaceflight-associated neuro-ocular syndrome (SANS). To determine the pathophysiology of SANS, NASA conducted a multi-investigator study in which 11 healthy participants underwent head-down tilt bed rest, mimicking microgravity-induced cephalad fluid shifts, combined with elevated ambient CO2 levels similar to those on the ISS (HDT+CO2). As part of that study, we examined the effects of HDT+CO2 on cerebral perfusion. Using arterial spin labeling, we compared cerebral perfusion before, during, and after HDT+CO2 in participants who developed SANS (n = 5) with those who did not (n = 6). All participants demonstrated a decrease in perfusion during HDT+CO2 (mean decrease of 25.1% at HDT7 and 16.2% at HDT29); however, the timing and degree of change varied between the groups. At day 7 of HDT+CO2, the SANS group experienced a greater reduction in perfusion than the non-SANS group (p =.05, 95% CI:-0.19 to 16.11, d=.94, large effect). Conversely, by day 29 of HDT+CO2, the SANS group had significantly higher perfusion (approaching their baseline) than the non-SANS group (p = .04, 95% CI:0.33 to 13.07, d=1.01, large effect). Compared with baseline and recovery, HDT+CO2 resulted in reduced cerebral perfusion which varied based on SANS status. Further studies are needed to unravel the relative role of HDT vs hypercapnia, to determine if these perfusion changes are clinically relevant, and whether perfusion changes contribute to the development of SANS during spaceflight.

Background Astronauts undergoing long-duration spaceflight are exposed to numerous health risks, including Spaceflight-Associated Neuro-Ocular Syndrome (SANS), a spectrum of ophthalmic changes that can result in permanent loss of visual acuity. The etiology of SANS is not well understood but is thought to involve changes in cerebrovascular flow dynamics in response to microgravity. There is a paucity of knowledge in this area; in particular, cerebrospinal fluid (CSF) flow dynamics have not been well characterized under microgravity conditions. Our study was designed to determine the effect of simulated microgravity (head-down tilt [HDT]) on cerebrovascular flow dynamics. We hypothesized that microgravity conditions simulated by acute HDT would result in increases in CSF pulsatile flow. Methods In a prospective cohort study, we measured flow in major cerebral arteries, veins, and CSF spaces in fifteen healthy volunteers using phase contrast magnetic resonance (PCMR) before and during 15° HDT. Results We found a decrease in all CSF flow variables [systolic peak flow (p = 0.009), and peak-to-peak pulse amplitude (p = 0.001)]. Cerebral arterial average flow (p = 0.04), systolic peak flow (p = 0.04), and peak-to-peak pulse amplitude (p = 0.02) all also significantly decreased. We additionally found a decrease in average cerebral arterial flow (p = 0.040). Finally, a significant increase in cerebral venous cross-sectional area under HDT (p = 0.005) was also observed. Conclusions These results collectively demonstrate that acute application of −15° HDT caused a reduction in CSF flow variables (systolic peak flow and peak-to-peak pulse amplitude) which, when coupled with a decrease in average cerebral arterial flow, systolic peak flow, and peak-to-peak pulse amplitude, is consistent with a decrease in cardiac-related pulsatile CSF flow. These results suggest that decreases in cerebral arterial inflow were the principal drivers of decreases in CSF pulsatile flow.

This is the first bed rest campaign examining sensorimotor adaptation and savings in response to the combined effect of HDBR + CO2 and to observe signs of spaceflight-associated neuro-ocular syndrome (SANS) in HDBR participants. Our findings suggest that HDBR + CO2 alters the way that individuals engage in sensorimotor processing. Individuals who developed signs of SANS seem to rely more on implicit rather than cognitive processing of adaptive behaviors than subjects who did not present signs of SANS.

