Challenges to the central nervous system during human spaceflight missions to Mars.

Space travel presents a number of environmental challenges to the central nervous system, including changes in gravitational acceleration that alter the terrestrial synergies between perception and action, galactic cosmic radiation that can damage sensitive neurons and structures, and multiple factors (isolation, confinement, altered atmosphere, and mission parameters, including distance from Earth) that can affect cognition and behavior. Travelers to Mars will be exposed to these environmental challenges for up to 3 years, and space-faring nations continue to direct vigorous research investments to help elucidate and mitigate the consequences of these long-duration exposures. This article reviews the findings of more than 50 years of space-related neuroscience research on humans and animals exposed to spaceflight or analogs of spaceflight environments, and projects the implications and the forward work necessary to ensure successful Mars missions. It also reviews fundamental neurophysiology responses that will help us understand and maintain human health and performance on Earth.

Astronauts eye-head coordination dysfunction over the course of twenty space shuttle flights.

BACKGROUND: Coordination of motor activity is adapted to Earth's gravity (1 g). However, during space flight the gravity level changes from Earth gravity to hypergravity during launch, and to microgravity (0 g) in orbit. This transition between gravity levels may alter the coordination between eye and head movements in gaze performance. OBJECTIVE: We explored how weightlessness during space flight altered the astronauts' eye-head coordination (EHC) with respect to flight day and target eccentricity. METHODS: Thirty-four astronauts of 20 Space Shuttle missions had to acquire visual targets with angular offsets of 20°, 30°, and 49°. RESULTS: Measurements of eye, head, and gaze positions collected before and during flight days 1 to 15 indicated changes during target acquisition that varied as a function of flight days and target eccentricity. CONCLUSIONS: The in-flight alterations in EHC were presumably the result of a combination of several factors, including a transfer from allocentric to egocentric reference for spatial orientation in absence of a gravitational reference, the generation of slower head movements to attenuate motion sickness, and a decrease in smooth pursuit and vestibulo-ocular reflex performance. These results confirm that humans have several strategies for gaze behavior, between which they switch depending on the environmental conditions.

Comparison of Asymmetry between Perceptual, Ocular, and Postural Vestibular Screening Tests.

BACKGROUND: A better understanding of how vestibular asymmetry manifests across tests is important due to its potential implications for balance dysfunction, motion sickness susceptibility, and adaptation to new environments. OBJECTIVE: We report the results of multiple tests for vestibular asymmetry in 32 healthy participants. METHODS: Asymmetry was measured using perceptual reports during unilateral centrifugation, oculomotor responses during visual alignment tasks, vestibulo-ocular reflex gain during head impulse tests, and body rotation during stepping tests. RESULTS: A significant correlation was observed between asymmetries of subjective visual vertical and verbal report during unilateral centrifugation. Another significant correlation was observed between the asymmetries of ocular alignment, vestibulo-ocular reflex gain, and body rotation. CONCLUSIONS: These data suggest that there are underlying vestibular asymmetries in healthy individuals that are consistent across various vestibular challenges. In addition, these findings have value in guiding test selection during experimental design for assessing vestibular asymmetry in healthy adults.

Finite amplitude, horizontal motion of a load symmetrically supported between isotropic hyperelastic springs.

The undamped, finite amplitude horizontal motion of a load supported symmetrically between identical incompressible, isotropic hyperelastic springs, each subjected to an initial finite uniaxial static stretch, is formulated in general terms. The small amplitude motion of the load about the deformed static state is discussed; and the periodicity of the arbitrary finite amplitude motion is established for all such elastic materials for which certain conditions on the engineering stress and the strain energy function hold. The exact solution for the finite vibration of the load is then derived for the classical neo-Hookean model. The vibrational period is obtained in terms of the complete Heuman lambda-function whose properties are well-known. Dependence of the period and hence the frequency on the physical parameters of the system is investigated and the results are displayed graphically.

Effects of motion paradigm on human perception of tilt and translation.

