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Biomarkers, ranging from molecules to behavior, can be used to identify thresholds beyond which performance of mission tasks may be compromised and could potentially trigger the activation of countermeasures. Identification of homologous brain regions and/or neural circuits related to operational performance may allow for translational studies between species. Three discussion groups were directed to use operationally relevant performance tasks as a driver when identifying biomarkers and brain regions or circuits for selected constructs. Here we summarize small-group discussions in tables of circuits and biomarkers categorized by (a) sensorimotor, (b) behavioral medicine and (c) integrated approaches (e.g., physiological responses). In total, hundreds of biomarkers have been identified and are summarized herein by the respective group leads. We hope the meeting proceedings become a rich resource for NASAs Human Research Program (HRP) and the community of researchers.

Abstract Microgravity alters vestibular signaling and reduces body loading, driving sensory reweighting. The unloading effects can be modelled using head-down tilt bedrest (HDT). Artificial gravity (AG) has been hypothesized to serve as an integrated countermeasure for the declines associated with HDT and spaceflight. Here, we examined the efficacy of 30 min of daily AG to counteract brain and behavior changes from 60 days of HDT. Two groups received 30 min of AG delivered via short-arm centrifuge daily (n = 8 per condition), either in one continuous bout, or in 6 bouts of 5 min. To improve statistical power, we combined these groups (AG; n = 16). Another group served as controls in HDT with no AG (CTRL; n = 8). We examined how HDT and AG affect vestibular processing by collecting fMRI scans during vestibular stimulation. We collected these data prior to, during, and post-HDT. We assessed brain activation initially in 12 regions of interest (ROIs) and then conducted an exploratory whole brain analysis. The AG group showed no changes in activation during vestibular stimulation in a cerebellar ROI, whereas the CTRL group showed decreased activation specific to HDT. Those that received AG and showed little pre- to post-HDT changes in left vestibular cortex activation had better post-HDT balance performance. Whole brain analyses identified increased pre- to during-HDT activation in CTRLs in the right precentral gyrus and right inferior frontal gyrus, whereas AG maintained pre-HDT activation levels. These results indicate that AG could mitigate activation changes in vestibular processing that is associated with better balance performance.

Abstract Spaceflight induces widespread changes in human brain morphology. It is unclear if these brain changes differ with varying mission duration or spaceflight experience history (i.e., novice or experienced, number of prior missions, time between missions). Here we addressed this issue by quantifying regional voxelwise changes in brain gray matter volume, white matter microstructure, extracellular free water (FW) distribution, and ventricular volume from pre- to post-flight in a sample of 30 astronauts. We found that longer missions were associated with greater expansion of the right lateral and third ventricles, with the majority of expansion occurring during the first 6 months in space then appearing to taper off for longer missions. Longer inter-mission intervals were associated with greater expansion of the ventricles following flight; crew with less than 3 years of time to recover between successive flights showed little to no enlargement of the lateral and third ventricles. These findings demonstrate that ventricle expansion continues with spaceflight with increasing mission duration, and inter-mission intervals less than 3 years may not allow sufficient time for the ventricles to fully recover their compensatory capacity. These findings illustrate some potential plateaus in and boundaries of human brain changes with spaceflight.