BACKGROUND: The impact of the spaceflight environment on endogenous estrogen production in female crewmembers and the resulting impact on other adaptations, like bone loss, is an under-investigated topic. Hence, we investigated the interaction of exogenous 17- estradiol (E2) treatment and disuse to test the hypothesis that E2 treatment would mitigate disuse-induced bone loss.METHODS: There were 40 virgin female Sprague-Dawley rats (5 mo old) randomized to placebo (PL; 0 ppm E2) or estrogen (E2; 10 ppm E2) treatments, delivered via custom-made rodent diets; half of each group was randomized to either weightbearing (WB) or hindlimb unloading (HU) for 39 d.RESULTS: We observed expected lower values after HU (615%) in volumetric BMD and cross-sectional areas at the proximal tibia metaphysis (PTM, by pQCT), 20% lower %BV/TV (nonsignificant) at the PTM, and 11% lower femoral neck maximal load; none of these HU-induced impacts were modified by E2. Impaired PTM periosteal expansion was observed in all E2-treated rats, with smaller (13 to 18%) cross-sectional areas. Midshaft tibial geometry was unaffected by E2 treatment, but large reductions (73 to 81%) in periosteal bone formation indices were observed in E2-treated rats.DISCUSSION: In summary, modest supplementation of exogenous E2 did not mitigate decrements in volumetric BMD, PTM cross-sectional geometry, or femoral neck strength observed with HU. However, numerous independent impacts of E2 treatment were observed, with significant suppression of periosteal bone formation indices. If maintained over time, this might impact negatively on cortical bone integrity during prolonged nonweightbearing.Mantri AV, Allaway HCM, Brezicha JE, Hogan HA, Bloomfield SA. Oral estradiol impact on mitigating unloading-induced bone loss in ovary-intact rats. Aerosp Med Hum Perform. 2021; 92(2):6574.

During spaceflight, the central nervous system (CNS) is exposed to a complex array of environmental stressors. However, the effects of long-duration spaceflight on the CNS and the resulting impact to crew health and operational performance remain largely unknown. In this review, we summarize the current knowledge regarding spaceflight-associated changes to the brain as measured by magnetic resonance imaging, particularly as they relate to mission duration. Numerous studies have reported macrostructural changes to the brain after spaceflight, including alterations in brain position, tissue volumes and cerebrospinal fluid distribution and dynamics. Changes in brain tissue microstructure and connectivity were also described, involving regions related to vestibular, cerebellar, visual, motor, somatosensory and cognitive function. Several alterations were also associated with exposure to analogs of spaceflight, providing evidence that brain changes likely result from cumulative exposure to multiple independent environmental stressors. Whereas several studies noted that changes to the brain become more pronounced with increasing mission duration, it remains unclear if these changes represent compensatory phenomena or maladaptive dysregulations. Future work is needed to understand how spaceflight-associated changes to the brain affect crew health and performance, with the goal of developing comprehensive monitoring and countermeasure strategies for future long-duration space exploration.

