Strict Head-down Tilt Bed Rest Research Articles

Optic disc edema during strict 6° head-down tilt bed rest is related to one-carbon metabolism pathway genetics and optic cup volume

Some astronauts on International Space Station missions experience neuroophthalmological pathologies as part of spaceflight associated neuro-ocular syndrome (SANS). Strict head-down tilt bed rest (HDTBR) is a spaceflight analog that replicates SANS findings and those who had 3–4 risk alleles (G and C alleles from the methionine synthase reductase [MTRR] A66G and serine hydroxymethyltransferase [SHMT1] C1420T, respectively) as compared to 1-2 risk alleles, had a greater increase in total retinal thickness (TRT). The objective of this study was to identify factors that contribute to the individual variability of the development of SANS in a 60 d HDTBR at the German Aerospace Center’s:envihab facility, Cologne Germany. 22 of 24 subjects who participated in the HDTBR study provided blood samples for genetic analysis. Total retinal thickness and optic cup volume were measured before and after bed rest. Subjects with 3–4 versus 0-2 risk alleles had greater ΔTRT during and after bed rest, and the model improved with the addition of baseline optic cup volume. This bed rest study confirms that variants of MTRR and SHMT1 are associated with ocular pathologies. Subjects with more risk alleles had the greatest HDTBR-induced ΔTRT, reaffirming that genetics predispose some individuals to developing SANS. Preflight optic cup volume and genetics better predict ΔTRT than either one alone. Whether nutritional supplements can override the genetic influences on biochemistry, physiology, and pathophysiology remains to be tested. These findings have significant implications for both aerospace and terrestrial medicine.

Effects of daily artificial gravity training on orthostatic tolerance following 60-day strict head-down tilt bedrest

PurposeOrthostatic intolerance commonly occurs following immobilization or space flight. We hypothesized that daily artificial gravity training through short-arm centrifugation could help to maintain orthostatic tolerance following head-down tilt bedrest, which is an established terrestrial model for weightlessness.MethodsWe studied 24 healthy persons (eight women; age 33.3 ± 9.0 years; BMI 24.3 ± 2.1 kg/m2) who participated in the 60-days head-down tilt bedrest (AGBRESA) study. They were assigned to 30 min/day continuous or 6 × 5 min intermittent short-arm centrifugation with 1Gz at the center of mass or a control group. We performed head-up tilt testing with incremental lower-body negative pressure until presyncope before and after bedrest. We recorded an electrocardiogram, beat-to-beat finger blood pressure, and brachial blood pressure and obtained blood samples from an antecubital venous catheter. Orthostatic tolerance was defined as time to presyncope. We related changes in orthostatic tolerance to changes in plasma volume determined by carbon dioxide rebreathing.ResultsCompared with baseline measurements, supine and upright heart rate increased in all three groups following head-down tilt bedrest. Compared with baseline measurements, time to presyncope decreased by 323 ± 235 s with continuous centrifugation, by 296 ± 508 s with intermittent centrifugation, and by 801 ± 354 s in the control group (p = 0.0249 between interventions). The change in orthostatic tolerance was not correlated with changes in plasma volume.ConclusionsDaily artificial gravity training on a short-arm centrifuge attenuated the reduction in orthostatic tolerance after 60 days of head-down tilt bedrest.

Cardiovascular responses to daily use of lower body negative pressure during 30 days of strict head-down tilt bedrest