Spaceflight has numerous untoward effects on human physiology. Various countermeasures are under investigation including artificial gravity (AG). Here, we investigated whether AG alters resting-state brain functional connectivity changes during head-down tilt bed rest (HDBR), a spaceflight analog. Participants underwent 60 days of HDBR. Two groups received daily AG administered either continuously (cAG) or intermittently (iAG). A control group received no AG. We assessed resting-state functional connectivity before, during, and after HDBR. We also measured balance and mobility changes from pre- to post-HDBR. We examined how functional connectivity changes throughout HDBR and whether AG is associated with differential effects. We found differential connectivity changes by group between posterior parietal cortex and multiple somatosensory regions. The control group exhibited increased functional connectivity between these regions throughout HDBR whereas the cAG group showed decreased functional connectivity. This finding suggests that AG alters somatosensory reweighting during HDBR. We also observed brain-behavioral correlations that differed significantly by group. Control group participants who showed increased connectivity between the putamen and somatosensory cortex exhibited greater mobility declines post-HDBR. For the cAG group, increased connectivity between these regions was associated with little to no mobility declines post-HDBR. This suggests that when somatosensory stimulation is provided via AG, functional connectivity increases between the putamen and somatosensory cortex are compensatory in nature, resulting in reduced mobility declines. Given these findings, AG may be an effective countermeasure for the reduced somatosensory stimulation that occurs in both microgravity and HDBR.

Abstract Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent six T 1-weighted 3 T MRI scans, twice prior to launch and four times following their return to Earth after ~ 6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established, automated segmentation algorithm. We validated our automated segmentation algorithm by comparing algorithm PVS counts with those identified by two trained raters in 50 randomly selected slices from this cohort; the automated algorithm performed similarly to visual ratings (r(48) = 0.77, p 0.50). Among the astronaut cohort, we found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (p = 0.020), suggesting that experienced astronauts may exhibit holdover effects from prior spaceflight(s). Greater pre-flight PVS load was associated with more prior flight experience (r = 0.60–0.71), though these relationships did not reach statistical significance (p > 0.05). Pre- to post-flight changes in ventricular volume were not significantly associated with changes in PVS characteristics, and the presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that PVSs can be consistently identified on T 1-weighted MRI scans, and that spaceflight is associated with PVS changes. Specifically, prior spaceflight experience may be an important factor in determining PVS characteristics.

Biomarkers, ranging from molecules to behavior, can be used to identify thresholds beyond which performance of mission tasks may be compromised and could potentially trigger the activation of countermeasures. Identification of homologous brain regions and/or neural circuits related to operational performance may allow for translational studies between species. Three discussion groups were directed to use operationally relevant performance tasks as a driver when identifying biomarkers and brain regions or circuits for selected constructs. Here we summarize small-group discussions in tables of circuits and biomarkers categorized by (a) sensorimotor, (b) behavioral medicine and (c) integrated approaches (e.g., physiological responses). In total, hundreds of biomarkers have been identified and are summarized herein by the respective group leads. We hope the meeting proceedings become a rich resource for NASA’s Human Research Program (HRP) and the community of researchers.

Abstract 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.

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.

Spaceflight induces lasting enlargement of the brain's ventricles as well as intracranial fluid shifts. These intracranial fluid shifts have been attributed to prolonged microgravity exposure, however, the potential effects of hypergravity exposure during launch and landing have yet to be elucidated. Here we describe a case report of a Crewmember who experienced an Aborted Launch (“CAL”). CAL's launch and landing experience was dissociated from prolonged microgravity exposure. Using MRI, we show that hypergravity exposure during the aborted launch did not induce lasting ventricular enlargement or intracranial fluid shifts resembling those previously reported with spaceflight. This case study therefore rules out hypergravity during launch and landing as a contributing factor to previously reported long-lasting intracranial fluid changes following spaceflight.

