STEM Today by Abhishek Sinha

STEM TODAY May 2019, No. 44

CONTENTS CBSÂSM6.1: Determine if sensorimotor dysfunction during and after longÂ duration spaceflight affects ability to control spacecraft and associated systems

Sensorimotor disturbances associated with spaceflight can lead to decrements in the ability to acquire information from instrumentation and spatial disorientation leading to performance and safety issues. It is necessary to determine if a crewmember can land and operate a vehicle after long duration spaceflight. This gap needs to be placed in the context of the expected operating environment of future vehicles. Design of future vehicles should account for human factors in the cockpit and task design to avoid provocative movements or physically difficult tasks.

Editorial Editor: Mr. Abhishek Kumar Sinha Editor / Technical Advisor: Mr. Martin Cabaniss

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Disclaimer ( Non-Commercial Research and Educational Use ) STEM Today is dedicated to STEM Education and Human Spaceflight. This newsletter is designed for Teachers and Students with interests in Human Spaceflight and learning about NASA’s Human Research Roadmap. The opinion expressed in this newsletter is the opinion based on fact or knowledge gathered from various research articles. The results or information included in this newsletter are from various research articles and appropriate credits are added. The citation of articles is included in Reference Section. The newsletter is not sold for a profit or included in another media or publication that is sold for a profit. Cover Page Canada’s sun glint-lit Gulf of St. Lawrence iss059e008350 (April 2, 2019) — Canada’s sun glint-lit Gulf of St. Lawrence and its coastal states of Nova Scotia, New Brunswick, Prince Edward Island and portions of Newfoundland are pictured as the International Space Station orbited nearly 258 miles above the North Atlantic Ocean. continent. Image Credit: NASA

Back Cover Cloudy formation in the south Indian Ocean iss059e006522 (March 30, 2019) — The International Space Station flew 265 miles above this cloudy formation in the south Indian Ocean. Image Credit: NASA

STEM Today , May 2019

Editorial Dear Reader All young people should be prepared to think deeply and to think well so that they have the chance to become the innovators, educators, researchers, and leaders who can solve the most pressing challenges facing our world, both today and tomorrow. But, right now, not enough of our youth have access to quality STEM learning opportunities and too few students see these disciplines as springboards for their careers. According to Marillyn Hewson, "Our children - the elementary, middle and high school students of today - make up a generation that will change our universe forever. This is the generation that will walk on Mars, explore deep space and unlock mysteries that we can’t yet imagine". "They won’t get there alone. It is our job to prepare, inspire and equip them to build the future." STEM Today will inspire and educate people about Spaceflight and effects of Spaceflight on Astronauts.

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Editor Mr. Abhishek Kumar Sinha

Editorial Dear Reader The Science, Technology, Engineering and Math (STEM) program is designed to inspire the next generation of innovators, explorers, inventors and pioneers to pursue STEM careers. According to former President Barack Obama, " Science is more than a school subject, or the periodic table, or the properties of waves. It is an approach to the world, a critical way to understand and explore and engage with the world, and then have the capacity to change that world..." STEM Today addresses the inadequate number of teachers skilled to educate in Human Spaceflight. It will prepare , inspire and educate teachers about Spaceflight. STEM Today will focus on NASA’S Human Research Road map. It will research on long duration spaceflight and put together latest research in Human Spaceflight in its monthly newsletter. Editor / Technical Advisor Mr. Martin Cabaniss

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Human Health Countermeasures (HHC) CBS-SM6.1: Determine if sensorimotor dysfunction during and after long-duration space ight a ects ability to control spacecraft and associated systems Sensorimotor disturbances associated with space ight can lead to decrements in the ability to acquire information from instrumentation and spatial disorientation leading to performance and safety issues. It is necessary to determine if a crew member can land and operate a vehicle after long duration space ight. This gap needs to be placed in the context of the expected operating environment of future vehicles. Design of future vehicles should account for human factors in the cockpit and task design to avoid provocative movements or physically di cult tasks.

Venous Function during Long-Duration Spaceflights

In a standing posture, gravity induces peripheral venous pooling that, when excessive, can lead to orthostatic intolerance and fainting. For cosmonauts returning to Earth, the risk of orthostatic intolerance and fainting is greater in part due to hypovolemia resulting from adaptation to the microgravity environment. However, this hypovolemia is moderate and cannot fully explain the observed orthostatic intolerance in cosmonauts following spaceflight. These adaptations are thought to primarily involve the arterial system, it should be noted that veins also possess autonomic adrenergic receptors that modulate functions including pooling capacity. Using ultrasound imaging, has shown that venous morphology is altered during spaceflight (Arbeille et al., 2001, 2015). Although commonly used in daily medical practice, ultrasound imaging does not provide a global assessment venous functions. Therefore, it is still unknown whether spaceflight results in alterations to venous autonomic control or general venous function that could contribute to orthostatic intolerance.