Introduction: Exposure to weightlessness causes a chronic headward fluid shift that is believed to underlie numerous risks associated with spaceflight, including the development of cephalad venous congestion, venous thromboembolism, and Spaceflight Associated Neuro-ocular Syndrome (SANS). Application of moderate levels (25 mmHg) of lower body negative pressure (LBNP) during spaceflight can partially reverse the headward fluid shift, and thus, may represent a promising countermeasure. Strict head-down tilt bed rest (HDTBR), a spaceflight analog, causes the development of some SANS findings and is used as a platform to test candidate countermeasures. Purpose: To measure the heart rate (HR) and mean arterial pressure (MAP) response during and subject tolerance to twice daily use of 3 hours of 25 mmHg LBNP during 30 days of HDTBR. Hypothesis: We hypothesized that during 3 hours of moderate LBNP MAP would be maintained, but HR would increase and that these responses would not be altered throughout 30 days of HDTBR. Methods: Twelve subjects (n = 12; 6 female) maintained strict 6˚ HDTBR for 30 days (HDT1 through HDT30) and were exposed to 2 separate 3-hour sessions of LBNP with continuous blood pressure and HR monitoring (Finapres, NOVA). Continuous data were averaged across 10-minute segments during each 3-hour LBNP period for statistical analyses to determine if MAP or HR changed within the 3-hour LBNP exposure, and whether the response to LBNP changed across all study days. Data were analyzed with generalized linear models with GEE effects to address repeated measures within subjects. Time trends over the 3 hours were modeled by the best fitting model utilizing linear or natural cubic splines of time. Results: All LBNP sessions (720 total) were completed across the 30 days of strict HDTBR, and no sessions were terminated early. In the first 10 minutes of LBNP MAP increased (+4 mmHg, p<0.01) and increased further over time (additional +3 mmHg by the final 10 minutes of LBNP exposure, p=0.02). This response did not change over the 30 days of HDTBR (p=0.67). Similarly, HR increased (+7 bpm, p<0.01) during the first 10 minutes of LBNP exposure but decreased towards pre-LBNP levels by the conclusion of LBNP (-6 bpm, p<0.0001). The HR response to LBNP did not change over 30 days of HDTBR (p=0.14). Conclusion: Twice daily use of 25 mmHg LBNP during 30 days of strict HDTBR was well-tolerated with no reported hypotensive symptoms or cardiovascular responses suggestive of impending syncope. Despite cardiovascular deconditioning expected to occur due to inactivity during HDTBR, neither the MAP or HR response to LBNP were significantly changed between HDT1 and HDT30. Prolonged use of moderate LBNP should be further investigated as a potential countermeasure for various risks associated with long-duration spaceflight. National Aeronautics and Space Administration Human Research Program Directed Research This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Bone metabolism during strict head-down tilt bed rest and exposure to elevated levels of ambient CO2

Astronauts on the International Space Station are exposed to levels of atmospheric carbon dioxide (CO2) above typical terrestrial levels. We explored the possibility that increased levels of ambient CO2 further stimulate bone resorption during bed rest. We report here data from 2 ground-based spaceflight analog studies in which 12 male and 7 female subjects were placed in a strict 6° head-down tilt (HDT) position for either 30 days at 0.5% ambient CO2 or 60 days with nominal environmental exposure to CO2. Bone mineral density (BMD) and bone mineral content (BMC) were determined using dual-energy X-ray absorptiometry (DXA). Blood and urine were collected before and after HDT for biochemical analysis. No change was detected in either BMD or BMC, as expected given the study duration. Bone resorption markers increased after bed rest as expected; however, elevated CO2 had no additive effect. Elevated CO2 did not affect concentrations of minerals in serum and urine. Serum parathyroid hormone and 1,25-dihydroxyvitamin D were both reduced after bed rest, likely secondary to calcium efflux from bone. In summary, exposure to 0.5% CO2 for 30 days did not exacerbate the typical bone resorption response observed after HDT bed rest. Furthermore, results from these strict HDT studies were similar to data from previous bed rest studies, confirming that strict 30–60 days of HDT can be used to evaluate changes in bone metabolism. This is valuable in the continuing effort to develop and refine efficacious countermeasure protocols to mitigate bone loss during spaceflight in low-Earth orbit and beyond.