Astronauts returning from spaceflight typically show transient declines in mobility and balance. Other sensorimotor behaviors and cognitive function have not been investigated as much. Here, we tested whether spaceflight affects performance on various sensorimotor and cognitive tasks during and after missions to the International Space Station (ISS). We obtained mobility (Functional Mobility Test), balance (Sensory Organization Test-5), bimanual coordination (bimanual Purdue Pegboard), cognitive-motor dual-tasking and various other cognitive measures (Digit Symbol Substitution Test, Cube Rotation, Card Rotation, Rod and Frame Test) before, during and after 15 astronauts completed 6 month missions aboard the ISS. We used linear mixed effect models to analyze performance changes due to entering the microgravity environment, behavioral adaptations aboard the ISS and subsequent recovery from microgravity. We observed declines in mobility and balance from pre- to post-flight, suggesting disruption and/or down weighting of vestibular inputs; these behaviors recovered to baseline levels within 30 days post-flight. We also identified bimanual coordination declines from pre- to post-flight and recovery to baseline levels within 30 days post-flight. There were no changes in dual-task performance during or following spaceflight. Cube rotation response time significantly improved from pre- to post-flight, suggestive of practice effects. There was also a trend for better in-flight cube rotation performance on the ISS when crewmembers had their feet in foot loops on the “floor” throughout the task. This suggests that tactile inputs to the foot sole aided orientation. Overall, these results suggest that sensory reweighting due to the microgravity environment of spaceflight affected sensorimotor performance, while cognitive performance was maintained. A shift from exocentric (gravity) spatial references on Earth toward an egocentric spatial reference may also occur aboard the ISS. Upon return to Earth, microgravity adaptions become maladaptive for certain postural tasks, resulting in transient sensorimotor performance declines that recover within 30 days.

Spaceflight has widespread effects on human performance, including on the ability to dual task. Here, we examine how a spaceflight analog comprising 30 days of head-down-tilt bed rest (HDBR) combined with 0.5% ambient CO2 (HDBR + CO2) influences performance and functional activity of the brain during single and dual tasking of a cognitive and a motor task. The addition of CO2 to HDBR is thought to better mimic the conditions aboard the International Space Station. Participants completed three tasks: (1) COUNT: counting the number of times an oddball stimulus was presented among distractors; (2) TAP: tapping one of two buttons in response to a visual cue; and (3) DUAL: performing both tasks concurrently. Eleven participants (six males) underwent functional MRI (fMRI) while performing these tasks at six time points: twice before HDBR + CO2, twice during HDBR + CO2, and twice after HDBR + CO2. Behavioral measures included reaction time, standard error of reaction time, and tapping accuracy during the TAP and DUAL tasks, and the dual task cost (DTCost) of each of these measures. We also quantified DTCost of fMRI brain activation. In our previous HDBR study of 13 participants (with atmospheric CO2), subjects experienced TAP accuracy improvements during bed rest, whereas TAP accuracy declined while in the current study of HDBR + CO2. In the HDBR + CO2 subjects, we identified a region in the superior frontal gyrus that showed decreased DTCost of brain activation while in HDBR + CO2, and recovered back to baseline levels before the completion of bed rest. Compared to HDBR alone, we found different patterns of brain activation change with HDBR + CO2. HDBR + CO2 subjects had increased DTCost in the middle temporal gyrus whereas HDBR subjects had decreased DTCost in the same area. Five of the HDBR + CO2 subjects developed signs of spaceflight-associated neuro-ocular syndrome (SANS). These subjects exhibited lower baseline dual task activation and higher slopes of change during HDBR + CO2 than subjects with no signs of SANS. Collectively, this pilot study provides insight into the additional and/or interactive effects of CO2 levels during HDBR, and information regarding the impacts of this spaceflight analog environment on the neural correlates of dual tasking.