Weightlessness can affect the vestibular function, primarily the otolith function, both directly due to the loss of gravitational influence and by eliminating the support and minimizing proprioceptive afferentation, influencing indirectly through the central integrative multisensory structures of the central nervous system (CNS), where the convergence of afferent signals of various sensory modality (primarily visual, vestibular, support and motor) occurs. All this prompted the study of the influence of various afferentations on the otolith-ocular reflex under the conditions of real and simulated weightlessness. Using the video oculography method, 58 Russian cosmonauts, members of long-term missions to the ISS (125–219 days, ~175 days on average), were examined by a static torsional otolith-cervical-ocular reflex (OCOR) with a head tilt to the shoulder at an angle of 30 deg, the otolith-ocular reflex (OOR) when the body is tilted at an angle of 30 deg, and the otolith-ocular reflex when exposed to centrifugal acceleration using a centrifuge (OORCF). Nine out of 58 cosmonauts were examined in microgravity (175 days) as part of the Virtual space experiment (Stage 1). The study of simulation of the spaceflight (SF) factors involved 30 subjects during five- or seven-day horizontal “dry” immersion (DI) and 12 subjects in 60-day head-down tilt (–8 deg) bed rest (BR). The procedure and the corresponding hardware and software used both in studies with the participation of cosmonauts and in model experiments were completely identical. In weightlessness, throughout the whole SF, all the cosmonauts surveyed had a significant OCOR decrease with the presence (from 11 to 55%, depending on the flight day) of the atypical (inversion or absence) otolith-ocular reflex. After SF, on days 1–4 of examination, 80% of the cosmonauts exhibited a significant OCOR/OOR decrease; 34% of the cosmonauts had atypical (inversion or absence of the otolith reflex) vestibular reactions, while no differences were found between OCOR and OOR. Statistically significant differences were found between the values ​of the OCOR/OOR and OORCF reflexes before and on days 4–5, 9–12 after SF. On days 2–3 after SF, no difference between OORCF and OCOR/OOR was observed. The return of the otolith reflex to the baseline took place only on day 9 after SF. The OCOR/OOR study on days 1–3 after DI showed that the otolith-ocular reflex in 47% of those examined was significantly reduced; in 13% of the subjects atypical reactions (absence or inversion of the reflex) were recorded. On days 4–6 after DI, OCOR/OOR returned to the baseline in all subjects. Analysis of OCOR/OOR after the BR experiment showed that only 14% of the surveyed had a significant decrease in OCOR/OOR on day 1 after the experiment. The atypical form of OCOR/OOR (inversion or complete absence of the otolith reflex) after BR was not revealed in contrast to the testers after DI. The results obtained demonstrated the influence of nonvestibular afferentation on the intensity of the otolith-ocular reflex and its dependence on other sensory inputs.

Adverse effects of spaceflight on musculoskeletal health increase the risk of bone injury and impairment of fracture healing. Its yet elusive molecular comprehension warrants immediate attention, since space travel is becoming more frequent. Here we examined the effects of spaceflight on bone fracture healing using a 2 mm femoral segmental bone defect (SBD) model. Forty, 9-week-old, male C57BL/6J mice were randomized into 4 groups: 1) Sham surgery on Ground (G-Sham); 2) Sham surgery housed in Spaceflight (FLT-Sham); 3) SBD surgery on Ground (G-Surgery); and 4) SBD surgery housed in Spaceflight (FLT-Surgery). Surgery procedures occurred 4 days prior to launch; post-launch, the spaceflight mice were house in the rodent habitats on the International Space Station (ISS) for approximately 4 weeks before euthanasia. Mice remaining on the Earth were subjected to identical housing and experimental conditions. The right femur from half of the spaceflight and ground groups was investigated by micro-computed tomography (µCT). In the remaining mice, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomic and metabolomic assays. µCT confirmed escalated bone loss in FLT-Sham compared to G-Sham mice. Comparing to their respective on-ground counterparts, the morbidity gene-network signal was inhibited in sham spaceflight mice but activated in the spaceflight callus. µCT analyses of spaceflight callus revealed increased trabecular spacing and decreased trabecular connectivity. Activated apoptotic signals in spaceflight callus were synchronized with inhibited cell migration signals that potentially hindered the wound site to recruit growth factors. A major pro-apoptotic and anti-migration gene network, namely the RANK-NFκB axis, emerged as the central node in spaceflight callus. Concluding, spaceflight suppressed a unique biomolecular mechanism in callus tissue to facilitate a failed regeneration, which merits a customized intervention strategy.

Background/Objectives Spaceflight associated neuro-ocular syndrome (SANS), a health risk related to long-duration spaceflight, is hypothesized to result from a headward fluid shift that occurs with the loss of hydrostatic pressure gradients in weightlessness. Shifts in the vascular and cerebrospinal fluid compartments alter the mechanical forces at the posterior eye and lead to flattening of the posterior ocular globe. The goal of the present study was to develop a method to quantify globe flattening observed by magnetic resonance imaging after spaceflight. Subjects/Methods Volumetric displacement of the posterior globe was quantified in 10 astronauts at 5 time points after spaceflight missions of ~6 months. Results Mean globe volumetric displacement was 9.88 mm3 (95% CI 4.56–15.19 mm3, p 3 (95% CI 3.73–14.27 mm3, p = 0.001) at R + 30 days; 6.53 mm3 (95% CI 1.24–11.83 mm3, p 3 (95% CI −0.96 to 9.86 mm3, p = 0.12) at R + 180 days; and 7.21 mm3 (95% CI 1.82–12.60 mm3, p Conclusions There was a consistent inward displacement of the globe at the optic nerve, which had only partially resolved 1 year after landing. More pronounced globe flattening has been observed in previous studies of astronauts; however, those observations lacked quantitative measures and were subjective in nature. The novel automated method described here allows for detailed quantification of structural changes in the posterior globe that may lead to an improved understanding of SANS.