Bone Metabolism During Strict Head-Down Tilt Bed Rest and CO2 Exposure

ObjectivesCarbon dioxide (CO2) levels on board the International Space Station reach 10× those of outdoor terrestrial levels. We report here studies assessing whether increased levels of ambient CO2 contribute to elevated bone resorption characteristically observed with bed rest as an analog for skeletal unloading during spaceflight.MethodsData are reported from two ground-based studies which included 12 male and 7 female subjects placed in a strict −6° head-down tilt (HDT) position for 30 days at 0.5% ambient CO2 or 60 days with nominal environment (0.04% CO2). Subjects were neither afforded a pillow nor allowed to use an elbow while eating to increase headward fluid pressure. Bone mineral density (BMD) and bone mineral content (BMC) were measured with dual-energy X-ray absorptiometry. Blood and urine were collected before and during HDT for analysis.ResultsThere was no change in BMD or BMC. Excretion of collagen crosslinks increased during HDT (p < 0.001) with no additive effect of CO2. Serum and urine mineral concentrations were not affected by CO2. Serum PTH and 1,25-deoxyhydroxyvitamin D were both reduced during bed rest (p < 0.0001), likely secondary to calcium efflux from bone, but with no additive effect of CO2 exposure. These changes reinforce the impact of decreased mechanical loading on bone and mineral homeostasis and the efficacy of the strict HDT model.ConclusionsExposure to 0.5% CO2 for 30 days did not exacerbate bone resorption during strict HDT bed rest. Future research on bone metabolism at varied CO2 levels is needed to clarify a risk ceiling for bone resorption, especially as missions progress beyond low-Earth orbit.Funding SourcesThe data reported here were from the NASA Human Research Program Standard Measures Cross-Cutting Project. Funding was provided by the NASA Human Research Program's Human Health Countermeasures Element. ERM was funded through a NASA Summer Science Institute Fellowship.

The Effects of 30 Minutes of Artificial Gravity on Cognitive and Sensorimotor Performance in a Spaceflight Analog Environment.

The altered vestibular signaling and somatosensory unloading of microgravity result in sensory reweighting and adaptation to conflicting sensory inputs. Aftereffects of these adaptive changes are evident postflight as impairments in behaviors such as balance and gait. Microgravity also induces fluid shifts toward the head and an upward shift of the brain within the skull; these changes are well-replicated in strict head-down tilt bed rest (HDBR), a spaceflight analog environment. Artificial gravity (AG) is a potential countermeasure to mitigate these effects of microgravity. A previous study demonstrated that intermittent (six, 5-mins bouts per day) daily AG sessions were more efficacious at counteracting orthostatic intolerance in a 5 day HDBR study than continuous daily AG. Here we examined whether intermittent daily AG was also more effective than continuous dosing for mitigating brain and behavioral changes in response to 60 days of HDBR. Participants (n = 24) were split evenly between three groups. The first received 30 mins of continuous AG daily (cAG). The second received 30 mins of intermittent AG daily (6 bouts of 5 mins; iAG). The third received no AG (Ctrl). We collected a broad range of sensorimotor, cognitive, and brain structural and functional assessments before, during, and after the 60 days of HDBR. We observed no significant differences between the three groups in terms of HDBR-associated changes in cognition, balance, and functional mobility. Interestingly, the intermittent AG group reported less severe motion sickness symptoms than the continuous group during centrifugation; iAG motion sickness levels were not elevated above those of controls who did not undergo AG. They also had a shorter duration of post-AG illusory motion than cAG. Moreover, the two AG groups performed the paced auditory serial addition test weekly while undergoing AG; their performance was more accurate than that of controls, who performed the test while in HDBR. Although AG did not counteract HDBR-induced gait and balance declines, iAG did not cause motion sickness and was associated with better self-motion perception during AG ramp-down. Additionally, both AG groups had superior cognitive performance while undergoing AG relative to controls; this may reflect attention or motivation differences between the groups.

Ophthalmic changes in a spaceflight analog are associated with brain functional reorganization.

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.

Continuous and Intermittent Artificial Gravity as a Countermeasure to the Cognitive Effects of 60 Days of Head-Down Tilt Bed Rest.

Environmental and psychological stressors can adversely affect astronaut cognitive performance in space. This study used a 6° head-down tilt bed rest (HDBR) paradigm to simulate some of the physiologic changes induced by microgravity. Twenty-four participants (mean ± SD age 33.3 ± 9.2 years, N = 16 men) spent 60 consecutive days in strict HDBR. They were studied in three groups of eight subjects each. One group served as Control, whereas the other two groups received either a continuous or intermittent artificial gravity (AG) countermeasure of 30 min centrifugation daily (1 g acceleration at the center of mass and 2 g at the feet). Participants performed all 10 tests of NASA’s Cognition battery and a brief alertness and mood survey repeatedly before, during, and after the HDBR period. Test scores were adjusted for practice and stimulus set difficulty effects. A modest but statistically significant slowing across a range of cognitive domains was found in all three groups during HDBR compared to baseline, most consistently for sensorimotor speed, whereas accuracy was unaffected. These changes were observed early during HDBR and did not further worsen or improve with increasing time in HDBR, except for emotion recognition performance. With increasing time spent in HDBR, participants required longer time to decide which facial emotion was expressed. They were also more likely to select categories with negative valence over categories with neutral or positive valence. Except for workload, which was rated lower in the Control group, continuous or intermittent AG did not modify the effect of HDBR on cognitive performance or subjective responses. Participants expressed several negative survey responses during HDBR relative to baseline, and some of the responses further deteriorated during recovery, which highlights the importance of adequate medical and psychological support during extended duration HDBR studies. In conclusion, 60 days of HDBR were associated with moderate cognitive slowing and changes in emotion recognition performance, but these effects were not mitigated by either continuous or intermittent exposure to AG for 30 min daily.