Astronauts on board the International Space Station (ISS) must adapt to several environmental challenges including microgravity, elevated carbon dioxide (CO2), and isolation while performing highly controlled movements with complex equipment. Head down tilt bed rest (HDBR) is an analog used to study spaceflight factors including body unloading and headward fluid shifts. We recently reported how HDBR with elevated CO2 (HDBR+CO2) affects visuomotor adaptation. Here we expand upon this work and examine the effects of HDBR+CO2 on brain activity during visuomotor adaptation. Eleven participants (34 ± 8 years) completed six functional MRI (fMRI) sessions pre-, during, and post-HDBR+CO2. During fMRI, participants completed a visuomotor adaptation task, divided into baseline, early, late and de-adaptation. Additionally, we compare brain activity between this NASA campaign (30-day HDBR+CO2) and a different campaign with a separate set of participants (60-day HDBR with normal atmospheric CO2 levels, n = 8; 34.25 ± 7.9 years) to characterize the specific effects of CO2. Participants were included by convenience. During early adaptation across the HDBR+CO2 intervention, participants showed decreasing activation in temporal and subcortical brain regions, followed by post- HDBR+CO2 recovery. During late adaptation, participants showed increasing activation in the right fusiform gyrus and right caudate nucleus during HDBR+CO2; this activation normalized to baseline levels after bed rest. There were no correlations between brain changes and adaptation performance changes from pre- to post HDBR+CO2. Also, there were no statistically significant differences between the HDBR+CO2 group and the HDBR controls, suggesting that changes in brain activity were due primarily to bed rest rather than elevated CO2. Five HDBR+CO2 participants presented with optic disc edema, a sign of Spaceflight Associated Neuro-ocular Syndrome (SANS). An exploratory analysis of HDBR+CO2 participants with and without signs of SANS revealed no group differences in brain activity during any phase of the adaptation task. Overall, these findings have implications for spaceflight missions and training, as ISS missions require individuals to adapt to altered sensory inputs over long periods in space. Further, this is the first study to verify the HDBR and elevated CO2 effects on the neural correlates of visuomotor adaptation.

Astronauts are exposed to microgravity and elevated CO2 levels onboard the International Space Station. Little is known about how microgravity and elevated CO2 combine to affect the brain and sensorimotor performance during and after spaceflight. Here we examined changes in resting-state functional connectivity (FC) and sensorimotor behavior associated with a spaceflight analog environment. Participants underwent 30 days of strict 6o head-down tilt bed rest with elevated ambient CO2 (HDBR+CO2). Resting-state functional magnetic resonance imaging and sensorimotor assessments were collected 13 and 7 days prior to bed rest, on days 7 and 29 of bed rest, and 0, 5, 12, and 13 days following bed rest. We assessed the time course of FC changes from before, during, to after HDBR+CO2. We then compared the observed connectivity changes with those of a HDBR control group that underwent HDBR in standard ambient air. Moreover, we assessed associations between post-HDBR+CO2 FC changes and alterations in sensorimotor performance. HDBR+CO2 was associated with significant changes in functional connectivity between vestibular, visual, somatosensory and motor brain areas. Several of these sensory and motor regions showed post-HDBR+CO2 FC changes that were significantly associated with alterations in sensorimotor performance. We propose that these FC changes reflect multisensory reweighting associated with adaptation to the HDBR+CO2 microgravity analog environment. This knowledge will further improve HDBR as a model of microgravity exposure and contribute to our knowledge of brain and performance changes during and after spaceflight.

Visual and auditory brain network connectivity decline with age, but less is known about age effects on vestibular functional connectivity and its association with behavior. We assessed age differences in the connectivity of the vestibular cortex with other sensory brain regions, both during rest and during vestibular stimulation. We then assessed the relationship between vestibular connectivity and postural stability. A sample of seventeen young and fifteen older adults participated in our study. We assessed the amount of body sway in performing the Romberg balance task, with degraded somatosensory and visual inputs. The results showed no significant difference in balance performance between age groups. However, functional connectivity analyses revealed a main effect of age and condition, suggesting that vestibular connectivity was higher in young adults than older adults, and vestibular connectivity increased from resting state to stimulation trials. Surprisingly, young adults who exhibited higher connectivity during stimulation also had greater body sway. This suggests that young adults who exhibit better balance are those who respond more selectively to vestibular inputs. This correlation is non-significant in older adults, suggesting that the relationship between vestibular functional connectivity and postural stability differs with age.