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Venous functions are complex and include factors such as filling and emptying properties, efficiency of themuscular venous pump, as well asmicrovascular filtration . Venous occlusion plethysmography is one method that has been proposed to assess venous function (Skoog et al.,2015). Studies using this method have shown that the filling function of veins is altered during simulated and real shortterm spaceflight. This study used venous occlusion plethysmography method to assess venous function with long-duration spaceflight. It was hypothesized that long duration spaceflight would result in alterations in venous function that may lead to greater pooling in an upright posture and reduced orthostatic tolerance. Twenty-four male cosmonauts from the Russian space program were studied between 2009 and 2015 during spaceflights (124-192 days) aboard the International Space Station. Their mean ± SD anthropometric characteristics were as follows: age 44.3 ± 6.1 years, weight 82.6 ± 6.7 kg, height 1.77 ± 0.05 m, body mass index 26.4 ± 2.3 kg/m2 . Data were collected on six testing days with two sessions occurring before spaceflight, two during the flight, and two after returning to Earth. The initial pre-flight session occurred more than 2 months before spaceflight (B > 2) with the second session occurring <2 months before the flight (B < 2). An early spaceflight session was conducted during the first 3 months of flight (F < 3) and a late flight session was conducted after the cosmonaut had spent 3 months in space (F > 3). Post-flight sessions occurred within 15 h of landing and 8 days after landing (L0 and L8, respectively). Each cosmonaut took selfmeasurements during the flight after having undergone training for the procedure before the flight. On Earth, all measurements were conducted with the cosmonaut in a supine position with the measurement leg supported at heart level according to the standard procedures. During spaceflight, cosmonauts were in a "free floating" position with the knee slightly bent and the thigh in weak abduction. Results One hundred and three plethysmography sessions were performed during this study (Table 1). Post-flight data were only collected on a small number of cosmonauts due to the late introduction of these measures into the study and operational limitations. Calf volume measures and venous plethysmography results for each testing day are presented in Table 1. Calf volume decreased during space flight and remained unchanged throughout the flight. Recovery to preflight volume began shortly after landing and was completed 8 days later. Absolute filling volume was not significantly altered during spaceflight or recovery from flight. However, relative to calf volume, venous filling significantly increased early during spaceflight and tended to remain elevated later in flight. Upon return to Earth, relative venous filling remained elevated on L0, but had recovered by L8. Venous distensibility, assessed through VFI, initially increased during the flight but recovered to pre-flight values later in flight. Following flight, VFI showed an exaggerated recovery on L0 and recovered to pre-flight values on L8.

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Initial venous emptying (VER50%) was not significantly changed during or after spaceflight while the late venous emptying (VER90%) was decreased on the first flight session with a further decrease later in flight. Additionally, this parameter did not return to preflight levels on either L0 or L8. A slight increase in microvascular filtration was seen early in spaceflight but was not changed on any other testing day. All the venous filling parameters had the same pattern of changes during space flight that was different from the one of calf volume and venous emptying parameters. This pattern showed a large change during the initial part of the space flight and a trend toward recovery of pre-flight values during the second part of the space flight (Table 1). Calf volume showed a large change that was maintained during the whole space-flight while the venous emptying parameters showed continuously increasing changes (Table 1). The pattern of change was similar between venous filling parameters and microvascular filtration (Table 1). The purpose of this study was to investigate venous function before and during long-duration spaceflight. Consistent with the hypothesis, results indicated alterations in venous functions with adaptation to microgravity. Changes were seen with both venous filling and emptying but different patterns in responses were noted that did not completely parallel changes in calf volume. Reduced calf volume leading to "bird legs" is a well-known result of spaceflight and was noted in the current study. It is generally believed that this reduction in calf volume is primarily due to muscular atrophy. Vein function is strongly linked to muscle mass due to the actions of the muscle pump and the influences of muscle on venous transmural pressure. However, upon return to Earth, venous function tended to recover after 8 days whereas muscle mass recovery requires additional time (6-8 weeks). Moreover, evidence of lower limb muscle atrophy during spaceflight has mainly been obtained from animal studies during which animals were completely inactive and food intake was uncontrolled. Today, cosmonauts perform daily exercise countermeasures and close attention is paid to food intake (Petersen et al., 2016). Recent work has alternatively focused on spinal muscle adaptation (Hides et al.,2016) as leg muscle atrophy is not readily apparent with the current countermeasures used. Therefore, it is unlikely that changes in leg muscle mass contributed to the changes in calf volume and venous function observed in this study. Calf volume changes were likely the result of fluid shifts during spaceflight as volume was seen to rapidly recover upon return to Earth. However, venous blood shift alone cannot fully explain the large calf volume changes suggesting the involvement of tissues and interstitial volumes. In general, these fluid shifts undoubtedly influenced venous functions. However, venous function showed an adaptation to these shifts since venous function tended to recover toward pre-flights value after 3 months of spaceflight. In 1998, White and Blomqvist proposed a model to explain the initial cardiovascular adaptations to spaceflight which included a substantial redistribution of fluid and pressure throughout the body that differed from that seen in Earth based spaceflight simulations. Results from the current study and recent long-duration spaceflight investigations also support the idea of fluid redistribution throughout the body not only throughout the

cardiovascular system but also within tissues and interstitial spaces. Venous plethysmography demonstrated a decrease in VER90% that indicated a decrease in venous resistance. The decrease in venous resistance is also consistent with the overall vasorelaxation observed during space flight (Norsk et al., 2015). Alteration in autonomic nervous control of venous functions with spaceflight could explain the decrease in venous resistance. Recent studies have, however, challenged the notion of reduced sympathetic activity with spaceflight suggesting that adaptations likely reflect sympathoexcitation . Norsk et al. (2015) observed that the increase in cardiac output during long duration spaceflights is more than previously observed during short duration spaceflights. Similarly, authors demonstrated a decrease in venous resistance during spaceflight with a further decrease later in flight (VER90%, Table 1). Decreased venous resistance promotes venous return and might explain the increased cardiac output observed by Norsk et al. (2015). Alteration of venous resistance and cardiac output are likely to be the result of the body fluid redistribution.