Intracranial pressure and visual acuity: The final frontier?

Intracranial pressure and visual acuity: The final frontier?

Unchanged cerebrovascular CO2 reactivity and hypercapnic ventilatory response during strict head-down tilt bed rest in a mild hypercapnic environment.

Carbon dioxide levels are mildly elevated on the International Space Station and it is unknown whether this chronic exposure causes physiological changes to astronauts. We combined ∼4mmHg ambient with the strict head-down tilt bed rest model of spaceflight and this led to the development of optic disc oedema in one-half of the subjects. We demonstrate no change in arterialized , cerebrovascular reactivity to CO2 or the hypercapnic ventilatory response. Our data suggest that the mild hypercapnic environment does not contribute to the development of spaceflight associated neuro-ocular syndrome. Chronically elevated carbon dioxide (CO2 ) levels can occur in confined spaces such as the International Space Station. Using the spaceflight analogue 30 days of strict 6° head-down tilt bed rest (HDTBR) in a mild hypercapnic environment ( = ∼4mmHg), we investigated arterialized , cerebrovascular reactivity and the hypercapnic ventilatory response in 11 healthy subjects (five females) before, on days 1, 9, 15 and 30 of bed rest (BR), and 6 and 13 days after HDTBR. During all HDTBR time points, arterialized was not significantly different from the pre-HDTBR measured in the 6° HDT posture, with a mean (95% confidence interval) increase of 1.2mmHg (-0.2 to 2.5mmHg, P = 0.122) on day 30 of HDTBR. Respiratory acidosis was never detected, although a mild metabolic alkalosis developed on day 30 of HDTBR by a mean (95% confidence interval) pH change of 0.032 (0.022-0.043; P<0.001), which remained elevated by 0.021 (0.011-0.031; P<0.001) 6 days after HDTBR. Arterialized pH returned to pre-HDTBR levels 13 days after BR with a change of -0.001 (-0.009 to 0.007; P = 0.991). Compared to pre-HDTBR, cerebrovascular reactivity during and after HDTBR did not change. Baseline ventilation, ventilatory recruitment threshold and the slope of the ventilatory response were similar between pre-HDTBR and all other time points. Taken together, these data suggest that the mildly increased ambient combined with 30 days of strict 6° HDTBR did not change arterialized levels. Therefore, the experimental conditions were not sufficient to elicit a detectable physiological response.

Optic Disc Edema and Choroidal Engorgement in Astronauts During Spaceflight and Individuals Exposed to Bed Rest

Optic disc edema develops in astronauts during long-duration spaceflight and is a risk for all future astronauts during spaceflight. Having a ground-based analogue of weightlessness that reproduces critical features of spaceflight-associated neuro-ocular syndrome will facilitate understanding, preventing, and/or treating this syndrome. To determine whether the ocular changes in individuals exposed to an analogue of weightlessness are similar to the ocular changes in astronauts exposed to a duration of spaceflight comparable to this analogue of weightlessness. This cohort study, conducted from 2012 to 2018, investigated 11 healthy test participants before, during, and after 30 days of strict 6° head-down tilt bed rest as well as 20 astronauts before and during approximately 30 days of spaceflight. Data were collected at NASA Johnson Space Center, the German Aerospace Center, and on board the International Space Station. Statistical analysis was performed from February 13 to April 24, 2019. Peripapillary total retinal thickness and peripapillary choroid thickness quantified from optical coherence tomography images. Peripapillary total retinal thickness increased to a greater degree among 11 individuals (6 men and 5 women; mean [SD] age, 33.4 [8.0 years]) exposed to bed rest than among 20 astronauts (17 men and 3 women; mean [SD] age, 46.0 [6.0] years), with a mean difference between groups of 37 μm (95% CI, 13-61 μm; P = .005). Conversely, choroid thickness did not increase among the individuals exposed to bed rest but increased among the astronauts, resulting in a mean difference between groups of 27 μm (95% CI, 14-41 μm; P < .001). These findings suggest that strict head-down tilt bed rest produces a different magnitude of edema than occurs after a similar duration of spaceflight, and no change in choroid thickness. It is possible that a mild, long-term elevation in intracranial pressure experienced by individuals exposed to bed rest is greater than the intracranial pressure experienced by astronauts during spaceflight, which may explain the different severity of optic disc edema between the cohorts. Gravitational gradients that remain present during bed rest may explain the lack of increase in choroid thickness during bed rest, which differs from the lack of gravitational gradients during spaceflight. Despite the possibility that different mechanisms may underlie optic disc edema development in modeled and real spaceflight, use of this terrestrial model of spaceflight-associated neuro-ocular syndrome will be assistive in the development of effective countermeasures that will protect the eyes of astronauts during future space missions.