Maintaining astronaut health throughout long-duration spaceflight is essential to the feasibility of a manned mission to Mars. The ground-based Mars500 experiment investigated long-duration health by isolating six astronauts for 520 days, the longest controlled human confinement study conducted to date. After 520 days, astronauts had uniform strength and lean body mass losses, and increased fasting plasma glucose, calprotectin, and neutrophil levels characteristic of intestinal inflammation but previous analyses revealed no common significant changes in gut microbiota. This study reanalysed data from early (days 7–45) and late (days 420–520) faecal samples and identified 408 exact sequence variants (ESVs), including 213 shared by all astronauts. Thirty-two ESVs were significantly differentially abundant over time, including depletion of keystone resistant starch degrading, anti-inflammatory and insulin sensitivity-associated species, such as Faecalibacterium prausnitzii, Ruminococcus bromii, Blautia luti, Anaerostipes hadrus, Roseburia faecis, and Lactobacillus rogosae, and enrichment of yet-to-be-cultured bacteria. Additionally, the extraordinary experimental confinement allowed observation of microbiota potentially shared between astronauts and their habitat. Forty-nine species were shared, representing 49% and 12% of the human and environmental microbiome diversity, respectively. These findings reveal the microbiota which significantly altered in relative abundance throughout confinement, including species known to influence inflammation and host glucose homeostasis consistent with astronaut symptoms. Identification of microbiome alterations after 520 days of isolation represents a missing piece connecting Mars500 astronaut physiological studies. Knowledge of the impact of long-term confinement upon the human microbiome helps to improve our understanding of how humans interact with their habitats and is a valuable step forward towards enabling long-duration spaceflight.

BACKGROUND The landmark National Aeronautics and Space Administration Twins Study represented an integrated effort to launch human space life science research into the modern age of molecular- and "omics"-based studies. As part of the first One-Year Mission aboard the International Space Station, identical twin astronauts Scott and Mark Kelly were the subjects of this "out of this world" research opportunity. Telomeres, the natural ends of chromosomes that shorten with cell division and a host of lifestyle factors and stresses, are key molecular determinants of aging and aging trajectories. METHODS We proposed that telomere length dynamics (changes over time) represent a particularly relevant and integrative biomarker for astronauts, as they reflect the combined experiences and environmental exposures encountered during spaceflight. Telomere length (quantitative polymerase chain reaction and telomere fluorescence in situ hybridization) and telomerase activity (quantitative polymerase chain reaction -telomere repeat amplification protocol) were longitudinally assessed in the space- and earth-bound twins. Chromosome aberrations (directional genomic hybridization), signatures of radiation exposure, were also evaluated. RESULTS The twins had relatively similar telomere lengths before spaceflight, and the earth-bound twins' telomeres remained relatively stable over the course of the study. Surprisingly, the space twins' telomeres were longer during spaceflight, and upon return to Earth shortened rapidly, resulting in many more short telomeres after spaceflight than before. Chromosomal signatures of space radiation exposure were also elevated during spaceflight, and increased inversion frequencies persisted after spaceflight, suggestive of ongoing genome instability. CONCLUSION Although the definitive mechanisms underlying such dramatic spaceflight-associated shifts in telomere length remain unclear, improved maintenance of telomere length has important implications for aging science and improving healthspan for those on Earth, as well.