The effect of varying sinusoidal linear acceleration on perception of human motion was examined using 4 motion paradigms: off-vertical axis rotation, variable radius centrifugation, linear lateral translation, and rotation about an earth-horizontal axis. The motion profiles for each paradigm included 6 frequencies (0.01-0.6 Hz) and 5 tilt amplitudes (5°-20°). Subjects verbally reported the perceived angle of their whole-body tilt and the peak-to-peak translation of their head in space and used a joystick capable of recording 2-axis motion in the sagittal and transversal planes to indicate the phase between the perceived and actual motions. The amplitudes of perceived tilt and translation were expressed in terms of gain, i.e., the ratio of perceived tilt to equivalent tilt angle, and the ratio of perceived translation to equivalent linear displacement. Tilt perception gain decreased, whereas translation perception gain increased, with increasing frequency. During off-vertical axis rotation, the phase of tilt perception and of translation perception did not vary across stimulus frequencies. These motion paradigms elicited similar responses in roll tilt and interaural perception of translation, with differences likely due to the influence of naso-occipital linear accelerations and input to the semicircular canals that varied across motion paradigms.

Multiple field tests on landing day: Early mobility may improve postural recovery following spaceflight.

Adaptation to microgravity causes astronauts to experience sensorimotor disturbances during return to Earth leading to functional difficulties. Recently, the Field Test (FT) study involving an incrementally demanding sensorimotor functional test battery has allowed for an unprecedented view into early decrements and recovery from multiple tests conducted on the landing day following 6-months International Space Station missions. Although the protocol was challenging and temporarily increased motion sickness symptoms, there were anecdotal reports that performing these tasks within the first few hours of landing accelerated their recovery. Therefore, results from computerized dynamic posturography (CDP) following return to Houston were used to compare recovery between crewmembers that participated in FT (n = 18) with those that did not (controls, n = 11). While there were significant decrements in postural performance for both groups, some FT participants tended to perform closer to their preflight baseline in the most challenging condition of the CDP sensitive to vestibular function-eyes closed, unstable support and head movements. However, the distribution of difference scores appeared bimodal with other FT participants in the lower range of performance. We attribute these observations to the manner in which the field tests were implemented-some benefitted by encouraging early movement to drive adaptation when performed in a constrained incremental fashion; however, movements above aversive thresholds may have impaired adaptation in others. Challenging the sensorimotor system with increasingly provocative movements performed as close to landing as possible, as long as within individual thresholds, could be a useful intervention to accelerate astronaut's sensorimotor readaptation that deserves further study.

Tandem Walk in Simulated Martian Gravity and Visual Environment.

Astronauts returning from long-duration spaceflights experience visual-vestibular conflicts that causes motion sickness, perceptions that the environment is moving when it is not, and problems with walking and other functional tasks. To evaluate whether astronauts will have similar decrements after they land on Mars following exposure to weightlessness, participants were held by a device that offloads their weight, first entirely (0 G), and then partially (0.38 G) or not at all (1 G). Tandem (heel-to-toe) walk on a medium-density foam surface was used to assess the subject's walking performance. Two visual conditions in virtual reality were investigated: normal vision and a visual-vestibular conflict generated by disorienting optokinetic stimulation (DOS). Tandem walking performance with DOS was better in 0.38 G compared to 1 G. Tandem walking performance in DOS in 1 G was not significantly different from tandem walking performance after spaceflight or bed rest. The increased tandem walking performance in 0.38 G compared to 1 G was presumably due to an increased cone of stability, allowing a larger amplitude of body sway without resulting in a fall. Tandem walking on a compliant foam surface with a visual-vestibular conflict is a potential analog for simulating postflight dynamic balance deficits in astronauts.

Improving balance function using vestibular stochastic resonance: optimizing stimulus characteristics.