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The small but significant effect of spaceflight onmicrovascular filtration contrasts with the strong effects on venous filling and emptying functions. The pattern of change is, however, similar between venous filling function and microvascular filtration and the lack of change could be due to the large standard deviations of the filtrations assessment. Stewart (2003) showed that microvascular filtration function is changed in patients with a postural orthostatic tachycardia syndrome (POTS) suggesting that increased microvascular filtration could be related to the development of orthostatic intolerance. However, not all cosmonauts experience orthostatic intolerance after spaceflight and few of those with orthostatic intolerance exhibit symptoms of POTS (Coupe et al., 2011). Further studies are needed to determine whether microvascular filtration can be used as a measure for identifying cosmonauts who will experience orthostatic intolerance and POTS after long-duration spaceflight. This study demonstrated that both venous filling and emptying functions are altered during longduration spaceflight. While partially associated with changes in calf volume, the changes in venous function may indicate a redistribution of fluid unique to microgravity adaptations.

Drain Brain

Drain Brain studies how blood returns to the heart from the brain through veins in an astronautâ&#x20AC;&#x2122;s neck. This can help scientists better understand the mechanisms that ensure proper blood flow in microgravity. ISS Crewmembers report a variety of neurological symptoms that may be related to changes in this blood flow. The project also studies how blood flow changes in response to crewmember schedules in space, which do not follow the typical day-night schedule of most humans on Earth. The Drain Brain experiment developed by prof. Paolo Zamboni of the Vascular Disease Center of the University of Ferrara, selected by the Italian Space Agency to be held on the International Space Station during the FUTURA mission. The start of operations was a real challenge for the project team. The first version of the instrument was lost in October 2014 in the accident of the American vehicle Orbital-3. To try to stay within the established times, the University of Ferrara and its partners have created a new tool that arrived on January 12 with the SpaceX-5 Dragon, which started two days earlier from Cape Canaveral, allowing Samantha to start measuring. As Samantha Cristoforetti (ESA Astronaut) told us in her Log Book, "the specific tools for Drain Brain include three strain gauge plethysmographs, which look like collars of an extensible material ... In reality they are sensors capable of measuring blood flow in the veins in a very simple and non-invasive way that does not depend on the skills and interpretation of the operator, as in the case of ultrasound. Wearing these collars at the neck, arm and leg, I performed a series of breaths at 70% of the capacity of the lungs staying still, or stretching and contracting the hand or ankle. " The preliminary results of the investigation have been published. In particular, comparison of plethysmography data confirmed that long duration spaceflights lead to a redistribution of venous blood volume, and showed 6

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interesting differences in the amplitude of cardiac oscillations measured at the level of the neck veins.

Dysfunctional vestibular system causes a blood pressure drop in astronauts returning from space

The cause of orthostatic hypotension is attributed to an excessive fall of cardiac output or a defect vasoconstrictor mechanism. Orthostatic intolerance can lead to dizziness and even evoke syncope, that is, fainting. A blood pressure drop upon standing is typically linked to the dispensability of the arteries in the lower limbs, as well as failure of the arteries to constrict timeously. Consequently, blood pools in the lower parts of the body. Thus, the functional changes accompanying OI can be understood as a temporal mismatch between cardiac output and vascular resistance. Conversely, a successful constriction leads to a redistribution of blood and an increase in blood pressure. The symptoms of OI can cause serious problems and have a strong impact on the quality of life of the affected person. The sympathetic nervous system (SNS), which is responsible for cardiac regulation, has been pointed out as a key factor in blood pressure control. During postural changes a range of feedback mechanisms serve to increase firing in the sympathetic nerves, which, among other effects, leads to an increased blood pressure. One of the reflexes that contributes to these mechanisms is thought to originate in the vestibular organs.

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The vestibular organs, located in the inner ears, sense rotations by means of three semi-circular canals, and they sense linear accelerations, including gravity, by means of the otoliths. Together with information provided by the visual and proprioceptive system, the vestibular organs ensure gaze stabilization and balance as well as orientation and navigation. This task is so fundamental to life on Earth that most animals have a highly specialized vestibular system, the mammalian one being very similar across many species. Early animal studies suggest that the vestibular system plays an important role in the activation of the SNS. By selective natural and electrical vestibular stimulation, an increase of the activity in the SNS and of the blood pressure has been measured. Those results strengthen the evidence for a presence of a vestibulo-sympathetic reflex (VSR) in animals. This reflex links a stimulation of the vestibular system with an activation of the cardiovascular system. Vestibular signals have been shown to affect mainly the sympathetic outflow to the blood vessels. In fact, all the activated nerves contain vasoconstrictor efferents. The VSR is therefore thought to be particularly important in the prevention of a drop in blood pressure and of OI because the VSR can be elicited at the first sensing of motion. The otoliths detect a position change with respect to gravity within milliseconds and play a key role in the activation of the VSR. Altered sympathetic nerve activity has been registered upon their stimulation with a short latency (660 ms), suggesting that this may be one of the earliest mechanisms to sustain blood pressure upon standing up. The latency in animals has been shown to be as short as 50-100 ms3 . Based on the information from the otoliths, the activation of the SNS increases pre-emptively before an actual drop in blood pressure is detected, constituting a feed-forward mechanism. For instance, the baroreceptors are not activated until an actual blood pressure drop is measured in the carotid arteries. Hence, they initiate a feed-backward mechanism with a latency of 1.2-1.4 s. A few later studies show that the same theory might be applicable to humans. However, all the studies on this phenomenon have so far focused on an activation of the otoliths. None of these experiments allows a selective suppression of the otolith reflex. Thus, little evidence exists for a decreased VSR in humans as a result of otolith deficiency. However, isolation of the otolith system is essential to studying a hampered VSR. Authors aim to elucidate the VSR in the case of a so-called â&#x20AC;&#x2122;deconditioned otolith systemâ&#x20AC;&#x2122;, which means that the functioning of the system is decreased. Such deconditioned otoliths can uniquely be found in astronauts returning from a spaceflight. A majority of the astronauts returning from a long-term exposure to microgravity suffer from OI during the first days after their return . Since the beginning of manned spaceflight, symptoms such as dizziness, postural control problems and even cases of syncope have been reported. It has been hypothesized that the decreased cardiovascular response is due to the prolonged weightlessness experienced during a spaceflight, presumably caused by the adaptation of autonomic control and the deconditioning of cardiac regulation mechanisms. A number of countermeasures to fluid shift and OI have been tried out during the history of spaceflight, but so far with little success for the returning astronauts suffering from OI.