Spaceflight missions to the International Space Station (ISS) expose astronauts to microgravity, radiation, isolation, and elevated carbon dioxide (CO2), among other factors. Head down tilt bed rest (HDBR) is an Earth-based analog for spaceflight used to study body unloading, fluid shifts, and other factors unrelated to gravitational changes. While in space, astronauts need to use mental rotation strategies to facilitate their adaptation to the ISS environment. Therefore, spatial working memory is essential for crewmember performance. Although the effects of HDBR on spatial working memory have recently been studied, the results are still inconclusive. Here, we expand upon past work and examine the effects of HDBR with elevated CO2 (HDBR + CO2) on brain activation patterns during spatial working memory performance. In addition, we compare brain activation between 30 days of HDBR + CO2 and 70 days of HDBR to test the isolated effect of CO2. Eleven subjects (6 males, 5 females; mean age = 34 ± 8 years) underwent six functional magnetic resonance imaging (fMRI) sessions pre-, during, and post-HDBR + CO2. During the HDBR + CO2 intervention, we observed decreasing activation in the right middle frontal gyrus and left regions of the cerebellum, followed by post-intervention recovery. We detected several correlations between brain and behavioral slopes of change with the HDBR + CO2 intervention. For example, greater increases in activation in frontal, temporal and parietal regions were associated with larger spatial working memory improvements. Comparing the HDBR + CO2 group to data from our previous 70-day HDBR study, we found greater decreases in activation in the right hippocampus and left inferior temporal gyrus for the HDBR + CO2 group over the course of the intervention. Together, these findings increase our understanding of the neural mechanisms of HDBR, elevated levels of CO2 and spaceflight-related changes in spatial working memory performance.

Evaluating countermeasures designed to reduce the impact of microgravity exposure on astronaut performance requires the development of effective methods of assessing changes to sensorimotor function in 1g analog systems. In this study, somatosensation at the ankle and fingers, lower leg muscle activity and visuomotor control were assessed using a full body loading and acute unloading model to simulate microgravity. It was hypothesized that the function of the hands and eyes are not constrained to ‘weight bearing’ postures for optimal function and would not differ between the loaded and acute unloaded conditions, whereas lower leg muscle activity and ankle somatosensation would be reduced in the acute unloaded condition. Somatosensation was recorded using the Active Movement Extent Discrimination Apparatus (AMEDA) protocol where participants were required to make an absolute judgment of joint position sense. A score closer to 1.0 demonstrates higher accuracy. Lower leg muscle activity was recorded using electromyography of major lower leg musculature to observe peak muscle activity and duration of contraction. The King Devick infrared eye tracking test was used to asses visuomotor control by monitoring saccade velocity and fixation time. In acute unloading, it was found that ankle somatosensation had decreased accuracy (loaded 0.68, unloaded 0.66, p = 0.045) while finger somatosensation improved (loaded 0.77, unloaded 0.79, p = 0.006). When acutely unloaded, peak lower leg muscle activation reduced ( > 27%) and total contraction time increased (2.02 × longer) compared to loading. Visuomotor assessment results did not vary between the loaded and acute unloaded postures, however the underlying techniques used by the participant to complete the task (saccade velocity and fixations time) did increase in acute unloaded conditions.SignificanceThis research provides an insight to how to the human body responds immediately to acute changes of gravitational load direction. It provides insight to the acute affects’ astronauts may encounter when in microgravity.