Introduction. Prophylactic surgery before spaceflight may eliminate the risk of appendicitis and cholecystitis in astronauts on deep space missions. However, even minimally invasive surgery increases the risk of small bowel obstruction (SBO). Probabilistic risk assessment (PRA) is a method that can be used to estimate the benefits and risks of prophylactic surgery. Methods. Risks of appendicitis and cholecystitis during a 2.5-year Mars mission are compared to the risk of SBO after laparoscopic removal of the appendix, gallbladder, or both. A PRA model using Monte Carlo methodology was used to forecast the risks. Results. Prophylactic appendectomy and cholecystectomy combined, conferred an increased probability of medical evacuation (pEVAC) due to SBO as compared to the no surgery group. A slightly higher probability for the loss of crew life (pLOCL) was found in the no surgery group when compared to the cases in which either prophylactic appendectomy alone, or appendectomy plus cholecystectomy are performed. Discussion. The need for medical evacuation can be viewed as a potential risk for death in the context of a space mission where evacuation is not possible. Because of the higher pEVAC due to SBO and relatively small benefit in the reduction of pLOCL in the prophylactic surgery groups, this analysis does not support the prophylactic removal of appendix and/or gallbladder for spaceflight. Future advances in surgical or medical technique or mission medical capabilities may change these results. This work demonstrates the utility of PRA in providing quantitative answers to “what if” questions where limited information is available.

Introduction. From 1960 to 2018, 282 people were enrolled in cosmonaut groups in the USSR and Russia. Extreme special training and working conditions could lead to health disorders, which may be reflected in the causes and rates of mortality in the future. The goal of this work is to study the causes and rates of mortality in two cohorts of cosmonauts: those with and without spaceflight experience. The study aim is to research the causes and mortality rates of astronauts who have made and did not fly into space. Methods. A cohort study of mortality of 263 male cosmonauts was conducted, 118 cosmonauts with spaceflight experience formed cohort 1, 145 cosmonauts without it - cohort 2. The follow-up period was 59 yrs. (01.01.1960-31.12.2018) with 8351,4 person-years obtained. The reference group for both cohorts was the male population of Russia, cohort 2 was also the reference group for the cohort 1. Mortality risk was assessed using standardized mortality ratio (SMR) with 95% confidence interval (95% CI). Results. Death risk from all causes (A00-Y98) for each cohort was significantly lower than that for the male population (SMR=0,39, 95% CI 0,28-0,54 for cohort 1; SMR=0,53, 95% CI 0,41-0,69 for cohort 2). Moreover, the risk of death for cosmonauts with spaceflight experience is also lower than for cosmonauts without it (SMR=0,66, 95% CI 0,46-0,91). The most common causes of death in both cohorts were circulatory system diseases, and cosmonauts without spaceflight experience died at a younger age. Conclusion. Further research is required to understand the true influence of extreme working conditions on cosmonauts’ health, especially in the long-term period.

As NASA prepares for longer space missions aiming for the Moon and Mars, astronauts’ health and performance are becoming a central concern due to the threats associated with galactic cosmic radiation, unnatural gravity fields, and life in extreme environments. In space, the human brain undergoes functional and structural changes related to fluid shift and changes in intracranial pressure. Behavioral abnormalities, such as cognitive deficits, sleep disruption, and visuomotor difficulties, as well as psychological effects, are also an issue. We discuss opportunities and challenges of noninvasive brain stimulation (NiBS) methods — including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES) — to support space exploration in several ways. NiBS includes safe and portable techniques already applied in a wide range of cognitive and motor domains, as well as therapeutically. NiBS could be used to enhance in-flight performance, supporting astronauts during pre-flight Earth-based training, as well as to identify biomarkers of post-flight brain changes for optimization of rehabilitation/compensatory strategies. We review these NiBS techniques and their effects on brain physiology, psychology, and cognition.