In space, the cardiovascular system is no longer exposed to the transitions generated by a position change, which stimulates the reflex needed to counteract gravity. Similarly to the cardiovascular system, the otoliths are also forced, during spaceflight, to adapt to a situation where there is no longer a preferred direction given by the acceleration of gravity. For some years now, it has been shown that the otolith system, due to the absence of perceived gravity, is suppressed in returning astronauts. In addition, results from the Neurolab shuttle mission demonstrated that the otolith function was maintained during and after flight in payload crewmembers exposed to in-flight 1-g centripetal acceleration during centrifugation (’artificial gravity’). Non-centrifuged crewmembers however exhibited clear signs of OI, whereas astronauts exposed to ’artificial gravity’ did not. Authors hypothesized that the otoliths play a key role in OI, affecting the astronauts during their first days after spaceflight. The goal of this study has been to investigate if a suppressed otolith system affects the ability to regulate blood pressure upon standing, on return from space. In this way they could study the link between the vestibular and the cardiovascular system to elucidate the VSR.

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In order to study the VSR, authors needed to evaluate brainstem-mediated reflexes that were based on information from the vestibular system, in particular ocular counter-rolling (OCR). OCR is an otolith-mediated reflex that serves as a compensatory eye movement. It is generated when we tilt the head sideways (head changes with respect to the gravitational vector), turn around a corner or undergo off-axis centrifugation. During centrifugation, the otolith system perceives a tilt caused by the combination of centripetal forces and gravity and therefore generates OCR. Similarly, the cardiovascular system can be quantified by specific parameters. Mean arterial pressure (MAP) is one of the most important parameters resulting from the cardiac and cardiovascular control mechanisms. Indeed, MAP is considered to be the perfusion pressure seen by the organs and is directly influenced by stroke volume (SV), heart rate (HR), systemic vascular resistance (SVR) and central venous pressure (CVP): MAP = (SV ∗ HR ∗ SVR) + CVP—————————————————————————————————(1) As a result, MAP can be considered the output of the overall cardiovascular system. The goal is to maintain an appropriate perfusion of all organs via action on the cardiac function (HR, SV) and the vascular system (SVR, CVP). However, HR and heart rate variability (HRV) are also markers of the autonomic control of the cardiovascular system. The primary outcomes in this study are the values of the OCR, the MAP and their correlation. The experiments was conducted at the Gagarin Cosmonaut Training Centre (Star City) near Moscow, Russia. A group of 12 male (47 + /-5 years, 78.3 + /-5.8 kg, 179.3 + /-4.0 cm) cosmonauts from the Russian Space Agency (Roscosmos) and one from European Space Agency (ESA) (all denoted as astronauts) took part in the study. The astronauts were tested before and after a 6-month stay in the International Space Station (ISS). The pre-flight data were based on two baseline experiments that were conducted on average 66 (SD = 26) days before launch. The post-flight data consist of one experiment performed in the early days (3.8, SD = 1.7 days) after return back to earth, and another experiment performed 9-10 days (9.6, SD = 0.51) after return. The two experiments will be denoted as "early post-flight" and "late post-flight". Due to medical and administrative issues authors were not able to test all the astronauts on the same day after return. Results This study on astronauts who spent six months in space, offered a unique opportunity to investigate the impact of a deconditioned otolith system on blood pressure and cardiac autonomic control. In addition, it allowed us to study a temporarily hampered VSR in humans in an unprecedented way. Comparison of pairwise pre-flight data with post-flight data, for each astronaut individually, resulted in a statistically significant decrease of ∆OCR (p = 0.00076). This result agrees with earlier studies showing a decreased OCR on return after spaceflight. More importantly, for the early post-flight experiment there was a significant correlation between the ∆OCR, and a reduced blood pressure response; ∆MAP (r = 0.67, p = 0.018). (Fig. 2) MAP is represented as the average of 2/3 DBP + 1/3 SBP.

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Authors found that individuals with a decreased otolith function also had a reduced cardiovascular function on their return to Earth. Conversely, astronauts whose otolith function seemed unaffected by spaceflight also had a low or no decrease of their blood pressure control function. Hence, they demonstrate a significant oneto-one relationship between the otolith reflex OCR and the MAP. In addition, both OCR and MAP were back at baseline level at the late post-flight experiment (R + 10). (Fig. 3) In all the diagrams presenting cardiovascular data, the triangular data points represent data collected during standing position and circular data points represent data collected during supine position.

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Further on, the HR (presented as RRI), HF and the total power of HRV (Fig. 4), did not show such a correlation with the OCR. Additionally, the HR and HF remained decreased late postflight (p < 0.05), while this was not the case for MAP. Again, MAP was back at pre-flight level at the late post-flight experiment, just as the OCR. The two correlated parameters showed a similar pattern of alteration and recovery. (Figure 3) Pulse pressure was significantly decreased (p < 0.05) on the second experiment after spaceflight. On late 11

post-flight it was back at the same level as before flight (BDC), indicating a full recovery from the microgravity effect, just as OCR. No significant changes were observed in the supine posture. A decrease is observed on the first experiment after spaceflight (R + 2), but not significant due to the low number of subject tested that day (n = 5) (Fig. 5). To the best of authorâ&#x20AC;&#x2122;s knowledge, this is the closest anyone has come so far to show a relation between a suppression of the otolith response and a parallel decrease of blood pressure control in humans. They are convinced that this is a unique dataset revealing the link between the otoliths and blood pressure control mechanisms. A correlation by itself is not the shear proof of causality but together with the rest of our findings it strongly suggest that there is one. In addition, the conclusion is also based on results from earlier research studies showing that a defect otolith system could affect the ability to control the blood pressure. A decreased OCR and a depression of all blood pressure and cardiac control parameters were observed during the first days after return from space. After ten days the OCR was back at the same level as before flight. This indicates that the otolith deficiency is temporary. The MAP showed the same type of recovery as the OCR (Fig. 3) after return, while on the contrary, HR and HF remained depressed.