Astronauts return to Earth from spaceflight missions with impaired mobility and balance; recovery can last weeks postflight. This is due in large part to the altered vestibular signaling and sensory reweighting that occurs in microgravity. The neural mechanisms of spaceflight-induced vestibular changes are not well understood. Head-down-tilt bed rest (HDBR) is a common spaceflight analog environment that allows for study of body unloading, fluid shifts, and other consequences of spaceflight. Subjects in this context still show vestibular changes despite being in Earth’s gravitational environment, potentially due to sensory reweighting. Previously, we found evidence of sensory reweighting and reduced neural efficiency for vestibular processing in subjects who underwent a 70-day HDBR intervention. Here we extend this work by evaluating the impact of HDBR paired with elevated carbon dioxide (CO2) to mimic International Space Station conditions on vestibular neural processing. Eleven participants (6 males, 34 ± 8 years) completed 30 days of HDBR combined with 0.5% atmospheric CO2 (HDBR + CO2). Participants underwent six functional magnetic resonance imaging (fMRI) sessions pre-, during, and post- HDBR + CO2 while we measured brain activity in response to pneumatic skull taps (a validated method of vestibular stimulation). We also measured mobility and balance performance several times before and after the intervention. We found support for adaptive neural changes within the vestibular system during bed rest that subsequently recovered in several cortical and cerebellar regions. Further, there were multiple brain regions where greater pre- to post- deactivation was associated with reduced pre- to post- balance declines. That is, increased deactivation of certain brain regions associated with better balance post-HDBR + CO2. We also found that, compared to HDBR alone (n = 13 males; 29 ± 3 years) HDBR + CO2 is associated with greater increases in activation of multiple frontal, parietal, and temporal regions during vestibular stimulation. This suggests interactive or additive effects of bed rest and elevated CO2. Finally, we found stronger correlations between pre- to post- HDBR + CO2 brain changes and dependence on the visual system during balance for subjects who developed signs of Spaceflight-Associated Neuro-ocular Syndrome (SANS). Together, these findings have clear implications for understanding the neural mechanisms of bed rest and spaceflight-related changes in vestibular processing, as well as adaptation to altered sensory inputs.

Abstract The neural correlates of spaceflight-induced sensorimotor impairments are unknown. Head down-tilt bed rest (HDBR) serves as a microgravity analog because it mimics the headward fluid shift and axial body unloading of spaceflight. We investigated focal brain white matter (WM) changes and fluid shifts during 70 days of 6° HDBR in 16 subjects who were assessed pre (2x), during (3x), and post-HDBR (2x). Changes over time were compared to those in control subjects (n = 12) assessed four times over 90 days. Diffusion MRI was used to assess WM microstructure and fluid shifts. Free-Water Imaging was used to quantify distribution of intracranial extracellular free water (FW). Additionally, we tested whether WM and FW changes correlated with changes in functional mobility and balance measures. HDBR resulted in FW increases in fronto-temporal regions and decreases in posterior-parietal regions that largely recovered by two weeks post-HDBR. WM microstructure was unaffected by HDBR. FW decreases in the post-central gyrus and precuneus correlated negatively with balance changes. We previously reported that gray matter increases in these regions were associated with less HDBR-induced balance impairment, suggesting adaptive structural neuroplasticity. Future studies are warranted to determine causality and underlying mechanisms.

Abstract Humans undergo extensive sensorimotor adaptation during spaceflight due to altered vestibular inputs and body unloading. No studies have yet evaluated the effects of spaceflight on human brain structure despite the fact that recently reported optic nerve structural changes are hypothesized to occur due to increased intracranial pressure occurring with microgravity. This is the first report on human brain structural changes with spaceflight. We evaluated retrospective longitudinal T2-weighted MRI scans and balance data from 27 astronauts (thirteen ~2-week shuttle crew members and fourteen ~6-month International Space Station crew members) to determine spaceflight effects on brain structure, and whether any pre to postflight brain changes are associated with balance changes. Data were obtained from the NASA Lifetime Surveillance of Astronaut Health. Brain scans were segmented into gray matter maps and normalized into MNI space using a stepwise approach through subject specific templates. Non-parametric permutation testing was used to analyze pre to postflight volumetric gray matter changes. We found extensive volumetric gray matter decreases, including large areas covering the temporal and frontal poles and around the orbits. This effect was larger in International Space Station versus shuttle crew members in some regions. There were bilateral focal gray matter increases within the medial primary somatosensory and motor cortex; i.e., the cerebral areas where the lower limbs are represented. These intriguing findings are observed in a retrospective data set; future prospective studies should probe the underlying mechanisms and behavioral consequences.