Stochastic resonance (SR) is a phenomenon whereby the response of a non-linear system to a weak periodic input signal is optimized by the presence of a particular non-zero level of noise. Stochastic resonance using imperceptible stochastic vestibular electrical stimulation, when applied to normal young and elderly subjects, has been shown to significantly improve ocular stabilization reflexes in response to whole-body tilt; improved balance performance during postural disturbances and optimize covariance between the weak input periodic signals introduced via venous blood pressure receptors and the heart rate responses. In our study, 15 subjects stood on a compliant surface with their eyes closed. They were given low-amplitude binaural bipolar stochastic electrical stimulation of the vestibular organs in two frequency ranges of 1-2 and 0-30 Hz over the amplitude range of 0 to ±700 µA. Subjects were instructed to maintain an upright stance during 43-s trials, which consisted of baseline (zero amplitude) and stimulation (non-zero amplitude) periods. Measures of stability of the head and trunk using inertial motion unit sensors attached to these segments and the whole body using a force plate were measured and quantified in the mediolateral plane. Using a multivariate optimization criterion, our results show that the low levels of vestibular stimulation given to the vestibular organs improved balance performance in normal healthy subjects in the range of 5-26% consistent with the stochastic resonance phenomenon. In our study, 8 of 15 and 10 of 15 subjects were responsive for the 1-2- and 0-30-Hz stimulus signals, respectively. The improvement in balance performance did not differ significantly between the stimulations in the two frequency ranges. The amplitude of optimal stimulus for improving balance performance was predominantly in the range of ±100 to ±400 µA. A device based on SR stimulation of the vestibular system might be useful as either a training modality to enhance adaptability or skill acquisition, or as a miniature patch-type stimulator that may be worn by people with disabilities due to aging or disease to improve posture and locomotion function.

Efficacy of Gradient Compression Garments in the Hours After Long-Duration Spaceflight.

The incidence of presyncopal events is high soon after a long-duration spaceflight;>60% of returning astronauts could not complete a 10-min 80° head-up tilt test on landing day (R+0) after ~6 months of spaceflight. The objective of this study was to demonstrate the ability of a lower body gradient compression garment (GCG) to protect against an excessive increase in heart rate and a decrease in blood pressure during standing after long-duration spaceflight. Methods: Eleven astronauts (9 M, 2 F) volunteered to participate. The stand test protocol consisted of 2 min of prone rest followed by 3.5 min of standing. Subjects completed one familiarization session, two preflight data collection sessions in standard clothing, and three tests on landing day while wearing GCG. Postflight tests were conducted 1-4 h (R+0A), ~12 h (R+0B), and ~28 h after landing (R+0C). Results: All astronauts completed the stand test preflight. Three astronauts were unable to attempt the stand test at R+0A, and one of these was unable to start the test at R+0B. One astronaut was unable to complete 3.5 min of standing at R+0B (test ended at 3.3 min). Review of the individual's blood pressure data revealed no hypotension but the astronaut reported significant motion sickness. Of the astronauts who participated in testing on landing day, the heart rate and mean arterial pressure responses to standing (stand-prone) were not different than preflight at any of the postflight sessions. Conclusion: Wearing the GCG after spaceflight prevented the tachycardia that normally occurs while standing after spaceflight without compression garments and protected against a decrease in blood pressure during a short stand test.

Vestibular and Cardiovascular Responses After Long-Duration Spaceflight.

BACKGROUND: The vestibulo-sympathetic reflex operates during orthostatically challenging movements to initiate cardiovascular responses in advance of a baroreceptor-mediated response. The objective of this study was to determine whether there was an association between changes in vestibular function and cardiovascular responses during a prone-to-stand movement in astronauts after return from long-duration spaceflight.METHODS: Thirteen crewmembers who participated in International Space Station missions were tested before spaceflight and 1 d after landing. Vestibular function was evaluated by computerized dynamic posturography while their head was erect and while they performed dynamic head tilts. Heart rate and mean arterial blood pressure were measured while the subjects were in prone and standing positions.RESULTS: The 21.4% increase in the astronauts' heart rate during the prone to stand maneuver after spaceflight correlated significantly with their spaceflight-induced 48.7% decrease in postural stability during dynamic head tilts. The larger mean arterial pressure in the prone position after spaceflight compared to preflight (+7%) also correlated with the postflight decrease in postural stability during dynamic head tilts.CONCLUSION: These results indicate that an appropriate vestibular function is important to evoke optimum vestibulo-sympathetic response during orthostatically challenging voluntary movements performed after spaceflight. They also suggest that there may be a greater need to generate an anticipatory cardiovascular response after spaceflight.Deshpande N, Laurie SS, Lee SMC, Miller CA, Mulavara AP, Peters BT,Reschke MF, Stenger MB, Taylor LC, Wood SJ, Clément GR, Bloomberg JJ. Vestibular and cardiovascular responses after long-duration spaceflight. Aerosp Med Hum Perform. 2020; 91(8):621-627.