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Neither were they significantly correlated with OCR at the first place. For those parameters (HR and HF)they saw that their response to orthostatic challenge remained low for all of the experiments after spaceflight, which means that on the late postflight experiment they still measured lower values than before flight. The values were not much different late postflight compared to the early postflight recording session. This indicates an independence from the vestibular activation. These findings raise evidence for a link between the otolith system and the BP regulation, namely the VSR. At the same time, most of the returning astronauts report that symptoms like dizziness and balance problems ease after a couple of days after return, which also indicating a relatively fast recovery. While this is not the case for cardiac autonomic control (HR and HF) which remains depressed but is not associated with the dizziness symptoms. A decrease in pulse pressure could theoretically be the cause of a lower stimulation of the baroreceptors. This could in turn induce a sympathetic activation (which is what authors observe), and therefore end in a better blood pressure control (maintenance of MAP). However, to explain the observed decreased MAP control, the pulse pressure data should then demonstrate an increased pulse pressure after spaceflight. An increased pulse pressure could elicit a peripheral vasodilatation, responsible for the observed decrease in MAP. But this is not what they found. On the contrary, they measured a decrease in pulse pressure after spaceflight, something that is very unlikely to explain the decreased MAP on return. As the standing values were taken 10 minutes after the tilt, they can stress the evidence that a sympathetic activation, on early postflight, was not able to counteract the decrease in MAP. MAP still remained lower than normal. However, late postflight, they observed a similar sympathetic activation as early postflight (similar decrease in HR and in HF) but MAP returned back to normal. For the OCR they saw the same recovery pattern as for the MAP, a full recovery at late postflight. Therefore the data suggest that the return back to normal values of blood pressure control is to due the VSR. Rather than due to the central autonomic control of the cardiovascular system, which remains under a high sympathetic activation. Authors speculate that, when the otolith function returns back to normal, the VSR helps preventing a blood pressure drop that the activation of the sympathetic system can not do alone. The finding that a decreased ability to maintain blood pressure upon standing is correlated with a decreased otolith response do not only has important implications for human space exploration. The acquired knowledge possibly suggests looking at OI problems also from a vestibular point of view. Currently, the cardiovascular clinical approach to OI does not consider a vestibular component, but this is understandable since only recently the evaluation of the otolith system has become more readily available to the clinicians. Nevertheless, for the future, they anticipate that the current findings may spur interdisciplinary research regarding a vestibulo-sympathetic reflex. Besides these important applications, they consider their finds to be of fundamental scientific interest, since they strengthens the evidence of a fundamental physiological otolith-sympathetic reflex (VSR) in humans.

Long-duration spaceflight adversely affects post-landing operator proficiency

For future exploration-class missions to asteroids or other planetary bodies crewmembers will be required to perform operational tasks following extended periods of microgravity exposure. It is well documented that astronauts returning from long-duration missions to the International Space Station (ISS) exhibit adverse sensorimotor, cardiovascular and neuromuscular effects upon return to Earth due to in-flight adaptation to microgravity. How these physiological changes affect post-landing operator proficiency is not well understood, but results from the shuttle era demonstrate that even short-duration missions adversely affect pilot performance. The analysis of touchdown speeds for the first 100 missions demonstrated that 20% of orbiter landings were outside of acceptable limits, and the maximum speed of 217 kts (main gear tire limit) had been equaled or exceeded six times.

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The hardest touchdown on record (STS-90 at 224 kts) occurred following the commander’s momentary loss of orientation (’tumbling the gyros’) after an active head movement just prior to touchdown, and the second hardest touchdown (STS-3 at 220 kts) involved a pilot-induced oscillation after main-gear touchdown and prior to derotation (nose-gear touchdown). Although no piloted landings have occurred following long-duration missions, the collision of the unmanned Progress 234 with the Mir space station in 1997 suggests that prolonged spaceflight can negatively impact operator performance. In this instance the commander, after 136 days on orbit, was tasked to remotely pilot the Progress from a distance of 6 km to dock with Mir. The collision was initially attributed to piloting errors in the form of ’late realization that the closing rate was too high’ and ’ incorrect final avoidance maneuvering’ , although subsequent reviews determined that a variety of other factors contributed to the accident, such as fatigue (the commander’s request to withdraw from a sleep study due to chronic lack of sleep was refused by mission control prior to the collision), issues with the range radar (it was turned off for the final docking attempt at the behest of mission control), and inadequate planning and crew training. There have been five significant teleoperation incidents aboard the ISS, including a collision between the Space Station Remote Manipulator System (SSRMS, aka Canadarm) and the shuttle payload door; and close calls between the SSRMS and an external UHF antennae, and between the SSRMS and the Shuttle Remote Manipulator System (SRMS, aka Canadarm), in which the two robotic arms crossed within 1.5 m of each other. What is the basis for post-mission decrements in operator proficiency? Most of the acute physiological effects associated with spaceflight occur at the gravitational transitions, from 1-g to 0-g at launch and 0-g back to 1-g during landing. For the first 24 to 72 hours in-flight and for several days post-flight crewmembers experience Space Adaptation Syndrome, with motion sickness-like symptoms triggered by head movement. Two likely contributors are the shift of fluid to the upper body and head in microgravity and vestibular conflict. Astronauts returning from spaceflight are particularly prone to spatial disorientation; almost all shuttle crewmembers reported illusions of self- and/or surround-motion during active pitch and roll head movements during reentry and at wheels stop. It is likely that post-flight spatial disorientation is due to in-flight deconditioning of otolith-mediated reflexes, which on Earth maintain posture and gaze utilizing information from the otoliths regarding the relative orientation of the head to gravity. For example, pitch and roll head tilt on Earth generates both angular (semicircular canal) and linear (gravitational) acceleration (otolith) afferent signals from the vestibular endorgans that are integrated in the brainstem. In microgravity the same head motion produces only canal output, which conflicts with the expected response and proves provocative until a steady state is reached through adaptation to the microgravity environment, presumably by central reweighting of sensory input to reflect the predominance of angular information in the absence of gravity. During landing this process is reversed. Gravitational otolithic input is reintroduced, and during the period of readaption/reweighting to the gravitational field similar motion sickness symptoms occur as encountered in the first days of spaceflight. In-flight studies have reported changes in fine motor control during manual tracking (joystick cursor control), 13