Long duration head down tilt bed rest (HDBR) has been widely used as a spaceflight analog environment to understand the effects of microgravity on human physiology and performance. Reports have indicated that crewmembers onboard the International Space Station (ISS) experience symptoms of elevated CO2 such as headaches at lower levels of CO2 than levels at which symptoms begin to appear on Earth. This suggests there may be combinatorial effects of elevated CO2 and the other physiological effects of microgravity including headward fluid shifts and body unloading. The purpose of the current study was to investigate these effects by evaluating the impact of 30 days of 6° HDBR and 0.5% CO2 (HDBR + CO2) on mission relevant cognitive and sensorimotor performance. We found a facilitation of processing speed and a decrement in functional mobility for subjects undergoing HDBR + CO2 relative to our previous study of HDBR in ambient air. In addition, nearly half of the participants in this study developed signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), a constellation of ocular structural and functional changes seen in approximately one third of long duration astronauts. This allowed us the unique opportunity to compare the two subgroups. We found that participants who exhibited signs of SANS became more visually dependent and shifted their speed-accuracy tradeoff, such that they were slower but more accurate than those that did not incur ocular changes. These small subgroup findings suggest that SANS may have an impact on mission relevant performance inflight via sensory reweighting.New And NoteworthyWe examined the effects of long duration head down tilt bed rest coupled with elevated CO2 as a spaceflight analog environment on human cognitive and sensorimotor performance. We found enhancements in processing speed and declines in functional mobility. A subset of participants exhibited signs of Spaceflight Associated Neuro-ocular Syndrome (SANS), which affects approximately one in three astronauts. These individuals increased their visual reliance throughout the intervention in comparison to participants who did not show signs of SANS.

Aging is associated with peripheral and central declines in vestibular processing and postural control. Here we used functional MRI to investigate age differences in neural vestibular representations in response to pneumatic tap stimulation. We also measured the amount of body sway in multiple balance tasks outside of the MRI scanner to assess the relationship between individuals' balance ability and their vestibular neural response. We found a general pattern of activation in canonical vestibular cortex and deactivation in cross modal sensory regions in response to vestibular stimulation. We found that activation amplitude of the vestibular cortex was correlated with age, with younger individuals exhibiting higher activation. Deactivation of visual and somatosensory regions increased with age and was associated with poorer balance. The results demonstrate that brain activations and deactivations in response to vestibular stimuli are correlated with balance, and the pattern of these correlations varies with age. The findings also suggest that older adults exhibit less sensitivity to vestibular stimuli, and may compensate by differentially reweighting visual and somatosensory processes.

Astronauts exposed to microgravity face sensorimotor challenges affecting balance control when readapting to Earth's gravity upon return from spaceflight. Small amounts of electrical noise applied to the vestibular system have been shown to improve balance control during standing and walking under discordant sensory conditions in healthy subjects, likely by enhancing information transfer through the phenomenon of stochastic resonance. The purpose of this study was to test the hypothesis that imperceptible levels of stochastic vestibular stimulation (SVS) could improve short-term adaptation to a locomotor task in a novel sensory discordant environment. Healthy subjects (14 males, 10 females, age = 28.7 ± 5.3 years, height = 167.2 ± 9.6 cm, weight = 71.0 ± 12.8 kg) were tested for perceptual thresholds to sinusoidal currents applied across the mastoids. Subjects were then randomly and blindly assigned to an SVS group receiving a 0–30 Hz Gaussian white noise electrical stimulus at 50% of their perceptual threshold (stim) or a control group receiving zero stimulation during Functional Mobility Tests (FMTs), nine trials of which were done under conditions of visual discordance (wearing up/down vision reversing goggles). Time to complete the course (TCC) was used to test the effect of SVS between the two groups across the trials. Adaptation rates from the normalized TCCs were also compared utilizing exponent values of power fit trendline equations. A one-tailed independent-samples t-test indicated these adaptation rates were significantly faster in the stim group (n = 12) than the control (n = 12) group [t(16.18) = 2.00, p = 0.031]. When a secondary analysis was performed comparing “responders” (subjects who showed faster adaptation rates) of the stim (n = 7) group to the control group (n = 12), independent-samples t-tests revealed significantly faster trial times for the last five trials with goggles in the stim group “responders” than the controls. The data suggests that SVS may be capable of improving short-term adaptation to a locomotion task done under sensory discordance in a group of responsive subjects.