Mitigation of spaceflight-related pathologies such as spaceflight-associated neuro-ocular syndrome (SANS) and the recently discovered risk of venous thrombosis must happen before deep space exploration can occur. Lower body negative pressure (LBNP) can simulate gravitational stress during spaceflight that is likely to counteract SANS and venous thrombosis, but the ideal dose and method of delivery have yet to be determined. We undertook a review of current LBNP literature and conducted a gap analysis to determine the steps needed to adapt LBNP for in-flight use. We found that to use LBNP in flight, it must be adapted to long time duration/low pressure use that should be compatible with crew activities. A lack of understanding of the etiology of the pathologies that LBNP can counteract hinders the application of LBNP as a countermeasure during spaceflight. Future research should aim at filling the knowledge gaps outlined in this review.

The gravitostat is purported to function as a leptin-independent, osteocyte-dependent mechanism for regulation of energy balance. If correct, reduced activation of gravitostat signaling caused by prolonged sitting may contribute to obesity. The gravitostat concept is supported by reduced body mass in rodents following surgical implantation of weighted capsules. However, the procedure induces a confounding injury response. We, therefore, sought to confirm a gravitostat by decreasing (microgravity and simulated microgravity) or increasing (simulated gravity) weight using less invasive models (spaceflight, hindlimb unloading and centrifugation). We also evaluated changes in weight following non-surgical injury (radiation). Male rats (Wistar, Sprague–Dawley and Fischer 344) ranging in age from 5–12 weeks at launch and flown for 4–19 days in low Earth orbit exhibited slightly lower (4-day flight) or no difference (all other studies) in weight compared to ground controls. Rats subjected to inflight (1.0 G) or ground (1.04 G and 1.56 G) centrifugation during a 19-day mission did not differ in weight. In female rats (Fischer 344), spaceflight (14 days) did not alter ovariectomy-induced weight gain. Finally, hindlimb unloading resulted in weight loss in lean and obese mice. The aforementioned findings are inconsistent with outcomes predicted by a gravitostat namely increased mass during weightlessness and decreased mass when subjected to >1 G simulated gravity. Injury (dose-associated graded increases in radiation) mimicked the leptin-independent weight changes attributed to a gravitostat. Taken together, these findings do not support gravitostat regulation of energy balance and suggest injury/stress as an alternative mechanism for weight loss induced by weighted capsules.

PURPOSE OF REVIEW During prolonged spaceflight, astronauts often experience ocular changes, due to constant head-ward fluid shifts in space as compared with Earth. This article reviews symptoms, likely causes, and potential solutions, such as lower body negative pressure, to counteract space-associated neuroocular syndrome (SANS). RECENT FINDINGS Low gravity conditions and other aspects of spaceflight affect the eye detrimentally, causing SANS which is characterized by optic disc edema, choroidal thickening, cotton wool spots, and a hyperopic shift. SANS is probably caused by altered hemodynamic flows in the head and neck as well as mildly elevated intracranial and intraocular pressures. Carbon dioxide and other chemicals in space-craft may influence SANS as well. SANS may be counteracted by using lower body negative pressure, thigh cuffs, spacecraft engineering, and/or artificial gravity by a centrifuge. SUMMARY Prolonged space missions are associated with optic disc edema, choroidal thickening, cotton wool spots, and a hyperopic shift. Possible causes and countermeasures are currently being researched to reduce the risk of SANS. Although many countermeasures to SANS are under investigation lower body negative pressure exhibits great promise in counteracting the headward fluid shifts in space. Understanding and prevention of SANS is critical to future space exploration, especially to long-duration missions to the moon and Mars.