indicative of an underestimation of the mass of the hand in microgravity, decreased limb stiffness, reduced peak velocity and acceleration in early stages of motion, maintenance of final accuracy by prolongation of the deceleration phase, and a post-flight reduction in tracking gain. Basic cognitive function has consistently proven to be unaffected by spaceflight in a number of studies.

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Performance on simple and choice reaction time, Stroop interference, spatial processing, memory search and mental rotation tasks was maintained in-flight and after landing. Results on dual tasking (performing manual tracking with a simultaneous distracting task) were less consistent. In-flight performance decrements in manual tracking with concurrent memory search were observed throughout a short-duration flight and for the first two weeks and for one week following a long-duration mission.

In contrast, tracking of targets with a parallel reaction time task were impaired on a shuttle mission in the same manner as on Earth. Finally, in addition to microgravity, crewmembers are exposed to a variety of in-flight stressors that cumulatively could impact post-flight operator proficiency, such as altered light-dark cycle, sleep deprivation, elevated CO2 concentration, confinement, and high mental and physical workload. Is operator proficiency even necessary? The space shuttle was capable of a fully automated landing (although never fully realized), and the Soviet shuttle (Buran) performed its only orbital flight and landing in 1988 without crew. The next generation NASA Earth-return spacecraft (Orion) plans to implement an Apollo-like water recovery of the crew module, although lunar and Mars landing craft may require some form of operator control or supervision. There is a compelling argument for maintenance of operator proficiency during and after spaceflight, even during automated tasks. The margin for error in the harsh environment of space is small, and in-flight failures of automatic control requiring corrective action from the crew have occurred in both the US and Russian space programs. Automated guidance of Voskhod 2 (1965) failed prior to reentry and the crew took control and manually positioned the spacecraft for reentry, selected the landing point and determined the correct timing and duration of the deorbit burn. A manual retro-fire was also carried out on Soyuz 1 (1967) after on-orbit failure of the attitude control system led to an emergency return (ultimately unsuccessful due to failure of the parachute deployment pressure sensor). In 1966, a â&#x20AC;&#x2122;stuckâ&#x20AC;&#x2122; thruster in the attitude maneuvering system of Gemini VIII resulted in a roll rate approaching 60 rpm. Although severely disoriented and with vision impaired, the crew regained control of the spacecraft by disabling the attitude control system and engaging the reentry control system. An oxygen tank explosion in the service module during the 1970 Apollo 13 mission forced the crew to utilize the lunar module (LM) to maintain life support while shutting down the command module to preserve power for reentry. The commander regained control of the combined service/command/lunar module stack using the LM thrusters to reestablish a slow roll to maintain thermal distribution. The crew, with support from mission control, performed a number of manually controlled burns with the LM descent engine (a contingency they had not trained for) to position the spacecraft for a successful return to Earth. More recently, Soyuz crew traveling to the ISS have twice disabled 14

the automated docking system due to technical issues and performed manual docking with the ISS complex. This study was selected by NASA in 2009 to determine the impact of long-duration spaceflight on post-landing operator proficiency during seated tasks. Within 24-h of landing after an average of 171 days aboard the ISS, eight crewmembers were assessed with a cognitive/sensorimotor test battery and three full-motion simulations driving a car, piloting a T38 jet, and navigation and docking of a Mars rover. In this report we present results from the test battery and car driving simulations. Eight astronauts (all male), assigned to missions aboard the ISS from October 2012 until June 2015, participated in the flight study. Mean age was 47.5 years (SD 6.7; range 36-53), and time aboard the ISS ranged from 142 to 200 days (mean 170.8 SD 20.4). In addition to the flight study, two groups of healthy subjects participated as ground-based controls; the ’shadow’ group of twelve male subjects (mean age 39.0 years SD 9.7; range 25-58), and nine subjects (5 males; 4 females) in a sleep restriction group (mean age 40.0 years SD 10.6; range 26-57).