PurposeSpaceflight negatively affects sensorimotor behavior; exercise mitigates some of these effects. Head down tilt bed rest (HDBR) induces body unloading and fluid shifts, and is often used to investigate spaceflight effects. Here, we examined whether exercise mitigates effects of 70 days HDBR on the brain and if fitness and brain changes with HDBR are related.MethodsHDBR subjects were randomized to no-exercise (n = 5) or traditional aerobic and resistance exercise (n = 5). Additionally, a flywheel exercise group was included (n = 8). Exercise protocols for exercise groups were similar in intensity, therefore these groups were pooled in statistical analyses. Pre and post-HDBR MRI (structure and structural/functional connectivity) and physical fitness measures (lower body strength, muscle cross sectional area, VO2 max, body composition) were collected. Voxel-wise permutation analyses were used to test group differences in brain changes, and their associations with fitness changes.ResultsComparisons of exercisers to controls revealed that exercise led to smaller fitness deterioration with HDBR but did not affect brain volume or connectivity. Group comparisons showed that exercise modulated post-HDBR recovery of brain connectivity in somatosensory regions. Posthoc analysis showed that this was related to functional connectivity decrease with HDBR in non-exercisers but not in exercisers. Correlational analyses between fitness and brain changes showed that fitness decreases were associated with functional connectivity and volumetric increases (all r >.74), potentially reflecting compensation. Modest brain changes or even decreases in connectivity and volume were observed in subjects who maintained or showed small fitness gains. These results did not survive Bonferroni correction, but can be considered meaningful because of the large effect sizes.ConclusionExercise performed during HDBR mitigates declines in fitness and strength. Associations between fitness and brain connectivity and volume changes, although unadjusted for multiple comparisons in this small sample, suggest that supine exercise reduces compensatory HDBR-induced brain changes.

Adverse effects of spaceflight on sensorimotor function have been linked to altered somatosensory and vestibular inputs in the microgravity environment. Whether these spaceflight sequelae have a central nervous system component is unknown. However, experimental studies have shown spaceflight-induced brain structural changes in rodents' sensorimotor brain regions. Understanding the neural correlates of spaceflight-related motor performance changes is important to ultimately develop tailored countermeasures that ensure mission success and astronauts' health.Head down-tilt bed rest (HDBR) can serve as a microgravity analog because it mimics body unloading and headward fluid shifts of microgravity. We conducted a 70-day 6° HDBR study with 18 right-handed males to investigate how microgravity affects focal gray matter (GM) brain volume. MRI data were collected at 7 time points before, during and post-HDBR. Standing balance and functional mobility were measured pre and post-HDBR. The same metrics were obtained at 4 time points over ~90 days from 12 control subjects, serving as reference data.HDBR resulted in widespread increases GM in posterior parietal regions and decreases in frontal areas; recovery was not yet complete by 12 days post-HDBR. Additionally, HDBR led to balance and locomotor performance declines. Increases in a cluster comprising the precuneus, precentral and postcentral gyrus GM correlated with less deterioration or even improvement in standing balance. This association did not survive Bonferroni correction and should therefore be interpreted with caution. No brain or behavior changes were observed in control subjects.Our results parallel the sensorimotor deficits that astronauts experience post-flight. The widespread GM changes could reflect fluid redistribution. Additionally, the association between focal GM increase and balance changes suggests that HDBR also may result in neuroplastic adaptation. Future studies are warranted to determine causality and underlying mechanisms.