Postural reflexes, balance control, and functional mobility with long-duration head-down bed rest.

INTRODUCTION: Spaceflight has functionally significant effects on sensorimotor behavior, but it is difficult to separate the effects of ascending somatosensory changes caused by postural muscle and plantar surface unloading from descending visual-vestibular neural changes. To differentiate somatosensory changes from graviceptor changes in post-spaceflight sensorimotor behavior, bed rest may serve as an exclusionary analog to spaceflight. METHODS: Four separate tests were used to measure changes in sensorimotor performance: 1) the monosynaptic stretch reflex (MSR); 2) the functional stretch reflex (FSR); 3) balance control parameters associated with computerized dynamic posturography (CDP); and 4) a functional mobility test (FMT). RESULTS: A mixed model regression analysis showed significant increases in median MSR start and peak latencies, while the median FSR latency showed no significant increase. Median MSR peak magnitude showed a significant increase during the middle bed rest period (19-60 d). There were no significant effects of bed rest on balance control, but some indication that dynamic head movements may affect posture after bed rest. Time to complete the course for the FMT increased significantly with bed rest. DISCUSSION: The four primary tests indicate that long-duration head-down bed rest, through unloading and modification of the body's support surface, serves as an exclusionary analog for sensorimotor responses to spaceflight. Furthermore, the data suggest that procedures designed to alleviate modifications to the sensory substrate serving the soles of the feet may provide a countermeasure to help maintain support afferentation of the postural muscles.

Changes in gain of horizontal vestibulo-ocular reflex during spaceflight.

BACKGROUND: The vestibulo-ocular reflex (VOR) is a basic function of the vestibular system that stabilizes gaze during head movement. Investigations on how spaceflight affects VOR gain and phase are few, and the magnitude of observed changes varies considerably and depends on the protocols used. OBJECTIVE: We investigated whether the gain and phase of the VOR in darkness and the visually assisted VOR were affected during and after spaceflight. METHODS: We measured the VOR gain and phase of 4 astronauts during and after a Space Shuttle spaceflight while the subjects voluntary oscillated their head around the yaw axis at 0.33 Hz or 1 Hz and fixed their gaze on a visual target (VVOR) or imagined this target when vision was occluded (DVOR). Eye position was recorded using electrooculography and angular velocity of the head was recorded with angular rate sensors. RESULTS: The VVOR gain at both oscillation frequencies remained near unity for all trials. DVOR gain was more variable inflight and postflight. Early inflight and immediately after the flight, DVOR gain was lower than before the flight. The phase between head and eye position was not altered by spaceflight. CONCLUSION: The decrease in DVOR gain early in the flight and after the flight reflects adaptive changes in central integration of vestibular and proprioceptive sensory inputs during active head movements.

Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207.

BACKGROUND: There is no standard second-line treatment for advanced urothelial carcinoma (UC). Response rates to second-line chemotherapy for advanced UC are low and response duration is short. Bortezomib is a proteasome inhibitor with preclinical activity against UC. PATIENTS AND METHODS: Treatment consisted of bortezomib 1.3 mg/m(2) i.v. twice weekly for two consecutive weeks, followed by a 1-week break. The primary end point was objective response rate (complete response + partial response) by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included safety, toxicity, and progression-free and overall survival. RESULTS: In all, 25 patients with advanced UC previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Only 29% of patients had node-only metastases. Grade 3/4 drug-related toxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia (8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia (4%), fatigue (4%), neuropathic pain (6%), dehydration (4%), and vomiting (4%). No objective responses were observed [95% confidence interval (CI) = 0-12]. The median time to progression was 1.4 months (95% CI = 1.1-2.0 months), and the median survival time was 5.7 months (95% CI = 3.6-8.4 months). There were no treatment-related deaths. CONCLUSION: Although bortezomib is well tolerated, it does not have antitumor activity as second-line therapy in UC.

Color Doppler Ultrasound Study of Glomuvenous Malformations with its Clinical and Histologic Correlations. / Ecografía Doppler color en malformaciones glomuvenosas con correlación clínica e histológica.