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All subjects held a valid driving license. The astronaut subjects were tested four times pre-flight and three times post-flight. The first 90-minute session, scheduled on average 167.5 days (SD 62.6) prior to launch, was used to familiarize crewmembers with the cognitive/sensorimotor test battery and the driving simulations (data from these sessions were not analyzed). Baseline data were obtained from the subsequent three 60-min pre-flight sessions, which occurred 129.8 (SD 15.2), 82.1 (SD 10.5) and 73.8 (SD 10.0) days before launch. Crewmembers were tested at JSC on the day of return from the ISS (R + 0) approximately 20-22 h after touchdown in Kazakhstan, corresponding to late evening (10:00 pm - midnight) Houston time, following a ’direct return’ from Karaganda aboard a NASA Gulfstream III aircraft. Due to mission constraints one subject was not available for testing until 7:00am Houston time the day after landing (approximately 30 h after touchdown). The mean gap between the final pre-flight test and the first post-flight session was 244.6 days (SD 14.5; range 217-267). The second and third post-flight sessions were conducted 4.1 days (SD 0.8; range 3-5) and 8.1 days (SD 1.2; range 6-10) after return (labelled R + 4 and R + 8, respectively). Shadow testing was scheduled to closely mirror that of the astronaut subjects. Four baseline sessions (a 90-min familiarization followed by three 60-min baseline data collection sessions, analogous to the astronaut pre-flight schedule) were conducted with an average interval between sessions of 8.8 days (SD 1.1; range 7-12). The mean gap between the final baseline and first ’post-gap’ session (G + 0, analogous to R + 0) was 244.8 days (SD 7.6; range 236-257), which was almost identical to the mean interval between the final pre-flight and first post-flight session for the astronauts (244.6 days). The second (G + 4) and third (G + 8) post-gap sessions were held 3.5 (SD 0.8; range 3-5) and 7.3 (SD 0.8; range 6-8) days after the G + 0 session. Subjects participating in the sleep restriction group performed three 60-min baseline sessions (analogous to astronaut pre-flight testing) an average of 6.1 days (SD 2.4; range 4-10) apart; the first session was a combination familiarization/data collection session, the final two were data collection only. A week after the third baseline session (7.1 days SD 0.3; range 7-8) subjects participated in a ’post-sleep deprivation’ session (S + 0, analogous to R + 0), following a 30-h sleep restriction protocol. Results No significant post-flight changes were observed in reaction time, perspective taking, match to sample, manual tracking or static visual acuity (Table 2). Crewmembers’ self-reported sleepiness was significantly higher (U = 30; p = 0.001) on landing day (R + 0) relative to the pre-flight baseline, and was comparable to the significant increase in sleepiness (U = 12; p = 0.000005) observed in the sleep group after the 30-h sleep restriction protocol (Fig. 4a). Although there was no increase in error on R + 0 during the manual tracking task alone, when a distracting (dual) task was added there was a significant increase (U = 43; p = 0.03) in mean tracking error in the astronaut group, which was not observed in the shadow or sleep groups (Fig. 4b). The astronauts alone also exhibited a small but significant decrease in manual dexterity on R + 0 for the left (non-dominant) hand (U = 33; p = 0.002; Fig. 4c), and the reduction in inserted pins was just above the threshold of significance for the right hand (U = 63.5; p = 0.08) and for both hands simultaneously (U = 60; p = 0.06). These postflight changes in the astronaut group had returned to pre-flight levels by four days after landing (R + 4; Fig. 4). The astronauts exhibited a significantly reduced response (U = 47; p = 0.016) to pitch cabin motion at the lowest frequency (0.12 Hz) on landing day during the motion perception task (Table 3 and Fig. 5), and there 15

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was a tendency towards a blunted response on R + 0 in both pitch and roll for frequencies of 0.43 Hz and below. There was no consistent changes in roll or pitch perception in the shadow group (Table 3).

There were profound deficits in post-landing driving performance for the 3 km winding road simulation in the astronaut group (Table 4). Pre-flight and landing day performance from one crewmember demonstrates a significant post-flight loss of vehicle control, with many more deviations onto the wrong side of the road (Fig. 6). This was consistent across the eight astronauts on R + 0, with significant increases in lane crossings (U = 35.5; p = 0.003; Fig. 7b), time to recover (U = 37; p = 0.004; Fig. 7c) and time spent in the wrong lane (U = 13; p = 0.00003; Fig. 7d). Astronaut driving performance recovered to baseline by four days after landing (R + 4). There were no changes in mountain driving performance in the shadow group or in the sleep group following the 30-h sleep restriction protocol (Table 4 and Fig. 8). There were no significant changes in driving performance on the cone driving task for the astronaut, shadow and sleep restriction groups (Table 5).

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Cognitive/sensorimotor test battery The results of this study demonstrate subtle but significant changes in cognitive/sensorimotor performance on the day of return (R + 0) from ISS missions that adversely affected operator proficiency. Self-reported sleepiness, unsurprisingly, was higher in the astronauts on landing day. There was a small but significant decline in manual dexterity, and manual tracking performance during dual tasking was significantly impaired. Although not conclusive, there was some evidence of a degradation in motion perception at frequencies below 0.43 Hz.

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None of these changes were observed in the shadow group. The sleep cohort, who reported a significant increase in sleepiness after the 30-h sleep restriction protocol analogous to the astronaut group, did not exhibit

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impaired tracking during dual tasking. These findings demonstrate that, with the exception of subjective sleepiness, the changes in performance on the cognitive/sensorimotor test battery observed in the astronaut group on R + 0 were likely due to factors associated with spaceflight, rather than simply fatigue alone or lack of practice.

The mild sensorimotor effects (manual dexterity declined by around 10%) suggest a general post-flight malaise in motor function and motion perception. Adding a distracting task significantly impaired manual tracking performance, indicating post-flight limitations in available central processing resources in the astronauts; a lack of cognitive reserve apparent only when faced with competing tasks. In isolation, none of these spaceflight-induced changes suggest major cause for concern; however, as discussed below, taken together they significantly affected operator proficiency.