MTRR 66 and SHMT1 1420 Variants Are Associated with Optic Disc Edema During 30-d Strict Head-down Tilt Bed Rest and CO2 Exposure (P24-036-19)

Abstract Objectives Some astronauts returning from missions to the International Space Station (ISS) have developed ophthalmic structural changes, including optic disc edema. Incidence of optic disc edema among astronauts has been linked to one-carbon pathway genetic variants and B-vitamin status. A recent 30-d 6-degree head-down tilt bed rest study in which all subjects were exposed to 0.5% CO2 documented the occurrence of optic disc edema in 5 of 11 subjects. The objective of this study was to determine the effect of one-carbon pathway genetics and B-vitamin status on the incidence of optic disc edema in the bed rest subjects. Methods The study was conducted at the : envihab facility at the German Aerospace Center in Cologne, Germany. Subjects (6 M/5F) were healthy volunteers, 33 ± 8 y (mean ± SD), having a mean BMI of 23.4 ± 2.2 kg/m2. After a 14-d ambulatory phase in a standard environment (i.e., not hypercapnic), a blood sample was collected to assess vitamin status and single nucleotide polymorphisms (SNPs) associated with one carbon metabolism. We focused on two SNPs (rs1801394, MTRR 66 and rs1979227, SHMT1 1420) based on our earlier findings in astronauts (Zwart et al., FASEB J, 30:141–8, 2016). The 30-d bed rest began after collection of this sample. Optical coherence tomography images were collected before, during (days 15 and 30), and after (6 and 13 days after reambulation) bed rest, and the change in total retinal thickness (TRT) at various distances from Bruch's membrane opening (BMO) was evaluated against the number of MTRR A66G G alleles and SHMT1 C1420T C alleles. Results The change in TRT at various distances from the BMO in bed rest subjects exposed to mild hypercapnia and headward fluid shifts was strongly associated with the number of MTRR 66 G and SHMT1 1420 C alleles. Conclusions This finding may increase understanding of mechanisms involved in optic disc edema in astronauts and patients on Earth, and hence lead to development of targeted countermeasures. Funding Sources This work was funded by the NASA Human Health Countermeasures Element of the NASA Human Research Program.

Optic Disc Edema after 30 Days of Strict Head-down Tilt Bed Rest

Optic Disc Edema after 30 Days of Strict Head-down Tilt Bed Rest

The Double Sensor—A non-invasive device to continuously monitor core temperature in humans on earth and in space

The objective of our study was to establish whether rectal temperature recordings in humans could be replaced by a non-invasive skin temperature sensor combined with a heat flux sensor (Double Sensor) located at the forehead to monitor core body temperature changes due to circadian rhythms. Rectal and Double Sensor data were collected continuously for 24h in seven men undertaking strict head-down tilt bed-rest. Individual differences between the two techniques varied between -0.72 and +0.55 degrees C. Nonetheless, when temperature data were approximated by cosinor analysis in order to compare circadian rhythm profiles between methods, it was observed that there were no significant differences between mesor, amplitude, and acrophase (P>0.310). It was therefore concluded that the Double Sensor technology is presently not accurate enough for performing single individual core body temperature measurements under resting conditions at normal ambient room temperature. Yet, it seems to be a valid, non-invasive alternative for monitoring circadian rhythm profiles.