Glomuvenous malformations are hamartomatous lesions characterized by the presence of glomus cells in the vascular smooth muscle. We present the clinical and color Doppler ultrasound features of a series of 13 cases of histologically confirmed glomuvenous malformations. In all cases, the ultrasound study revealed moderately delimited superficial dermal and hypodermal pseudonodular structures of mixed echogenicity, with hypoechoic and heterogeneous areas and anechoic, pseudocystic tubular and lacunar zones. Arterial and venous vessels, mainly with a low flow (≤ 15cm/s) were observed in 85% of patients, but no arteriovenous shunts were present. Deeper structures were not affected and no phleboliths were detected. The clinical and ultrasound findings could facilitate diagnosis, surgical planning, and noninvasive follow-up in these tumors.

Relationship between motion sickness susceptibility and vestibulo-ocular reflex gain and phase.

BACKGROUND: It has been proposed that individual susceptibility to motion sickness is related to the vestibulo-ocular reflex (VOR) through the activation of the velocity storage mechanism. OBJECTIVE: We investigated whether motion sickness level was related to the gain and phase of the VOR. METHODS: VOR gain and phase were measured in 214 subjects while they rotated in yaw at 0.01 Hz, 0.02 Hz, 0.04 Hz, 0.08 Hz, and 0.16 Hz in darkness, and results were compared to the severity of symptoms the subjects experienced during subsequent tests to provoke motion sickness. These tests included cross-coupled angular accelerations, sudden stops in light or in dark, off-vertical axis rotation, and parabolic flight. The subjects were grouped according to the motion sickness level reached during these tests (none, low, medium, or high). RESULTS: No correlation was found between the horizontal VOR gain and motion sickness level. However, for the subjects with high motion sickness level, the VOR phase lead was significantly lower during rotation at frequencies ranging from 0.04 Hz to 0.16 Hz (i.e. the VOR time constant was longer) than the other motion sickness groups. CONCLUSION: These results support the theory that the longer the time constant for velocity storage, the more severe the motion sickness.

Vibrotactile Feedback Improves Manual Control of Tilt After Spaceflight.

The objectives of this study were to quantify decrements in controlling tilt on astronauts immediately after short-duration spaceflight, and to evaluate vibrotactile feedback of tilt as a potential countermeasure. Eleven subjects were rotated on a variable radius centrifuge (216°/s <20 cm radius) in a darkened room to elicit tilt disturbance in roll (≤± 15°). Nine of these subjects performed a nulling task in the pitch plane (≤±7.5°). Small tactors placed around the torso vibrated at 250 Hz to provide tactile feedback when the body tilt exceeded predetermined levels. The subjects performed closed-loop nulling tasks during random tilt steps with and without this vibrotactile feedback of tilt. There was a significant effect of spaceflight on the performance of the nulling tasks based on root mean square error. Performance returned to baseline levels 1-2 days after landing. Vibrotactile feedback significantly improved performance of nulling tilt during all test sessions. Nulling performance in roll was significantly correlated with performance in pitch. These results indicate that adaptive changes in astronauts' vestibular processing during spaceflight impair their ability to manually control tilt following transitions between gravitational environments. A simple vibrotactile prosthesis improves their ability to null-out tilt within a limited range of motion disturbances.

Ocular Counter Rolling in Astronauts After Short- and Long-Duration Spaceflight.

Ocular counter-rolling (OCR) is a reflex generated by the activation of the gravity sensors in the inner ear that stabilizes gaze and posture during head tilt. We compared the OCR measures that were obtained in 6 astronauts before, during, and after a spaceflight lasting 4-6 days with the OCR measures obtained from 6 astronauts before and after a spaceflight lasting 4-9 months. OCR in the short-duration fliers was measured using the afterimage method during head tilt at 15°, 30°, and 45°. OCR in the long-duration fliers was measured using video-oculography during whole body tilt at 25°. A control group of 7 subjects was used to compare OCR measures during head tilt and whole body tilt. No OCR occurred during head tilt in microgravity, and the response returned to normal within 2 hours of return from short-duration spaceflight. However, the amplitude of OCR was reduced for several days after return from long-duration spaceflight. This decrease in amplitude was not accompanied by changes in the asymmetry of OCR between right and left head tilt. These results indicate that the adaptation  of otolith-driven reflexes to microgravity is a long-duration process.