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Driving performance The ability to maintain lane position during the mountain driving simulation was significantly impaired in astronauts on R + 0. Crewmembers made more crossings into the wrong lane, took longer to correct, and spent a greater percentage of time in the wrong lane compared to before flight. These changes were not observed in the shadow or sleep cohorts, which strongly suggest that the degradation in astronaut driving performance was related to spaceflight rather than fatigue alone. Performance on the cone course was unaffected in all three cohorts. One possible explanation may be the different frequency characteristics of the mountain and cone driving tasks. Slaloming about the cones induced rapid changes in the orientation of the gravito-inertial acceleration (GIA) vector (the sum of gravity and centripetal acceleration, utilized by the brain to perceive tilt, simulated by roll tilts of the cabin) in the coronal plane at a frequency of around 0.3 Hz. The large curves on the mountain course generated GIA tilts at much lower frequencies (<0.05 Hz). Motion perception was impaired at very low (tilt) frequencies in the astronaut group on landing day, thus it may have been harder for crewmembers to maintain a long sweeping curve on the mountain course as opposed to a rapid oscillation of the vehicle about the cones. Time course of recovery Performance decrements in manual dexterity, dual tasking and motion perception observed in the astronaut group on R + 0, and subjective sleepiness, recovered by the second post-flight session (3-5 days post-landing). Lane control on the mountain driving course also recovered by R + 4. Possible causes of degradation in post-flight operator proficiency The linear accelerometers of the inner ear, the otoliths, sense the orientation of the head with respect to gravity, and contribute to a range of physiological functions including balance, gaze, movement and perception of motion. Missions to the ISS place crewmembers in a microgravity environment where ’tilt’ (in the vestibular sense of head position with regard to gravity) has no meaning. Several studies have documented in- and post-flight deficits in low-frequency (’tilt’) otolith function, including our recently published study of the ocular counterrolling reflex (OCR). OCR is an otolith-mediated response that rolls the eyes in the opposite direction to roll head tilt on Earth, and is a direct measure of low-frequency otolith function. Authors found a significant post-flight reduction in OCR gain in 25 cosmonauts that persisted up to 5 days after return from the ISS. The human tilt response is frequency limited to approximately 0.33 Hz, and the motion perception results from the current study demonstrated evidence of a reduction in sensitivity to roll and pitch motions of the cabin at low frequencies, consistent with flight studies showing impairment in low-frequency otolith function. 22

Post-flight blunting of the tilt response would affect operator proficiency on tasks that require perception of or alignment with tilted visual or inertial cues, such as the mountain driving course. Fatigue is likely a factor in post-flight performance decrements, but the results of the sleep restriction study suggest that sleepiness alone was not responsible. Astronauts were sleepier on R + 0 but reaction time was unchanged, so subjects could attend to a task for short periods despite their fatigue. The impairment in manual dexterity perhaps reflects persistence of in-flight adaptation of fine motor control to microgravity that is maladapted to the terrestrial environment. However, the reduction in the number of pins placed on landing day was less than 10%, and it seems unlikely that the dramatic post-flight inability to maintain lane control was due primarily to ’finger trouble’. The degradation in manual tracking during dual tasking points to post-landing limitations in cognitive processing resources that were unique to the astronaut cohort. The results do not support a vestibular basis for this post-flight dual-tasking impairment. Cognitive tasks that utilized cortical areas receiving vestibular input, such as perspective taking (parietal-temporal junction and superior parietal lobule) and match-to-sample (hippocampus), were unaffected on R + 0 (Table 2).

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Moreover, performance on the same dual-tasking paradigm was unchanged by application of pseudorandom Galvanic vestibular stimulation in a recent ground study. The post-flight impairment of operator proficiency may also be related to environmental factors unique to spaceflight. The partial pressure of CO2 on the ISS, averaging slightly less than 4 mm Hg over a 7-day period, is considerably higher than on Earth (0.3 mm Hg), and elevated CO2 levels have been linked to an increased probability of headache in ISS crewmembers. However, current US Environmental Protection Agency guidelines state that the maximum exposure limit is indefinite at CO2 levels below 7.6 mm Hg. The altered light-dark cycle, sleep deprivation, high mental and physical workload of astronauts, all experienced in a confined space, have been simulated in laboratory studies such as Mars520, in which 6 male subjects lived and worked in a 550 m 3 facility (a little more than half the volume of the ISS) from June 3rd 2010 until November 4th 2011. Subjects were found to exhibit decreased cortical activity associated with sensory deprivation and monotony, and diminished sleep quality, although any functional impact on cognition and operator proficiency was not elucidated . Similarly, studies of cognitive performance in personnel over-wintering in Antarctica found no significant changes. The results suggest that a range of subtle physiological changes in spaceflight combine to leave astronauts vulnerable to performance decrements on the day of landing, particularly when faced with low-frequency GIA or visual tilts and multiple and competing task requirements. A striking feature of the results is the disparity between the subtle nature of the changes observed in astronaut performance on the cognitive/sensorimotor test battery on landing day and the profound impact these changes had on operator proficiency. The results suggest that countermeasure development should target the cumulative effect of the subtle physiological changes observed on landing day, rather than focusing on individual cognitive or sensorimotor impairments. Based on the results, the following countermeasure recommendations were made to NASA’s Mission Architecture Team: • In-flight high-fidelity ’just-in-time’ refresher training for landing and post-flight manual control tasks. • Improved displays/non-visual aids to support crewmembers during manual control maneuvers with a tilt component (visual or gravito-inertial). • Cognitive/sensorimotor self-assessments to gauge fitness for duty before conducting challenging manual control tasks. • Consider limitations in dual tasking when assigning crewmember assignments during critical stages of manual control.

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