During a deep space mission, the central nervous system (CNS) and other organs are exposed to galactic cosmic rays and solar particle events. Health risks associated with various organs and systems are important issues in a long-term spaceflight. Potential CNS damage during a space mission could alter cognitive functions which might impact performance and individual’s health. The neuronal injury originating from exposure to 56Fe particle irradiation involves the elevated oxidative stress which can be inhibited by melatonin pretreatment. Melatonin exerts potent neuroprotective effects against carbon ion-induced mitochondrial dysfunction and apoptosis in the mouse brain. A significant increase in the count of immature neurons and proliferating cells was detected in the mice under 56Fe particle irradiation cotreated with the melatonin metabolite, AFMK. Melatonin treatment also significantly reduced the carbon ion-induced apoptotic cells and elevated oxidative stress in the mouse testis. The results suggest that melatonin treatment is a potential strategy to protect against space radiation hazards. Spaceflight-induced molecular, cellular, and physiologic changes lead to alterations across many organs and systems. Epigenetic, gene expression, inflammatory, and metabolic responses to spaceflight should be examined and means to safe-guard against these changes in upcoming missions. Precision medicine will be crucial for assessing and augmenting efficacy of melatonin or other medications in astronauts. In addition, enhancing radio-resistance of humans is a novel strategy for a long-term space mission. Further investigations with a combination of melatonin and other novel technologies are warranted to better alleviate HZE particle irradiation-induced damage to astronauts on long-term space exploration missions.

Background Microgravity-induced fluid shifts and the resulting changes in cerebral hemodynamics may be linked to cognitive performance alterations in spaceflight. Head-down tilt (HDT) bed rest serves as a well-validated spaceflight analog for microgravity-induced cephalic fluid shifts. This study examined the effects of short-term (t Methods In this within-subject cross-over study, ten male subjects without significant medical comorbidities (mean ± standard deviation [SD] age: 34 years ±3, weight: 81 kg ± 11, height: 1.77 m ± 0.06, body mass index: 26 kg/m2 ± 3) performed the Cognition test battery on an iPad at baseline (45° upright), after 1, 2, 3, and 4 h in the −12° HDT or supine position, and after 30-minute recovery in 45° upright position. The order of conditions (−12° HDT or supine) was randomized, with >1 week washout between test days. Results Mixed model analyses of z-transformed Cognition test scores indicate a small (0.21–0.25 SD) decrease in accuracy that did not survive adjustment for multiple testing and no change in speed (0.00–0.12 SD) across cognitive domains in the supine and −12° HDT position relative to upright. A true decrease in speed may have been masked by practice effects, as speed was found to increase by 0.06 SD per test bout in condition (95% confidence interval 0.03; 0.10). Performance differences between −12° HDT and supine positions across cognitive domains were less than small ( Discussion This study on short-term positional changes on cognitive performance suggests that performing Cognition in the supine or −12° HDT position on a tablet is associated with small decreases in accuracy and, if practice effects are taken into account, potentially also speed, but with no relevant differences between positions. These findings help interpret bed rest studies that use the new −12° HDT paradigm.

Bed rest is necessary for many medical conditions but also used as a ground-based model for space flight (along with head-down tilt to simulate fluid shifts in microgravity). The purpose of this review is to examine nutritional interventions during bed rest and spaceflight for prevention of muscle and strength loss, glucose intolerance, bone resorption, and cardiovascular problems. Increased dietary protein intake and supplementation with amino acids, β-hydroxy-β-methylbutyrate, or cofactors with antioxidant properties are effective for ameliorating bed rest-induced loss of muscle mass and strength. Previous literature involving bed rest with dietary protein/amino acid supplementation had mixed findings, likely due to differences in dosage. Although high protein intake in some studies prevents bed rest-induced muscle loss, it also increases bone resorption. High calcium intake and vitamin D supplementation are not beneficial for preventing bone degradation during bed rest or spaceflight. Very few studies investigated countermeasures to prevent glucose intolerance and cardiovascular risks during bed rest/spaceflight. Low-glycemic index diets might be beneficial for the prevention of bed rest-induced glucose intolerance and cardiovascular problems. The present evidence warrants additional studies on the exact threshold of protein/amino acid intake to prevent the loss of muscle mass and strength during bed rest/spaceflight specifically to maintain the beneficial effects of proteins on muscle mass and function without increasing bone resorption. Furthermore, it is suggested to study the effects of vitamin K supplementation on bone health during bed rest/spaceflight and determine the role of long-term low-glycemic index diets on glucose regulation and cardiovascular health during extended bed rest.