Effect of spaceflight on the spatial orientation of the vestibulo-ocular reflex during eccentric roll rotation: A case report.

BACKGROUND: Ground-based studies have reported shifts of the vestibulo-ocular reflex (VOR) slow phase velocity (SPV) axis toward the resultant gravito-inertial force vector. The VOR was examined during eccentric roll rotation before, during and after an 8-day orbital mission. On orbit this vector is aligned with the head z-axis. Our hypothesis was that eccentric roll rotation on orbit would generate horizontal eye movements. METHODS: Two subjects were rotated in a semi-supine position with the head nasal-occipital axis parallel to the axis of rotation and 0.5 m off-center. The chair accelerated at 120 deg/s2 to 120 deg/s, rotated at constant velocity for one minute, and then decelerated to a stop in similar fashion. RESULTS: On Earth, the stimulation primarily generated torsional VOR. During spaceflight, in one subject torsional VOR became horizontal VOR, and then decayed very slowly. In the other subject, torsional VOR was reduced on orbit relative to pre- and post-flight, but the SPV axis did not rotate. CONCLUSION: We attribute the shift from torsional to horizontal VOR on orbit to a spatial orientation of velocity storage toward alignment with the gravito-inertial force vector, and the inter-individual difference to cognitive factors related to the subjective straight-ahead.

A Case Study of Severe Space Motion Sickness.

BACKGROUND: Motion sickness remains a significant and unpredictable problem during spaceflight. One of the major difficulties in understanding the etiology of space motion sickness has been a lack of data at the time the symptoms occur, i.e., immediately after entry into space and during return to Earth; in these phases of the mission is when critical operational tasks are performed. CASE REPORT: We report here the case of a crewmember who experienced severe motion sickness symptoms immediately after launching into space and for several days into the mission. Verbal reports recorded during and immediately after the flight describe in detail the symptoms and their underlying causes. The prominent cause was oscillopsia that was induced by moving the head, wearing prescription eyeglasses, and translating the whole body. DISCUSSION: In this case, space motion sickness was sudden and induced by voluntary or involuntary head or body movements in any plane. These head movements caused a visual disturbance that induced the perception that the environment was oscillating. The exaggerated motion perceptions suggest an increased vestibular sensitivity and/or decreased pursuit-optokinetic mechanisms in orbit and immediately after landing.Reschke MF, Wood SJ, Clément GR. A case study of severe space motion sickness. Aerosp Med Hum Perform. 2018; 89(8):749-753.

Psychophysiological assessment and correction of spatial disorientation during simulated Orion spacecraft re-entry.

The National Aeronautics and Space Administration (NASA) has identified a potential risk of spatial disorientation, motion sickness, and degraded performance to astronauts during re-entry and landing of the proposed Orion crew vehicle. The purpose of this study was to determine if a physiological training procedure, Autogenic-Feedback Training Exercise (AFTE), can mitigate these adverse effects. Fourteen men and six women were assigned to two groups (AFTE, no-treatment Control) matched for motion sickness susceptibility and gender. All subjects received a standard rotating chair test to determine motion sickness susceptibility; three training sessions on a manual performance task; and four exposures in the rotating chair (Orion tests) simulating angular accelerations of the crew vehicle during re-entry. AFTE subjects received 2 h of training before Orion tests 2, 3, and 4. Motion sickness symptoms, task performance, and physiological measures were recorded on all subjects. Results showed that the AFTE group had significantly lower symptom scores when compared to Controls on test 2 (p = .05), test 3 (p = .03), and test 4 (p = .02). Although there were no significant group differences on task performance, trends showed that AFTE subjects were less impaired than Controls. Heart rate change scores (20 rpm minus baseline) of AFTE subjects indicated significantly less reactivity on Test 4 compared to Test 1 (10.09 versus 16.59, p = .02), while Controls did not change significantly across tests. Results of this study indicate that AFTE may be an effective countermeasure for mitigating spatial disorientation and motion sickness in astronauts.